Miami Breast Cancer Conference

Updated Data From the Phase II HORIZON Study in Patients With RRMM

By Sarah LaCorte


ORLANDO— Researchers provided the final update on data from the phase II HORIZON (OP-106) trial evaluating melflufen in relapsed/refractory multiple myeloma at the 2019 ASH Annual Meeting (Abstracts 1883, 3487, 3124, 3163, 1839).

With current therapeutic options, multiple myeloma remains an incurable disease. Melflufen, a peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells, is a promising novel therapy. Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and is immediately cleaved by peptidases to deliver an entrapped hydrophilic alkylator payload. Peptidases play a key role in protein homeostasis and feature in cellular processes such as cell-cycle progression and programmed cell death.

In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the increased intracellular alkylator concentration. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies.

The ongoing HORIZON study in patients with MM refractory to pomalidomide (pom) and/or daratumumab (dara) includes subgroups of patients who were triple-class refractory and/or had relapsing extramedullary disease (EMD) and/or had cytogenetic high-risk features.

As of the conclusion of the study, 157 patients were enrolled. Patients in the HORIZON study had a median of five prior lines of therapy, 71 percent of patients were triple-class refractory, 97 percent were refractory to the last line of treatment, and 32 percent suffered from EMD. The efficacy population (n=125) reflects patients dosed on or before May 15, 2019, with additional follow-up of 20 weeks until October 1, 2019 at the time for the data cutoff. The safety population (N=154) reflects patients dosed on or before the data cutoff on October 1, 2019. The patients in the study are refractory to pomalidomide and/or daratumumab after failing on immunomodulatory drugs and proteasome inhibitors.

“HORIZON trial data is very intriguing—not only does it show response rates in a range of 30 percent in patients even with a high-risk disease such as triple refractory, [but it’s] particularly interesting that there is a 24 percent response rate in patients with extramedullary disease, which would be an even more aggressive subset of patients with relapsed/ refractory disease,” said Agne Paner, MD, Associate Professor of Hematology and Medical Oncology at Rush University Medical Center in Chicago. “So, besides this activity, it is nice that melflufen shows very little of non-hematologic toxicity and it is really what helps to differentiate the drug from other alkylators available for treatment of multiple myeloma.”

When asked why melflufen had a significant response rate for patients with extramedullary disease, Paner said the biology of RRMM needs more scrutiny.

“It is hard to tell at this point whether it is the biology of the disease that is more susceptible to alkylator. I think we all have known this in our practices, that patients who progress through novel agents relapse more with the highly proliferative disease, as well as extramedullary plasmacytomas and whether it is a susceptibility to DNA damage from alkylator or the mechanism of the action of melflufen is yet to be answered,” she said.

In the ITT population (n=125), the overall response rate (ORR) was 29 percent and the clinical benefit rate was 37 percent. The safety profile remained consistent with prior reports from the HORIZON study.

In patients with triple-class refractory disease (n=97), the ORR was 24 percent with a median progression-free survival (PFS) of 4.0 months, a median duration of response (DOR) of 7.5 months, and a median overall survival (OS) of 11.3 months.

In patients with EMD (n=42), the ORR was 24 percent with a median PFS of 3.0 months, a median DOR of 5.1 months, and a median OS of 8.1 months.

“In the HORIZON study, response rates were in the range of 30 percent, but clinical benefit rate was about 44 percent. These findings were very similar in triple class refractory patients. Overall survival in patients treated with melflufan and dexamethasone was about a year. While in patients with extramedullary disease, it was about 8 months,” said Paner.

Grade 3 and 4 adverse events (AE) were primarily hematologic and the incidence of non-hematologic AEs was low. “There was very little of non-hematologic toxicities—that could be important for quality of patients such as nausea, diarrhea, ulcers or hair loss. We did not see these side effects with melflufen,”said Paner.

Paner said researchers in the ANCHOR (OP-104) study examined if treatment with melflufen and dexamethasone is well-tolerated as a triplet regimen with bortezomib or daratumumab. That research was also presented at the ASH 2019 meeting (Abstract 3124).

“The phase II ANCHOR trial is exploring melflufen combination with daratumumab. They showed the response rate in the 75 percent range in patients with 1-4 prior lines of therapy and PFS of 14.3 percent. These results are also very encouraging and will inform phase III trial subsequently,” Paner noted.

The next step is to submit the data to the FDA in 2020 as part of a New Drug Application.

“I think it will provide us another good treatment option for patients with RRMM disease and I am really looking forward to see what the results will be of melflufen in combination with other standard of care regimens,” she stated. “Those phase II and III studies are also currently ongoing. I am going to guess that this is where we will see the greatest application of melflufen in combination regimens, but even for the time being, combinations with dexamethasone will be helpful to manage patients with RRMM.

“I think potential is great, not only in studies that I already mentioned. I think this drug could find applicability in amyloidosis. This concept of this study was also presented at this meeting and we are looking forward to seeing what the results will be in the first-in-human trial. I think a lot of us are interested whether melflufen would eventually be an alkylator of choice for high-dose chemotherapy with stem cell support.”


Sarah LaCorte is a contributing writer.

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