European Commission Approves Merck’s KEYTRUDA® (pembrolizumab) as Adjuvant Therapy for Certain Patients With Renal Cell Carcinoma (RCC) Following Surgery

KEYTRUDA Is Now Approved as Monotherapy for Adults With RCC at Increased Risk of Recurrence Following Nephrectomy, or Following Nephrectomy and Resection of Metastatic Lesions

KEYTRUDA Is the First Immunotherapy Approved in Europe in the Adjuvant Setting for These Patients With RCC

KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the European Commission has approved KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the adjuvant treatment of adults with renal cell carcinoma (RCC) at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. This approval is based on results from the Phase 3 KEYNOTE-564 trial, in which KEYTRUDA demonstrated a statistically significant improvement in disease-free survival (DFS), reducing the risk of disease recurrence or death by 32% (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010) after a median follow-up of 23.9 months compared to placebo, in patients at increased risk of recurrence (defined in the clinical trial protocol as intermediate-high or high risk following nephrectomy and those with resected advanced disease).

“KEYTRUDA addresses a critical unmet need for treatment options that help patients reduce their risk of cancer returning following surgery,” said Dr. Thomas Powles, professor of Genitourinary Oncology and director of Barts Cancer Centre at St. Bartholomew’s Hospital. “The European Commission’s approval of KEYTRUDA brings certain patients with renal cell carcinoma a long-awaited therapy that has demonstrated a statistically significant reduction in the risk of disease recurrence or death by almost a third.”

“KEYTRUDA is the first adjuvant therapy approved for certain patients with renal cell carcinoma in Europe, providing the option of immunotherapy earlier in the course of their treatment,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “This approval demonstrates our progress in bringing KEYTRUDA to patients with earlier stages of cancer, with the goal of helping more patients around the globe prevent disease recurrence.”

This approval allows marketing of KEYTRUDA monotherapy in all 27 European Union member states plus Iceland, Lichtenstein, Norway and Northern Ireland.

Merck has a broad clinical development program exploring KEYTRUDA, as monotherapy or in combination, as well as several other investigational and approved medicines across multiple settings and stages of RCC, including adjuvant and advanced or metastatic disease.

Data Supporting the European Approval

The approval was based on data from KEYNOTE-564 (NCT03142334), a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 994 patients with increased risk of recurrence of RCC defined as intermediate-high or high risk, or M1 with no evidence of disease (NED). Patients must have undergone a partial or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion[s] in M1 NED participants) with negative surgical margins for at least four weeks prior to the time of screening. Patients with active autoimmune disease or a medical condition that required immunosuppression were excluded from the study. The primary efficacy outcome measure was investigator-assessed DFS. The secondary efficacy outcome measure was overall survival (OS). Patients with RCC with clear cell component were randomized (1:1) to receive KEYTRUDA 200 mg administered intravenously every three weeks (n=496) or placebo (n=498) for up to one year until disease recurrence or unacceptable toxicity.

At a pre-specified interim analysis with a median follow-up time of 23.9 months, KEYTRUDA demonstrated a statistically significant improvement in DFS, reducing the risk of disease recurrence or death by 32% (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010) compared with placebo in patients with RCC at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Updated efficacy results with a median follow-up time of 29.7 months demonstrated KEYTRUDA reduced the risk of disease recurrence or death by 37% (HR=0.63 [95% CI, 0.50-0.80]; p<0.0001) compared with placebo. Median DFS has not been reached for either group. The trial will continue to assess OS as a secondary outcome measure.

The safety of KEYTRUDA as monotherapy has been evaluated in 7,148 patients with advanced melanoma, resected stage III melanoma (adjuvant therapy), non-small cell lung cancer, classical Hodgkin lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, colorectal cancer, endometrial, gastric, small intestine, biliary, pancreatic cancer or adjuvant therapy of RCC across four doses (2 mg/kg bodyweight [bw] every three weeks, 200 mg every three weeks, or 10 mg/kg bw every two or three weeks) in clinical studies. In this patient population, the most frequent adverse reactions with KEYTRUDA were fatigue (31%), diarrhea (22%) and nausea (21%). The majority of adverse reactions reported for KEYTRUDA monotherapy were of Grades 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions. The incidences of immune-related adverse reactions were 36.1% for all Grades and 8.9% for Grades 3-5 for KEYTRUDA monotherapy in the adjuvant setting (n=1,480) and 24.2% for all Grades and 6.4% for Grades 3-5 in the metastatic setting (n=5,375). No new immune-related adverse reactions were identified in the adjuvant setting.

About Renal Cell Carcinoma

Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCCs. Renal cell carcinoma is about twice as common in men than in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In Europe, it is estimated there were more than 138,000 new cases of kidney cancer diagnosed and more than 54,000 deaths from the disease in 2020.

About Merck’s Early-Stage Cancer Clinical Program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

About KEYTRUDA® (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,700 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicatedfor the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

• stage III where patients are not candidates for surgical resection or definitive chemoradiation, or

• metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

• who are not eligible for any platinum-containing chemotherapy, or

• who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

• in combination with platinum- and fluoropyrimidine-based chemotherapy, or

• as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

First-line treatment of advanced RCC in combination therapy with axitinib (KEYNOTE-426)

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or mUC. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or mUC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).

The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression, who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).

Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use

In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months).

Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For over 130 years, Merck, known as MSD outside the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s 2020 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf .

Immunocore announces FDA approval of KIMMTRAK® (tebentafusp-tebn) for the treatment of unresectable or metastatic uveal melanoma

KIMMTRAK is the first and only FDA approved therapy for the treatment of unresectable or metastatic uveal melanoma (mUM)

KIMMTRAK is the first T cell receptor (TCR) therapeutic to receive regulatory approval

KIMMTRAK demonstrated statistically and clinically meaningful overall survival (OS) benefit, hazard ratio of 0.51, with median OS of almost 22 months

Company to host an investor call today at 8:30 AM ET

(OXFORDSHIRE, England & CONSHOHOCKEN, Penn. & ROCKVILLE, Md., US, Wednesday, January 26, 2022) Immunocore Holdings plc (Nasdaq: IMCR) (“Immunocore” or the “Company”), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, autoimmune and infectious diseases today announces approval from the United States Food and Drug Administration (FDA) of KIMMTRAK® (tebentafusp-tebn) for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM).

KIMMTRAK’s approval establishes many firsts as the first TCR therapeutic to receive regulatory approval from the FDA, the first bispecific T cell engager to receive regulatory approval from the FDA to treat a solid tumor, and the first and only therapy for the treatment of unresectable or metastatic uveal melanoma to be approved by the FDA.

Bahija Jallal, Chief Executive Officer of Immunocore, said: “Today’s approval of KIMMTRAK is a historic milestone and the culmination of years of dedication by the Immunocore team, patients, and our healthcare partners. Every year in the United States, hundreds of people are diagnosed with metastatic uveal melanoma who, until now, had no approved treatment options. KIMMTRAK is the first therapy to demonstrate a survival benefit to patients with this disease and we are focused on making KIMMTRAK available as quickly as possible.

Dr. Jallal continues, “We’re also proud to have developed the world’s first approved TCR therapeutic, which we believe validates the strength of our platform and opens doors for us to explore further breakthrough discoveries in TCR therapeutics for the treatment of other cancers and diseases with high unmet need.”

“Uveal melanoma is a devastating disease that has historically resulted in death within a year of metastasis for our patients,” said John Kirkwood, MD, director of the Melanoma Center at the UPMC Hillman Cancer Center. “The approval of KIMMTRAK (tebentafusp-tebn) represents a major paradigm shift in the treatment of metastatic uveal melanoma, and for the first time offers hope to those with this aggressive form of cancer.”

