Enrollment Postponed by Merck for 2 Pembrolizumab Trials in Multiple Myeloma

Merck has announced that enrollment for the phase III KEYNOTE-183 and KEYNOTE-185 multiple myeloma trials has been postponed due to deaths in patients treated with pembrolizumab (Keytruda), the company’s blockbuster anti—PD-1 therapy.

An external Data Monitoring Committee recommended halting new enrollment while the company collects more data “to better understand” reported deaths in the pembrolizumab arms. This decision does not affect other pembrolizumab studies.

KEYNOTE-183 is comparing the combination of pembrolizumab, pomalidomide (Pomalyst) and low-dose dexamethasone against pomalidomide and low-dose dexamethasone alone in patients with relapsed/refractory multiple myeloma who have undergone at least 2 lines of prior treatment. Patients are randomized to pomalidomide at 4 mg daily on days 1 to 21 and 40 mg of daily dexamethasone on days 1, 8, 15, and 22, with or without pembrolizumab at 200 mg every 3 weeks, in 28-day cycles. Treatment continues until progression or unacceptable toxicity.

KEYNOTE-185 is comparing pembrolizumab, lenalidomide (Revlimid) and low-dose dexamethasone with lenalidomide and low-dose dexamethasone alone in patients with newly diagnosed and treatment-naïve multiple myeloma who are ineligible for autologous stem cell transplant. Patients are randomly assigned to lenalidomide at 25 mg daily on days 1 to 21 and 40 mg of dexamethasone on days 1, 8, 15, and 22, with or without 200 mg of pembrolizumab every 3 weeks, in 28-day cycles. Treatment will continue until progression or unacceptable toxicity.

Both trials were initiated in October 2015.

Ashraf Z. Badros, MD, professor of medicine with the Greenebaum Cancer Center at the University of Maryland School of Medicine, presented phase II data at the 2016 ASH Annual Meeting showing that the pembrolizumab/pomalidomide/dexamethasone combination was active in patients with relapsed/refractory multiple myeloma.

In the single-center trial conducted at the University of Maryland (N = 48), the overall response rate (ORR) was 65% with the pembrolizumab-containing triplet regimen. Overall, 29% of patients experienced a very good partial remission (VGPR) or better. The stringent complete remission (sCR) rate was 7% and the CR rate was 2%. Responses remained consistent in those with double-refractory disease and for those with high-risk cytogenetics.

At the data cutoff of October 15, 2016, the median follow-up time was 9.6 months. The median duration of response was 16.3 months (95% CI, 9.8-19.1) and the median progression-free survival (PFS) was 17.4 months (95% CI, 11.7-18.8). At the time of the analysis, the median overall survival was not yet reached (95% CI, 18.8-not reached).

In those with double-refractory disease (n = 32), the ORR was 68% and the VGPR rate or better was 24%. In those with high-risk cytogenetics (n = 27), the ORR was 56% and the VGPR or better rate was 15%.

PD-L1 expression was assessable for 29 patients in the study, with positivity defined as expression on ≥50% of cells. In those with PD-L1-positive disease (n = 13), the combination elicited an ORR of 77%, with a VGPR or better of 54% (P= .05; versus PD-L1-negative). Those with PD-L1-negative disease (n = 10) had an ORR of 60% and a VGPR rate of 20%. There were no CRs. The median PFS in the PD-L1-negative arm was 17.4 months (95% CI, 10.6-18.4). In those with PD-L1-positive disease, the median PFS was not yet reached.

The most common, ≥5%, grade ≥3 adverse events (AEs) were neutropenia (40%), hyperglycemia (25%), anemia (21%), upper respiratory tract infections (21%), lymphopenia (15%), fatigue (15%), rash (10%), and thrombocytopenia (8%). Immune-related AEs included interstitial pneumonitis (13%), hypothyroidism (10%), and transaminitis (6%).

Overall, 5 patients discontinued therapy due to adverse events (11%), including pneumonitis (n = 3), shortness of breath (n = 1), and fatigue (n = 1). Half of patients required a pembrolizumab dose reduction.

The FDA first approved pembrolizumab for the treatment of advanced or unresectable melanoma in 2014. The PD-1 inhibitor is approved for unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed and for whom there are no alternative treatment options, making it the first tissue/site agnostic cancer treatment in the United States. The drug has also been approved for lung cancer, head and neck cancer, Hodgkin lymphoma, and urothelial carcinoma.

Reference:

Badros AZ, Hyjek E, Ma N, et al. Pembrolizumab in Combination with Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM). Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 490.