Silver Spring, MD (Press Release) – Based on data from two recently halted clin­i­cal trials, the U.S. Food and Drug Admin­istra­tion today is issuing this state­ment to inform the public, health care professionals, and on­col­ogy clin­i­cal investigators about the risks asso­ci­ated with the use of KEYTRUDA® (pem­bro­lizu­mab) in com­bi­na­tion with dexa­meth­a­sone and an immuno­modu­la­tory agent (lena­lido­mide or poma­lido­mide) for the treat­ment of patients with multiple myeloma. KEYTRUDA® (pem­bro­lizu­mab) is not approved for treat­ment of multiple myeloma.

The FDA state­ment is based on review of data from two clin­i­cal trials (KEYNOTE-183 and KEYNOTE-185) eval­u­ating the use of KEYTRUDA® (pem­bro­lizu­mab) com­bined with other treat­ments in patients with multiple myeloma. On July 3, 2017, the FDA required that all patients in these trials be dis­con­tinued from further in­ves­ti­ga­tion with this drug, because interim results from both trials dem­onstrated an in­­creased risk of death for patients receiving KEYTRUDA® (pem­bro­lizu­mab) when it was com­bined with an immuno­modu­latory agent as compared to the control group (see statistical analysis section below). Merck & Co., Inc. was made aware of the issue through an external data monitoring committee recom­men­da­tion and suspended the trials to enrollment on June 12, 2017.

This state­ment does not apply to patients taking KEYTRUDA® (pem­bro­lizu­mab) for an approved in­di­ca­tion. The safety and efficacy of using KEYTRUDA® (pem­bro­lizu­mab) for approved, on-label uses have been proven. Patients on KEYTRUDA® (pem­bro­lizu­mab) for an approved use should con­tinue to take their medication as directed by their health care professional.

KEYTRUDA® (pem­bro­lizu­mab) is cur­rently approved by the FDA for treat­ment of:

• Melanoma
• Lung Cancer
• Head and Neck Cancer
• Classical Hodgkin Lymphoma
• Urothelial Carcinoma
• Microsatellite Instability-High (MSI-H) Cancer

Other multiple myeloma clin­i­cal trials of KEYTRUDA® (pem­bro­lizu­mab), other PD-1/PD-L1 cancer drugs and other com­bi­na­tions are cur­rently undergoing clin­i­cal evaluation. The FDA will be work­ing directly with sponsors of KEYTRUDA® and other PD-1/PD-L1 cancer drugs, as well as clin­i­cal investigators conducting clin­i­cal trials in patients with multiple myeloma, to determine the extent of the safety issue. The agency will communicate any new in­­for­ma­tion to the public as soon as it is able.

Health care professionals and consumers are encouraged to report any adverse events or side effects related to the use of these prod­ucts and other similar prod­ucts to FDA’s MedWatch Adverse Event Reporting pro­gram ^[1] by:

• Completing and submitting the report online at MedWatch online voluntary reporting form ^[2]; or
• Downloading and completing the form, then submitting it via fax at 1-800-FDA-0178.

Statistical Analysis and Findings

Following is a summary of findings from Merck’s clin­i­cal trials. A full safety and efficacy analysis based on a June 2, 2017 data cutoff date was conducted for studies KEYNOTE-183 and KEYNOTE-185. A summary of these results is presented below.

KEYNOTE-183

KEYNOTE-183 is a phase 3, ran­domized, controlled trial of poma­lido­mide and low-dose dexa­meth­a­sone with or without pem­bro­lizu­mab in patients with re­lapsed and refractory multiple myeloma who had received at least two prior lines of ther­apy.

Using a data cutoff date of June 2, 2017, a com­plete evaluation of safety and efficacy was per­formed. There were 249 ran­domized patients in­cluded in the analysis. The median follow-up was 8.1 months. For over­all survival, there were 29 deaths on the pem­bro­lizu­mab-containing inves­ti­ga­tional arm and 21 deaths on the control arm. The hazard ratio of the pem­bro­lizu­mab-containing inves­ti­ga­tional arm compared to the control arm was 1.61 (95% CI: 0.91, 2.85), in­creas­ing the relative risk of death by more than 50% compared to the control arm.

^[3]

The objective response rate was 34% in the inves­ti­ga­tional arm compared to 40% in the control arm. In an exploratory time-to-progression analysis, a hazard ratio of 1.14 (95% CI: 0.75, 1.74) was observed.

^[4]

There was an 18% in­­crease of severe, grade 3-5 toxicity (83% vs. 65%, inves­ti­ga­tional vs. control arm). The incidence of serious adverse events was 63% compared to 46% in the control arm. The fol­low­ing non-disease pro­gres­sion causes of death were identified in the pem­bro­lizu­mab arm: myocarditis, Stevens-Johnson syn­drome, myo­cardial infarction, pericardial hemorrhage, cardiac failure, res­pira­tory tract in­fec­tion, neu­tro­penic sepsis, sepsis, multiple organ dysfunction, res­pira­tory failure, and unknown.

KEYNOTE-185

KEYNOTE-185 is a phase 3, ran­domized, controlled trial of lena­lido­mide and low-dose dexa­meth­a­sone with or without pem­bro­lizu­mab in patients with newly diag­nosed patients with multiple myeloma who are in­el­i­gible for au­tol­o­gous stem cell trans­plant.

The data cutoff date of June 2, 2017, was used for these analyses. There were 301 ran­domized patients in­cluded in the analysis. The median follow-up was 6.6 months. For over­all survival, there were 19 deaths on the pem­bro­lizu­mab-containing inves­ti­ga­tional arm, and 9 deaths on the control arm. The hazard ratio of the pem­bro­lizu­mab-containing inves­ti­ga­tional arm compared to the control arm was 2.06 (95% CI: 0.93, 4.55), more than doubling the relative risk of death compared to the control arm.

^[5]

Additional efficacy analyses based on a June 2, 2017 data cutoff date dem­onstrated an objective response rate of 64% in the inves­ti­ga­tional arm compared to 62% in the control arm. In an exploratory time-to-progression analysis, a hazard ratio of 0.55 (95% CI: 0.20, 1.50) was observed.

^[6]

In the safety analysis based on a June 2, 2017, data cutoff date, there was a 22% in­­crease of severe, grade 3-5 toxicity (72% vs. 50%, inves­ti­ga­tional vs. control arm). The incidence of serious adverse events was 54% compared to 39 % in the control arm. The fol­low­ing non-disease pro­gres­sion causes of death were identified in the pem­bro­lizu­mab arm: intestinal ischemia, cardio-respiratory arrest, suicide, pul­mo­nary embolism, cardiac arrest, pneu­monia, sudden death, myocarditis, large intestine perforation, and cardiac failure.

Source: United States Food and Drug Admin­istra­tion.