The Oncologic Drug Advisory Committee voted 9 to 4 that the current benefits of poziotinib did not outweigh its risks for the treatment of patients with nonsmall cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations.1
The decision was made on day 1 of the September 22/23 ODAC Meeting by 14 voting members. The vote followed an extensive discussion about the overall risk/benefit of poziotinib 16 mg once daily with consideration of the limited response the drug has shown, short durability of response, high toxicity, inadequate dosage optimization, and the fact the confirmatory clinical trial was delayed.
A new drug application was submitted to the FDA for poziotinib as a potential treatment option for previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 20 insertion mutations. The proposed indication was supported by results from the phase 2 ZENITH20 clinical trial. The NDA was accepted by the FDA on February 11, 2022, but then raised to the ODAC.
ZENITH20 is a multicenter, multicohort, open-label phase 2 study (NCT03318939) primarily evaluating objective response rate by independent review committee (IRC) in patients with advanced or metastatic NSCLC. The secondary outcomes of the study include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), safety/tolerability, and quality of life.2
Results reported in 2021 were from 90 patients who had received a median of 2 prior lines of therapy. Poziotinib achieved an ORR of 27.8% (95% CI, 18.9%-38.2%) with partial response observed in 25 patients. The DCR achieved with poziotinib was 70.0% (95% CI, 59.4%-79.2%). Seventy-four percent of patients treated with poziotinib in the study had tumor reduction at a median shrinkage of 22%.
The agent showed a 5.1-month (95% CI, 4.2 to 5.5) median duration of response, and clinical benefit with poziotinib in the study was irrespective of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations.
The median PFS observed with the agent was 5.5 months (95% CI, 3.9-5.8) with a 5.1-month median DOR.
Safety findings from ZENITH20 showed that the grade 3 or higher treatment-related adverse events (TRAEs) observed were rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). The majority of patients in the study (76.7%) required dose reduction. Due to TRAEs, 13.3% of patients Permanently discontinued poziotinib.
I think the bottom line from this study is that it clearly does have substantial activity in the population was studied in when you consider the alternatives that are available and the lack of oral medications that are approved for these patients. I think it's unquestionably from my clinical perspective, it's a clinically meaningful activity. We have some patients that have been on the drug for years and are doing quite well on it and are very grateful that they had this oral drug available. I think this could potentially provide an important option for patients and for healthcare providers for this important unmet need. And it's worth pointing out that if this is approved, well her two mutations occur not just in lung cancer but in more than 20 Different malignancies. One would love to see then that if this is approved If we could build on those studies and look at the activity in those other tumor types as well, said John Heymach, MD, PhD, a medical oncologist, and chair of the Department of Thoracic-Head & Neck Med Onc, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center.
Despite the results from ZENITH20, the FDA holds that better therapies are now available for patients with HER2 exon 20 insertion mutation-positive NSCLC.
Poziotinib, as demonstrated by the limited response rate with poor durability observed in the primary efficacy population is not improved over available therapies, explained Nicole Drezner, MD, clinical team lead in the Division of Oncology 2 at the FDA, during the FDA presentation.
For patients with nonsmall cell lung cancer, who have received both prior platinum-based chemotherapy and an immune checkpoint inhibitor, available therapy includes docetaxel in combination with ramucirumab [Cyramza] with a benchmark or are of 23%. Anti-PD-L1 therapies are considered available therapy that is not previously received and are associated with lower ORRs with more substantial durability than what is observed with chemotherapy. Trastuzumab dereuxtecan [Enhertu], a HER2- targeting antibody drug conjugate received accelerated approval last month for the treatment of patients with HER2-mutated non-small cell lung cancer as an indication which would include the patients who comprise the primary efficacy population in this application. The drug demonstrated a response rate of 58%, with a duration of response is 8.7 months, both considerably greater than what was observed with poziotinib, Drezner added.
