Due to the potential detriment in overall survival, its failure to demonstrate a progression-free survival benefit, and the lack of a known appropriate dose, ODAC has voted that melphalan flufenamide is not favorable in relapsed/refractory multiple myeloma.
The FDA’s Oncologic Drugs Advisory Committee voted 14 to 2 that melphalan flufenamide (Pepaxto) is not favorable for the currently indicated patient population of adult patients with relapsed or refractory multiple myeloma.1
The vote was announced on day 1 of the September 22/23 ODAC Meeting, during which members discussed the benefit-risk profile of melphalan flufenamide for this patient population while considering the results of the confirmatory phase 3 OCEAN trial (NCT03151811).
In 2021, melphalan flufenamide was granted accelerated approval in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least 4 prior lines of therapy and whose disease was refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.
The approval was based on positive results from the phase 2 HORIZON study (NCT02963493). However, the confirmatory trial examining the agent demonstrated a worse overall survival and failed to verify its clinical benefit.
“We got accelerated approval for melphalan flufenamide, which is a targeted agent. It's a peptide drug conjugate [and works] to ensure that it minimizes off-target effects and maximizes cytotoxic effect on the myeloma itself. In a series of trials, we've shown that melphalan flufenamide clearly is active in patients with relapsed/refractory myeloma, in particular, those patients in whom the 3 other major classes of drugs have failed them. Those are immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies,” said Paul Richardson, MD, in an interview with Targeted Oncology™.
Shortly after the accelerated approval, the FDA placed partial clinical hold on all trials of melphalan flufenamide in combination with dexamethasone. Oncopeptides A.B. then pulled the drug from the market in October 2021 and re-applied for FDA approval of melphalan flufenamide under the new brand name.
During the meeting, the Oncopeptides A.B. presented its case on melphalan flufenamide while the FDA presented their concerns. Then, the committee ultimately decided where they landed on the matter: Melphalan flufenamide is not favorable in relapsed/refractory multiple myeloma.
Data Surrounding Melphalan Flufenamide
“[OCEAN] was a randomized trial looking at a head-to-head comparison between pomalidomide and dexamethasone, and melphalan flufenamide and dexamethasone in relapsed/refractory myeloma, but critically in a much less heavily pretreated population. It was looking specifically at a population of patients in whom lenalidomide had failed them,” stated Paul Richardson, MD, in an interview with Targeted OncologyTM.
Specifically, the OCEAN study met its primary end point of PFS improvement (HR, 0.792; 95% CI, 0.640-0.979, P = .0311),but there were mixed OS results in the relapsed or refractory myeloma subgroups (HR, 1.104; 95% CI, 0.846-1.441) in July of 2021. This partial clinical hold halted accrual of patients into any study using the agent. Not long after, the FDA issued a warning about a death risk associated with the OCEAN study.
“If you were older, your hazard ratios for survival, even if you received pomalidomide and had progression-free survival benefit, the survival hazard ratios were 1.5. Clearly, the image was performing poorly in the elderly vs the younger counterparts,” said Richardson, a hematologist/oncologist, clinical program leader of the Jerome Lipper Multiple Myeloma Center, director of Clinical Research, at the Jerome Lipper Multiple Myeloma Center, and institute physician at Dana-Farber Cancer Center, as well as the RJ Corman professor of Medicine at Harvard Medical School. “When you take into account that variance, it helps us understand that one size does not fit all. In the elderly patients an IMiD [immunomodulatory drug] didn't perform well, and then in younger patients, it did. If you factor that into the analysis, you've got a much different read, and OCEAN becomes a positive trial.”
Other findings concluded that the ORR was 29% in the overall population and 26% in the triple-class refractory population. The median DOR was 5.5 months, with a median PFS of 4.6 months. The median overall survival at the median follow-up of 14 months was 11.6 months.
Regarding safety, grade 3 or greater AEs occurred in 96% of the 157 patients evaluated. The most common AEs were neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most common grade 3 or 4 nonhematologic event was pneumonia (10%), and reversible thrombocytopenia and bleeding were also observed in the trial.
“The important point about the OCEAN trial is that it was a positive trial overall, for its primary end point of PFS and it attained statistical significance. The problem was survival. When you see the hazard ratio 1.104, once it tips across that boundary, the FDA is by law to say, wait a second.”
“In the old days, we probably would have had an around the table discussion and just thought this through and looked to other trials to help us get across the goal line. In the current era where accelerated approval as a pathway is under intense scrutiny and pressure, and at the same time the COVID era, it's becoming much more challenging. In that setting, this ODAC represents a real step forward,” stated Richardson.
