Another First as FDA grant accelerated approval to tovorafenib for patients with r/r BRAF-altered pediatric low-grade glioma

On April 23, 2024, the Food and Drug Administration granted accelerated approval to tovorafenib (Ojemda, Day One Biopharmaceuticals, Inc.) for patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.

This represents the first FDA approval of a systemic therapy for the treatment of patients with pediatric LGG with BRAF rearrangements, including fusions.

Full prescribing information for Ojemda will be posted here.

Efficacy and Safety

Efficacy was evaluated in 76 patients enrolled in FIREFLY-1 (NCT04775485), a multicenter, open-label, single-arm trial in patients with relapsed or refractory pediatric LGG harboring an activating BRAF alteration detected by a local laboratory who had received at least one line of prior systemic therapy. Patients were required to have documented evidence of radiographic progression and at least one measurable lesion. Patients with tumors harboring additional activating molecular alterations (e.g., IDH1/2 mutations, FGFR mutations) or with a known or suspected diagnosis of neurofibromatosis type 1 were excluded. Patients received tovorafenib based on body surface area (range: 290 to 476 mg/m2, up to a maximum dose of 600 mg) once weekly until they experienced disease progression or unacceptable toxicity.

The major efficacy outcome measure was overall response rate (ORR), as defined as the proportion of patients with complete response (CR), partial response (PR), or minor response (MR) by blinded independent central review (BICR) based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria. Additional efficacy outcome measures included duration or response (DoR). The ORR was 51% (95% CI: 40, 63) and median DoR was 13.8 months (95% CI: 11.3, not estimable).

The most common adverse reactions (≥30%) were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased phosphate, decreased hemoglobin, increased creatinine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.

The recommended tovorafenib dose based on body surface area (BSA) is 380 mg/m2 orally once weekly (the maximum recommended dosage is 600 mg orally once weekly) with or without food until disease progression or intolerable toxicity. Tovorafenib is available as an immediate release tablet or as an oral suspension. A recommended dosage for patients with BSA less than 0.3 m2 has not been established.

Expedited Programs

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

This application was granted accelerated approval based on overall response rate and duration of response. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

This application was granted priority review, breakthrough designation and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

First FDA approval of a radiopharmaceutical for pediatric patients 12+ with SSTR-positive GEP-NETs

On April 23, 2024, the Food and Drug Administration approved lutetium Lu 177 dotatate (Lutathera, Advanced Accelerator Applications USA, Inc., a Novartis company) for pediatric patients 12 years and older with somatostatin receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors. Lutetium Lu 177 dotatate received approvalExternal Link Disclaimer for this indication for adults in 2018.

This represents the first FDA approval of a radioactive drug, or radiopharmaceutical, for pediatric patients 12 years of age and older with SSTR-positive GEP-NETs.

Full prescribing information for Lutathera will be posted here.

Efficacy and Safety

Approval was based on pharmacokinetic (PK), dosimetry, and safety data from NETTER-P (NCT04711135), an ongoing, international, multi-center, open-label, single-arm study of lutetium Lu 177 dotatate in adolescent patients with locally advanced/inoperable or metastatic SSTR-positive GEP-NETs or pheochromocytoma/paraganglioma (PPGL). Approval was also based on the extrapolation of efficacy outcomes observed in NETTER-1 (NCT01578239), a randomized, multicenter, open-label, active-controlled trial in 229 patients with locally advanced/inoperable or metastatic SSTR-positive midgut carcinoid tumors, which supported the original approval of lutetium Lu 177 dotatate in adult patients.

Safety was evaluated in 9 pediatric patients in NETTER-P, including 4 patients with GEP-NETs. The major outcome measures were absorbed radiation doses in target organs and incidence of adverse reactions after the first treatment cycle. Additional outcome measures included short-term adverse reactions following treatment with lutetium Lu 177 dotatate. The adverse reaction profile observed in NETTER-P was similar to that observed in adults.

The recommended lutetium Lu 177 dotatate dose is 7.4 GBq (200 mCi) every 8 weeks (± 1 week) for a total of 4 doses. Premedications and concomitant medications should be administered as recommended. A post-marketing requirement was issued to assess the long-term safety of lutetium Lu 177 dotatate in adolescents.

Expedited Programs

NETTER-P was conducted as part of a pediatric Written Request (WR) under the Best Pharmaceuticals for Children Act (BPCA). This application was granted priority review and orphan drug designation; FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA approves Altor BioScience's Anktiva (nogapendekin alfa inbakicept) for BCG-unresponsive non-muscle invasive bladder cancer

On April 22, 2024, the Food and Drug Administration approved nogapendekin alfa inbakicept-pmln (Anktiva, Altor BioScience, LLC) with Bacillus Calmette-Guérin (BCG) for adult patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.

Full prescribing information for Anktiva will be posted here.

Efficacy and Safety

Efficacy was evaluated in QUILT-3.032 (NCT0302285), a single-arm, multicenter trial of 77 patients with BCG-unresponsive, high-risk NMIBC with CIS with or without Ta/T1 papillary disease following transurethral resection. Patients received nogapendekin alfa inbakicept-pmln induction via intravesical instillation with BCG followed by maintenance therapy for up to 37 months.

