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Nivolumab response rates low among some patients with diffuse large B-cell lymphoma
Nivolumab monotherapy appeared associated with low overall response rates among patients with diffuse large B cell lymphoma who failed or were ineligible for autologous hematopoietic stem cell transplant, according to results of a phase 2 study published in the Journal of Clinical Oncology.
The anti-PD-1 monoclonal antibody did, however, exhibit a favorable safety profile.
“In an initial phase 1 clinical trial, a small cohort of [patients with] DLBCL was treated with nivolumab, and a preliminary response rate of approximately 35% was seen,” Stephen M. Ansell, MD, PhD, professor of medicine at the Mayo Clinic in Rochester, Minn., and a HemOnc Today Editorial Board Member, told HemOnc Today. “This generated significant optimism to test immune checkpoint blockade in a larger phase 2 trial to determine whether optimization of the immune response would result in substantial clinical benefit.”
In the single-arm, open label study, Ansell and colleagues evaluated the safety and efficacy of nivolumab (Opdivo, Bristol-Myers Squibb) among 121 patients with relapsed or refractory DLBCL who had failed treatment with autologous HSCT (n = 87; median age, 62 years; range, 24-75; 64% men) or were ineligible for transplantation (n = 34; median age, 68 years; range, 28-86; 62% men).
Overall, patients who failed autologous HSCT were younger and had better baseline performance status and longer time since diagnosis than patients ineligible for transplant. In each group, patients had received a median three prior systemic treatments.
Patients in both groups received nivolumab 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity or study withdrawal.
The researchers evaluated tumor response and, in patients with accessible archival tumor biopsies, genetic alterations of chromosome 9p24.1, where genes that encode PD-L1 and PD-L2 are located.
Objective response rate as assessed by an independent radiology review committee served as the primary endpoint. Secondary objectives included committee-assessed duration of response and PFS, as well as OS, safety, tolerability and biomarker assessment.
Median follow-up was 9 months in the group that failed autologous HSCT and 6 months in the autologous HSCT-ineligible group.
Researchers reported objective response rates of 10% in the transplant-failure group, with a median duration of response of 11 months, and 3% in the transplant-ineligible group, with a median duration of response of 8 months. The transplant-failure cohort achieved longer median PFS (1.9 months vs. 1.4 months) and median OS (12.2 months vs. 5.8 months) than the transplant-ineligible cohort.
transplant-failure group had stable disease or better response. Three of the nine responders in that group achieved complete remission, with durable responses of 11 or more months, 14 or more months, and 17 months.
Only one patient in the transplant-ineligible group achieved partial response, with a duration of response of 8.3 months.
“Biomarker studies showed that only a small subset of patients had copy number gain or amplification of chromosome 9p24.1 resulting in increased expression of PD-L1, and this may account for the low response rate,” Ansell told HemOnc Today.
Results showed mostly low-level copy gain in 16% of samples evaluable for 9p24.1 analysis and amplification in 3% of evaluable samples.
The majority of treated patients (62%) experienced grade 3 or 4 adverse events, 24% of which were treatment-related. These events included neutropenia (4%), thrombocytopenia (3%) and increased lipase (3%). Most treatment-related adverse events were grade 1 or 2.
None of the 78 deaths in the study group was attributable to nivolumab toxicity.
“Although a negative study, the results of this clinical trial are important as they show that simply blocking an inhibitory signal, such as the signaling through PD-1, does not result in activation of the suppressed immune response in DLBCL,” Ansell told HemOnc Today. “Additional research will be needed to determine whether intratumoral T cells in DLBCL are able to be activated or whether they are actually terminally exhausted. As one looks to future clinical trials in DLBCL, it may be important to provide additional immune-activating signals in combination with inhibition of immune suppression to generate appropriate immune function.”
Disclosure s : Ansell reports honoraria from Research to Practice and WebMD and research funding to his institution from Affimed Therapeutics, Bristol-Myers Squibb, Lam Therapeutics, Pfizer, Regeneron, Seattle Genetics and Trillium. Please see the study for all other authors’ relevant financial disclosures.