Oncopeptides Withdraws Melphalan Flufenamide Myeloma Indication in the United States

FDA

Oncopeptides AB (publ) has made the decision to withdraw the indication of melphalan flufenamide (Pepaxto; melflufen) in combination with dexamethasone in select adult patients with relapsed or refractory multiple myeloma from the US market.¹

In February 2021, the FDA approved melflufen plus dexamethasone for use in adult patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.²

The decision was based on findings from the phase 2 HORIZON trial (NCT02963493), which showed that the doublet elicited an overall response rate (ORR) of 23.7% (95% CI, 15.7%-33.4%) in the efficacy population (n = 97).³ Of these patients, 14.4% achieved partial response and 9.3% experienced a very good partial response. The median duration of response was 4.2 months (95% CI, 3.2-7.6).

esuts from the confirmatory phase 3 OCEAN study (NCT03151811), which evaluated the safety and efficacy of melflufen and dexamethasone vs pomalidomide (Pomalyst) and dexamethasone in patients with relapsed/refractory disease and showed that the hazard ratio (HR) for overall survival (OS) in the intent-to-treat population was 1.104.

The global biotechnology company made the decision to withdraw the indication after speaking with the FDA. During the dialogue, the regulatory agency expressed that it did not consider OCEAN to meet the criteria of a confirmatory trial. Oncopeptides stated that they believe that the findings from the trial are “scientifically meaningful,” and they warrant further evaluation.

“The decision to withdraw [melflufen] from the market has been a difficult decision that has been made with great consideration and with the best intentions for patients and shareholders,” Marty J. Duvall, chief executive officer at Oncopeptides, stated in a press release. “The Company now needs to refocus its resources and energy on R&D and remain true to its mission of bringing hope to patients through science. We believe that this is the only viable path forward to accomplish this goal.”

The open-label, phase 3 OCEAN trial enrolled a total of 495 patients relapsed/refractory multiple myeloma.⁴ To be eligible for enrollment, patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 2, and have received 2 to 4 prior lines of therapy including lenalidomide (Revlimid) and a proteasome inhibitor. Patients also needed to be refractory to lenalidomide and their last line of therapy.

Study participants were randomized 1:1 to receive either intravenous melflufen at a dose of 40 mg on day 1 of each treatment cycle plus oral dexamethasone once weekly (n = 246), or 4 mg of pomalidomide on days 1 through 21 of each cycle plus 40 mg of oral dexamethasone once weekly (n = 249).

The primary end point of the trial was progression-free survival (PFS) per independent review committee (IRC) assessment and International Myeloma Working Group criteria. Key secondary end points comprised ORR, OS, and safety.

The median age in the investigative arm was 68 years (IQR, 60-72) and 57% were male. In the control arm, the median age was also 68 years (IQR, 61-72) and 56% of patients were male.

Data presented during the 18th Annual International Myeloma Workshop showed that at a median follow-up of 15.5 months with melflufen and 16.3 months with pomalidomide, the IRC-assessed PFS was 6.8 months (95% CI, 5.0-8.5) vs 4.9 months (95% CI, 4.2-5.7), respectively (HR, 0.79; 95% CI, 0.64-0.98; P = .03).

The melflufen combination also elicited an ORR of 33% (95% CI, 27%-39%) vs 27% (95% CI, 22%-33%) with pomalidomide plus dexamethasone. Seven patients in the investigative arm and 3 patients in the control arm achieved complete responses to treatment.

Results from a subgroup analysis showed that patients who received melflufen and did not previously undergo autologous stem cell transplantation (ASCT) derived a PFS benefit. The median PFS was 9.3 months (95% CI, 7.2-11.8) vs 4.6 months (95% CI, 3.5-6.3) with pomalidomide (HR, 0.59; 95% CI, 0.44-0.79; P < .001).

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) were reported in 99% of those in the investigative arm and 98% of those in the control arm; grade 3 or higher AEs were experienced by 90% and 77% of patients, respectively.

Grade 3 or higher non-hematologic TEAEs that were experienced by more than 2% of patients in both the investigative and control arms, respectively, included pneumonia (4% vs 8%), muscular weakness (2% vs 2%), hyperglycemia (2% vs 3%), asthenia (2% vs 2%), COVID-19 pneumonia (2% vs 2%), and hypertension (2% vs 2%). Grade 3 or 4 TEAEs of special interest included thrombocytopenia (76% vs 13%), neutropenia (64% vs 49%), infection (13% vs 22%), and infection (13% vs 22%), and infective pneumonia (5% vs 12%).

In July 2021, the FDA requested that a partial hold be placed on all clinical studies examining melflufenbecause of differences in OS observed in prespecified patient subgroups.⁵ Later that month, the regulatory agency issued an alert that evidence from OCEAN indicated that melflufen combination resulted in an increased risk of death in patients with relapsed or refractory multiple myeloma.⁶

In this most recent announcement, Oncopeptides announced plans to refocus the company and return to being a Sweden-based research and development company that is dedicated to further developing their peptide drug conjugate platform. Moreover, the organization will be scaled down, with commercial business units in the United States and Europe closed down and the Stockholm-based organization reduced.

An application for the potential conditional marketing authorization of melflufen in relapsed/refractory multiple myeloma to the European Medicines Agency is pending, with an opinion from the Committee for Medicinal Products for Human Use anticipated in Q2 of 2022.

References

1. Oncopeptides withdraws Pepaxto in US, scale down organization and focus on R&D. News release. Oncopeptides AB (publ). October 22, 2021. Accessed October 22, 2021. https://bit.ly/3vzvjGc
2. FDA approves Oncopeptides' PEPAXTO (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides AB (publ). February 26, 2021. Accessed October 22, 2021. http://cisn.co/3q2bZgq
3. Melphalan flufenamide. Prescribing information. Oncopeptides AB; 2021. Accessed October 22, 2021. https://bit.ly/3sTyfeQ
4. Schjesvold F, Dimopoulos MA, Delimpasi S, et al. OCEAN (OP-103): a Phase 3, randomized, global, head-to-head comparison study of melflufen and dexamethasone (Dex) versus pomalidomide (Pom) and dex in relapsed refractory multiple myeloma (RRMM). Presented at: International Myeloma Workshop; September 8-11, 2021; Vienna, Austria. Accessed October 22, 2021.
5. Updated results from phase 3 OCEAN study shows melflufen met primary endpoint of superior PFS – overall survival data lead to partial clinical hold. News release. Oncopeptides AB. July 8, 2021. Accessed October 22, 2021. https://bit.ly/3dSSunm
6. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). News release. FDA. July 28, 2021. Accessed October 22, 2021. https://bit.ly/3f81zJu