Behind the ODACs Decision Against Melphalan Flufenamide in R/R Multiple Myeloma

In an interview with Targeted Oncology, Paul Richardson, MD, discussed the outcome of the ODAC meeting and provided his personal insights on what may be next for melphalan flufenamide.

On day 1 of the September 22-23Oncologic Drigs Advisory Committee (ODAC) Meeting, members discussed the benefit-risk profile of melphalan flufenamide (Pepaxto; formerly Melflufen) for the currently indicated patient population of adult patients with relapsed or refractory multiple myeloma, while taking into account the results of the confirmatory phase 3 OCEAN trial (NCT03151811).

While melphalan flufenamide was granted accelerated approval in combination with dexamethasone for 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 in 2021, the confirmatory trial examining the agent demonstrated an inferior overall survival (OS) despite an improvement in progression free survival when compared to an active control, specifically pomalidomide and dexamethasone.

The drug was ultimately pulled from the market in October 2021 after the FDA placed a partial clinical hold on all trials of melphalan flufenamide in combination with dexamethasone. Oncopeptides A.B. then re-applied for FDA approval of melphalan flufenamide based upon further analysis of the OCEAN data which revealed new information regarding an interaction between pomalidomide and age as well as a detrimental effect of melphalan flufenamide immediately after or close to a prior autologous stem cell transplant.

During the ODAC meeting to discuss whether melphalan flufenamide is favorable or not in this indicated patient population, the applicant stated that while interactions overlap due to the correlation between patient age and autologous stem cell transplant eligibility, these data clarify the results from the OCEAN trial and support a positive benefit/risk profile for melphalan flufenamide in a targeted population.

“We know that we have wildly different myelomas and we cannot be treated in the same way. We need different tools in the toolbox… Over 75% of patients had clear benefit on the melphalan flufenamide arm which is a plus for patients who cannot have transplant. We have gone a very long way but we need to go further,” said Jenny Ahlstrom, chief executive officer and founder of HealthTree Foundation, during the ODAC meeting. “I want to have all options on the table when I talk to my doctor about what I am going to do next. There is utility for this drug and [one should be able to] assess the risk and benefits of its use for their individual situation. More choices equals better outcomes.”

However, the FDA disagreed based on the topline results of the OCEAN and emphasized the fact that the trial failed to demonstrate significant progression-free survival (PFS) superiority according to their analysis, which differed in methodology to that of the applicant, and the OS was worse in the melphalan flufenamide treatment arm vs the control arm.

Ultimately, the Committee voted 14 to 2 that given the potential detriment in OS, despite a significant PFS benefit according to the applicant’s previously approved statistical analysis plan and the positive subgroup analysis presented, the benefit-risk profile of melphalan flufenamide was not favorable in patients with relapsed and refractory multiple myeloma.

In an interview with Targeted OncologyTM, Paul Richardson, MD, Clinical Program Leader of the and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, and institute physician at Dana-Farber Cancer Institute, as well as the RJ Corman professor of Medicine at Harvard Medical School, further discussed the outcome of the ODAC meeting and provided his personal insights on what may be next for the agent.

Targeted Oncology: Can you provide an overview of what was discussed during the September 22 ODAC meeting?

Richardson: The focus of the oncology drug advisory meeting was to review the results of the phase 3 OCEAN trial, which had been developed as a confirmatory study conducted internationally to support the accelerated approval of melfufen as a novel, first-in-class peptide drug conjugate. Early phase studies had shown it to be active in highly resistant disease with manageable toxicity, reflecting its ability to overcome resistance in preclinical models to conventional chemotherapeutics, including melphalan.

Specifically, it is a way of delivering an alkylator warhead in a targeted fashion into a tumor cell by leveraging aminopeptidases which are overexpressed in myeloma. Moreover, its medicinal chemistry allows it to enter the cell preferentially and to be retained within the cell in such a way as to maximally induce cytotoxic injury to the target tumor, sparing normal tissues. In addition, it is a lipophilic drug, whereas melphalan is lipophobic. This makes it particularly important in myeloma because to have an agent that is strongly lipophilic has been shown to a clear advantage, especially in the bone marrow milieu.

In sum, as a peptide drug conjugate, it has a lot of attractive features to its medicinal chemistry which were first validated in preclinical models and further explored in early phase clinical trials. Fixed doses were established in a carefully dose-escalated design to then inform further studies, with the convenience of monthly infusion schedules and a 30-minute infusion time.

Can you discuss the design of HORIZON and OCEAN studies?

The OCEAN study was built with the FDA’s support as part of a special protocol approval (also known as a SPA) in support of HORIZON, which was a single arm, international and multi-center trial to examine the role of melfufen and dexamethasone in triple class refractory myeloma, in which CD38 antibody therapy and prior pomalidomide treatment had failed the patient.In this latter study, we were able to show a durable response rate of around 30% and importantly show activity in extramedullary disease. The study was large with around 150 patients; because of durability of response and the promising overall response rate as well as novel mechanism of action together with manageable toxicity, an accelerated approval was granted in March of 2021.

The OCEAN data were reported several months later in a different and less heavily treated population, who had received 2-4 prior lines of therapy, but importantly were lenalidomide refractory. It was dominated by European participation and included patients who had had prior transplant within 1-3 years, as well as longer.