Comparing the data from DESTINY-Lung02 (NCT04644237) which supported the accelerated approval of trastuzumab dereuxtecan to the ZENITH20 data3, Dezner noted that the ORR observed with poziotinib was low with poor durability. Further, the safety profile of poziotinib was brought into question.
The applicant states that the safety profile of poziotinib is similar to other drugs in class. However, in our assessment, poziotinib is more toxic than other tyrosine kinase inhibitors [TKIs] for lung cancer, especially at the 16-milligram dose. Eight of 10 patients experienced grades 3 to 4 adverse events. Similarly, over 80% of patients require a drug interruption and over 50% of patients needed a dose reduction, said Justin N. Malinou, MD, clinical reviewer, Division of Oncology 2 Thoracic and Head and Neck Oncology Office of Oncologic Diseases at the FDA, during the FDA presentation.
Regarding dose optimization, the FDA highlighted that dose reductions occurred within the first months of treatment. Beyond the 24-week mark, most patients were receiving a 12 mg once daily dose of poziotinib.
In FDA review of the applicants clinical pharmacology package, we identified significant areas of concern regarding the lack of dosage optimization. Given that the applicant has provided insufficient data over the clinically relevant dose range, we cannot determine if alternative dosages may provide acceptable efficacy and an improved toxicity profile. Therefore, we continue to assert that the applicant failed to adequately justify their proposed dosage of 16 milligrams once daily, said Jeanne Fourie Zirkelbach, PhD, team lead, Clinical Pharmacology Division of Cancer Pharmacology 2 Office of Clinical Pharmacology at the FDA, during the FDA presentation.
Finally, the FDA originally recommended that a confirmatory trial for poziotinib start recruitment in 2020. To date, no patients have been enrolled in the confirmatory trial. The FDA noted that it would be 4 years before results from the confirmatory trial would be available.
With Spectrum Pharmaceuticals alluding to their success and progress with poziotinib and the FDA asserting that they are unhappy with the development of poziotinib, ODAC members carried out an in-depth discussion.
A point was raised by Spectrum Pharmaceuticals was that poziotinib showed similar dose reduction and discontinuations as other approve TKIs like mobocertinib (Exkivity) and neratinib (Nerlynx). Moreover, poziotinib had the same ORR as agents like mobocertinib. However, the FDA responded that the duration of response with mobocertinib greatly exceeded poziotinib.
The applicant also mentioned that multiple sites for the confirmatory trials have been opened and will started enrolled patients in the next few weeks. But the FDA pointed out that only 3 of the sites were in the Unites States (US) and that failure to accrue patients at US sites would results in findings that are not reflective a US population.
During the open public hearing,7 out of 8 presentations were from patients who testified that poziotinib has either helped them or a family member. The patients did mentioned toxicities but noted that they were manageable.
Joshua K. Sabari,MD, a medical oncologist and assistant professor,Department of Medicine at NYU Grossman School of Medicine, as medical director, Kimmel Pavilion 12, at NYU Langone Health stated that although trastuzumab deruxtecan is now standard for HER2 exon 20 insertion mutation-positive NSCLC, some patients are not eligible to receive it. Therefore, poziotinib may be another option, according to Sabari.
ODAC member opinions varied during the discussion. Some oncologists noted that the risk-benefit profile of poziotinib was acceptable considering that toxicities related to TKIs can be managed in the clinic. One member noted that the short duration of response observed with poziotinib in ZENITH20 could be due to toxicity.
Importantly, poziotinib is an oral agent, which means patients can take their medication in an outpatient setting. One ODAC member raised the point that if toxicities associated with poziotinib required patients to come back to the clinic, it impacts. the favorability of the risk-benefit profile.
