RxTROSPECT Remembers 🌹

Tomorrow is "Remembrance Sunday"...

This day is celebrated every second Sunday of November, on November 13 this year. The closest Sunday to Armistice Day or Remembrance Day (November 11), Remembrance Sunday is held to celebrate the bravery of those who fought in World War I and II. We look back on the peace that was restored by the action of these men and women — an act of bravery and courage we will never forget.

FDA approves cemiplimab in combination with platinum-based chemotherapy for first-line NSCLC

FDA has approved Enhertu for patients with the HER2-low breast cancer subtype

Today, the U.S. Food and Drug Administration approved Enhertu (fam-trastuzumab-deruxtecan-nxki), an IV infusion for the treatment of patients with unresectable (unable to be removed) or metastatic (spread to other parts of the body) HER2-low breast cancer. This is the first approved therapy targeted to patients with the HER2-low breast cancer subtype, which is a newly defined subset of HER2-negative breast cancer. 

It is estimated that 287,850 new cases of female breast cancer will be diagnosed in 2022 in the U.S. Approximately 80-85% of those new cases were previously considered to be HER2-negative subtype (including hormone receptor positive and triple negative breast cancer), which means the tumors do not overexpress, or make too many copies of the HER2 protein. Of that proportion of breast cancer diagnoses, about 60% of patients previously classified as having HER2-negative subtype can now be considered as HER2-low. Prior to today’s approval, HER2-low patients received endocrine therapy or chemotherapy.  

“Today’s approval highlights the FDA’s commitment to be at the forefront of scientific advances, making targeted cancer treatment options available for more patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Having therapies that are specially tailored to each patient’s cancer subtype is a priority to ensure access to safe and innovative treatments.” 

As part of the Administration’s Cancer Moonshot program, President Biden tapped federal agencies to develop ways to reduce the rate of cancer deaths and improve the lives of cancer patients and their families through advancements in cancer research and technology, and development of new programs. Enhertu’s approval further illustrates how the FDA’s efforts align with the Cancer Moonshot goals of targeting the right treatments to the right patients, speeding progress against the most deadly and rare cancers, and learning from the experience of all patients.

HER2 receptors, which are proteins made by the HER2 gene, are important in determining a patient’s treatment. HER2-negative includes hormone receptor positive and triple negative breast cancers. HER2-low is a new classification of the HER2 subtype. It describes a new subtype of breast cancer that has some HER2 proteins on the cell surface, but not enough to be classified as HER2-positive.

Patients with HER2-low breast cancer are eligible for Enhertu if they have received a prior chemotherapy in the metastatic setting, or their cancer returned during, or within 6 months of completing, adjuvant chemotherapy.

This approval is based on DESTINY-Breast04, a randomized, multicenter, open label clinical trial that enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer. The trial included two cohorts: 494 hormone receptor positive (HR+) patients and 63 hormone receptor negative (HR-) patients. Of these patients, 373 randomly received Enhertu by intravenous infusion every three weeks and 184 randomly received physician’s choice of chemotherapy (eribulin, capecitabine, gemcitabine, nab paclitaxel or paclitaxel). The results showed improvement in both progression-free survival and overall survival in people with unresectable or metastatic HER2-low breast cancer.

The median age of trial participants was 57 years old, ranging from 28 to 81 years of age. Among the 557 patients, 24% were age 65 or older. Females comprised 99.6% of the trial population. Trial participants’ race was reported as 48% White, 40% Asian, 2% Black or African American, and 3.8% Hispanic/Latino. 

The most common adverse reactions in patients receiving Enhertu in DESTINY-Breast04 are nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, musculoskeletal pain and diarrhea. The prescribing information includes a boxed warning to advise health care professionals of the risk of interstitial lung disease and embryo-fetal toxicity. Enhertu is not recommended for women who are pregnant.

Enhertu received priority review and breakthrough therapy designations for this indication. The FDA granted the approval of Enhertu to Daiichi Sankyo four months ahead of the Prescription Drug User Fee Act (PDUFA) deadline.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies.

FDA approves Bayer' darolutamide for metastatic hormone-sensitive prostate cancer

On August 5, 2022, the Food and Drug Administration approved darolutamide (Nubeqa, Bayer HealthCare Pharmaceuticals Inc.) tablets in combination with docetaxel for adult patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Efficacy was based on ARASENS (NCT02799602), a randomized, multicenter, double-blind, placebo-controlled clinical trial in 1306 patients with mHSPC. Patients were randomized to receive either darolutamide 600 mg orally twice daily plus docetaxel 75 mg/m2 intravenously administered every 3 weeks for up to 6 cycles or docetaxel plus placebo. All patients received a gonadotropin-releasing hormone analog concurrently or had a bilateral orchiectomy.

The primary efficacy measure was overall survival (OS). Time-to-pain progression was an additional efficacy measure. Median OS was not reached (NR) (95% CI: NR, NR) in the darolutamide plus docetaxel arm and 48.9 months (95% CI: 44.4, NR) in docetaxel plus placebo arm (HR 0.68; 95% CI: 0.57, 0.80; p<0.0001). Treatment with darolutamide and docetaxel resulted in a statistically significant delay in time-to-pain progression (HR 0.79; 95% CI: 0.66, 0.95; 1-sided p=0.006).

