PD-1/PD-L1 inhibitors stall in development for hematologic malignancies
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Despite early advances, immunotherapy with PD-1 and PD-L1 inhibitors faces an unknown future for the treatment of hematologic malignancies.
In July, the FDA placed a clinical hold on three studies — KEYNOTE-183, KEYNOTE-185 and KEYNOTE-023 — designed to evaluate pembrolizumab (Keytruda, Merck) as part of combination treatment for multiple myeloma.
The agency’s decision followed a data monitoring committee review that showed an increased risk for death among patients treated with pembrolizumab, an anti-PD-1 therapy, in two of those trials. Following that review, Merck paused new patient enrollment on June 12.
Based on available data from these trials, the FDA determined that the risks associated with pembrolizumab in combination with pomalidomide (Pomalyst, Celgene) or lenalidomide (Revlimid, Celgene) outweigh any potential benefit for patients with multiple myeloma.
The agency also decided available data on risks associated with pembrolizumab extended to any PD-1/PD-L1 regimen for multiple myeloma. Thus, on Sept. 7 the FDA placed partial clinical hold on three trials of nivolumab (Opdivo, Bristol-Myers Squibb)-based combinations for the treatment of patients with relapsed or refractory multiple myeloma.
On the same day, the agency also placed a partial clinical hold on five trials and a full clinical hold on one trial, each designed to evaluate durvalumab (Imfinzi, AstraZeneca) in combination with immunomodulatory and chemotherapy agents for the treatment of hematologic malignancies.
“The FDA has informed multiple investigators who have ongoing clinical trials using PD-1/PD-L1 oncology drugs in combination with immunomodulatory agents or in hematologic malignancies combined with other classes of drugs whether their trials must be temporarily stopped to allow for modifications or must be permanently stopped,” the FDA wrote in a statement issued to HemOnc Today.
Pembrolizumab and nivolumab are now included on the FDA’s adverse event reporting system, or FAERS, watch list to identify any signals of serious risk for complications with allogeneic hematopoietic stem cell transplantation. The FDA is evaluating the need for regulatory action, according to the FAERS web site.
Pembrolizumab
The FDA placed a full clinical hold on:
- the phase 3 KEYNOTE-183 trial, designed to evaluate treatment with pomalidomide and low-dose dexamethasone with or without pembrolizumab for patients with refractory or relapsed and refractory multiple myeloma; and
- the phase 3 KEYNOTE-185 study, designed to investigate treatment with lenalidomide and low-dose dexamethasone with or without pembrolizumab for patients with newly diagnosed and treatment-naive multiple myeloma.
The FDA placed a partial clinical hold on one cohort of KEYNOTE-023, a phase 1 multicohort trial designed to evaluate pembrolizumab in combination with backbone treatments for patients with myeloma. The hold relates to cohort 1, designed to evaluate pembrolizumab in combination with lenalidomide and dexamethasone among patients with myeloma who underwent prior treatment with an immunomodulatory agent, such as lenalidomide, pomalidomide or thalidomide (Thalomid, Celgene).
In September, the FDA presented Merck with further guidance related to multiple myeloma studies or cohorts of studies within their pembrolizumab clinical development program.
That guidance led to the partial clinical hold on:
- cohort 2 of the KEYNOTE-023 trial;
- the KEYNOTE-668 trial;
- the multiple myeloma cohort of KEYNOTE-155; and
- cohorts 2 and 5 of KEYNOTE-013.
The FDA requested that Merck modify the existing protocols and revise the informed consent to address the partial holds.
“Merck will continue to work with the FDA to evaluate the data from these multiple myeloma studies,” Roy Baynes, MD, PhD, senior vice president of global clinical development and chief medical officer at Merck, said in a statement issued to HemOnc Today. “Patient safety remains Merck’s primary concern, and we will continue to closely monitor the safety of Keytruda across all trials.”
Nivolumab
The FDA’s terms for the clinical holds on nivolumab trials allow already enrolled patients who are experiencing clinical benefit to continue treatment; however, no new patients will enroll in the studies.
The partial clinical hold included:
- the open-label, randomized phase 3 CheckMate 602 trial, designed to evaluate nivolumab in combination with elotuzumab (Empliciti, Bristol-Myers Squibb), pomalidomide and dexamethasone in relapsed and refractory multiple myeloma;
- the phase 1 CheckMate 039 study, designed to establish the tolerability of nivolumab in combination with daratumumab (Darzalex, Janssen) — with or without pomalidomide and dexamethasone — in relapsed and refractory multiple myeloma; and
- the phase 2 CA204142 multiple cohort study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, to treat patients with relapsed or refractory multiple myeloma prior to treatment with lenalidomide.
“Patient safety is of the utmost importance to us and, at this time, we have not identified indications of safety signals or an increased risk [for] death in these studies,” Candace Greene, associate director of worldwide immuno-oncology communications at Bristol-Myers Squibb, told HemOnc Today. “We continue to regularly monitor for safety as part of our rigorous monitoring protocols.”
Greene noted that ongoing studies of nivolumab across other tumor types will continue as planned.
“Regarding CheckMate 602, -039 and CA204142, we’re working diligently with the FDA to address concerns and will provide an update in the future, as appropriate,” she added.
Durvalumab
Celgene has not determined an imbalance in the risk-benefit profile associated with its FUSION program — designed to evaluate durvalumab — but the clinical holds allow for additional information to be collected to improve understanding of the drug’s benefits and risks.
Trials placed on partial clinical hold included:
- the multicenter, open-label phase 1b MEDI4736-MM-001 trial, designed to determine the recommended dose regimen for durvalumab monotherapy and in combination with pomalidomide — with or without low-dose dexamethasone — among patients with relapsed and refractory multiple myeloma;
- the multicenter, open-label phase 2 MEDI4736-MM-003 trial, designed to evaluate the efficacy and safety of durvalumab in combination with daratumumab among patients with relapsed and refractory multiple myeloma;
- the multicenter, single-arm phase 2 MEDI4736-MM-005 trial, designed to investigate the efficacy and safety of durvalumab in combination with daratumumab among patients with relapsed or refractory multiple myeloma who have progressed on a treatment regimen with daratumumab;
- the multicenter, open-label phase 1/phase 2 MEDI4736-NHL-001 trial, designed to assess the safety and tolerability of durvalumab monotherapy and in combination regimens for the treatment of patients with lymphoma or chronic lymphocytic leukemia; and
- the multicenter, open-label MEDI4736-DLBCL-001 trial, designed to evaluate the safety and clinical activity of durvalumab in combination with R-CHOP or with lenalidomide plus R-CHOP among patients with previously untreated, high-risk, diffuse large B-cell lymphoma.
Patients enrolled on a trial placed on partial clinical hold who have demonstrated clinical benefit from treatment may continue receiving durvalumab regimens. No new patients will be enrolled into durvalumab trials.
The FDA placed the multicenter, open-label phase 1b MEDI4736-MM-002 trial — designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, for patients with newly diagnosed multiple myeloma — on full clinical hold. All patients enrolled on the trial discontinued treatment.
“Our partner Celgene has provided available safety information to the FDA and is currently undertaking detailed analyses of the data,” AstraZeneca said in a statement issued to HemOnc Today. “We expect discussions will happen on the different options for removing the clinical holds. We are working closely with Celgene to offer any support needed to address the concerns raised by the FDA.” – by Kristie L. Kahl
For more information:
www.fda.gov/Drugs/DrugSafety/ucm574305.htm