The approval of KIMMTRAK is based on the results of Immunocore’s Phase 3 IMCgp100-202 clinical trial, which were published in the September 23, 2021 issue of the New England Journal of Medicine. The randomized pivotal trial evaluated overall survival (OS) of KIMMTRAK compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in patients with previously untreated mUM. 378 patients were randomized in a 2:1 ratio to either KIMMTRAK or investigator’s choice. Data from the trial, the largest Phase 3 trial undertaken in mUM, showed that KIMMTRAK demonstrated unprecedented median OS benefit as a first-line treatment. The OS Hazard Ratio (HR) in the intent-to-treat population favored KIMMTRAK, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine). In the clinical trials, across both arms, patients stopped treatment for disease progression, unless the patient was otherwise deriving benefit, or for unacceptable toxicity.

“When my husband, Gregg, was diagnosed with metastatic uveal melanoma, it was devastating to learn that there were no treatment options shown to extend life.” said Sara Selig, MD, MPH, Co-Founder and Director of the Melanoma Research Foundation’s (MRF) CURE OM initiative. “Now, for the first time in the history of this disease, we will soon see extended survival in the next generation of metastatic uveal melanoma patients.”

In the randomized Phase 3 trial of KIMMTRAK (tebentafusp-tebn), treatment-related adverse reactions were manageable and consistent with the proposed mechanism. Among the patients treated with KIMMTRAK, the most common Grade 3 or higher adverse reactions were rash (18%), pyrexia (4%), and pruritus (5%). In the 245 patients treated with KIMMTRAK, Grade 3 cytokine release syndrome (CRS) occurred in <1% of patients and were generally well-managed. There were no Grade 4 or fatal CRS events observed in the Phase 3 trial. A boxed warning is included for CRS as it has the potential to become serious or life-threatening if not managed appropriately.

“Until now, effective treatment options for metastatic uveal melanoma patients were virtually non-existent. The approval of KIMMTRAK represents not only a new therapy but a new hope for the individuals and the families of those diagnosed with the deadliest form of eye cancer,” said Kyleigh LiPira, MBA, CEO of the MRF.

The company is ready to commercialize KIMMTRAK and expects to make the product commercially available in the United States within weeks.

KIMMTRAK was granted Breakthrough Therapy Designation for unresectable or metastatic uveal melanoma by the FDA in February 2021. The Biologics License Application (BLA) approval followed review under the Real-Time Oncology Review (RTOR) program, an initiative of the FDA's Oncology Center of Excellence designed for efficient delivery of safe and effective cancer treatments to patients. The approval was granted four weeks ahead of the assigned PDUFA date of February 23, 2022. Immunocore provided an Assessment AID to facilitate FDA review. KIMMTRAK is being reviewed under the FDA’s Project Orbis initiative, which enabled concurrent review by the health authorities in partner countries that have requested participation.

The European Medicines Agency (EMA), the United Kingdom’s Medicines and Healthcare Regulatory Agency (MHRA), Health Canada, and the Australian Government Department of Health Therapeutic Goods Administration (TGA) have accepted the submission of the Company’s Marketing Authorisation Application. Additionally, Immunocore launched a global early access program to make KIMMTRAK readily available to mUM patients. There are currently over 200 patients in 13 countries in the early access program.

Immunocore is committed to helping patients who need KIMMTRAK obtain access via its KIMMTRAKConnect program. The program provides services with dedicated nurse case managers who provide personalized support, including educational resources, financial assistance, and site of care coordination. To learn more, visit KIMMTRAKConnect.com, which will launch later this week, or call 844-775-CARE (2273).

Conference Call Information

Immunocore will host a conference call and webcast today, Wednesday, January 26th at 8:30 AM EST. A live webcast of the conference call will be available under “Events” in the Investor Relations section of Immunocore Holdings’ website at www.immunocore.com. To access the live conference call by phone, please dial (US) 877-405-1224 / (Non-US) +1-201-389-0848. The presentation from today’s call and the archived webcast will be available on Immunocore’s website after the conference call concludes and will be available for 60 days following the call.

About Uveal Melanoma
Uveal melanoma is a rare and aggressive form of melanoma, which affects the eye. Although it is the most common primary intraocular malignancy in adults, the diagnosis is rare, and up to 50% of people with uveal melanoma will eventually develop metastatic disease. Unresectable or metastatic uveal melanoma typically has a poor prognosis and had no approved treatment until KIMMTRAK.

About KIMMTRAK®
KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognize and kill tumor cells. KIMMTRAK has been granted Breakthrough Therapy Designation, Fast Track designation and orphan drug designation by the FDA in the United States, Accelerated Assessment by the EMA, and Promising Innovative Medicine (PIM) designation under the UK Early Access to Medicines Scheme for metastatic uveal melanoma.
About Phase 3 IMCgp100-202 Trial
The IMCgp100-202 (NCT03070392) is a randomized pivotal trial that evaluated overall survival (OS) of KIMMTRAK (tebentafusp-tebn) compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in HLA-A*02:01-positive adult patients with previously untreated mUM. KIMMTRAK demonstrated an unprecedented OS benefit with a Hazard Ratio (HR) in the intent-to-treat population favoring KIMMTRAK, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine).

IMPORTANT SAFETY INFORMATION

Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS occurred in 89% of patients who received KIMMTRAK with 0.8% being grade 3 or 4. Ensure immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS.

Skin Reactions

Skin reactions, including rash, pruritus, and cutaneous edema occurred in 91% of patients treated with KIMMTRAK. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions.

Elevated Liver Enzymes

Elevations in liver enzymes occurred in 65% of patients treated with KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity.  

Embryo-Fetal Toxicity

KIMMTRAK may cause fetal harm. Advise pregnant patients of potential risk to the fetus and patients of reproductive potential to use effective contraception during treatment with KIMMTRAK and 1 week after the last dose.

The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate.

Please see full Prescribing Information, including BOXED WARNING for CRS.

About KIMMTRAKConnect
Immunocore is committed to helping patients who need KIMMTRAK obtain access via our KIMMTRAKConnect program. The program provides services with dedicated nurse case managers who provide personalized support, including educational resources, financial assistance, and site of care coordination. To learn more, visit KIMMTRAKConnect.com or call 844-775-2273.

About ImmTAC® Molecules
Immunocore’s proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognize and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognize intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumors, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumors, regardless of mutational burden or immune infiltration, including immune “cold” low mutation rate tumors. 

About Immunocore
Immunocore is a commercial-stage biotechnology company pioneering the development of a novel class of TCR bispecific immunotherapies called ImmTAX – Immune mobilizing monoclonal TCRs Against X disease – designed to treat a broad range of diseases, including cancer, autoimmune, and infectious disease. Leveraging its proprietary, flexible, off-the-shelf ImmTAX platform, Immunocore is developing a deep pipeline in multiple therapeutic areas, including five clinical stage programs in oncology and infectious disease, advanced pre-clinical programs in autoimmune disease and multiple earlier pre-clinical programs. Immunocore’s most advanced oncology TCR therapeutic, KIMMTRAK (tebentafusp-tebn), has been approved by the U.S. FDA for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM) having demonstrated an overall survival benefit in a randomized Phase 3 clinical trial in metastatic uveal melanoma, a cancer that has historically proven to be insensitive to other immunotherapies.

