BCMA Antibody-Drug Conjugate Belantamab Mafodotin Succeeds in Phase II Myeloma Trial

Belantamab mafodotin met the primary endpoint of demonstrating a clinically meaningful overall response rate in patients with relapsed/refractory multiple myeloma, according to topline results from the phase II DREAMM-2 trial.

Hal Barron, MD

Belantamab mafodotin (GSK2857916) met the primary endpoint of demonstrating a clinically meaningful overall response rate (ORR) in patients with relapsed/refractory multiple myeloma, according to topline results from the phase II DREAMM-2 trial announced by GSK, the manufacturer of the anti-BCMA antibody-drug conjugate.1

Patients enrolled in the study were refractory to treatment with an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory drug. Full data from the study have not yet been made available. GSK noted in a press release that the safety and tolerability results for DREAMM-2 were similar to the findings reported in the first-in-human phase I DREAMM-1 trial.

“I am pleased with the results of the DREAMM-2 study and excited about what these data could mean for patients with multiple myeloma who have exhausted other lines of treatment. We are on track to file belantamab mafodotin later this year and continue to investigate how it could help even more patients with this disease,” Hal Barron, MD, chief scientific officer and president R&D, GSK, said in the press release.

The open-label phase II DREAMM-2 study randomized 196 patients with relapsed/refractory myeloma to receive 1 of two doses of belantamab mafodotin. The primary endpoint of ORR was defined as the percentage of patients achieving a confirmed partial response (PR), very good partial response, complete response (CR), or stringent CR per the 2016 International Myeloma Working Group Response Criteria by Independent Review Committee.

The latest data from DREAMM-1 were reported in a March 2019 update. The data, which were from more than 1 year of follow-up and included all patients whose data were reported in an earlier interim analysis, showed that the antibody-drug conjugate elicited an ORR of 60% and there were 3 CRs and 2 stringent CRs.2,3 The median progression-free survival (PFS) was 12 months (95% CI, 3.1—not estimable [NE]), and the median duration of response was 14.3 months (95% CI, 10.6—NE).

Among heavily pretreated patients who were refractory to both an immunomodulatory agent and a proteasome inhibitor (n = 32), the median PFS was 7.9 months (95% CI, 2.3¬—NE) and the ORR was 56.3%. In patients who did not receive prior treatment with daratumumab (Darzalex; n = 21), the ORR was 71.4% and the median PFS was 15.7 months (95% CI, 2.3–NE). Patients who were double refractory and were previously treated with daratumumab (n = 13) had a median PFS of 6.2 months (95% CI, 0.7-7.9) and an ORR of 38.5%. In those patients who did previously receive daratumumab, the median PFS was 6.8 months (95% CI, 1.3–NE).

Regarding safety, there were no new safety signals compared with the initial analysis. The most commonly reported adverse events (AEs) were thrombocytopenia (63%), blurred vision (51%), and cough (40%), which were mostly grade 1/2. The most commonly reported grade 3/4 AEs were thrombocytopenia (35%) and anemia (17%).

The FDA granted belantamab mafodotin a breakthrough therapy designation in November 2017 for the treatment of patients with relapsed/refractory multiple myeloma who have failed ≥3 prior lines of therapy, including an anti-CD38 antibody, and who are refractory to a proteasome inhibitor and an immunomodulatory agent. The agent also received PRIME designation from the European Medicines Agency.

In the open-label, first-in-human, DREAMM-1 study, investigators evaluated the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical activity of belantamab mafodotin in patients with relapsed/refractory multiple myeloma and other advanced BCMA-expressing hematologic malignancies.

BCMA expression was not required for eligibility, patients had an ECOG performance status of 0 or 1, and albuminuria ≤500 mg per 24 hours. Premedication for infusion reactions was not permitted with the first dose and was not mandated at subsequent doses.

The study consisted of 2 parts: a dose-escalation phase, in which patients received belantamab mafodotin at escalating doses, and a dose-expansion phase in which all patients received belantamab mafodotin at the recommended phase II dose. The primary endpoint was safety; secondary endpoints included response rate, pharmacokinetics, and immunogenicity.

Results from part 1 of the trial, which were presented at the 2016 ASH Annual Meeting, showed that there were no dose-limiting toxicities in the 38 enrolled patients, and the phase II dose was determined as 3.4 mg/kg administered as a 1-hour infusion once every 3 weeks for up to 16 cycles.4

In part 2 of the study, 35 patients were enrolled independent of their BCMA expression levels, and there were 2 cohorts. In December 2017, cohort 1 comprised patients with relapsed/refractory multiple myeloma and the second cohort included those with BCMA-positive relapsed diffuse large B-cell lymphoma or follicular lymphoma.

Interim data on cohort 1 of the part 2 expansion phase were presented at the 2017 ASH Annual Meeting. The median patient age was 60 (range, 46-75) and 57% of patients had received ≥5 prior lines of therapy. A total 30% of patients were considered to have high-risk disease.

All patients had received an immunomodulatory agent and a proteasome inhibitor, and 89% of patients were double refractory to both agents. Forty percent of patients previously received daratumumab (Darzalex), and all but one patient was refractory to the monoclonal antibody. Thirty-four percent of patients were double-refractory to an immunomodulatory agent, a proteasome inhibitor, and had received daratumumab.

The median follow-up was 6.6 months (range, 1-10) and the median number of infusions administered was 5 (range, 1-13). The median duration of response for responding patients has not yet been reached (95% CI, 6.7—NE).

Interim results showed that the ORR was 43% among patients who previously received daratumumab, 58% in those who were double refractory to an immunomodulatory agent and a proteasome inhibitor, and 42% in patients who were double-refractory to both agents and were exposed to daratumumab.5

Regarding safety, all patients experienced an AE, 80% had grade 3/4 AEs, and 14% had a serious AE related to study treatment. Infusion-related reactions occurred in 23% of patients. Dose modifications were required in approximately two-thirds of patients, the majority of which were related to corneal toxicity or thrombocytopenia. The most frequent grade ≥3 AEs were thrombocytopenia (34%) and anemia (14%), and there were no patient deaths.

References

  1. GSK announces positive headline results from the pivotal DREAMM-2 study for multiple myeloma. Posted August 23, 2019. Accessed August 23, 2019. https://bit.ly/30ul1qB.
  2. GSK Announces Further Positive Data From DREAMM-1 Study of Anti-BCMA Antibody-Drug Conjugate in Patients With Relapsed/Refractory Multiple Myeloma. GlaxoSmithKline. Published March 22, 2019. https://bit.ly/2TRRaZZ. Accessed March 22, 2019.
  3. Trudel S, Lendvai N, Popat R, et al. Antibody—drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019;9(37).
  4. Cohen AD, Popat R, Trudel S, et al. First in human study with GSK2857916, an antibody drug conjugated to microtubule-disrupting agent directed against b-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma (MM): results from study BMA117159 part 1 dose escalation. Blood. 2016;128(22):1148.
  5. Trudel S, MD, Lendvai N, Popat R, et al. Deep and durable responses in patients (Pts) with relapsed/refractory multiple myeloma (MM) treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen (BCMA): preliminary results from part 2 of study BMA117159. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 741.