Tumor status was assessed with cystoscopy and urine cytology every 3 months for up to 2 years and biopsy (random or cystoscopy-directed) was required within the first 6 months after treatment initiation. Subsequent assessment was performed per local community standards. 

The major efficacy outcome measures were CR at any time and duration of complete response (DOR). CR was defined by a negative cystoscopy (with TURBT/biopsies as applicable) and urine cytology. 

The CR rate was 62% (95% CI: 51, 73). Fifty-eight percent of patients with CR had a DOR ≥ 12 months and 40% had a DOR ≥ 24 months.

The most common adverse reactions (≥15%), including laboratory test abnormalities, were increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills, and pyrexia.

The recommended nogapendekin alfa inbakicept-pmln dose is 400 mcg administered intravesically with BCG once a week for 6 weeks as induction therapy. A second induction course may be administered if CR is not achieved at month 3. For maintenance after induction therapy, the recommended dose is 400 mcg administered intravesically with BCG once a week for 3 weeks at months 4, 7, 10, 13, and 19 (for a total of 15 doses). For patients with an ongoing CR at month 25 or later, maintenance instillations with BCG may be administered once a week for 3 weeks at months 25, 31, and 37 for a maximum of 9 additional instillations. Treatment should be discontinued for disease persistence after second induction, disease recurrence or progression, or unacceptable toxicity. The maximum treatment duration is 37 months.

Expedited Programs

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

This application was granted breakthrough designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA Approves Genentech's Alecensa as First Adjuvant Treatment for People With ALK-Positive Early-Stage Lung Cancer

On April 18, 2024, the Food and Drug Administration approved alectinib (Alecensa, Genentech, Inc.) for adjuvant treatment following tumor resection in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.

Full prescribing information for Alecensa will be posted here.

Efficacy was demonstrated in a global, randomized, open-label trial (ALINA, NCT03456076) in patients with ALK-positive NSCLC who had complete tumor resection. Eligible patients were required to have resectable Stage IB (tumors ≥ 4 cm) to IIIA NSCLC (by AJCC 7th edition) with ALK rearrangements identified by a locally performed FDA-approved ALK test or by a centrally performed VENTANA ALK (D5F3) CDx assay. A total of 257 patients were randomized (1:1) to receive alectinib 600 mg orally twice daily or platinum-based chemotherapy following tumor resection.

The major efficacy outcome measures were disease-free survival (DFS) in the subgroup of patients with stage II-IIIA NSCLC and DFS in the overall study population (stage IB-IIIA), as assessed by investigator. In patients with stage II-IIIA NSCLC, median DFS was not reached (95% CI: not estimable [NE], NE) in the alectinib arm and 44.4 months (95% CI: 27.8, NE) in the chemotherapy arm (HR 0.24 [95% CI: 0.13, 0.45]; p<0.0001). Similar results were seen in the overall study population with median DFS not reached (95% CI: NE, NE) in the alectinib arm and 41.3 months (95% CI: 28.5, NE) in the chemotherapy arm (HR 0.24 [95% CI: 0.13, 0.43]; p<0.0001).

The most common (≥ 20%) adverse reactions in patients taking alectinib were hepatotoxicity, constipation, myalgia, COVID-19, fatigue, rash, and cough.

The recommended alectinib dose is 600 mg orally twice daily with food for 2 years or until disease recurrence or unacceptable toxicity.

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, Switzerland’s Swissmedic, and United Kingdom’s Medicines and Healthcare products Regulatory Agency. The application reviews are ongoing at other regulatory agencies involved with Project Orbis.

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 one month ahead of the FDA goal date.

This application was granted priority review and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

CARVYKTI Becomes First and Only BCMA-Targeted Treatment Approved by the U.S. FDA in Second-line Multiple Myeloma

FDA grants tumor agnostic accelerated approval to Enhertu for unresectable or metastatic HER2-positive solid tumors

On April 5, 2024, the Food and Drug Administration granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

Full prescribing information for Enhertu will be posted here.

Efficacy was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). All three trials excluded patients with a history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status >1. Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.

The major efficacy outcome measure in all three trials was confirmed objective response rate (ORR), and an additional efficacy outcome was duration of response (DOR). All outcomes were assessed by independent central review (ICR) based on RECIST v1.1. In DESTINY-PanTumor02, ORR was 51.4% (95% CI: 41.7, 61.0) and median DOR was 19.4 months (range 1.3, 27.9+). In DESTINY-Lung01, ORR was 52.9% (95% CI: 27.8, 77.0) and median DOR was 6.9 months (range 4.0, 11.7+). In DESTINY-CRC02, ORR was 46.9% (95% CI: 34.3, 59.8), and DOR was 5.5 months (range 1.3+, 9.7+).

The most common adverse reactions (≥20%), including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea,  decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection. The prescribing information includes a Boxed Warning advising health professionals of the risk of interstitial lung disease and embryo-fetal toxicity.