Forward Looking Statements
This press release contains “forward-looking statements” within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in this press release are forward-looking statements. These statements include, but are not limited to, statements regarding the marketing and therapeutic potential of KIMMTRAK for metastatic uveal melanoma (mUM); the expected clinical benefits of KIMMTRAK including extended overall survival benefit; expectations regarding the timing of the commercial launch of KIMMTRAK, the timing of commercial availability and the ability to reach patients in a timely manner; the value proposition of KIMMTRAK in mUM and benefit as an orphan indication including expectations regarding the potential market size opportunity; Immunocore’s sales and marketing plans in the United States; and future development plans of KIMMTRAK, including the timing or likelihood of expansion into additional markets or geographies. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements, many of which are beyond the Company’s control. These risks and uncertainties include, but are not limited to, the impact of the ongoing COVID-19 pandemic and the Omicron variant on the Company’s business, strategy, clinical trials and financial position; Immunocore’s ability to maintain regulatory approval of KIMMTRAK; its ability to execute its commercialization strategy for KIMMTRAK; its ability to develop, manufacture and commercialize its other product candidates including plans for future development of KIMMTRAK and other product candidates, including the timing or likelihood of expansion into additional markets or geographies; commercial supply of KIMMTRAK or any future approved products, and launching, marketing and selling of KIMMTRAK or any future approved products; Immunocore’s ability and plans in continuing to establish and expand a commercial infrastructure and to successfully launch, market and sell KIMMTRAK; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials or future regulatory approval; Immunocore’s ability to obtain, maintain and enforce intellectual property protection for KIMMTRAK or any product candidates it is developing; unexpected safety or efficacy data observed during preclinical studies or clinical trials; clinical trial site activation or enrollment rates that are lower than expected; changes in expected or existing competition; Immunocore’s ability to obtain, maintain and enforce intellectual property protection for KIMMTRAK or any product candidates it is developing; and the success of Immunocore’s current and future collaborations, partnerships or licensing arrangements. These and other risks and uncertainties are described in greater detail in the section titled "Risk Factors" in Immunocore’s filings with the Securities and Exchange Commission, including Immunocore’s most recent Annual Report on Form 20-F for the year ended December 31, 2020 filed with the Securities and Exchange Commission on March 25, 2021, as well as discussions of potential risks, uncertainties, and other important factors in the Company’s subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and the Company undertakes no duty to update this information, except as required by law.

Gilead withdraw accelerated FL/SLL Zydelig® indications from US market; cites enrollment challenges

Gilead Statement on Zydelig® U.S. Indication for Follicular Lymphoma and Small Lymphocytic Leukemia

Foster City, Calif., January 14, 2022 – In 2014, Zydelig® (idelalisib) received accelerated approval from the U.S. Food and Drug Administration (FDA) to treat relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL). Approval was based on a Phase 2 study in indolent non-Hodgkin lymphoma showing that 54% of those with FL and 58% of those with SLL had an objective response as assessed by an Independent Review Committee.

Continued approval for these indications was contingent upon providing evidence supporting confirmation of clinical benefit in FL and SLL. As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge. As a result, Gilead Sciences, Inc. (Nasdaq: GILD) formally notified the FDA of its decision to voluntarily withdraw these indications from the U.S. market.

Zydelig was also approved in 2014 to treat relapsed chronic lymphocytic leukemia (CLL) in the U.S. Additionally, Zydelig has marketing authorization to treat CLL and FL in the EU, UK, Canada, Australia, New Zealand and Switzerland. None of these approvals are affected by the proposed withdrawal. Thus, Zydelig will remain on the market in the U.S. for CLL and for CLL and FL in the EU, UK, Canada, Australia, New Zealand, and Switzerland.

Gilead continues to work collaboratively with the FDA to complete the withdrawal of the FL and SLL indications in the U.S. and with healthcare professionals to support those currently being treated with Zydelig. People receiving Zydelig for relapsed FL or SLL in the U.S. should discuss their treatment options with their healthcare provider.

About Zydelig
Zydelig® (idelalisib) is approved in the U.S. for the treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities. Currently, Zydelig is also approved under the accelerated approval pathway for relapsed FL and SLL in patients who have received at least two prior systemic therapies. Accelerated approval was granted for FL and SLL based on overall response rate since an improvement in patient survival or disease-related symptoms has not been established. Zydelig is not indicated or recommended for first-line treatment for any use or in combination with bendamustine and/or rituximab for the treatment of FL. The Zydelig U.S. Prescribing Information has a Boxed Warning for the risks of fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation; see below for Important Safety Information.

U.S. Important Safety Information for Zydelig
BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

• Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig.

• Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig.

• Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig.

• Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.

• Fatal and serious intestinal perforation can occur in Zydelig-treated patients. Discontinue Zydelig if intestinal perforation is suspected.

Contraindications

• History of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or patients with a history of toxic epidermal necrolysis (TEN) with any drug.

Warnings and Precautions

• Hepatotoxicity: Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with Zydelig monotherapy and 16% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold Zydelig and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue Zydelig for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs.

• Severe diarrhea or colitis: Severe diarrhea or colitis (Grade ≥3) occurred in 14% of patients treated with Zydelig monotherapy and 20% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.

• Pneumonitis: Fatal and serious pneumonitis occurred in 4% of patients treated with Zydelig compared to 1% on the comparator arms in randomized clinical trials of combination therapies. Time to onset of pneumonitis ranged from <1 to 15 months. Clinical manifestations included interstitial infiltrates and organizing pneumonia. Monitor patients on Zydelig for pulmonary symptoms. In patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5%, interrupt Zydelig until the etiology has been determined. If symptomatic pneumonitis or organizing pneumonia is diagnosed, initiate appropriate treatment with corticosteroids and permanently discontinue Zydelig.

• Infections: Fatal and/or serious infections occurred in 21% of patients treated with Zydelig monotherapy and 48% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. The most common infections were pneumonia, sepsis, and febrile neutropenia. Treat infections prior to initiation of Zydelig therapy and interrupt Zydelig for Grade 3 or higher infection. Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in <1% of patients treated with Zydelig. Provide PJP prophylaxis during treatment with ZYDELIG. Interrupt Zydelig in patients with suspected PJP infection of any grade, and permanently discontinue Zydelig if PJP infection of any grade is confirmed. Regular clinical and laboratory monitoring for CMV infection is recommended in patients with a history of CMV infection or positive CMV serology at the start of treatment with Zydelig. Interrupt Zydelig in the setting of positive CMV PCR or antigen test until the viremia has resolved. If Zydelig is subsequently resumed, patients should be monitored (by PCR or antigen test) for CMV reactivation at least monthly.

• Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue Zydelig permanently in patients who experience intestinal perforation.

• Severe cutaneous reactions: Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred in patients treated with Zydelig. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also occurred. If suspected, interrupt Zydelig until the etiology of the reaction has been determined. If SJS or TEN, or DRESS is confirmed, permanently discontinue Zydelig. Other severe or life-threatening (Grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and permanently discontinue Zydelig.

• Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients on Zydelig. Zydelig is contraindicated in patients with a history of serious hypersensitivity reactions to idelalisib, including anaphylaxis. Permanently discontinue Zydelig and institute appropriate supportive measures if a reaction occurs.

• Neutropenia: Grade 3-4 neutropenia occurred in 25% of patients treated with monotherapy and 58% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Monitor blood counts at least every 2 weeks for the first 6 months, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L. Interrupt Zydelig until resolution and resume at reduced dose.

• Embryo-fetal toxicity: Zydelig may cause fetal harm. Females who are or become pregnant while taking Zydelig should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to avoid pregnancy while taking Zydelig and to use effective contraception during and at least 1 month after treatment with Zydelig.

Adverse Reactions

• Most common adverse reactions in patients treated with Zydelig in combination trials (incidence ≥30%, all grades) were diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea; and in the monotherapy trial (incidence ≥20%, all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash.

• Most frequent serious adverse reactions (SAR) in clinical studies in combination with rituximab were pneumonia (23%), diarrhea (10%), pyrexia (9%), sepsis (8%) and febrile neutropenia (5%); SAR were reported in 59% of patients, and 17% discontinued therapy due to adverse reactions. Most frequent SAR in clinical studies when used alone were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients, and 53% discontinued due to adverse reactions.

