FDA Grants Priority Review to Melphalan Flufenamide for Triple-Class Refractory Myeloma

The FDA has granted a priority review to a new drug application (NDA) for melphalan flufenamide (Melflufen) for use in combination with dexamethasone in adult patients with multiple myeloma whose disease is refractory to at least 1 proteasome inhibitor (PI), 1 immunomodulatory agent (IMiD), and 1 anti-CD38 monoclonal antibody, according to an announcement from Oncopeptides, the drug developer.¹

The application was based on data from the pivotal phase 2 HORIZON trial (NCT02963493), which showed that the combination of the first-in-class anticancer peptide-drug conjugate and dexamethasone elicited an overall response rate (ORR) of 26% in patients with triple-refractory disease.

Under the Prescription Drug User Fee Act, the FDA must make a decision on the NDA by February 28, 2021.

“This is very exciting news. It is an important milestone for Oncopeptides, and a major step in making melflufen available for patients with multiple myeloma, who desperately need new treatment options,” Marty J. Duvall, CEO of Oncopeptides AB, stated in a press release. “I am looking forward to a continuing dialogue with the FDA while we make the product available to [patients with] relapsed/refractory multiple myeloma in the United States through an expanded access program, in an FDA approved trial called sEAPort.”

In the phase 2 trial, investigators enrolled a total of 157 patients with relapsed/refractory multiple myeloma who had received 2 or more lines of therapy, were exposed to an IMiD and a PI, and were refractory to pomalidomide (Pomalyst) and/or daratumumab (Darzalex). Patients had triple-class refractory disease and/or extramedullary disease (EMD) and/or high-risk cytogenetic features. Patients had to have had an ECOG performance status of 0 to 2.

On the trial, a total of 157 participants were given 40 mg of melflufen on day 1 along with 40 mg of dexamethasone on days 1, 8, and 15; patients aged 75 years or older received 20 mg of dexamethasone instead. Patients received treatment in 28-day cycles until either disease progression or intolerable toxicity.

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

Results from HORIZON were presented during the 2020 European Hematology Association Annual Meeting and demonstrated an ORR of 29% (95% CI, 22%-37%) in the intent-to-treat (ITT) population (n = 157).2 When broken down by subgroup, the ORR was 26% (95% CI, 18%-

35%) in the 119 patients who were triple-class refractory, and 24% (95% CI, 13-37) in the 55 patients who had extramedullary disease (EMD).²

The median DOR reported with the regimen in the ITT population, the triple-refractory subgroup, and the EMD subgroup was 5.5 months (95% CI, 3.9-7.6), 4.4 months (95% CI, 3.4-7.6), and 5.5 months (95% CI, 1.8–not evaluable [NE]), respectively. Additionally, the median time to best response was 1.9 months in the ITT population. Notably, responses achieved with the treatment were found to deepen the longer that patients received it.

Among participants who achieved responses, the median PFS was 8.5 months (95% CI, 5.4-13.4) in the ITT population, 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. The median OS in the ITT population, the triple-class refractory subgroup, and the EMD subgroup 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.

With regard to safety, the combination did not show any new safety signals, proving to be consistent with previously reported findings. The most commonly reported grade 3 or 4 adverse effects (AEs) included neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most commonly experienced non-hematologic toxicity that was grade 3 or 4 in severity was pneumonia (10%).

Results from an exploratory analysis of time to next treatment also reported during the meeting showed that the melflufen regimen resulted in disease stabilization in 69% of participants; this translated to a median time to next treatment of 5.8 months in the overall population, including those with triple-refractory disease and those with EMD.³

Although these data proved to be consistent with previous findings of time to next treatment in this population, it was the first report to examine this measurement in a population with such advanced disease, according to investigators.

At an earlier analysis presented during the 2019 ASH Annual Meeting, a total of 97 patients comprised the heavily-refractory subgroup and the ORR with melflufen/dexamethasone was 24%.⁴ Moreover, the median PFS was 4 months, the median OS was 11.3 months, and the median DOR was 7.5 months.

The analysis of the ITT population shared during the meeting showed that of the 125 patients included in this group, the median lines of prior therapy received was 5, 97% of patients were refractory to their last line of therapy, 71% were triple-class refractory, and 32% had EMD. In this population, the ORR reported with melflufen was 29%, with a clinical benefit rate of 37%.

In the subgroup of patients with EMD, which was comprised of 42 patients, the ORR was 24%, the median PFS was 3 months, the median OS was 8.1 months, and the median DOR was 5.1 months.

The FDA-approved sEAPort trial (OP-110) will further examine melflufen in combination with dexamethasone in US patients with triple-class refractory multiple myeloma.⁵ To participate, patients will need to have received at least 2 previous lines of treatment and be triple-class refractory or intolerant to at least 1 PI, 1 IMiD, and 1 anti-CD38 antibody.

The primary end point of the trial is safety and tolerability with a specific focus on serious AEs and non-serious events that are grade 3 or higher in severity. The secondary end point of the trial is ORR per investigator assessment, and an exploratory end point of the trial will focus on disease-associated pain and quality of life based on patient-reported outcomes.

References:

1. FDA grants priority review of melflufen for patients with triple-class refractory multiple myeloma. News release. Oncopeptides AB. August 29, 2020. Accessed August 31, 2020. https://bit.ly/2YSfwTT.
2. 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. https://bit.ly/2CO3hPY.
3. 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. https://bit.ly/3dTqayA.
4. Oncopeptides presents updated efficacy and safety data from pivotal phase 2 HORIZON study in patients with RRMM at ASH Annual Meeting 2019. News release. Oncopeptides AB. March 26, 2020. Accessed August 31, 2020. https://bit.ly/2xn7qb8.
5. sEAPort: Expanded Access Program. Oncopeptides AB. Accessed August 30, 2020. https://bit.ly/2YOgGjp.