REFERENCES:
1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. September 22, 2022. Accessed September 22, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-22-23-2022-meeting-oncologic-drugs-advisory-committee-meeting-announcement-09222022
2. Le X, Cornelissen R, Garassino M, et al. Poziotinib in non-small-cell lung cancer HarboringHER2exon 20 insertion mutations after prior therapies: ZENITH20-2 Trial. J Clin Oncol. 2022;40(7): 710-718. doi: 10.1200/JCO.21.01323
3. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA website. August 11, 2022. Accessed September 22, 2022. https://bit.ly/3LyWDMK
See more here:
FDA's ODAC Votes That Benefits Do Not Outweigh Risks for Poziotinib in HER Exon 20 Ins+ NSCLC - Targeted Oncology
- Cell-Based Regenerative Medicine Market Size to Witness Rapid Growth at a CAGR of 15% by 2032 | insightSLICE - EIN News - May 9th, 2023
- Indian Pharma Congress: Gene-cell therapy, preventive medicine future of health care, says expert - Economic Times - January 21st, 2023
- Cell culture - Wikipedia - December 18th, 2022
- The Legacy of Henrietta Lacks - Hopkins Medicine - December 10th, 2022
- HOME | Stem cell & Cancer - October 4th, 2022
- CAR T Cell Therapy Offers a New Hope in the Treatment of Severe and Refractory Systemic Lupus Erythematosus - Rheumatology Network - October 4th, 2022
- Cell and Gene Therapy: Rewriting the Future of Medicine - Technology Networks - October 4th, 2022
- Outlook on the Automated Cell Counters Global Market to 2028 - Use of Cell Counters in Personalized Medicine Presents Opportunities -... - October 4th, 2022
- Jcr Pharmaceuticals Co., Ltd. and Sysmex Establish A Joint Venture in the Field of Regenerative Medicine and Cell Therapy - Marketscreener.com - October 4th, 2022
- Growth in Cell and Gene Therapy Market - BioPharm International - October 4th, 2022
- Breakthrough in production of cancer-treating drug - Stanford University News - October 4th, 2022
- CRISPR Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to CTX130 for the Treatment of Cutaneous T-Cell... - October 4th, 2022
- Mary Munson elected fellow of the American Society for Cell Biology - UMass Medical School - October 4th, 2022
- 5 FDA decisions to watch in the fourth quarter - BioPharma Dive - October 4th, 2022
- bit.bio Adds Two New Human Cell Products to Address the Translation Gap and Accelerate Research and Drug Discovery for Neurodegenerative Disease -... - October 4th, 2022
- Laser Focus World highlights UC research that uses light to restore cell function - University of Cincinnati - October 4th, 2022
- The Institute of Regenerative Medicine | Non-Surgical, Cell-Based ... - September 25th, 2022
- CAR T-Cell Therapy Shows Promise in Treating Lupus - Healthline - September 25th, 2022
- ProKidney to Present at the Jefferies Cell and Genetic Medicine Summit - El Paso Inc. - September 25th, 2022
- Allogene Therapeutics Announces Participation in the Jefferies Cell and Genetic Medicine Summit - GlobeNewswire - September 25th, 2022
- Alzheimer's disease risk linked to newly discovered protein mutation - Medical News Today - September 25th, 2022
- Biological Links Identified Between an Aggressive Breast Cancer Type and African Ancestry - Weill Cornell Medicine Newsroom - September 25th, 2022
- The Use of Nanorobotics in the Treatment Therapy of Cancer and Its Future Aspects: A Review - Cureus - September 25th, 2022
- UW Health, UW-Madison School of Medicine and Public Health: Innovative clinical trial targets recurrent BK infection in kidney transplant recipients -... - September 25th, 2022
- Shutting down backup genes leads to cancer remission in mice - University of Michigan News - September 25th, 2022