• Most common lab abnormalitiesinclude neutropenia, ALT elevations, and AST elevations.

Drug Interactions

• CYP3A inducers: Avoid coadministration with strong CYP3A inducers.

• CYP3A inhibitors: Avoid coadministration with strong CYP3A inhibitors. If unable to use alternative drugs, monitor patients more frequently for Zydelig adverse reactions.

• CYP3A substrates: Avoid coadministration with sensitive CYP3A substrates.

Dosage and Administration

• Recommended Dosage: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown.

• Dose modification: Consult the Zydelig full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: ALT/AST elevations, bilirubin elevations, diarrhea, pneumonitis, infections, intestinal perforation, severe cutaneous reactions, hypersensitivity reactions, neutropenia, and thrombocytopenia. For other severe or life-threatening adverse reactions, withhold Zydelig until resolution. If resuming Zydelig after interruption for other severe or life-threatening toxicities, reduce the dosage to 100 mg twice daily. Permanently discontinue Zydelig for recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge.

About Gilead Sciences
Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Gilead Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials within currently anticipated timelines or at all, including those involving Zydelig; the possibility of unfavorable results from ongoing or additional trials, including those involving Zydelig; Gilead’s ability to receive regulatory approvals in a timely manner or at all, including additional regulatory approvals of Zydelig, and the risk that any such approvals may be subject to significant limitations on use; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2021, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Investors are cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and are cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements.

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Shout Out: Congratulations to 'Friends of Cancer Research' on their 25 year anniversary

1996

• Ellen Sigal and Marlene Malek establish Friends of Cancer Research, (Friends), to mark the 25th anniversary of the National Cancer Act. Friends sets out to bring together researchers, leaders of federal health agencies, industry, and elected officials, through town hall events across the country to discuss ways cancer treatment should improve.

1998

• Friends begins to hold town halls across the country on the importance of cancer research with federal support.

• March to Conquer Cancer brings 80,000 people to the National Mall.

2003

• Friends plays important role leading to the doubling of the NIH budget.

2004

• Friends begins to pivot focus to the U.S. Food and Drug Administration (FDA), which historically had not been the focus of any cancer research organization.

• Friends leads the entire research community to advocate for the creation of a new office at the FDA dedicated entirely to oncology products, the FDA Oncology Office.

2008

• Stemming from the development of the Oncology Office at FDA, cancer research shifts toward patient-centered outcomes so government, advocates, and patients could work together.

2010

• As part of the nationwide effort to pass and establish the Affordable Care Act, Friends pioneers comparative effectiveness research and works with bipartisan leadership establishing the Patient-Centered Outcomes Research Institute or PCORI.

2011

• Friends and the Engelberg Center for Healthcare Reform at the Brookings Institution co-host the First Annual Conference on Clinical Cancer Research to discuss potential approaches to speed the FDA approval process for drugs that show large treatment effects early in development while still ensuring drug safety and efficacy.

2012

• Friends took ‘Breakthrough’ from concept, to scientific whitepaper, to bipartisan legislative solution, to a tool in full use by FDA to expedite the approval of multiple drugs in 13 months.

2014

• Lung-MAP, the lung cancer master protocol, is first proposed at the 2012 Annual Conference on Clinical Cancer Research with the final trial design announced at the 2013 conference. The Lung-MAP trial launches in 2014 at more than 400 sites across the country.

2015

• The Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) tool is launched at the annual Conference on Clinical Cancer Research.

2016

• Ellen Sigal appointed to the National Cancer Institute's Blue Ribbon Panel, advising the National Cancer Advisory Board on Vice President Joe Biden's Cancer Moonshot Initiative.

• Friends holds a Congressional briefing to discuss establishing the FDA Oncology Center of Excellence.

• As a result of months of work led by Friends and other advocacy organizations, President Barack Obama signs the 21st Century Cures Act into law, including $1.8 billion for the Cancer Moonshot, and formally establishing the Oncology Center of Excellence at FDA.

• American Society of Clinical Oncology (ASCO) and Friends begin a joint project to develop and advance specific strategies to change the exclusionary nature of clinical trial eligibility criteria.

• The Annual Alexandria Summit and Friends Blueprint for Breakthrough Forum focuses on the potential utility of Real-World Evidence (RWE) in clinical trials.

2017

• A panel of experts explore the issue of outdated product labels and release a whitepaper detailing a framework for updating product labels at the Friends Annual Meeting.

• ASCO-Friends joint research statement and four supporting manuscripts about eligibility criteria are published in the Journal of Clinical Oncology.

2018

• Exploring the use of Circulating Tumor DNA (ctDNA) to monitor treatment response (ctMoniTR) Whitepaper presented at the Friends Annual Meeting.

• Friends convenes a multi-stakeholder group to discuss the Pilot Project 1.0: Operationalizing and Validating Real-World Evidence.

• Senators Orrin Hatch (R-UT) and Michael Bennet (D-CO) introduce the MODERN Labeling Act.

• Friends present in silico assessment of variation in TMB quantification across diagnostic platforms: Phase 1 of the Friends Harmonization Project at the SITC Annual Meeting.

• ASCO and Friends submit recommended language for five guidance documents on ways to broaden eligibility criteria for cancer clinical trials to the FDA.

2019

• Pilot Project 2.0 of Real-World Evidence project is presented at the Friends and Alexandria Real Estate Equities, Inc. Annual Blueprint for Breakthrough Forum.

• Senate health committee Chairman Lamar Alexander (R-Tenn.) and Ranking Member Patty Murray (D-Wash.) introduced S.1895, the Lower Health Care Costs Act of 2019, which addresses the public health issue of outdated labels identified by Friends work.

2020

• Friends presents the results of Step 1 of the CtMoniTR Project convening clinical and academic leaders, government, industry, and leading advocates to align on a methodology to analyze ctDNA.

• Friends presents RWE whitepaper informed by RWE Pilot Projects.

• Reagan-Udall Foundation for the FDA, in collaboration with Friends, launches the COVID-19 Evidence Accelerator initiative.

• Phase 2B of the Friends TMB Harmonization Project, alignment of TMB measured on clinical samples, is presented at the AACR Annual Meeting.

• Phase II of the Friends TMB Harmonization Project, TMB standardization by alignment to reference standards, is presented at the ASCO Annual Meeting.

European Commission Grants Janssen Conditional MA for RYBREVANT (amivantamab)

The Janssen Pharmaceutical Companies of Johnson & Johnson announced Conditional Marketing Authorisation (CMA) of RYBREVANT® ▼ (amivantamab) for the treatment of adult patients with advanced NSCLC with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations, after failure of platinum-based therapy.1 Amivantamab is the first approved treatment in the European Union specifically targeting EGFR exon 20 insertion mutations for NSCLC.

“Patients with NSCLC harbouring EGFR exon 20 insertion mutations represent a specific population who have been underserved by current treatment options that are limited in both number and efficacy. The decision made by the European Commission represents an important milestone and recognises that amivantamab offers a new treatment specifically targeted for patients with this alteration,” said Antonio Passaro, M.D., Ph.D, Medical Oncologist at the Division of Thoracic Oncology of the European Institute of Oncology in Milan, Italy.

The CMA is based on results from the Phase 1 CHRYSALIS study, a multicentre, open-label, clinical study evaluating amivantamab as a monotherapy in patients after previous treatment with platinum-based therapy, which demonstrated efficacy and a generally well-tolerated safety profile. The investigator-assessed overall response rate was 37 percent (95 percent CI, 28% - 46%), with a median duration of response of 12.5 months (95 percent CI, 6.5 – 16.1) and 64 percent of patients having a duration of response greater than or equal to 6 months. These results were consistent with those reported by blinded independent central review assessment, which showed an overall response rate of 43 percent (34% – 53%), with a median duration of response of 10.8 months (95 percent CI, 6.9 – 15.0) and 55 percent of patients having a duration of response greater than or equal to 6 months.

