Janet Woodcock, MD
The FDA released a statement today providing specific data from 2 phase III trials of pembrolizumab (Keytruda) in multiple myeloma that the agency placed clinical holds on in July.
The agency wanted to alert oncology researchers about the risks associated with treating myeloma patients with the regimens explored in the phase III KEYNOTE-183 and KEYNOTE-185 trials: pembrolizumab combined with an immunomodulatory agent (lenalidomide or 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 pembrolizumab arm compared with the control arm. Merck, the manufacturer of pembrolizumab, 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, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement.
KEYNOTE-183 evaluated pembrolizumab (200 mg every 3 weeks) in combination with pomalidomide (Pomalyst) and low-dose dexamethasone against pomalidomide and low-dose dexamethasone alone in patients with relapsed/refractory multiple myeloma who had received at least 2 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 pembrolizumab arm and 124 patients randomized to pomalidomide and dexamethasone alone.
At median follow-up of 8.1 months, there were 29 deaths in the pembrolizumab arm versus 21 deaths in the control arm. The hazard ratio (HR) for overall survival (OS) for the pembrolizumab group compared with the control arm was 1.61 (95% CI, 0.91-2.85), translating into a greater than 50% increase in the relative risk of death.
The objective response rate (ORR) was 34% versus 40% in the pembrolizumab and control arms, respectively. An exploratory analysis found that the median time-to-progression (TTP) was 8.1 months versus 8.7 months, respectively (HR, 1.14; 95% CI, 0.75-1.74).
The rate of severe, grade 3/5 toxicity was 83% in the investigational arm versus 65% in the control group. The rates of serious adverse events (AEs) were 63% versus 46%, respectively.
Causes of death unrelated to disease progression identified in the pembrolizumab 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 pembrolizumab (200 mg every 3 weeks), 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.
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 pembrolizumab arm and 150 patients randomized to lenalidomide/dexamethasone alone.
At a median follow-up of 6.6 months there were 19 deaths in the pembrolizumab group compared with 9 in the control arm (HR for OS, 2.06; 95% CI, 0.93-4.55). The relative risk of death in the pembrolizumab arm was more than double that of the control group.
The ORR was 64% versus 62% in the pembrolizumab and control arms, respectively. An exploratory analysis found that the median TTP had not yet been reached in either arm (HR, 0.55; 95% CI, 0.20-1.50).
The rate of severe, grade 3/5 toxicity was 72% in the investigational arm versus 50% in the control group. The rates of serious AEs were 54% versus 39%, respectively.
Causes of death unrelated to disease progression identified in the pembrolizumab 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 pembrolizumab’s approved indications, which include melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability-high cancer.
FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about Two Clinical Trials on Hold Evaluating KEYTRUDA® (pembrolizumab) in Patients with Multiple Myeloma. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Accessed August 31, 2017.