FDA Approval Sought for Melphalan Flufenamide in Triple-Class Refractory Myeloma

A new drug application (NDA) has been submitted to the FDA seeking an accelerated approval for melphalan flufenamide (Melflufen) in combination with dexamethasone in the treatment of adult patients with triple-refractory multiple myeloma, according to Oncopeptides, the manufacturer of the agent.¹

“I am very proud and humbled by the organization’s ability to timely submit the NDA for accelerated approval of melflufen. This is a major milestone for Oncopeptides and is a result of dedicated research and development activities throughout the last decade,” Jakob Lindberg, Oncopeptide’s CEO, said in a press release. “I would like to express my sincere gratitude to all patients, co-workers, investigators, and shareholders who have provided relentless support to enable a novel treatment option for a fast-growing patient population with a significant unmet need.”

A first-in-class aminopeptidase-targeting peptide-drug conjugate, melphalan flufenamide was designed to rapidly deliver an alkylating payload into cancer cells. The NDA submission is based is based on data from the phase 2 HORIZON study, which demonstrated durable responses that often deepened with prolonged treatment.

In the pivotal single-arm, multicenter trial, investigators are examining melphalan flufenamide in combination with dexamethasone in patients with relapsed/refractory disease who had previously received ≥2 prior lines of therapy and were refractory to pomalidomide (Pomalyst) and/or a CD38-directed monoclonal antibody. Patients had to have had an ECOG performance status of 0 to 2.

A total of 157 patients were given 40 mg of melphalan flufenamide on day 1 in combination with 40 mg of dexamethasone on days 1, 8, 15, and 22. Patients who were aged 75 years or older received 20 mg of dexamethasone instead. Patients received this treatment in 28-day cycles until they experienced either disease progression or unacceptable toxicity.

The primary end point of the trial was overall response rate (ORR) and secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), clinical benefit rate, time to response, time to progression, time to next treatment, safety, and health-related quality of life.

Results presented during the 2020 European Hematology Association (EHA) Annual Congress showed an ORR of 29% (95% CI, 22%-37%) in the intent-to-treat population (n = 157), 26% (95% CI, 18%-35%) in the triple-class refractory population (n = 119), and 24% (95% CI, 13-37) in the subgroup of patients with extramedullary disease (EMD; n = 55).²

Additionally, the median DOR reported with the agent was 5.5 months (95% CI, 3.9-7.6) in the ITT group, 4.4 months (95% CI, 3.4-7.6) in the triple-class refractory group, and 5.5 months (95% CI, 1.8–not evaluable [NE]) in the EMD group. Notably, the median time to best response was 1.9 months in the ITT population and responses were observed to deepen the longer that patients were on the treatment.

Of those who responded to the treatment, the median PFS was 8.5 months (95% CI, 5.4-13.4) in the ITT subgroup, 8.5 months (95% CI, 5.3-13.4) in the triple-class refractory subgroup, and 17.3 months (95% CI, 5.3-NE) in the EMD subgroup. In the ITT, triple-class refractory, and EMD subgroups, the median OS was 11.6 months (95% CI, 9.3-15.4), 11.2 months (95% CI, 7.7-13.2), and 6.5 months (95% CI, 5.1-9.7), respectively.

The toxicity profile of melphalan flufenamide plus dexamethasone proved to be consistent with previously reported data, and no new safety signals were observed. The most common grade 3/4 adverse events (AEs) included neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most common non-hematologic grade 3/4 AE reported was pneumonia (10%).

Results from an exploratory analysis of time to next treatment were also reported during this year’s EHA meeting.³ Here, investigators found that the combination led to disease stabilization in 69% of patients; this translated to a median time to next treatment of 5.8 months in heavily pretreated patients with relapsed/refractory disease, including those who were triple refractory and who had EMD.

These results proved to be consistent with prior findings of time to next treatment in this patient population; however, notably, this was the first report of time to next treatment in a population with such advanced disease.

Following the submission, Oncopeptides plans to initiate an Expanded Access Program in the United States to enable patients with a significant unmet need to access melphalan flufenamide treatment.

References

1. Oncopeptides submits a new drug application to the FDA for accelerated approval of melflufen in triple-class refractory multiple myeloma patients. News release. Oncopeptides. June 30, 2020. Accessed June 30, 2020. bit.ly/2CO3hPY.
2. Richardson PG, Oriol A, Larocca A, et al. HORIZON (OP-106): Melflufen plus dexamethasone in relapsed/refractory multiple myeloma refractory to pomalidomide and/or an anti-CD39 monoclonal antibody – primary and subgroup analysis. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020; Virtual. bit.ly/3dTqayA.
3. Mateos M-V, Oriol A, Larocca A, et al. HORIZON (OP-106): an exploratory analysis of time to next treatment in patients with relapsed/refractory multiple myeloma who received melflufen plus dexamethasone. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020; Virtual. bit.ly/2CPSTqY.