Oncopeptides’ Pepaxto: US FDA Vexed By Adverse Survival, Failed PFS, Lack Of Dose Optimization
Executive Summary
ODAC will weigh current benefit-risk profile for melphalan flufenamide, which holds accelerated approval in relapsed/refractory multiple myeloma. FDA rejects Oncopeptides’ use of numerous post hoc subgroup analyses to overcome negative survival trend in OCEAN confirmatory trial.
Oncopeptides AB’s bid for continued approval of the multiple myeloma drug Pepaxto (melphalan flufenamide) in the US appears to be on life support heading into an FDA Oncologic Drugs Advisory Committee meeting, notwithstanding the drug’s recent approval in Europe.
In a briefing document released ahead of the 22 September ODAC meeting, Food and Drug Administration oncology reviewers said melphalan flufenamide, or melflufen, demonstrated a potential detriment in overall survival in the OCEAN confirmatory trial, which was required as a condition of accelerated approval, and failed to demonstrate a benefit in progression-free survival, the study’s primary endpoint.
The agency rejected a host of post hoc, subgroup analyses that Oncopeptides asserted support a positive benefit-risk profile in certain types of patients. Specifically, the company said that melflufen has a positive benefit-risk profile in patients who have not received an autologous stem cell transplant (ASCT), as well as those who progressed >36 months after an ASCT regardless of age.
Furthermore, safety concerns and toxicity observed in OCEAN indicate the current dose is not optimized to support a favorable benefit-risk profile, and the sponsor’s recommended reductions in dosing are not supported by clinical data, the FDA said.
“At this time, the overall available evidence indicates a potential for harm, uncertain clinical benefit and suggests that the overall benefit-risk profile of melphalan flufenamide is unfavorable,” the agency said. “Additional dose exploration to identify a tolerable dose with dosing based on weight or body surface area is warranted.”
European Approval Not Relevant
In a joint briefing document that employs the point/counterpoint style, the back and forth between Oncopeptides and the FDA suggests an unusual level of disagreement and rancor between the agency and a sponsor, not to mention impatience on the part of the FDA. This is perhaps not surprising since the ODAC review of Pepaxto’s continued availability under accelerated approval is taking place almost 11 months later than originally planned.
Pepaxto received accelerated approval in February 2021 for treatment of patients with relapsed/refractory multiple myeloma 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 CD-38-directed monoclonal antibody. Approval was based on the single-arm, Phase II HORIZON trial.
In July 2021, the agency issued a safety alert about the increased risk of death associated with Pepaxto in OCEAN, in which melflufen with dexamethasone was compared to pomalidomide plus dexamethasone. (Also see "Pepaxto’s Accelerated Approval In Myeloma May Sink On OCEAN Trial's Adverse Survival Data" - Pink Sheet, 28 Jul, 2021.)
An advisory committee meeting scheduled for October 2021 was canceled after Oncopeptides decided to withdraw Pepaxto. (Also see "239 Days: Oncopeptides' Myeloma Drug Pepaxto Comes Off Market Just Months After Accelerated Approval" - Pink Sheet, 22 Oct, 2021.)
However, several months later Oncopeptides rescinded that withdrawal. (Also see "Oncopeptides Rescinds Pepaxto Voluntary Withdrawal, Which Could Set Up Battle With US FDA" - Pink Sheet, 24 Jan, 2022.) The drug is not currently being marketed in the US.
The FDA said that in requesting voluntary withdrawal of Pepaxto in October 2021, the company also requested cancellation of the ODAC meeting scheduled for later that month and that the briefing document prepared for that meeting not be made public.
In the current briefing document, Oncopeptides said Pepaxto was briefly withdrawn from the US market “following FDA pressure.”
Since 2020, the Oncology Center of Excellence has been pushing for voluntary market removal of accelerated approval drugs with confirmatory studies that either failed ("dangling" approvals) or were never completed ("delinquent" approvals). (Also see "‘Dangling’ Accelerated Approvals: US FDA Flags Concerns About ‘Marginal’ Response Rates" - Pink Sheet, 22 Apr, 2021.)