This time difference between transplant and salvage had never been explored before. What was a hard lesson for OCEAN was that in Europe, most of the patients progressing on lenalidomide had received a fixed exposure to lenalidomide and they couldn't go in the study unless they were actually refractory to lenalidomide, which meant they could have only been on the drug for at most 2-3 years since transplant. Conversely, in the United States, we treat with lenalidomide maintenance until progression, so patients could be on maintenance therapy for 6 or 7 years or more, and thus the populations could be meaningfully different both in the transplant eligible group and those who had not received transplant.

Can you explain some of the findings of the trial seen and explained at the ODAC meeting?

We saw that if pomalidomide was given to the patients who had progressed on lenalidomide, and were relatively close to transplant as well as younger, these patients did very well. Conversely, in older patients who had not been transplanted, there was a significant effect in favor of Melflufen and against pomalidomide.

This trial was complicated. It generated a PFS end point that was positive in favor of melfufen and dexamethasone. However, OS was confounded because in those patients who had recently undergone a transplant and who received Melflufen, they did worse than their pomalidomide counterparts. Conversely, if patients were older and never had a transplant, they did well with Melflufen, thus rendering 2 very divergent results.

Overall, there was a PFS advantage at a statistical significance level of 0.03 in favor of the Melflufen arm. The difference in median PFS gain was 2 months and in myeloma we typically see a 3 to 6 months PFS gain. Thus in this study, which was a head-to-head comparison of 2 different mechanisms, the PFS benefit was not as robust as is normally seen. The response rates were broadly similar, although there was some evidence of greater advantage to Melflufen. In terms of OS assessment, however, a survival difference with a hazard ratio of 1.14 against Melflufen was reported and this was the trigger for concern.

What was the cause of this hazard ratio and why do you think this is important to discuss?

The good news is that it did not appear to be from excess toxicity. Specifically, there was no evidence that adverse events were driving this loss of OS benefit. What was going on, based on a pre-specified analysis, was that the differential effect of transplant was impacting on that hazard ratio. This analysis then took out the transplanted patients, and when this was done the subgroup analysis for the target population moved strongly in favor of Melflufen.

What was the question discussed at the ODAC meeting and what was the outcome?

What the ODAC was focused on was trying to make sense of a complex question. Specifically, Melflufen had been on the United States market as an approved novel agent for heavily pretreated patients who had received 4 or more lines of therapy, and does the OCEAN study in an earlier population support that indication? To most of the reviewers, that was not the case as they felt the study lacked sufficient evidence to support the current indication. Two of the 16 members, however, felt that it did and explained why they did very clearly in the context of a positive primary endpoint and an informed pre-specified subgroup analysis with a strong biological rationale.

It's important to note that OCEAN as a study also had several challenges. The question now is, what do you make sense of these complicated pieces of data? Do they mean this drug doesn't work and is dangerous? I personally did not see that in any of the information presented. Conversely it does have a novel mechanism of action, with clinical benefit shown in several other studies and especially in combination.

A positive thing from this meeting is that I think there was a recognition that one size does not fit all, and that patients need treatment tailored for their specific situation, with a key component being targeted populations. If patients with advanced disease are elderly, never or not recently transplanted, and/or they have had multiple immune-based therapies, how then does the targeted peptide drug conjugate perform? In my experience, and for our center, it has been very favorable, so I do think there's a way forward with the FDA to make sense of this and for us to provide an effective treatment option for our patients accordingly.

What do you think is next for this agent?

A further confirmatory trial is definitely going to be needed, as well as others to better explore the potential of this drug – especially in key subgroups such as those with extra-medullary myeloma. The question in the interim is access for patients, because this drug has value in my opinion with a meaningful role in advanced disease and in older, potentially frail patients. I think the other gorilla in the room is the fact that there is full European Medicine Agency [EMA] approval. To have one major regulatory organization have a different perspective on the same data and a drug approved in Europe and available to European patients, but not available to patients in the United States is challenging.

I would suggest we need to understand where middle ground can be found to make sense of these divergent perspectives. This can then result in harmonization and be supported by a confirmatory trial which helps in both jurisdictions. I think the EMA’s approach has been especially constructive, and I am hopeful that the FDA will have the same view going forward.

What research is currently going on in this space that may create a new solution for these patients?

There are several proposals in development for more studies to further confirm the benefit of Melflufen recognizing that as a novel peptide drug conjugate it can synergize in various combinations, and then studying it with multiple other drugs to fulfill its potential is a very logical next step.

What are key clinical takeaways from this ODAC meeting and more generally for mephlan flufenamide?

Melflufen is a drug infused once a month and it's given as an outpatient, making it practical with adverse events that are predominantly hematologic and generally manageable. As a patient, you don't lose your hair, you don't get mouth sores, and your rates of infection are low, all of which are very important, especially in the era of COVID. In the OCEAN study, a quality-of-life analysis supported this favorable profile. In terms of activity, as a peptide drug conjugate it offers a platform for improved efficacy when other backbone agents have exhausted theirs, and an ability to conveniently treat specific populations in this context, including high risk patients. Continued vigilance regarding safety and long-term follow-up remains key, with well-designed future studies developed in close collaboration with investigators and regulatory authorities being a clear way forward.



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