Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma

Abstract

Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.

Conflict of interest statement

Conflict-of-interest disclosure: P.A. has consulted for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, and Celgene; received institutional research funding from Merck, Bristol Myers Squibb, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, and IGM; and received honoraria from Merck and Bristol Myers Squibb. A.J. received an educational grant from Janssen; travel grants from Janssen, Celgene, AbbVie, and Roche; speaker fees from Janssen, Roche, AbbVie, Novartis, Amgen, Sanofi-Genzyme, and Celgene; and has consulted for Janssen, Roche, Gilead, AbbVie, Novartis, Amgen, and Sanofi-Genzyme. G.G. has consulted or advised for Autolus and Bioveloc ITA; served on a speakers’ bureau for Amgen; received research funding from Gilead; and received travel and accommodation from Roche, AbbVie, and Becton Dickinson. J.R. has received honoraria or advised for Takeda, Seattle Genetics, ADC Therapeutics, and Bristol Myers Squibb; received research funding from Takeda and ADC Therapeutics; and has stock ownership (spouse) in AstraZeneca and GlaxoSmithKline. J.T. holds stock or other ownership in Genmab, Corvus, Marker Therapeutics, and Bluebird Bio; has served in a consulting or advisory role with Kite, a Gilead Company, Celgene, Immune Design, and Celldex Therapeutics; has received research funding from Bristol Myers Squibb, Kite, a Gilead Company, Spectrum Pharmaceuticals, and Merck; and has received travel, accommodations, or expenses from Bristol Myers Squibb and Kite, a Gilead Company. A.P. has served on speakers’ bureaus for Roche, Celgene, Bristol Myers Squibb, Merck Sharp & Dohme, Servier, and Novartis. P.J. has received honoraria from Takeda, Bristol Myers Squibb, Novartis, Celgene, Kite Pharma, Genmab, and Incyte; has had a consulting or advisory role with Janssen Pharmaceuticals, Epizyme, and Boehringer Ingelheim; has received institutional research funding from Epizyme and Janssen Pharmaceuticals; has patents, royalties, or other intellectual property (combined use of Fc γ RIIb (CD32b) and CD20, specific antibodies, WO Patent, PCT/GB2011/051572; EU11760819.0); and has received travel, accommodation, and expenses from Zenyaku Kogyo. D.C. has received research funding from Amgen, Sanofi, Merrimack, AstraZeneca, Celgene, MedImmune, Bayer, 4SC, Clovis, Eli Lilly, Janssen, and Merck. J.P.L. has had a consulting or advisory role with Sutro, Gilead, Kite, AstraZeneca, Celgene, Roche/Genentech, ADC Therapeutics, Sandoz, Karyopharm, Miltenyi, Regeneron, and MEI Pharma. S.J.R. has received research funding from Bristol Myers Squibb, Affimed, KITE/Gilead, and Merck. P.M.-R. is an employee of and has equity ownership in Bristol Myers Squibb. A.S. is an employee of Bristol Myers Squibb. S.M.A. has received research funding from Bristol Myers Squibb, Merck, Seattle Genetics, Takeda, AI Therapeutics, Regeneron, Affimed, Trillium, and Pfizer. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Best change in target lesions in response-evaluable patients per IRC. Response-evaluable patients (n = 83) were those with a target lesion(s) assessed at baseline and with at least 1 on-study time point with all baseline target lesion(s) assessed. Negative values indicate maximum tumor reduction; positive values indicate minimum tumor increase; best change is based on evaluable target lesion measurements up to progression or start of subsequent therapy. Dashed horizontal line indicates the 50% reduction consistent with a response per revised 2007 International Working Group criteria.

Figure 2.

Kaplan-Meier estimates. (A) DOR per IRC, (B) PFS per IRC, and (C) OS. Open triangles represent censored observations. NE, not estimable.

Figure 3.

Multispectral immunofluorescence. (A) CD3, (B) CD3 and PD-1, and (C) CD68 and PD-L1 in patients with and without response to nivolumab. ns, not significant.

Figure 4.

Outcomes by gene signatures. (A) PFS per IRC by TLR5, C3AR1, and FCGR1A expression. (B) Best objective response per investigator by TLR5, C3AR1, and GCGR1A score. (C) Best objective response by IR-2 complete signature score. PD, progressive disease.