Oncopeptides said Pepaxto was briefly withdrawn from the US market “following FDA pressure.”
“However, the emergence of historical registrational and non-registrational clinical data demonstrating heterogeneity” of immunomodulatory drug (IMiD) overall survival outcomes by age (i.e., better response in patients <65 years of age), prompted Oncopeptides to rescind this action in January 2022, the company said.
Oncopeptides said it started work in June 2021 to investigate potential heterogeneity of age-related outcomes with IMiDs. The findings from these investigations supported the June 2022 positive opinion of melflufen (branded as Pepaxti) by the European Medicines Agency’s Committee for Medicinal Products for Human Use. (Also see "EMA Gives Oncopeptides’ Multiple Myeloma Drug The Thumbs Up; Keeps US FDA In Loop" - Pink Sheet, 24 Jun, 2022.) The European Commission granted marketing authorization in August.
Oncopeptides included the CHMP assessment report as an appendix to the advisory committee briefing document.
However, the CHMP positive opinion and EC approval have no impact on regulatory review for the US market, the FDA said.
“The regulatory actions of other agencies are not relevant to the discussion at the ODAC and FDA regulatory decisions,” the agency said. “The FDA must make regulatory decisions that are consistent with the US legal and regulatory framework. That framework requires us to consider whether the OCEAN confirmatory study verifies that melphalan flufenamide is of clinical benefit to patients when used in accordance with its US-approved indication. The information discussed at the ODAC should be viewed independently to inform decisions regarding benefits and risks of melphalan flufenamide for the indicated US patient population.”
Based on the FDA’s tone in the joint briefing document and its systematic rejection of Oncopeptides’ arguments on the drug’s efficacy and safety, a positive outcome for the sponsor at the ODAC meeting would seem to be a long shot.
Subgroup Analyses Cannot Rescue Survival Results
In discussing the overall survival imbalance in OCEAN, the agency noted there were higher rates of deaths on the melflufen arm (47.6% vs. 43.4%), and observed median overall survival was 5.3 months shorter than in the pomalidomide arm.
The higher death rate was most notable in events that occurred beyond 60 days after the last dose, with 31% of deaths in the melflufen/dexamethasone arm versus 25% in the pomalidomide/dexamethasone arm. This raises a concern that treatment with melflufen may impact the ability to receive and tolerate subsequent lines of therapy, the agency said.
In addition, there was a higher rate of Grade 3-4 treatment-emergent adverse events in the MelDex arm (90%) compared to the PomDex arm (74%). “The increase in Grade 3-4 TEAEs were primarily due to higher rates of cytopenia.”
“Results from subgroup analyses cannot be used to conclude benefit in a subset of patients, when the overall patient population has shown a detrimental treatment effect.” – FDA
“OS is an efficacy and safety endpoint. A negative trend in OS, particularly in the context of drugs with substantial toxicity, is an important determinant of safety,” the FDA said. “Although not statistically significant, the OS results suggest an increased risk of death in patients receiving melphalan flufenamide compared to pomalidomide.”
The FDA said the sponsor conducted multiple post hoc, exploratory, subgroup analyses and initially proposed that the OS imbalance was driven primarily by patients who previously had received ASCT.
“More recently, the sponsor contends that the concerning OS results may be limited to patients who have had a transplant and have a time to progression (TTP) after transplant <36 months,” the FDA said, citing several limitations with the sponsor’s arguments.
“The subgroups identified by the sponsor in the statistical analysis plan (SAP) were listed as exploratory analyses and were not powered prospectively to control for type I error. Subgroup analyses should only be used to confirm a consistent treatment effect across subgroups. Results from subgroup analyses cannot be used to conclude benefit in a subset of patients, when the overall patient population has shown a detrimental treatment effect.”
Oncopeptides also has hypothesized that the OS imbalance in OCEAN could be explained by the differential treatment effect of pomalidomide on survival based on age rather than due to a safety signal with melflufen – specifically, that in the pomalidomide arm older patients do poorly in terms of survival compared with younger patients.
