Updated Response Data for Melflufen Combination Calls for NDA in Multiple Myeloma

Melphalan flufenamide (melflufen) in combination with dexamethasone achieved an overall response rate (ORR) of 26% in patients with relapsed/refractory multiple myeloma, according to results from the pivotal phase II HORIZON study. The achievement serves as the basis for the submission of a New Drug Application to the FDA, which developer Oncopeptides AB plans to complete in the second quarter of 2020.¹

Two patients with unconfirmed responses as of January have since been confirmed for an ORR in the intention-to-treat population of 31%. Additionally, the safety profile was found to be consistent with prior results from the HORIZON study with most adverse events (AEs) being hematologic and a low incidence of non-hematologic AEs reported. The detailed results from the study will be published later this year in a peer-reviewed publication.

Updated efficacy data from the HORIZON study were presented at the 2019 American Society of Hematology (ASH) Annual Meeting. In 113 patients who had a response to treatment, the ORR was 28% with a stringent complete response (sCR) observed in 1 patient. Nine percent of patients achieved a very good partial response (VGPR), and 19% achieved a partial response (PR). The clinical benefit rate observed in the study was 40%.²

A total of 121 patients were treated altogether. The median progression-free survival (PFS) was 4.0 months (95% CI, 3.7-4.6), the median overall survival (OS) was 11.2 months (95% CI, 8.1-13.9), and the median duration of response (DOR) was 4.4 months (95% CI, 3.6-8.3).

A subgroup analysis was conducted for patients with poor risk, which included those with triple-class refractory disease—no response to or progression on at least 1 immunomodulatory drug, a proteasome inhibitor, and a CD38-directed monoclonal antibody—and high-risk cytogenetics. Among the triple-class refractory patients, the ORR was 20%, with a 3.6-month median DOR, and the ORR for patients with high-risk cytogenetics was 28% with a median 5.1-month DOR.

Grade 3 treatment-related AEs occurred in 24% of patients and grade 4 events were seen in 49%. The most common grade 4 treatment-related AEs were thrombocytopenia (36%) and neutropenia (31%). Non-hematologic treatment-related AEs were uncommon, but of those observed in the study, the most frequent were pneumonia (3%), fatigue (2%), and upper respiratory tract infection (2%). Twenty percent of patients experienced serious treatment-related AEs. No AEs led to death in the study.

The study population consisted of patients with a median age of 64 years (range, 35-86). A significant proportion of patients (29%) had International Staging System stage 3 disease, and 62% with available cytogenetic data had high-risk cytogenetics. Patients had a median of 5 prior lines of therapy (range, 2-12), and all patients in the study were refractory to pomalidomide (Pomalyst) and daratumumab (Darzalex). Seventy-four percent of patients were identified as triple-class refractory.

During the study, patients were given 40-mg melflufen intravenously on day 1 of each 28-day cycle and 40-mg weekly dexamethasone or 20 mg for patients aged 75 years or older until progressive disease (PD) or unacceptable toxicity.

As of May 2019, 29% of patients were on ongoing treatment. Overall 71% of patients discontinued treatment with melflufen, which was due to PD in 69%, AEs in 20%, and for other reasons in 12%.

The primary end point of the ongoing HORIZON study is ORR and the secondary end points include safety, CBR, PFS, OS, and DOR.

Patients were eligible to enroll in the study given they had a prior diagnosis of multiple myeloma with disease progression, measurable disease, at least 2 prior lines of therapy to which they had become refractory, a life expectancy of at least 6 months and an ECOG performance status of 2 or lower.

Patients were unable to be treated in the HORIZON study if they showed evidence of mucosal or internal bleeding, were platelet-transfusion refractory, had known infection, were diagnosed with another malignancy requiring treatment, had any illnesses that would infer with treatment at the investigator’s discretion, or had prior treatment that did not match the study protocol.

At the time these data were presented at ASH, investigators shared that melflufen plus dexamethasone was undergoing further clinical investigation in the OCEAN phase III study in comparison with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (OP-103; NCT03151811).

Melflufen is a first-in-class anticancer peptide-drug conjugate. The drug has demonstrated cytotoxic activity against myeloma cell lines that are resistant to other treatments.¹

References

1. Oncopeptides announces 26% overall response rate of melflufen in triple-class refractory multiple myeloma patients from the pivotal horizon study [news release]. Stockholm, Sweden: Oncopeptides AB; March 26, 2020. https://prn.to/39kEsFR. Accessed March 27, 2020.
2. Mateos MV, Oriol A, Larocca A, et al. Clinical activity of melflufen in patients with triple-class refractory multiple myeloma and poor-risk features in an updated analysis of horizon (op-106), a phase 2 study in patients with relapsed/refractory multiple myeloma refractory to pomalidomide and/or daratumumab.Blood. 2019;(134);Suppl 1: 1883.