Analysis showed the median progression-free survival (time experienced without progression or death) was 8.3 months (95 percent CI, 6.5 – 10.9) and the median overall survival in patients treated with amivantamab was 22.8 months (95 percent CI, 14.6 – not reached).

The most common adverse events (AEs) at all grades included rash (76 percent), infusion-related reactions (67 percent) and nail toxicity (47 percent), and these were predominantly Grade 1-2. Treatment-related discontinuations due to adverse events were seen in three percent of patients. Ninety-nine percent of infusion-related reactions occurred with the first infusions and rarely impacted the ability to continue with subsequent treatments (1.1 percent led to treatment discontinuation).

“This marketing authorisation addresses a high unmet need by bringing a new treatment option to this patient population and their healthcare professionals for the first time in Europe. It is an important step towards our goal to deliver innovative therapies that will transform the trajectory of lung cancer,” commented Peter Lebowitz, M.D., Ph.D., Global Therapeutic Area Head, Oncology, Janssen Research & Development, LLC.

Conditional marketing authorisation is the approval of a medicine that addresses unmet medical needs of patients based on less comprehensive data than normally required, where the benefit of immediate availability of the medicine outweighs the risk, and the applicant is able to provide comprehensive clinical data in the future. This CMA follows other recent approvals for amivantamab, including the U.S. Food and Drug Administration (FDA), who approved the treatment in May 2021 for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy. Additional regulatory applications have been submitted and are being reviewed by other regulatory bodies worldwide.

“We are committed to changing the face of cancer care,” said Mathai Mammen, M.D., Ph.D., Global Head, Janssen Research & Development, Johnson & Johnson. “At Janssen, we’re striving to transform long-term patient outcomes and improve quality of life with the right treatment, for the right patient, at the right time.”

† Dr Passaro has previously provided paid consultancy services for Janssen in relation to research and advisory boards. He has not been compensated for any media work.

‡ Results reported in the SmPC are from 114 patients with a median follow up of 12.5 months. Results reported in Park et al are from 81 patients and a median follow up of 9.7 months. Not all efficacy endpoints were reported in the SmPC.

About Amivantamab
Amivantamab is a fully-human EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating and resistance EGFR mutations and MET mutations and amplifications, approved for patients with advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations after failure of platinum-based therapy.1,9,10,11,12 Amivantamab is being studied in multiple clinical trials, including:

• the Phase 1/1b, CHRYSALIS-2 (NCT04077463) study assessing the combination of amivantamab and lazertinib in patients who have progressed after treatment with osimertinib and chemotherapy, as well as lazertinib as a monotherapy

• as first-line therapy in the Phase 3 MARIPOSA (NCT04487080) study assessing amivantamab in combination with lazertinib, a novel third-generation EGFR tyrosine kinase inhibitor (TKI), against osimertinib and against lazertinib alone in untreated advanced EGFR-mutated NSCLC

• the Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of lazertinib, amivantamab and carboplatin-pemetrexed vs. with carboplatin-pemetrexed in participants with locally advanced or metastatic EGFR Exon 19del or Exon 21 L858R substitution NSCLC after osimertinib failure

• the Phase 3 PAPILLON (NCT04538664)study assessing amivantamab in combination with carboplatin-pemetrexed vs carboplatin-pemetrexed for patients with advanced or metastatic EGFR-mutated NSCLC with exon 20 insertion mutations

• the Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab SC delivery with the aim to find effective solutions that positively impact patient management.

About the CHRYSALIS Study
CHRYSALIS (NCT02609776) is an open-label, multicentre, first-in-human Phase 1 study to evaluate the safety, pharmacokinetics and preliminary efficacy of amivantamab as a monotherapy, in combinations with lazertinib and in combination with platinum-based chemotherapy, in patients with advanced NSCLC with various EGFR mutations. In the study, investigators assessed efficacy using overall response rate per Response Evaluation Criteria in Solid Tumours Version 1.1* (RECIST v1.1), clinical benefit rate, median duration of response and median progression-free survival, as well as the safety profile of amivantamab.

The study will enrol 780 patients with advanced NSCLC. The study consists of two parts: the first consists of amivantamab monotherapy and combination dose escalations, and the second consists of amivantamab monotherapy and combination dose expansions.

The first cohort of participants received intravenous infusions of amivantamab as monotherapy.

*RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumours, which is a standard way to measure how well solid tumours respond to treatment and is based on whether tumours shrink, stay the same or get bigger.

About Non-Small Cell Lung Cancer (NSCLC)
In Europe, it is estimated that 477,534 patients were diagnosed with lung cancer in 2020, with around 85 percent diagnosed with NSCLC. Lung cancer is Europe’s biggest cancer killer, with more deaths than breast cancer and prostate cancer combined.

The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase supporting cell growth and division. EGFR mutations are present in 16 to 19 percent of Caucasian patients with NSCLC and present in 37 to 41 percent of Asian patients who have NSCLC adenocarcinoma. The five-year survival rate for all people with metastatic NSCLC and EGFR mutations who are treated with EGFR TKIs is less than 20 percent. Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival (OS) of 8 percent in the frontline setting, which is worse than patients with EGFR exon 19 deletions or L858R mutations, who have a real-world five-year OS of 19 percent.

About the Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology and Pulmonary Hypertension.

Learn more at www.janssen.com/emea/. Follow us at www.twitter.com/JanssenEMEA for our latest news. Janssen Research & Development, LLC; Janssen-Cilag, S.A. and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Cautions Concerning Forward-Looking Statements
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding amivantamab and lazertinib. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC any of the other Janssen Pharmaceutical Companies, and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 3, 2021, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

References:

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1 European Medicines Agency. Rybrevant CMA Approval. December 2021.
2 Remon, J et al. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treatment Reviews. 90 (2020).
3 ClinicalTrials.gov. Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS). Available at: https://clinicaltrials.gov/ct2/show/NCT02609776. Accessed November 2021.
4 European Medicines Agency. Rybrevant Summary of Product Characteristics. December 2021.
5 Vyse S et al. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther 2019; 4: 5. 2, Riess J et al. JTO 2018; 13(10): 1560–1568.
6 Park et al. Amivantamab in EGFR Exon 20 Insertion–Mutated Non–Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. Available at https://ascopubs.org/doi/10.1200/JCO.21.00662?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed. Accessed November 2021.
7 Conditional marketing authorisation. The European Medicines Agency. Available at: https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/conditional-marketing-authorisation
8 Johnson and Johnson. RYBREVANT® (amivantamab-vmjw) Receives FDA Approval as the First Targeted Treatment for Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. Available at: https://www.jnj.com/rybrevanttm-amivantamab-vmjw-receives-fda-approval-as-the-first-targeted-treatment-for-patients-with-non-small-cell-lung-cancer-with-egfr-exon-20-insertion-mutations. Accessed November 2021.
9 Grugan et al. Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells. MAbs. 2017;9(1):114-126.
10 Moores et al. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. Cancer Res. 2016;76(13)(suppl 27216193):3942-3953.
11 Yun et al. Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC. Cancer Discov. 2020;10(8):1194-1209.
12 Vijayaraghavan et al. Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis. Mol Cancer Ther. 2020;19(10):2044-2056.
13 ClinicalTrials.gov. Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT02609776. Accessed November 2021
14 A Study of Lazertinib as Monotherapy or in Combination With Amivantamab in Participants With Advanced Non-small Cell Lung Cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT04077463. Accessed November 2021
15 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). Available at: https://clinicaltrials.gov/ct2/show/NCT04487080. Accessed November 2021
16 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non- Small Cell Lung Cancer After Osimertinib Failure (MARIPOSA-2). Available at https://clinicaltrials.gov/ct2/show/NCT04988295 Accessed November 2021
17 ClinicalTrials.gov. A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions (PAPILLON). Available at: https://clinicaltrials.gov/ct2/show/NCT04538664?term=PAPILLON&cond=NSCLC&draw=2&rank=1. Accessed November 2021.
18 ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies. Available at: https://clinicaltrials.gov/ct2/show/NCT04606381. Accessed November 2021.
19 Park et al, Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). Available at https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.9512. Accessed November 2021.
20 Globocan 2020. Estimated number of incident cases deaths in 2020, Europe, both sexes, all ages. Available at: www.gco.iarc.fr. Accessed November 2021.
21 Zappa C et al. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res 2016; 5(3): 288–300.
22 Wee,P, Wang, Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel). 2017 May; 9(5): 52.
23 Zhang et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016. 7 (48): 78985 – 78993.
24 Lin JJ, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Jänne PA, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 2016 Apr;11(4):556-65.
25 Girard N, BazhenovaL, MinchomA, OuSI, GadgeelSM, Trigo J, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.

