FDA Provides an Update on Halted Myeloma Trials

Janet Woodcock, MD

Janet Woodcock, M.D.

The Food and Drug Administration (FDA) recently released a statement providing data from the two phase 3 trials testing Keytruda (pembrolizumab) in patients with multiple myeloma. The trials were placed on clinical holds by the FDA in July, after concerns arose regarding the drug’s safety in this group of patients.

The agency wanted to alert oncology researchers about the risks associated with treating patients who have myeloma with the regimens explored in the phase 3 KEYNOTE-183 and KEYNOTE-185 trials: Keytruda combined with an immunomodulatory agent (lenalidomide [Revlimid] or Pomalyst [pomalidomide]) and dexamethasone.

On July 3, 2017, the FDA required that all patients enrolled in KEYNOTE-183 and KEYNOTE-185 be discontinued from further examination with this drug, after interim results from the studies showed an increased risk of death for the Keytruda arm compared with the control arm. Merck, the manufacturer of Keytruda, had suspended new enrollment to these trials on June 12, 2017, following the recommendation of an external data monitoring committee.

“The FDA is actively examining the data from the Keytruda trials and working directly with Merck to better understand the true cause of the safety concerns. In addition, the agency is working with sponsors of other similar cancer drugs, known as PD-1/PD-L1 inhibitors, to examine other trials in which these drugs are being studied in combination with other drugs, known as immunomodulatory agents, and in which they’re being studied in combination with other classes of drugs in hematologic malignancies,” Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research, said in a statement.

KEYNOTE-183 evaluated Keytruda (200 mg every three weeks) in combination with Pomalyst and low-dose dexamethasone against Pomalyst and low-dose dexamethasone alone in patients with relapsed/refractory multiple myeloma who had received at least two lines of prior treatment.

At a data cutoff of June 2, 2017, the FDA’s safety and efficacy analysis included 249 patients: 125 randomized to the Keytruda arm and 124 patients randomized to Pomalyst and dexamethasone alone.

At median follow-up of 8.1 months, there were 29 deaths in the Keytruda arm versus 21 deaths in the control arm. The hazard ratio (HR) for overall survival (OS) for the Keytruda group compared with the control arm was 1.61, translating into a greater than 50 percent increase in the relative risk of death.

The objective response rate (ORR) was 34 percent versus 40 percent in the Keytruda and control arms, respectively. An exploratory analysis found that the median time-to-progression (TTP) was 8.1 months versus 8.7 months, respectively.

The rate of severe, grade 3/5 toxicity was 83 percent in the investigational arm versus 65 percent in the control group. The rates of serious adverse events (AEs) were 63 percent versus 46 percent, respectively.

Causes of death unrelated to disease progression identified in the Keytruda cohort included myocarditis, Stevens-Johnson syndrome, myocardial infarction, pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, multiple organ dysfunction and respiratory failure.

KEYNOTE-185 compared Keytruda (200 mg every three weeks), Revlimid and low-dose dexamethasone with Revlimid and low-dose dexamethasone alone in patients with newly diagnosed and treatment-naïve multiple myeloma who are ineligible for autologous stem cell transplant.

There were 301 patients included in the safety and efficacy analysis. At the June 2, 2017, cutoff date, there were 151 patients randomized to the Keytruda arm and 150 patients randomized to Revlimid /dexamethasone alone.

At a median follow-up of 6.6 months there were 19 deaths in the Keytruda group compared with nine in the control arm. The relative risk of death in the Keytruda arm was more than double that of the control group.

The ORR was 64 percent versus 62 percent in the Keytruda and control arms, respectively. An exploratory analysis found that the median TTP had not yet been reached in either arm.

The rate of severe, grade 3/5 toxicity was 72 percent in the investigational arm versus 50 percent in the control group. The rates of serious AEs were 54 percent versus 39 percent, respectively.

Causes of death unrelated to disease progression identified in the Keytruda cohort included intestinal ischemia, cardio-respiratory arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia, sudden death, myocarditis, large intestine perforation and cardiac failure.

The FDA noted that its statement did not apply to any of Keytruda’s approved indications, which include melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma and microsatellite instability-high cancer.