Oncopeptides Reports Positive Results from HORIZON Trial of Melflufen Combo

The combination therapy of melflufen (melphalan flufenamide) and dexamethasone continues to be safe and to elicit deep and durable responses in hard-to-treat patients with relapsed or refractory multiple myeloma, top-line data from a Phase 2 clinical trial shows.

The findings will support Oncopeptides‘ submission of a new drug application  requesting accelerated approval of melflufen for treating relapsed or refractory myeloma patients in the U.S., which remains on track for later this year, despite the COVID-19 pandemic.

Trial findings were presented in a poster, titled, “HORIZON (OP‑106): Melflufen Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma Refractory to Pomalidomide and/or an Anti‑CD38 Monoclonal Antibody — Primary and Subgroup Analysis,” at the 25^th European Hematology Association meeting (EHA), which took place virtually, June 11–21.

Melflufen is an investigational therapy that belongs to a new class of compounds known as peptidase-enhanced agents. It works by rapidly delivering a cancer-killing agent — an alkylating peptide — to malignant cancer cells that contain high levels of aminopeptidases, which are enzymes that break down peptides.

In this way, the therapy preferentially targets and destroys cancer cells containing excessive amounts of these enzymes, while healthy cells are spared.

The medication is intended for triple refractory myeloma patients,who received and failed to respond to treatment with at least one immunomodulatory drug (IMiD), one proteasome inhibitor, and one anti-CD38 monoclonal antibody.

The HORIZON Phase 2 trial (NCT02963493), assessing the safety and effectiveness of melflufen with dexamethasone, is one of the clinical studies whose findings will play a key role in the anticipated approval of melflufen for the treatment of relapsed or refractory myeloma patients in the U.S.

HORIZON enrolled a total of 157 patients who had received at least two prior therapies, including one IMiD and one proteasome inhibitor, and failed to respond to treatment with Darzalex (daratumumab) and/or Pomalyst (pomalidomide).

Interim data from HORIZON showed the combination therapy was safe and able to at least stabilize the disease in a majority (86%) of the 113 patients with measurable treatment responses who were included in the analyses.

Top-line data from all 157 patients enrolled in the trial, now announced by the company, showed the combination therapy continues to be safe, well-tolerated, and leads to deep and durable responses.

As of Jan. 14 (cutoff date), 131 patients (83%) had discontinued the therapy and 26 patients (17%) were still receiving treatment. In more than half of the cases (56%), treatment discontinuation was due to disease progression.

At a median follow-up of 14 months, 29% of the patients in the overall trial population responded to the combination therapy. Treatment response rates were identical in hard-to-treat patient subgroups, including in triple-refractory patients (26%) and in those with extramedullary disease (24%).

Those in the overall population lived a median of 4.2 months without showing signs of disease progression (progression-free survival, or PFS), but this increased to 8.5 months in patients who responded at least partially to treatment. Notably, median PFS increased from 2.9 months in the overall patients with extramedullary disease to 17.3 months among those who responded.

Median overall survival was identical in the overall study population (11.6 months) and in patients with triple-refractory disease (11.2 months). For those with extra medullary disease it was 6.5 months.

In the overall population, the median duration of response (DOR) was 5.5. months, and the time to best response was 1.9 months, with treatment responses becoming stronger with longer treatment duration.

The safety profile of the melflufen combo therapy was consistent with previous data. No new safety concerns were identified.

Nearly all patients (94%) in HORIZON experienced severe or life-threatening adverse events (side effects), with the most common being low white blood cell counts (79%), low platelet counts (76%), and anemia. Fatal adverse events occurred in 10 patients, but none of them was found to be related to treatment.

“The results are in line with results from previous interim analyses. Notably, the PFS of 8.5 months in responding patients (both all treated and triple-class refractory), was materially higher than the DOR, which is explained by the relatively long-time it took for patients to respond (median 1.9 months). This is very encouraging for patients with an unmet need; ultimately this is the period patients benefit from treatment with melflufen,” Klaas Bakker, MD,  chief medical officer of Oncopeptides, said in a press release.

“The fact that the treatment also seems to be well tolerable makes this a potentially attractive treatment option for a fast-growing patient population with a significant unmet medical need,” Bakker said.

In addition to HORIZON, findings from the OCEAN Phase 3 trial (NCT03151811), assessing the potential superiority of melflufen and dexamethasone to standard-of-care Pomalyst and dexamethasone in relapsed or refractory myeloma patients, are also expected to support Oncopeptides’ future regulatory submissions.

These include a supplemental new drug application the company is planning to submit to the FDA next year, followed by a marketing authorization application to the European Medicines Agency.

The trial, which already has reached its final stage of patient recruitment, is enrolling patients who had received at least two prior therapies, including one IMiD and one proteasome inhibitor, and no longer responded to treatment with Revlimid (lenalidomide).

The main goal of the study is to assess the effects of the combination therapy on PFS, compared to standard care. This endpoint will be assessed once 339 patients have shown signs of disease progression.

A recent analysis of the study has shown that patients are remaining on treatment longer than expected. As a result, Oncopeptides is now estimating top-line findings from OCEAN will become available in 2021, instead of later this year as initially planned.

“A recent analysis indicates that patients enrolled in the OCEAN-study continue treatment for a longer period of time than originally estimated, which speaks to the potential benefit patients can have by participating in this trial,” Jakob Lindberg, CEO of Oncopeptides, said in a press release.

“However, this most likely increases the time required to reach the number of disease progression events needed to complete the study. We will continue patient enrollment to enable an analysis of results within a reasonable timeframe,” Lindberg said.

In addition to HORIZON and OCEAN, two other open-label clinical trials — Phase 1/2 ANCHOR (NCT03481556) and Phase 2 BRIDGE (NCT03639610) — are investigating the safety and effectiveness of melflufen in combination with other therapies in myeloma patients.

Approximately two months after pausing patient recruitment into BRIDGE and ANCHOR due to the COVID-19 outbreak, Oncopeptides announced the reopening of trial sites that are now enrolling new participants into both studies.

“I am really pleased that despite the ongoing pandemic we can restart our clinical program for melflufen in a safe and responsible way,” Bakker said in a press release.

The pandemic also delayed the launch of a new Phase 3 trial called LIGHTHOUSE that is designed to assess if the combination therapy of melflufen and Darzalex is superior to Darzalex alone in relapsed or refractory myeloma patients. The study, which was planned to start earlier this year, is now expected to start after summer.