The US Food and Drug Administration (FDA) has issued a statement about the risks associated with the investigational use of the immunotherapy pembrolizumab (Keytruda, Merck) when that agent is added to standard treatment regimens for multiple myeloma.
Pembrolizumab has not been not approved for treatment of multiple myeloma, and its use in multiple myeloma was being explored in two clinical trials (KEYNOTE-183 and KEYNOTE-185).
The FDA halted both trials on July 3 because interim results revealed that there was a higher mortality risk for patients in the pembrolizumab treatment arm compared to those in the placebo arm when pembrolizumab was added onto standard regimens containing the immunomodulatory agents lenalidomide (Revlimid, Celgene) or pomalidomide (Pomalyst, Celgene), as well as dexamethasone (multiple brands).
The FDA says that the manufacturer was made aware of the issue through an external data monitoring committee recommendation, and trial enrollment was suspended on June 12.
“Today’s alert underscores the importance of why new therapies are thoroughly studied to ensure the benefits of taking them outweigh the risks to patients, and we will continue to aggressively monitor clinical trials to ensure patients are protected when safety concerns arise,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, in a statement.
“We are communicating now, given the serious nature of the safety issue, to remind doctors and patients that pembrolizumab is not approved for the treatment of multiple myeloma and should not be given to patients in combination with any immunomodulatory agents,” Dr Woodcock said.
KEYNOTE-183
KEYNOTE-183 was a phase 3, randomized, controlled trial that compared the use of pomalidomide and low-dose dexamethasone with or without the addition of pembrolizumab in 249 patients with relapsed and refractory multiple myeloma who had received at least two prior lines of therapy.
At a median follow-up of 8.1 months, 29 deaths occurred in the investigational arm that included pembrolizumab; 21 deaths occurred in the control arm.
The hazard ratio of the investigational vs control arm was 1.61 (95% confidence interval [CI], 0.91 – 2.85), which extrapolates to an increase in the relative risk for death of more than 50%.
The objective response rate was 34% for the pembrolizumab group vs 40% for the control group. An exploratory time-to-progression analysis revealed a hazard ratio of 1.14 (95% CI, 0.75 – 1.74),
An 18% increase of severe, grade 3-5 toxicity was observed for the investigational group (83% vs 65%), and the incidence of serious adverse events was also higher, at 63% vs 46%.
KEYNOTE-185
KEYNOTE-185, which was also a phase 3, randomized, controlled trial, investigated the addition of pembrolizumab in the first-line setting. The trial included 301 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant. The patients were randomly assigned to receive lenalidomide and low-dose dexamethasone with or without pembrolizumab.
At a median follow-up of 6.6 months, there were 19 deaths in the pembrolizumab arm and 9 deaths among the control group. The hazard ratio was 2.06 (95% CI, 0.93 – 4.55); thus, the relative risk for death among patients receiving pembrolizumab was more than twice that among patients in the control arm.
The objective response rate was 64% in the investigational arm and 62% in the control arm. An exploratory time-to-progression analysis showed a hazard ratio of 0.55 (95% CI, 0.20 – 1.50).
A 22% increase of severe, grade 3-5 toxicity was observed in the pembrolizumab group (72% vs 50%). The incidence of serious adverse events was also higher, at 54% vs 39%.
Continued Surveillance
Pembrolizumab is currently approved by the FDA for use in treating a number of malignancies, including melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high (MSI-H) cancers.
Other trials of pembrolizumab in the treatment of multiple myeloma are ongoing, as well as trials of other PD-1/PD-L1 inhibitors and in other combinations. The FDA notes that it will be working directly with sponsors of pembrolizumab 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 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,” said Dr Woodcock.
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