Myeloma Immunotherapy Trials Paused

After some patients died, Merck announced that it will postpone enrollment in the phase 3 KEYNOTE-183 and KEYNOTE-185 trials, investigating the use of Keytruda (pembrolizumab) in patients with multiple myeloma.

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

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

KEYNOTE-185 is comparing Keytruda, Revlimid (lenalidomide) 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 one to 21 and 40 mg of dexamethasone on days one, eight, 15, and 22, with or without 200 mg of Keytruda every three weeks, in 28-day cycles. Treatment will continue until progression or unacceptable toxicity.

Both trials were initiated in October 2015.

Ashraf Z. Badros, M.D., professor of medicine with the Greenebaum Cancer Center at the University of Maryland School of Medicine, presented phase 2 data at the 2016 ASH Annual Meeting showing that the Keytruda / Pomalyst /dexamethasone combination was active in patients with relapsed/refractory multiple myeloma.

In the single-center trial conducted at the University of Maryland (48 patients), the overall response rate (ORR) was 65 percent with the Keytruda -containing triplet regimen. Overall, 29 percent of patients experienced a very good partial remission (VGPR) or better. The stringent complete remission (sCR) rate was 7 percent and the CR rate was 2 percent. 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 and the median progression-free survival (PFS) was 17.4 months. At the time of the analysis, the median overall survival was not yet reached.

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

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

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

Overall, five patients discontinued therapy due to adverse events (11 percent), including pneumonitis (three patients), shortness of breath (one patient) and fatigue (one patient). Half of patients required a Keytruda dose reduction.

The FDA first approved Keytruda 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.