The recommended fam-trastuzumab deruxtecan-nxki dosage for this indication is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

This tumor agnostic indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

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 (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada, and Singapore’s Health Sciences Authority (HSA). The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application almost 2 months ahead of the FDA goal date.

This application was granted Priority Review and Breakthrough Therapy Designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA issued CRLs to Regeneron for odronextamab BLA in r/r follicular lymphoma & in r/r diffuse large B-cell lymphoma

REGENERON PROVIDES UPDATE ON BIOLOGICS LICENSE APPLICATION FOR ODRONEXTAMAB

TARRYTOWN, N.Y., March 25, 2024 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced that the U.S. Food and Drug Administration (FDA) has issued Complete Response Letters (CRLs) for the Biologics License Application (BLA) for odronextamab in relapsed/refractory (R/R) follicular lymphoma (FL) and in R/R diffuse large B-cell lymphoma (DLBCL), each after two or more lines of systemic therapy. The only approvability issue is related to the enrollment status of the confirmatory trials. The CRLs – one for R/R FL and one for R/R DLBCL – did not identify any approvability issues with the odronextamab clinical efficacy or safety, trial design, labeling or manufacturing.

Regeneron has been actively enrolling patients in multiple Phase 3 trials for odronextamab as part of the OLYMPIA program – one of the largest clinical programs in lymphoma. As the OLYMPIA program is intended to change the treatment paradigm of several B-cell non-Hodgkin lymphoma subtypes – including in earlier lines of therapy – in agreeing to the program, the FDA required that the trials include both dose-finding and confirmatory portions. Enrollment in the dose-finding portion has begun, but the CRLs indicate that the confirmatory portions of these trials should be underway and that the timelines to completion be agreed prior to resubmission. Regeneron is committed to working closely with the FDA and investigators to bring odronextamab to patients with R/R FL and R/R DLBCL as quickly as possible. Regeneron plans on sharing updates on enrollment and regulatory timelines later this year.

Regulatory review of odronextamab remains ongoing by the European Medicines Agency (EMA) for the treatment of R/R DLBCL and R/R FL. In the European Union, odronextamab was granted Orphan Drug Designation in DLBCL and FL.

The potential use of odronextamab in R/R DLBCL and R/R FL is currently under clinical development and has not been approved by any regulatory authority.

About Regeneron
Regeneron is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for over 35 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to numerous FDA-approved treatments and product candidates in development, almost all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, hematologic conditions, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune®, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center®, which is conducting one of the largest genetics sequencing efforts in the world.

For more information about Regeneron, please visit www.Regeneron.com or follow Regeneron on LinkedIn.

FDA is working to release guidance documents that regulate use of Artificial Intelligence

By: Robert M. Califf, M.D., Commissioner of Food and Drugs

At the FDA, we’ve been working for years to anticipate and prepare for the challenges of Artificial Intelligence (AI), and also to harness its potential. Some in the nonscientific community may be surprised by the seemingly sudden amount of attention on AI. But for scientists and regulators, this issue is not new—we’ve seen it coming for a long time, and I’d like to catch up with you today on this exciting topic.  

AI Enables Extraordinary Advances in Medical Products and Food

AI has the potential to enable major advances in the development of more effective, less risky medical products and more nutritious food. To give you an idea of its impact, consider that since 1995 the FDA has received over 300 submissions for drugs and biological products with AI components, and more than 700 submissions for AI-enabled devices.  

Submissions have included aspects related to drug discovery and repurposing, enhancing clinical trial design elements, dose optimization, endpoint/biomarker assessment, and postmarket surveillance. These submissions also cover a growing diversity of medical devices that leverage AI to improve clinical workflows and patient experiences or outcomes in addition to sophisticated prediction algorithms. 

And the areas of nutrition and food safety are on the verge of a revolutionary improvement due to the combination of digitization, AI and growth in computing power.  

AI Technologies Facilitate Internal Operations and Regulatory Processes

The FDA is also exploring the use of AI technologies to facilitate our internal operations and regulatory processes, which could benefit both agency experts and the public by streamlining workflows and facilitating high quality, novel medical products more quickly reaching the patients who need them.  

At its most basic, AI can strengthen our operational systems and bring increased productivity, opportunity, and efficiency to our work, helping us process and analyze complex data faster, including data from medical imaging or digital health technologies, for example. We can free up staff by automating repetitive administrative functions and enable them to focus on more complex meaningful activities to weigh the evidence and arrive at better decisions. Our workforce should also have more time to explain those decisions to the public and learned intermediaries in the biomedical and clinical world.  

The AI landscape is expanding every day and there is a lot more to say on this topic. We’ve issued: “Artificial Intelligence & Medical Products: How CBER, CDER, CDRH, and OCP are Working Together,” and I hope you’ll check it out. The paper reaffirms our commitment to promoting the responsible and ethical development, deployment, use, and maintenance of safe and effective medical products that incorporate or are developed with AI.

Catch up with you next time.