“Again, this a post hoc exploratory analysis that can only be hypothesis-generating,” the FDA said. “While our own analyses do not suggest significant interaction with age and IMiDs on OS, even if there were an interaction, this does not negate the overall results observed in the OCEAN trial and it does not provide substantial evidence of safety and effectiveness of melphalan flufenamide,” the agency said.
“The preponderance of evidence from the prespecified analysis on the ITT population and in all other subgroups suggests an increased risk of death in patients and a potential for harm with melphalan flufenamide.”
Disagreement On PFS Benefit
Oncopeptides asserted that OCEAN met the PFS primary endpoint with a hazard ratio of 0.79 favoring the melflufen arm.
However, “FDA does not agree with the applicant’s assertion that the OCEAN trial met the primary endpoint of PFS superiority.”
“The lower survival observed negates the clinical benefit of the observed PFS improvement.” – FDA
According to the FDA, the original primary analysis showed that OCEAN failed to meet the primary endpoint of statistically significant improvement in PFS. The sponsor subsequently conducted a reassessment of 29 patients and contended that PFS superiority was met.
Because the PFS definition for the primary analysis required confirmation of progressive disease in two consecutive assessments, the FDA said the PFS primary analysis should be based on patients with confirmed PD as an event. “The FDA’s analysis considering only patients with confirmed PD as an event demonstrated that PFS was not statistically significant; HR 0.833 (95% CI: 0.665, 1.044; p-value = 0.1122).”
“Regardless of the p-value and the statistical significance, the treatment effect estimates with respect to the difference in median PFS is only two months,” the agency said. “Additionally, the two-month difference in PFS improvement did not translate to a benefit in survival; rather, a detriment in survival is observed. The lower survival observed negates the clinical benefit of the observed PFS improvement.”
Dose Optimization Needed
The agency’s criticisms regarding lack of an appropriate dose for melflufen are indicative of its emphasis under Project Optimus that sponsors need to do more work early in development to optimize the dose. (Also see "US FDA Uses PI3K Inhibitor Experience To Spell Out What It Wants In Dose Optimization Studies" - Pink Sheet, 29 Apr, 2022.)
“The safety concerns and the toxicity observed indicate that that the flat dose of 40 mg is not optimized to support a favorable benefit-risk profile,” the FDA said.
At the time of accelerated approval, pharmacokinetic data were only available from 12 subjects, eight of whom received the 40 mg starting dose. In HORIZON, no PK data were collected and no population PK or exposure-response analyses were conducted. “As such, the safety and efficacy of lower doses could not be adequately evaluated and the clinical efficacy and safety evaluations for doses lower than 40 mg or alternative dosing regimens were not fully explored,” the FDA said.
Oncopeptides has proposed additional dose modifications for neutropenia and thrombocytopenia, and a lower flat dose of 30 mg for patients ≤60 kg to try to address the risk. “However, these proposals have not been evaluated in clinical trials,” the FDA said.
A body weight-based dosing or body surface area-based dosing may be better tolerated and should be explored further in a clinical trial to support a favorable benefit-risk profile, the agency said.
The Pepaxto review is part of a two-day, three-drug meeting for ODAC.
On the morning of 22 September, the panel will take up Spectrum Pharmaceuticals Inc.’s new drug application for poziotinib in a targeted subset of patients with previously treated non-small cell lung cancer. The FDA’s poziotinib review has raised concerns about the high rate of toxicity and inadequate dose optimization, as well as the delayed confirmatory trial. (See sidebar for story.)
On 23 September, the committee will consider the benefit-risk profile for Secura Bio, Inc.’s Copiktra (duvelisib) in its current indications for relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Although these indications received regular approval, updated survival information from a Phase III trial suggest an adverse survival trend. (Also see "US FDA Panel To Weigh Safety, Tolerability Issues For One New, Two Approved Cancer Drugs" - Pink Sheet, 21 Jul, 2022.)