- Pembrolizumab in Combination with Lenvatinib as First-Line Treatment for Non Clear Cell Renal Cell Carcinoma (nccRCC), KEYNOTE-B61 - Laurence Albiges... - September 25th, 2022
- Courageous Lanarkshire teen who survived leukaemia thanks to a clinical trial pursues nursing dream - Daily Record - September 25th, 2022
- Discovery Reveals How the Immune System Tolerates Friendly Gut Bacteria - Weill Cornell Medicine Newsroom - September 8th, 2022
- Study: New Factors Are Associated With Increased PFS from BCMA-Targeted T-Cell Therapy - Pharmacy Times - September 8th, 2022
- Study Uncovers Possible Path for Improving T Cell Therapies - University of Arizona - September 8th, 2022
- Trodelvy Significantly Improved Overall Survival in Pre-Treated HR+/HER2- Metastatic Breast Cancer Patients in TROPiCS-02 Study - Gilead Sciences - September 8th, 2022
- Manipulating Astrocytes in Tumor Environment Effective Against Glioblastoma - Inside Precision Medicine - September 8th, 2022
- Jane Fonda Diagnosed with Non-Hodgkin's Lymphoma: What to Know - Healthline - September 8th, 2022
- Dr Hatim Husain: Biomarker Testing Is a Treatment Cornerstone in NSCLC - AJMC.com Managed Markets Network - August 30th, 2022
- Porton Advanced and Kun Tuo Announce Strategic Partnership to Deepen Gene and Cell Therapy CDMO and Clinical Research Services - PR Newswire - August 30th, 2022
- The Role of Eosinophils as a Biomarker to Inform Treatment Decisions for Patients With COPD - Consultant360 - August 30th, 2022
- Scientists Discover Surprise Anticancer Properties of Common Lab Molecule | Newsroom - UNC Health and UNC School of Medicine - August 30th, 2022
- Overall survival is similar for patients receiving CT-based or minimal follow-up after surgical resection of non-small-cell lung cancer - 2 Minute... - August 30th, 2022
- NSF Grant to Aid OSU Researchers Developing Treatment for Canine Cancer - The Corvallis Advocate - August 30th, 2022
- Researchers Identify the Target of Immune Attacks on Liver Cells in Metabolic Disorders - Weill Cornell Medicine Newsroom - August 22nd, 2022
- Why Is CAR T-Cell Therapy One of the Most Phenomenal Advances in Science? - University of Colorado Anschutz Medical Campus - August 22nd, 2022
- Porton Advanced Solutions completes a Series B financing round to expand its end-to-end Gene and Cell Therapy CDMO Platforms - PR Newswire - August 22nd, 2022
- Cell Analysis Global Market Report 2022: Growing Focus on Personalized Medicine & Introduction of Advanced Technologies in Cell Analysis Presents... - August 22nd, 2022
- Stress can throw off circadian rhythms and lead to weight gain - Medical News Today - August 22nd, 2022
- Cell Stress and Mitochondrial Dysfunction Found in Early Alzheimers Disease Patients, Findings Published in Science Translational Medicine - BioSpace - August 22nd, 2022
- Restoring cell and organ function after the heart stops - National Institutes of Health (.gov) - August 22nd, 2022
- Rolling the Dice: Gamble Pays Off For Cancer Patient in CAR T-Cell Clinical Trial - University of Colorado Anschutz Medical Campus - August 22nd, 2022
- Boosting neuron formation restores memory in mice with Alzheimer's disease - EurekAlert - August 22nd, 2022
- UTSW study finds p53 gene plays second role in suppressing genes tied to cancer - UT Southwestern - August 22nd, 2022
- GlyNAC supplementation reverses mitochondrial dysfunction, oxidative stress and aging hallmarks to boost strength and promote health in aging humans -... - August 22nd, 2022
- Multiple shots of the BCG vaccine protect type 1 diabetics from COVID-19 - EurekAlert - August 22nd, 2022
- Cell Regeneration Medicine Market Analysis by Type, Application, Growth, Demand, Status, and Forecast from 2022 to 2032 - Digital Journal - August 5th, 2022