FDA approves rituximab plus chemotherapy for pediatric cancer indications

On December 2, 2021, the Food and Drug Administration approved rituximab (Rituxan, Genentech, Inc.) in combination with chemotherapy for pediatric patients (≥6 months to <18 years) with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), or mature B-cell acute leukemia (B-AL). 

Efficacy was evaluated in Inter-B-NHL Ritux 2010 (NCT01516580), a global multicenter, open-label, randomized (1:1) trial of patients ≥ 6 months in age with previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL. Advanced stage was defined as Stage III with elevated lactose dehydrogenase (LDH) level (LDH greater than twice the institutional upper limit of normal values) or stage IV B-cell NHL or B-AL. Patients were randomized to Lymphome Malin B (LMB) chemotherapy (corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide, and triple drug [methotrexate/cytarabine/corticosteroid] intrathecal therapy) alone or in combination with rituximab or non-U.S. licensed rituximab, administered as 6 infusions of rituximab IV at a dose of 375 mg/m2 (2 doses during each of the 2 induction courses and 1 during each of the 2 consolidation courses) as per the LMB scheme. 

The main efficacy outcome measure was event-free survival (EFS), defined as progressive disease, relapse, second malignancy, death from any cause, or non-response as evidenced by detection of viable cells in residue after the second CYVE (Cytarabine [Aracytine, Ara-C], Veposide [VP16]) course, whichever occurs first. A prespecified interim efficacy analysis at 53% information fraction was performed in 328 randomized patients with a median follow-up of 3.1 years. There were 28 EFS events in the LMB group and 10 in the rituximab-LMB group (HR 0.32; 90% CI: 0.17, 0.58; p=0.0012). At the time of the interim analysis, there were 20 deaths in the LMB chemotherapy arm compared to 8 deaths in the rituximab plus LMB chemotherapy arm, with an estimated overall survival HR of 0.36 (95% CI: 0.16, 0.81). No formal statistical test was conducted for overall survival (OS) and the OS result is considered descriptive. Randomization was discontinued after the interim analysis and an additional 122 patients received rituximab plus LMB chemotherapy and contributed to the safety analysis. 

Adverse reactions (grade 3 or higher, >15%) occurring in pediatric patients treated with rituximab and chemotherapy were febrile neutropenia, stomatitis, enteritis, sepsis, increased alanine aminotransferase, and hypokalemia. Grade 3 or higher adverse reactions that occurred more often in the rituximab plus LMB chemotherapy arm compared to LMB chemotherapy included sepsis, stomatitis, and enteritis. Fatal adverse reactions occurred in <2% of patients in both the rituximab plus LMB chemotherapy and LMB chemotherapy arms.  

The recommended rituximab dose is 375 mg/m2 as an intravenous infusion given in combination with systemic LMB chemotherapy. In total, 6 infusions of rituximab are given, 2 doses during each of the induction courses, COPDAM1 [cyclophosphamide, Oncovin (vincristine), prednisolone, Adriamycin (doxorubicin), methotrexate] and COPDAM2, and 1 dose during each of the 2 consolidation courses of CYM (Cytarabine [Aracytine, Ara-C], methotrexate) and CYVE. 

View full prescribing information for Rituxan.  

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment, and Streamlined Review.  

This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088. 

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov. 

FDA approves Darzalex Faspro, Kyprolis, and Dexamethasone for Multiple Myeloma

On November 30, 2021, the Food and Drug Administration approved daratumumab + hyaluronidase-fihj (Darzalex Faspro, Janssen Biotech, Inc.) and carfilzomib (Kyprolis, Amgen, Inc.) plus dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.

Efficacy was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. This cohort enrolled 66 patients with relapsed or refractory multiple myeloma who received at least one prior line of therapy. Patients received Darzalex Faspro 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously in combination with Kyprolis (20/70 mg/m2 once weekly regimen) and dexamethasone.

The main efficacy outcome measure was overall response rate (ORR). The ORR was 84.8% (95% CI: 73.9%, 92.5%). At a median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2% (95% CI: 72.5, 92.3) maintained response for at least 6 months and 82.5% (95% CI: 68.9, 90.6) maintained response for at least 9 months.

The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

The recommended Darzalex Faspro dose is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24, and once every 4 weeks starting Week 25 until disease progression or unacceptable toxicity.

The recommended dosage regimens of Kyprolis when administered in combination with Darzalex Faspro are the following:

• Once weekly 20/70 mg/m2 regimen: Kyprolis 20 mg/m2 administered by IV infusion over 30 minutes on Cycle 1 Day 1 and if a dose of 20 mg/m2 is tolerated, 70 mg/m2 as a 30-minute IV infusion on Cycle 1, Day 8 and Day 15, and then Day 1, 8, and 15 of each 28-day cycle.

• Twice weekly 20/56 mg/m2 regimen: Kyprolis 20 mg/m2 administered by IV infusion over 30 minutes on Cycle 1 Day 1 and Day 2 and, if a dose of 20 mg/m2 is tolerated, 56 mg/m2 administered by IV infusion over 30 minutes on Cycle 1, Day 8, 9, 15, and 16, and then on Day 1, 2, 8, 9, 15, 16 of each 28-day cycle

View full prescribing information for Darzalex Faspro.

View full prescribing information for Kyprolis.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

For information on the COVID-19 pandemic, see the following resources:

• FDA: Coronavirus Disease 2019 (COVID-19)

• NCI: Coronavirus: What People With Cancer Should Know

• CDC: Coronavirus (COVID-19)

TG Therapeutics, Inc. plans to host ODAC meeting in connection with its review of the pending BLA/sNDA for the combination of ublituximab and UKONIQ®

TG Therapeutics Provides Regulatory Update

Nov 30, 2021

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COMPANY TO HOST CONFERENCE CALL TODAY, TUESDAY, NOVEMBER 30, 2021 AT 8:30 AM ET

NEW YORK, Nov. 30, 2021 (GLOBE NEWSWIRE) -- TG Therapeutics, Inc. (NASDAQ: TGTX), today announced the U.S. Food and Drug Administration (FDA) has notified the Company that it plans to host a meeting of the Oncologic Drugs Advisory Committee (ODAC) in connection with its review of the pending Biologics License Application (BLA)/supplemental New Drug Application (sNDA) for the combination of ublituximab and UKONIQ® (umbralisib) (combination referred to as U2) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

Michael S. Weiss, Chairman and Chief Executive Officer of TG Therapeutics stated, “We appreciate the FDA’s efforts in reviewing the U2 BLA/sNDA and its interest in obtaining the perspective of the ODAC regarding the benefit-risk of UKONIQ and the U2 combination. We believe UKONIQ is a unique PI3K inhibitor, with a differentiated toxicity and tolerability profile and believe the data submitted thus far are supportive of approval of U2 in CLL.”  

