The FDA’s Oncologic Drugs Advisory Committee (ODAC) will meet Thursday and Friday of this week to discuss the status of three cancer drugs, and considering the significant concerns and questions raised by FDA reviewers, the outlook appears dim for all three.
In a morning session on Thursday, ODAC will consider the application for accelerated approval for poziotinib tablets as a treatment for patients with previously treated, locally advanced or metastatic non-small cell lung cancer harboring HER2 exon 20 insertion mutations.
The evidence supporting this comes from the 90 patients with HER2 exon 20 insertion mutations enrolled in cohort 2 of the ZENITH20 trial, who received at least one prior systemic therapy and received the proposed recommended dosage of 16 mg once daily. The overall response rate (ORR) was 28% (95% CI 19-38), with a median duration of 5.1 months (95% CI 4.2-5.5).
The FDA briefing document indicated that the agency has several concerns, including what it said was a “low overall response rate with minimal duration of response,” in addition to a poorly tolerated safety profile at the current proposed dosage.
“If granted accelerated approval, this would be the least effective targeted therapy for lung cancer approved to date,” the FDA said, and since the committee is being asked to discuss the overall risk/benefit of poziotinib “given its limited response rate with poor durability, high rate of toxicity, inadequate dosage optimization, and delayed confirmatory trial,” a positive recommendation seems to be in doubt.
Melphalan Flufenamide (Pepaxto)
In an afternoon session on Thursday, ODAC will weigh in on the fate of melphalan flufenamide, which received accelerated approval in February 2021 for use in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have 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.
That approval was based on the OP-106 (HORIZON) trial. However, the confirmatory OCEAN trial, which compared melphalan flufenamide and dexamethasone with pomalidomide and dexamethasone, showed that the melphalan flufenamide arm failed to provide a progression-free survival (PFS) benefit, and had observed median overall survival (OS) that was 5.3 months shorter than that of the pomalidomide/dexamethasone arm (19.7 months vs 25.0 months).
The results of OCEAN “failed to confirm clinical benefit and suggests that the benefit-risk profile of melphalan flufenamide is unfavorable,” FDA reviewers said in a briefing document. “Additional clinical study is needed to identify an appropriate dose optimized for a favorable benefit-risk profile.”
Finally, on Friday ODAC will consider duvelisib (Copiktra), a PIK3 inhibitor indicated for the treatment of adults with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia after at least two prior therapies.
Duvelisib received regular approval in 2018 for this indication based on results from the DUO trial, which demonstrated a PFS advantage with duvelisib compared with ofatumumab (13.1 months vs 9.9 months), as well as an advantage in ORR.
Due to toxicity concerns and immature OS data, the FDA required OS data from DUO with 5 years of follow-up. That 5-year OS analysis showed that with a median follow-up of 63 months, there was a higher rate of death in the duvelisib arm compared with the ofatumumab arm in both the intention-to-treat population (50% vs 44%) and the indicated population (patients with at least two prior therapies, 56% vs 49%).
“While overall survival was a descriptive secondary endpoint in the DUO trial, the 5-year OS results in the setting of a benefit in PFS and ORR indicate that the potential detriment in OS is a primary safety concern,” the FDA said in its briefing document.