FDA-NCI Team Warns Against Single-Arm Pembrolizumab Trials in Multiple Myeloma

July 3, 2018

An analysis by FDA and NCI investigators recommended further study of the utility of immunotherapy in patients unable to mount adequate immune responses.

An analysis by a team from the US Food and Drug Administration (FDA) and the National Cancer Institute, looking at the pembrolizumab trials in multiple myeloma, may serve as a wake-up call to clinicians about the limitations of single-arm trials, especially with regard to detection of safety signals.

Aviva C. Krauss, MD, who is a pediatric hematology-oncology specialist and a medical officer with the FDA, looked at immune-related adverse events (irAEs) and responses related to pembrolizumab in two separate trials of patients with relapsed/refractory (RR) multiple myeloma. She and her colleagues concluded that the utility of immunotherapy in patients unable to mount adequate immune responses merits further study. The study was reported at the 2018 American Society of Clinical Oncology Annual Meeting. In addition, Krauss and her coauthors said, further study is warranted into why worse overall survival (OS) was observed in both trials.

Krauss noted that the development of irAEs in patients treated with checkpoint inhibitors may be associated with response in some disease settings. She and colleagues evaluated OS, safety, and objective response rates (ORRs) among patients who developed irAEs and those who did not in two trials of pembrolizumab (KEYNOTE 183 and KEYNOTE 185).

These studies investigated pomalidomide and dexamethasone with or without pembrolizumab in patients with R/R multiple myeloma (KEYNOTE 183), and lenalidomide and dexamethasone with or without pembrolizumab in patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant (KEYNOTE 185). The FDA placed both trials on clinical hold in July 2017, due to worse OS in the pembrolizumab arms.

“We performed an exploratory analysis of overall response rate by arm in patients who experienced an immune-related adverse event compared to those who did not on each trial. In the relapsed/refractory population, overall response rate was not significantly different in patients on the pembrolizumab arm who experienced an immune-related adverse event (37%) than in those who did not (31%),” Krauss told Cancer Network.

In the newly diagnosed population, patients on the pembrolizumab arm who experienced an irAE had a higher ORR (73%) compared with those who did not (45%). The researchers also found that, although patients in the pembrolizumab-containing arm had a higher rate of irAEs than those who received standard-of-care treatment in both trials, the difference was much more pronounced in the newly diagnosed patients.

“In this population, the rate of irAEs was almost 25% greater than that seen in patients on the control arm, and the rate of grade 3 or greater irAEs was four times that seen on the control arm (36% vs 8%),” Krauss said.

The question of whether experiencing an irAE is associated with increased response rates is one that is debated in the literature, with data on both sides, noted Krauss. “The surprising aspect of the results was the disparity between the findings on each trial, rather than the findings on either trial in particular,” she said.

It is possible that the immune response in the R/R multiple myeloma patients was dampened due to the prior therapies received. However, the lack of prior treatment in the newly diagnosed population may have allowed not only for a greater immune response but also greater toxicity, Krauss explained.