Mr. Weiss continued, “We look forward to the ODAC meeting as we believe it will provide us an opportunity to highlight the important role U2 can play in the treatment of CLL. As we have noted previously, while many patients with CLL are well-served with currently available therapies, there exists an underserved population, which for a variety of reasons, including tolerability concerns, access issues, and treatment failure, would benefit from an alternative treatment option.”

ABOUT THE ODAC MEETING
In general, the ODAC reviews and evaluates data concerning the safety and effectiveness of marketed and investigational human drug products for use in the treatment of cancer and makes appropriate recommendations to the Commissioner of Food and Drugs. Although the FDA will consider the recommendation of the ODAC Committee, the final decision regarding the approval of a product is made solely by the FDA. 

The FDA has notified the Company that potential questions and discussion topics for the ODAC include: the benefit-risk of the U2 combination in the treatment of CLL or SLL, and the benefit-risk of UKONIQ in relapsed/refractory marginal zone lymphoma (MZL) or follicular lymphoma (FL). In addition, as part of the benefit-risk analysis, the overall safety profile of the U2 regimen, including adverse events (serious and Grade 3-4), discontinuations due to adverse events, and dose modifications, is expected to be reviewed. The FDA’s concern giving rise to the ODAC meeting appears to stem from an early analysis of overall survival from the UNITY-CLL trial.

Overall survival was designated as a secondary efficacy outcome in the UNITY-CLL protocol but was not part of the primary analysis in accordance with the study’s statistical analysis plan agreed upon via a Special Protocol Assessment (SPA), and therefore, was not analyzed or included in the BLA/sNDA. Additionally, the study was not powered for overall survival. As part of the ongoing review of the BLA/sNDA, the FDA requested an early analysis of overall survival from the UNITY-CLL trial. As of September 2021, the cut-off date for the overall survival analysis requested by the FDA during their review, there was an imbalance in favor of the control arm (HR: 1.23) though this result was not statistically significant. However, when excluding deaths related to COVID-19, the two arms were approximately balanced (HR: 1.04) with again no statistically significant difference between the treatment groups with regard to overall survival. The overall survival results are preliminary and the Company will continue to evaluate this endpoint over time as more events are available and will continue to analyze how COVID-19 may be impacting the analysis.

The date of the ODAC meeting has not yet been determined, although the FDA has stated that it is targeting holding the ODAC in March or April 2022. Given this timing, we believe it is unlikely that the FDA will make a decision on the BLA/sNDA by the PDUFA goal date of March 25, 2022.   

ABOUT UNITY-CLL PHASE 3 TRIAL AND THE BLA/sNDA SUBMISSION
UNITY-CLL is a global, Phase 3, randomized, controlled clinical trial comparing the combination of ublituximab plus UKONIQ (umbralisib), or U2, to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL). The trial randomized patients into four treatment arms: ublituximab single agent, UKONIQ single agent, ublituximab plus UKONIQ, and an active control arm of obinutuzumab plus chlorambucil. A prespecified interim analysis was conducted to assess the contribution of ublituximab and UKONIQ in the U2 combination arm and allowed for the termination of the single agent arms. Accordingly, the UNITY-CLL Phase 3 trial continued enrollment in a 1:1 ratio into the two combination arms: the investigational arm of U2 and the control arm of obinutuzumab plus chlorambucil. Approximately 420 subjects enrolled to the two combination arms and approximately 60% of patients were treatment-naïve and 40% were relapsed or refractory. The primary endpoint for this study was superior progression-free survival (PFS) for the U2 combination compared to the control arm. The trial met its primary endpoint, with U2 significantly prolonging independent review committee (IRC) assessed PFS vs. control (median 31.9 months vs 17.9 months; hazard ratio 0.546 (p<0.0001)) at a median follow-up of 36.7 months, and results were presented at the American Society of Hematology (ASH) Annual Meeting in December 2020. The UNITY-CLL Phase 3 trial is being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA).

The BLA/sNDA submissions of U2 to treat CLL were based on the results of the UNITY-CLL trial. The FDA previously granted Fast Track designation to the U2 combination for the treatment of adult patients with CLL and orphan drug designation for ublituximab in combination with UKONIQ for the treatment of CLL. On May 25, 2021, FDA accepted the BLA for U2 as a treatment for patients with CLL and SLL and set a Prescription Drug User Fee Act (PDUFA) goal date of March 25, 2022. 

ABOUT CHRONIC LYMPHOCYTIC LEUKEMIA
Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia. It is estimated there will be more than 20,000 new cases of CLL diagnosed in the United States in 2020 and approximately 45,000 new cases globally in 2020.1,2 Although signs and symptoms of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of malignant cells.

CONFERENCE CALL INFORMATION
The Company will host a conference call today, November 30, 2021, at 8:30 AM ET, to discuss the regulatory updates.

To participate in the conference call, please call 1-877-407-8029 (U.S.), 1-201-689-8029 (outside the U.S.), Conference Title: TG Therapeutics Update Call. A live audio webcast will be available on the Events page, located within the Investors & Media section, of the Company's website at http://ir.tgtherapeutics.com/events. An audio recording of the conference call will also be available for a period of 30 days after the call.

ABOUT TG THERAPEUTICS
TG Therapeutics is a fully-integrated, commercial stage biopharmaceutical company focused on the acquisition, development and commercialization of novel treatments for B-cell malignancies and autoimmune diseases. In addition to an active research pipeline including five investigational medicines across these therapeutic areas, TG has received accelerated approval from the U.S. FDA for UKONIQ® (umbralisib), for the treatment of adult patients with relapsed/refractory marginal zone lymphoma who have received at least one prior anti-CD20-based regimen and relapsed/refractory follicular lymphoma who have received at least three prior lines of systemic therapies. Currently, the Company has three programs in Phase 3 development for the treatment of patients with relapsing forms of multiple sclerosis (RMS) and patients with chronic lymphocytic leukemia (CLL) and several investigational medicines in Phase 1 clinical development. For more information, visit www.tgtherapeutics.com, and follow us on Twitter @TGTherapeutics and Linkedin.

UKONIQ® is a registered trademark of TG Therapeutics, Inc.

ABOUT UKONIQ® (umbralisib)
UKONIQ is the first and only oral inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon. PI3K-delta is known to play an important role in supporting cell proliferation and survival, cell differentiation, intercellular trafficking and immunity and is expressed in both normal and malignant B-cells. CK1-epsilon is a regulator of oncoprotein translation and has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies.

UKONIQ is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen and for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.

These indications are approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

IMPORANT SAFETY INFORMATION
Infections: Serious, including fatal, infections occurred in patients treated with UKONIQ. Grade 3 or higher infections occurred in 10% of 335 patients, with fatal infections occurring in <1%. The most frequent Grade ≥3 infections included pneumonia, sepsis, and urinary tract infection. Provide prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and consider prophylactic antivirals during treatment with UKONIQ to prevent CMV infection, including CMV reactivation. Monitor for any new or worsening signs and symptoms of infection, including suspected PJP or CMV, during treatment with UKONIQ. For Grade 3 or 4 infection, withhold UKONIQ until infection has resolved. Resume UKONIQ at the same or a reduced dose. Withhold UKONIQ in patients with suspected PJP of any grade and permanently discontinue in patients with confirmed PJP. For clinical CMV infection or viremia, withhold UKONIQ until infection or viremia resolves. If UKONIQ is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.