- Higher Hydroxyurea Exposure Tied to Better Blood Parameters in US... - Sickle Cell Anemia News - August 5th, 2022
- Kiwis with multiple sclerosis patients thriving from overseas stem-cell treatment urge Government to approve it here - Newshub - July 27th, 2022
- MHRA grants marketing authorisation to Global Blood Therapeutics for sickle cell disease drug - PMLiVE - July 27th, 2022
- CAR T-Cell Therapy Turns 10 and Finally Earns the Word 'Cure' - Medscape - July 27th, 2022
- Oncology Peer Review On-The-Go: The Prognostic Significance of Peripheral Blood Biomarkers in Patients With Advanced NonSmall Cell Lung Cancer Treated... - July 27th, 2022
- CRISPR therapeutics can damage the genome - EurekAlert - July 27th, 2022
- To cell surface and beyond: Tracing subcellular glycoprotein transport using modified cholera toxin - EurekAlert - July 27th, 2022
- From Donor to Patient: Advancing the Future of Cell Therapies - Genetic Engineering & Biotechnology News - July 27th, 2022
- Five-Year Review of Biomedical Research Imaging Center, Center Director | Newsroom - UNC Health and UNC School of Medicine - July 27th, 2022
- Using Particles That Are Smaller Than the Head of a Pin to Treat Cancer - Yale School of Medicine - July 11th, 2022
- Stem Cell Assays Market Report 2022-2027: Increasing Awareness About Therapeutic Potency of Stem Cells Driving Growth - ResearchAndMarkets.com -... - July 11th, 2022
- Sickle cell disease could be treated with common plant, study finds - The Telegraph - July 11th, 2022
- Unexpected link between most common cancer drivers may yield more effective drugs - University of Wisconsin-Madison - July 11th, 2022
- Scientists Discover Key to Hepatitis A Virus Replication, Show Drug Effectiveness | Newsroom - UNC Health and UNC School of Medicine - July 11th, 2022
- How Erectile Dysfunction Drugs Can Help Treat Cancer and Save Thousands of Lives - SciTechDaily - July 11th, 2022
- Pune: Dr Mohan Wani appointed as director of National Centre for Cell Science - The Indian Express - July 11th, 2022
- Kite's CAR T-cell Therapy Yescarta Granted European Marketing Authorization for the Treatment of Relapsed or Refractory Follicular Lymphoma - Gilead... - July 3rd, 2022
- Important Factors for Regulating the Body's Immune Response - Neuroscience News - July 3rd, 2022
- Stem Cell Therapy Market Is Expected To Reach USD 455.61 Billion By 2027 At A CAGR Of 16 percent By Forecast 2027 Says Maximize Market Research (MMR)... - July 3rd, 2022
- Neurona Therapeutics Announces Initial Subject Dosed in First Clinical Trial of Regenerative Human Cell Therapy, NRTX-1001, in Adults with... - July 3rd, 2022
- Growing scope of Genetic Medicine and Stem Cell Research - The Hindu - June 22nd, 2022
- When children with sickle cell grow up, they face a system not designed for them - 89.3 WFPL News Louisville - June 22nd, 2022
- Precision BioSciences Announces In Vivo Gene Editing Collaboration with Novartis to Develop Potentially Curative Treatment for Disorders Including... - June 22nd, 2022
- Stem Cell Assays Market worth $4.5 billion by 2027 - Exclusive Report by MarketsandMarkets - PR Newswire - June 22nd, 2022
- Bringing heart and humanity to hematology | News | Harvard TH Chan School of Public Health - HSPH News - June 22nd, 2022
- Belzutifan Improves Survival in Patients With RCC and VHL - Targeted Oncology - June 22nd, 2022
- Immatics and Editas Medicine Enter Strategic Research Collaboration and Licensing Agreement to Combine Gamma-Delta T Cell Adoptive Cell Therapies and... - June 13th, 2022
- ASCO 2022: Gilead's tough weekend, bispecific progress and 'gamma delta' cell therapy - BioPharma Dive - June 13th, 2022