The median age of patients was 67 years (41 to 89) and 17% were 75 years or older. Selected demographics were reported as follows: 52% White, 36% Asian, 4% Black or African American, 7% Hispanic/Latino. Three percent of patients had M1a disease (spread to distant lymph nodes), 83% had M1b (spread to bones), and 14% had M1c (spread to organs).

The most common adverse reactions experienced by patients (incidence ≥10% with a ≥2% increase over placebo with docetaxel) were constipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia.

The recommended darolutamide dose for mHSPC is 600 mg (two 300 mg tablets) taken orally, twice daily, with food until unacceptable toxicity or disease progression. Docetaxel, 75 mg/m2 intravenously is administered every 3 weeks for up to 6 cycles. The first dose of docetaxel should be administered within 6 weeks after the start of darolutamide treatment.

View full prescribing information for Nubeqa.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Health Canada, the Singapore Health Sciences Authority, Switzerland’s Swissmedic, the United Kingdom’s Medicines and Healthcare products Regulatory Authority, and Australia’s Therapeutic Goods Administration. The application reviews may be ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately one month ahead of the FDA goal date.

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

FDA approves crizotinib for ALK-positive inflammatory myofibroblastic tumor

On July 14, 2022, the Food and Drug Administration approved crizotinib (Xalkori, Pfizer Inc.) for adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT).

The safety and efficacy of crizotinib were evaluated in two multicenter, single-arm, open-label trials that included 14 pediatric patients from trial ADVL0912 (NCT00939770) and 7 adult patients from trial A8081013 (NCT01121588) with unresectable, recurrent, or refractory ALK-positive IMT.

The major efficacy outcome measure of these trials was objective response rate (ORR). For the 14 pediatric patients, a total of 12 of the 14 patients (86%, 95% CI: 57, 98) experienced an objective response, assessed by an independent review committee. For the 7 adult patients, 5 patients had objective responses.

The most common adverse reactions (≥35%) in pediatric patients were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache. The most frequent adverse reactions (≥35%) in adult patients were vision disorders, nausea, and edema.

The recommended crizotinib dose in adult patients is 250 mg orally twice daily until disease progression or unacceptable toxicity. The recommended pediatric dose is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity.

View full prescribing information for Xalkori.

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

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. Crizotinib received orphan drug designation.

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.

Yescarta® (axicabtagene ciloleucel) gains EU approval for the treatment of adult patients with relapsed or refractory (3L+) FL

FDA approves Novartis Kymriah® CAR-T cell therapy for adult patients with relapsed or refractory follicular lymphoma

• 68% of patients receiving Kymriah in the ELARA trial experienced complete response, with an 86% overall response rate, along with a remarkable safety profile1

• Sustained clinical benefit from Kymriah treatment demonstrated – of patients who achieved a complete response, 85% were still in response at 12 months1

• Kymriah can be administered in the outpatient setting, offering increased flexibility and potentially reducing the burden of therapy for patients and their care teams1,2

• Kymriah is now FDA approved in three indications and remains the only CAR-T cell therapy approved in both adult and pediatric settings1

Basel, May 28, 2022 — Novartis today announced the US Food and Drug Administration (FDA) has granted accelerated approval for Kymriah® (tisagenlecleucel) for the treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy. In accordance with the Accelerated Approval Program, continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Kymriah is now FDA approved in three indications and remains the only CAR-T cell therapy approved in both adult and pediatric settings1.

"We are proud of today's FDA approval of a third indication for Kymriah. We hope this treatment option that has the potential for long-lasting results may help break the unrelenting cycle of treatment for patients with follicular lymphoma,” said Victor Bulto, President, Novartis Innovative Medicines US. “We are on a mission to build on our pioneering work in cell therapy and continue to innovate for patient impact.”

The approval is based on data from the Phase II ELARA trial, a single-arm, open-label trial, in which 90 patients were evaluated for efficacy with a median follow-up of approximately 17 months. Eighty-six percent of patients treated with Kymriah achieved a response including 68% who experienced a complete response1.

Prolonged durable response to treatment was demonstrated with an estimated 85% of patients who achieved a complete response still in response 12 months after initial response1. Kymriah was shown to be effective in high-risk patients including those who were heavily pretreated or had refractory disease, POD24, bulky disease or those with high Follicular Lymphoma International Prognostic Index (FLIPI) scores1.

For the 97 patients evaluable for safety at 21 months of median follow-up, the safety profile of Kymriah was remarkable1. Fifty-three percent of patients experienced any-grade cytokine release syndrome (CRS), as defined by the Lee scale, and there were no reported cases of high-grade (grade 3 or higher) CRS1. Forty-three percent of patients experienced any-grade neurologic events; grade 3 or higher neurologic events were seen in only 6% of patients1. Eighteen percent of patients (17 of 97 patients) were infused in an outpatient setting3.

