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FDA advisory panel votes against drugs for lung cancer, multiple myeloma subgroups

September 23, 2022

4 min read

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The FDA Oncologic Drugs Advisory Committee on Thursday voted against questions regarding the benefits vs. risks of two cancer treatments for which new drug applications have been filed.

The panel concluded 9-4 that the current benefits of the oral, irreversible tyrosine kinase inhibitor poziotinib do not outweigh its risks for treatment of patients with non-small cell lung cancer with HER2 exon 20 insertion mutations.

Anthony D Sung

Later Thursday, with additional members voting, the committee voted 14-2 that melphalan flufenamide, a peptide conjugated alkylating drug, did not have a favorable benefit-risk profile for the currently indicated population of patients with relapsed or refractory multiple myeloma. The drug received accelerated approval last year for use with dexamethasone among adults who received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent and one CD38-directed monoclonal antibody. However, the confirmatory randomized, phase 3 OCEAN trial showed shorter OS with the combination vs. pomalidomide (Pomalyst, Bristol Myers Squibb) and dexamethasone and failed to verify clinical benefit, according to FDA.


No oral therapies have been approved for patients with NSCLC who harbor HER2 exon 20 insertion mutations and progressed following standard platinum-based chemotherapy with or without a checkpoint inhibitor, according to a sponsor briefing document.

Poziotinib (Spectrum Pharmaceuticals) received FDA fast track designation for this subgroup in March 2021.

Most of the data to support the indication came from cohort 2 of a single-arm, phase 2 study. The cohort included 90 patients with NSCLC and HER2 exon 20 insertion mutations who received poziotinib at a starting dose of 16 mg once daily. Results showed an objective response rate of 27.8% (95% CI, 18.9-38-2), disease control rate of 70% (95% CI, 59.4-79.2), median duration of response of 5.1 months (95% CI, 4.2-5.5) and median PFS of 5.5 months (95% CI, 3.9-5.8).

Grade 3 adverse events occurred among 85.6% of patients, and 11.1% of patients experienced grade 4 adverse events. The most common grade 3 and grade 4 events included, rash (30%), diarrhea (26.7%) and stomatitis (23.3%). Forty percent of patients experienced serious adverse events, and 10 patients experienced fatal adverse events.

More than three-quarters of patients (77%) required a dose reduction and 87% required a dose interruption.

FDA noted major review issues, asserting that poziotinib did not improve efficacy compared with current therapies, including the antibody-drug conjugate fam-trastuzumab deruxtecan (Enhertu, AstraZeneca), which is available for these patients under FDA accelerated approval. It also cited the high toxicity rate at the proposed 16 mg once-daily dose, inadequate dose optimization and delayed confirmation of benefit.

Committee members acknowledged the activity poziotinib demonstrated among patients with NSCLC and HER2 exon 20 insertion mutations and the unmet need for effective therapies for this population. But many questioned whether it showed a meaningful benefit compared with other agents and expressed concerns about toxicities and the proposed dose.

“There may be a role for poziotinib in patients who fail trastuzumab, but the data [are] not there yet,” committee member Anthony D. Sung, MD, associate professor of medicine at Duke University School of Medicine and member of Duke Cancer Institute, said after voting no on whether the current benefits of the agent outweigh the risks for this patient population.

Committee member David E. Mitchell, founder of Patients for Affordable Drugs, voted yes to the question.

“The drug clearly has efficacy for some patients who are in real need of additional options,” he said. “Overall, this drug belongs in the armamentarium of those clinicians who are trying to treat these patients who lack sufficient numbers of options.”

Melphalan flufenamide

Results of the single-arm HORIZON trial served as the basis for FDA accelerated approval of melphalan flufenamide (Pepaxto, Oncopeptides) in February 2021. The study showed an overall response rate of 23.7% (95% CI, 15.7-33.4) and median duration of response of 4.2 months among 97 patients with multiple myeloma who received four or more previous lines of therapy and were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed antibody.

Topline results of the confirmatory OCEAN trial showed the melphalan flufenamide/dexamethasone combination failed to meet the primary endpoint of PFS superiority vs. pomalidomide/dexamethasone (median, 6.9 months vs. 4.9 months; HR = 0.81; 95% CI, 0.65-1.01). Oncopeptides later contended that a reassessment of 29 patients showed PFS superiority had been achieved.

The committee expressed concerns about the PFS results, the fact that the flat dose of 40 mg appeared to be poorly tolerated and, in particular, the 4-month shorter median OS in the melphalan flufenamide/dexamethasone vs. pomalidomide/dexamethasone group, according to updated results (20.2 months vs. 24 months; HR = 1.14; 95% CI, 0.91-1.43).

“We don’t agree that PFS statistical significance was demonstrated, but even if we did, we would have significant concerns because of the overall survival results,” said Nicole Gormley, MD, acting division director of the division of hematologic malignancies II in the FDA Office of Oncologic Diseases. “The most germane issue is that the data suggest worse overall survival.”

Nicole Gormley, MD

Nicole Gormley

Oncopeptides contended the concerning OS results could be limited to patients who underwent hematopoietic stem cell transplantation and had a time to progression after transplant of less than 36 months. Gormley said FDA does not “use subgroup analyses to carve out indications.”

Committee member Jorge J. Nieva, MD, associate professor of clinical medicine at Keck School of Medicine of USC, was one of the two panelists who voted yes to the question of whether melphalan flufenamide had a favorable benefit-risk profile.


Jorge J. Nieva

“It does appear that the OCEAN study confirms clinical response and benefit seen in HORIZON,” he said. “To say it does not looks to me like an exercise in moving the goalposts.”


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