The FDA has placed a clinical hold on the phase III KEYNOTE-183 and KEYNOTE-185 pembrolizumab (Keytruda) trials and ordered the discontinuation of the lenalidomide/dexamethasone/pembrolizumab arm of the KEYNOTE-023 trial in patients with multiple myeloma.
Roger M. Perlmutter, MD, PhD
The FDA has placed a clinical hold on the phase III KEYNOTE-183 and KEYNOTE-185 pembrolizumab (Keytruda) trials and ordered the discontinuation of the lenalidomide/ dexamethasone/ pembrolizumab arm of the KEYNOTE-023 trial. All 3 studies were evaluating the PD-1 inhibitor in patients with multiple myeloma.
The agency “determined that the data available . . . indicate that the risks of Keytruda plus pomalidomide or lenalidomide outweigh any potential benefit for patients with multiple myeloma,” Merck, the manufacturer of the PD-1 inhibitor, reported in a press release.
Just 2 weeks ago, Merck announced that it was postponing enrollment in KEYNOTE-183 and KEYNOTE-185 after an independent data monitoring committee noted an imbalance in deaths among patients with multiple myeloma assigned to combination therapy involving pembrolizumab and immunomodulatory treatment.
“Patient safety is Merck’s primary concern, and we are grateful to the study investigators and patients involved in these studies for their commitment to this important research,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a press release. “Merck’s development program for Keytruda, spanning more than 30 different tumor types, has one priority: helping patients suffering from cancer.”
KEYNOTE-183 evaluated pembrolizumab in combination with 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. KEYNOTE-185 compared 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.
KEYNOTE-023 was not included in the previous announcement. That phase I study is evaluating pembrolizumab in combination with lenalidomide and low-dose dexamethasone for patients with refractory or relapsed/refractory multiple myeloma, and in combination with carfilzomib (Kyprolis) and low-dose dexamethasone for patients with relapsed/refractory multiple myeloma. Research to determine maximum-tolerated dose/maximum administered dose, recommended phase II dose, and safety will continue in the carfilzomib group.
Phase II results from KEYNOTE-183 were presented 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 or mismatch repair deficient 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.
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.