“Patients with follicular lymphoma who relapse or don’t respond to treatment have a poor prognosis and may face a series of treatment options without a meaningful, lasting response,” said Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma in the Division of Hematology Oncology and Director, Lymphoma Program and Translational Research at the University of Pennsylvania’s Abramson Cancer Center, institutional Principal Investigator on the trial. “This new, effective option for patients with follicular lymphoma may offer long-term benefit.”

While follicular lymphoma is typically an indolent type of cancer, patients with FL may be exposed to a median of four lines of treatment, with an upper range of 13 lines4,5. Although there are multiple systemic therapies available, the efficacy of these regimens drops off rapidly in later lines6.

“The approval of Kymriah offers patients with relapsed or refractory follicular lymphoma a new treatment option and new hope for improving patient outcomes,” said Meghan Gutierrez, Chief Executive Officer at the Lymphoma Research Foundation. “Having this single infusion treatment option helps to transform the way healthcare providers approach this type of blood cancer and we commend those who have contributed to the acceleration of scientific research for the benefit of patients.”

In early May 2022, the European Commission approved Kymriah for the treatment of adult patients with r/r FL after two or more lines of systemic therapy, the third indication for which Kymriah is available to patients in the European Union.

About Novartis commitment to Oncology Cell Therapy
As part of the unique Novartis Oncology strategy to pursue four cancer treatment platforms – radioligand therapy, targeted therapy, immunotherapy and cell and gene therapy – we strive for cures through cell therapies in order to enable more patients to live cancer-free. We will continue to pioneer the science and invest in our manufacturing and supply chain process to further advance transformative innovation.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of the Novartis commitment to CAR-T cell therapy.

We have made strong progress in broadening our delivery of Kymriah, which is currently available for use in at least one indication in 30 countries and at more than 370 certified treatment centers, with clinical and real-world experience from administration to more than 6,900 patients. We continue to pioneer in cell therapy, leveraging our vast experience to develop next-generation CAR-T cell therapies. These therapies will utilize our new T-Charge™ platform being evaluated to expand across hematological malignancies and bring the hope for a cure to patients with other cancer types.

Novartis has a comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience and sustainability of the Novartis manufacturing and supply chain.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis is reimagining medicine to improve and extend people’s lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. Novartis products reach nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 108,000 people of more than 140 nationalities work at Novartis around the world. Find out more at https://www.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis at https://twitter.com/novartisnews
For Novartis multimedia content, please visit https://www.novartis.com/news/media-library
For questions about the site or required registration, please contact media.relations@novartis.com

References

1. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2022.

2. Fowler, NH. et.al. Assessment of Healthcare Resource Utilization and Costs in Patients with Relapsed or Refractory Follicular Lymphoma Undergoing CAR-T Cell Therapy with Tisagenlecleucel: Results from the Elara Study. Abstract #3533. 2021 American Society of Hematology (ASH) Annual Meeting, Dec 11-14, Atlanta, GA and Virtual.

3. Fowler, N.H., et al.Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nature Medicine. 2021;10.1038/s41591-021-01622-0.

4. Data on File, Novartis, 2020.

5. Schuster, S., et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. NEJM. 2017;377(26):2545–2554.

6. Sutamtewagul, G. & Link, B.K. Novel treatment approaches and future perspectives in follicular lymphoma. Ther Adv Hematol. 2019; 10:1–20.

FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer; Israel included for the first time in Orbis-approval

On May 4, 2022, the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.

In December 2019, fam-trastuzumab deruxtecan-nxki received accelerated approval for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. The following trial was the confirmatory trial for the accelerated approval.

Efficacy was based on DESTINY-Breast03 (NCT03529110), a multicenter, open-label, randomized trial that enrolled 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. Patients were randomized 1:1 to receive either Enhertu or ado-trastuzumab emtansine by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease.

The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review based on RECIST v.1.1. Overall survival (OS) and confirmed objective response rate (ORR) were the key secondary outcome measures. Median PFS was not reached (95% CI: 18.5, not estimable) in the Enhertu arm and 6.8 months (95% CI: 5.6, 8.2) in the ado-trastuzumab emtansine arm. The hazard ratio was 0.28 (95% CI: 0.22, 0.37; p-value<0.0001). At the time of the PFS analysis, 16% of patients had died and OS was immature. The ORR based on the patients with measurable disease assessed by BICR at baseline was 82.7% (95% CI: 77.4, 87.2) in the Enhertu arm and 36.1% (95% CI: 30.0, 42.5) for those receiving ado-trastuzumab emtansine.

The most common adverse reactions (incidence >30%) in patients receiving Enhertu were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious adverse reactions in >1% of patients who received Enhertu were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. The prescribing information includes a Boxed Warning to advise health professionals of the risk of interstitial lung disease and embryo-fetal toxicity.

The recommended Enhertu dose for breast cancer is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity

View full prescribing information for Enhertu.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, Israel’s Ministry of Health Pharmaceutical Administration, and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, breakthrough designation and orphan drug designation. 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.

Get a Demo

Get a Demo