The Applicant’s Position
The applicant believes that the ODAC discussion should be held in light of the heterogeneity of outcomes first identified in the randomized, head-to-head, controlled phase 3 OCEAN study, based on patient age interaction for IMiD and prior autologous stem cell transplant (ASCT) interaction for melphalan flufenamide. These interactions overlap due to the correlation between patient age and ASCT eligibility, and although they make interpretation of the data complex, they clarify the results from OCEAN and support a positive benefit/risk profile for melphalan flufenamide.
Though the age-dependent heterogeneity of IMiD OS outcomes in patients with relapsed/refractory multiple myeloma was first seen in the OCEAN trial, other investigations of have shown a heterogeneous treatment effect due to this interaction and prior IMiD publications have omitted OS discussions in patient subgroups. Because of the prevalent use of IMiD therapy in this space over the last decade, the company believes these data are important to communicate to patients and treating clinicians.
Regarding the benefit/risk profile of melphalan flufenamide, the agent has meaningful clinical activity with a manageable safety profile in patients with heavily pretreated relapsed/refractory multiple myeloma, as indicated by the HORIZON study. Then, OCEAN confirmed the safety of melphalan flufenamide and dexamethasone, demonstrated an important new understanding of optimal melphalan flufenamide use, and revealed a previously unknown safety signal for IMiD use in elderly patients with relapsed/refractory multiple myeloma.
Based on the findings of the studies, the applicant states that melphalan flufenamide provides a positive benefit/risk profile and because OCEAN met the primary end point of PFS with a positive HR of 0.79 with melphalan flufenamide and dexamethasone, the data support full NDA approval in adult patients with RRMM who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 PI, 1 immunomodulatory agent, and 1 CD38-directed mAb. However, physicians should be informed that potential harm cannot be excluded with the agent in patients with time to progression (TTP) <36 months after a previous ASCT.
According to Jakob Lindberg, chief executive officer and chief scientific officer at Oncopeptides AB Sweden, the OCEAN study met its primary end point of PFS based on IRC evaluation based on IMWG guidelines. While the hazard ratio in the full analysis population was 1.14% (95% CI, 0.91-1.43), Lindberg notes that heterogeneity confounds OS and identifies a group at risk.
“Melphalan flufenamide met its primary end point, with statistically significant superior PFS based on blinded IRC review. Therefore, it is appropriate to look further into subgroups to identify potential heterogeneity of treatment effect. The OS risk with melphalan flufenamide in comparison with pomalidomide is driven by patients with prior ASCT. Removal of this subgroup would risk improved efficacy and safety for melphalan flufenamide,” stated Lindberg during the meeting, “Additionally, melphalan flufenamide is an alkylating cytotoxic drug in the severely ill population with aggressive disease. Therefore, it is appropriate to administer at the maximum tolerated dose to establish tumor control. Looking at the recommended population, there were less dose modifications, higher response rates, and patients were able to remain on treatment longer.”
Both Richardson and Yvonne Efebera, MD, MPH, professor and medical director of the blood and marrow transplant and cellular therapy program at Ohio Health,note that the melphalan flufenamide has consistently demonstrated benefit across clinical studies of patients with high unmet need.
The FDA’s Stance:
The FDA disagrees with the Applicant due to the topline results of the OCEAN study after the trial failed to demonstrate PFS superiority, and the OS was worse in the melphalan flufenamide treatment arm vs the control arm.
Several post hoc exploratory analyses were submitted with the hopes of addressing the concerning OS results, but these analyses did not adequately address the FDA concerns regarding the benefit-risk for melphalan flufenamide.
The FDA noted that the OCEAN trial was not designed to compare or evaluate the effect of pomalidomide treatment in the various age subgroups evaluated by the sponsor and that treatment arm comparisons of age group noted by the sponsor do not provide information on t he treatment effect of melphalan flufenamide.
“Multiple factors other than those suggested by the sponsor can be found to explain the variability in OS,” stated Alexandria Schwarsin, MD, hematologist/oncologist at the Division of Hematologic Malignancies II at the FDA. “Exploratory analyses indicated the different modeling approaches yielded different results. However, this is considered hypothesis generation and not suitable for making conclusions.”
Overall, the FDA also does not agree with the applicant that ASCT with TTP <36 months is the strongest predictor of OS in the melphalan flufenamide arm and a different factor, age, is the predictor in the pomalidomide arm. According to the FDA, there have been previously outlined limitations of post hoc exploratory analysis and they have noted their concerns with the rationale for using the TTP of at least 36 months.
Once both sides discussed their stance on main issues with melphalan flufenamide, including the agents potential detriment in OS, its failure to demonstrate a PFS benefit, and the lack of a known appropriate dose, the voting question of whether melphalphan fleufenimide is favorable or not in this indicated patient population.
ODAC ultimately decided that given the potential detriment in OS failure to demonstrate PFS benefit, and lack of appropriate dose, the benefit-risk profile of melphalan flufenamide is not favorable in patients with relapsed/refractory multiple myeloma.