Neutropenia: Serious neutropenia occurred in patients treated with UKONIQ. Grade 3 neutropenia developed in 9% of 335 patients and Grade 4 neutropenia developed in 9%. Monitor neutrophil counts at least every 2 weeks for the first 2 months of UKONIQ and at least weekly in patients with neutrophil count <1 x 109/L (Grade 3-4) neutropenia during treatment with UKONIQ. Consider supportive care as appropriate. Withhold, reduce dose, or discontinue UKONIQ depending on the severity and persistence of neutropenia.

Diarrhea or Non-Infectious Colitis: Serious diarrhea or non-infectious colitis occurred in patients treated with UKONIQ. Any grade diarrhea or colitis occurred in 53% of 335 patients and Grade 3 occurred in 9%. For patients with severe diarrhea (Grade 3, i.e., > 6 stools per day over baseline) or abdominal pain, stool with mucus or blood, change in bowel habits, or peritoneal signs, withhold UKONIQ until resolved and provide supportive care with antidiarrheals or enteric acting steroids as appropriate. Upon resolution, resume UKONIQ at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue UKONIQ. Discontinue UKONIQ for life-threatening diarrhea or colitis.

Hepatotoxicity: Serious hepatotoxicity occurred in patients treated with UKONIQ. Grade 3 and 4 transaminase elevations (ALT and/or AST) occurred in 8% and <1%, respectively, in 335 patients. Monitor hepatic function at baseline and during treatment with UKONIQ. For ALT/AST greater than 5 to less than 20 times ULN, withhold UKONIQ until return to less than 3 times ULN, then resume at a reduced dose. For ALT/AST elevation greater than 20 times ULN, discontinue UKONIQ.

Severe Cutaneous Reactions: Severe cutaneous reactions, including a fatal case of exfoliative dermatitis, occurred in patients treated with UKONIQ. Grade 3 cutaneous reactions occurred in 2% of 335 patients and included exfoliative dermatitis, erythema, and rash (primarily maculo-papular). Monitor patients for new or worsening cutaneous reactions. Review all concomitant medications and discontinue any potentially contributing medications. Withhold UKONIQ for severe (Grade 3) cutaneous reactions until resolution. Monitor at least weekly until resolved. Upon resolution, resume UKONIQ at a reduced dose. Discontinue UKONIQ if severe cutaneous reaction does not improve, worsens, or recurs. Discontinue UKONIQ for life-threatening cutaneous reactions or SJS, TEN, or DRESS of any grade. Provide supportive care as appropriate.

Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5: UKONIQ contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons, frequently in patients who also have aspirin hypersensitivity.

Embryo-fetal Toxicity: Based on findings in animals and its mechanism of action, UKONIQ can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females and males with female partners of reproductive potential to use effective contraception during treatment and for at least one month after the last dose.

Serious adverse reactions occurred in 18% of 221 patients who received UKONIQ. Serious adverse reactions that occurred in ≥2% of patients were diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%). Permanent discontinuation of UKONIQ due to an adverse reaction occurred in 14% of patients. Dose reductions of UKONIQ due to an adverse reaction occurred in 11% of patients. Dosage interruptions of UKONIQ due to an adverse reaction occurred in 43% of patients.

The most common adverse reactions (>15%), including laboratory abnormalities, in 221 patients who received UKONIQ were increased creatinine (79%), diarrhea-colitis (58%, 2%), fatigue (41%), nausea (38%), neutropenia (33%), ALT increase (33%), AST increase (32%), musculoskeletal pain (27%), anemia (27%), thrombocytopenia (26%), upper respiratory tract infection (21%), vomiting (21%), abdominal pain (19%), decreased appetite (19%), and rash (18%).

Lactation: Because of the potential for serious adverse reactions from umbralisib in the breastfed child, advise women not to breastfeed during treatment with UKONIQ and for at least one month after the last dose.

Please visit www.tgtherapeutics.com/prescribing-information/uspi-ukon for full Prescribing Information and Medication Guide.

________________________________________________________

1 Cancer Stat Facts: Leukemia — Chronic Lymphocytic Leukemia (CLL). National Cancer Institute Surveillance, Epidemiology, and End Results Program website. https://seer.cancer.gov/statfacts/html/clyl.html. Accessed October 26, 2020.
2 EpiCast Report: Chronic Lymphocytic Leukemia – Epidemiology Forecast to 2025. Available at: https://store.globaldata.com/report/gdhcer164-17–epicast-report-chronic-lymphocytic-leukemia-epidemiology-forecast-to-2025/.

Cautionary Statement
This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, including statements relating to the BLA/sNDA submission of ublituximab in combination with UKONIQ® (umbralisib), the FDA’s planned ODAC meeting to review the benefit-risk of UKONIQ monotherapy and in combination with ublituximab, the FDA review and potential approval of the BLA/sNDA and the timing thereof, the potential benefits, safety and efficacy of ublituximab in combination with UKONIQ in CLL, the clinical development of our product candidates, and anticipated milestones. In addition to the risk factors identified from time to time in our reports filed with the U.S. Securities and Exchange Commission, factors that could cause our actual results to differ materially are the following: the risk that the FDA will not approve the BLA/sNDA submissions; the risk that FDA will withdraw approval of UKONIQ for the treatment of relapsed or refractory MZL or FL; the risk that safety issues or trends observed in the UNITY-CLL study, including rates of serious adverse events and Grade 3 or greater adverse events, discontinuation rates due to adverse events, and dose modifications due to adverse events  will prevent approval of ublituximab in combination with UKONIQ or, if approved, will lead to a REMS or other actions for risk management; the risk the Company will voluntarily withdraw the BLA/sNDA for ublituximab in combination with UKONIQ after further analysis of data from the UNITY-CLL study; the risk that the outcome of the ODAC meeting is not favorable or, even if favorable, the FDA does not approve the U2 combination or does so in a narrowly defined population or imposes certain restrictions or warnings that negatively impact the commercial potential of U2 in CLL, the currently approved indications of UKONIQ, or any future indications for UKONIQ or ublituximab; the risk that the FDA does not take action on the BLA/sNDA by the PDUFA target goal date of March 25, 2022; the risk that the overall survival data from UNITY-CLL included in this press release changes negatively with additional analysis and time; the risk that the FDA does not agree with the Company’s assessment of the impact of deaths associated with COVID-19 on overall survival analysis presented in this press release; the risk that ublituximab in combination with UKONIQ, or any other product candidates, will not be commercially successful if approved; the risk that the differentiated tolerability profile for UKONIQ previously observed in clinical trials will not be reproduced in the UNITY-CLL trial or any other on-going studies or the FDA will disagree with our interpretation of the safety of UKONIQ, ublituximab or any of our drug candidates; our ability to successfully and cost effectively complete preclinical and clinical trials, including clinical trials involving the U2 regimen; the uncertainties inherent in research and development; and the risk that the ongoing COVID-19 pandemic and associated government control measures have an adverse impact on our research and development plans or commercialization efforts.

Further discussion about these and other risks and uncertainties can be found in our Annual Report on Form 10-K for the fiscal year ended December 31, 2020, as updated by our subsequent Quarterly Reports on Form 10-Q, and in our other filings with the U.S. Securities and Exchange Commission. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof.

This press release and prior releases are available at www.tgtherapeutics.com. The information found on our website is not incorporated by reference into this press release and is included for reference purposes only.

CONTACT:

Investor Relations
Email: ir@tgtxinc.com
Telephone: 1.877.575.TGTX (8489), Option 4

Media Relations:
Email: media@tgtxinc.com
Telephone: 1.877.575.TGTX (8489), Option 6