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Merck previously disclosed the clinical hold on the three trials at the beginning of July; FDA says its announcement is meant to inform patients and healthcare providers about the danger of the safety signal.



The US FDA announced it is expanding its investigation into the broader field of PD-1/PD-L1 cancer drugs more than a month after the news of a clinical hold on three of Merck & Co. Inc.'s multiple myeloma clinical trials for Keytruda (pembrolizumab).


Merck announced the hold July 5, pausing three combination trials of Keytruda with Celgene Corp.'s immunomodulatory thalidomide analogues Pomalyst (pomalidomide) or Revlimid(lenalidomide), as well as dexamethasone. The hold came as a result of an increased risk of death in the Keytruda arms of each study. (Also see "FDA Clinical Hold Hits Keytruda Multiple Myeloma Studies" - Pink Sheet, 6 Jul, 2017.)


FDA came out with its own statement on the hold Aug. 31, which clarified that it was also investigating other programmed-death checkpoint inhibitors and included detailed results for two of the studies.


In one of the studies, KEYNOTE-183, there were 29 deaths among patients who took Keytruda in combination with Pomalyst and low-dose dexamethasone, compared with 21 deaths in the control arm, according to the agency. The risk of death was 50% higher in the Keytruda arm. The rate of severe adverse events also was higher in the investigational arm than in the control arm, 63% to 46%.


The Phase III KEYNOTE-183 trial studied 249 subjects with relapsed and refractory multiple myeloma who had received at least two prior lines of therapy.


Keytruda was studied in combination with Revlimid and low-dose dexamethasone in patients with multiple myeloma who are ineligible for autologous stem cell transplant in the Phase III KEYNOTE-185 trial. According to FDA, there were 19 deaths on the investigational arm versus nine in the control arm. The incidence of serious adverse events was 54% in the Keytruda arm compared to 39% in the control arm.


There was no analysis for the Phase I KEYNOTE-023 trial, which was examining Keytruda in combination with Revlimid and dexamethasone in multiple myeloma patients who received prior treatment with an immunomodulatory agent.


Merck reported the concerns to the agency in June and suspended enrollment at that time. FDA placed a full hold on the studies July 3. The hold only applies to the multiple myeloma trials, not across the significant breadth of the Keytruda development program. The multiple myeloma indication is not considered a major market for pembrolizumab.


Center for Drug Evaluation and Research Director Janet Woodcock issued a statement Aug. 31 with the details on the hold, noting that the agency is working with Merck to determine the cause of the safety signal.


Not Stopping With Keytruda

FDA's concerns, however, do not end with Keytruda.

Woodcock added that FDA is also working with sponsors of other PD-1/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."


"The FDA will take appropriate action as warranted to ensure patients enrolled in these trials are protected and that doctors and clinical trial researchers understand the risks associated with this investigational use," Woodcock said.


The agency did not comment on whether it has received any other similar safety reports for PD-1/PD-L1 inhibitors.


The only other industry-sponsored Phase III trial for an immune checkpoint inhibitor in multiple myeloma appears to be Bristol-Myers Squibb Co.'s Opdivo (nivolumab) in combination with dexamethasone, pomalidomide and BMS's SLAMF7 inhibitor Empliciti (elotuzumab), which is already approved for MM, in the CheckMate 602 trial.


Why Now?

There are a few reasons why FDA may have come out with a statement of its own more than a month after the hold. It could have been waiting for the detailed analyses. Another reason, however, could be that physicians have continued administering Keytruda off-label for treatment of multiple myeloma.


"We are communicating now, given the serious nature of the safety issue, to remind doctors and patients that Keytruda is not approved for the treatment of multiple myeloma and should not be given to patients in combination with any immunomodulatory agents, including Revlimid (lenalidomide) and Pomalyst (pomalidomide), for the treatment of multiple myeloma," Woodcock said.


Woodcock also emphasized that patients taking Keytruda and other PD-1/L1 inhibitors for approved uses should continue to do so, as "the FDA still believes the benefits of taking these drugs for their approved uses and as indicated in the labels continue to outweigh their risks."


Keytruda is currently approved for the treatment of melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma and microsatellite instability-high cancer.

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