Pembrolizumab with R-CHOP in Previously Untreated Diffuse Large B-Cell Lymphoma: Potential for Biomarker Driven Therapy

Abstract

Background: Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. We hypothesized that the first-line immunologically-replete setting may be an opportune time for introducing PD-1 inhibition. We thus evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Methods: Eligible patients were age 18 or older, had adequate organ function, and had DLBCL or grade 3B FL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP for 6 cycles, every 21 days, measuring toxicity as the primary endpoint. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Findings: Among 30 treated patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. Only 1 of 4 partial responders has progressed. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 tumor expression was associated with non-GCB subtype, and improved PFS and survival.InterpretationPembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, and supports further trials evaluating PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy. Trial Registration: NCT02541565. Funding Statement: In addition to primary funding from Merck Sharpe and Dohme Corp, the authors recognize additional support from grant K24CA184039, NIH/NCI Cancer Center Support Grant P30 CA015704, and donations from Frank and Betty Vandermeer and Sonya and Tom Campion. Declaration of Interests: S.D.S. reports grants and nonfinancial research support from Acerta Pharma BV, Astrazeneca, De Novo Biopharma, Genentech, Jannsen Pharmaceuticals, Incyte Corporation, Merck Sharp and Dohme Corp., Pharmacyclics, Portola Pharmaceuticals, and Seattle Genetics; S.D.S.’ spouse receives research support from Ayala, Bristol Myers Squibb, Merck Sharp Dohme Corp, and Ignyta. S.D.S reports personal fees from Merck Sharp and Dohme Corp and Astrazeneca. A.K.G. reports grants and nonfinancial research support from Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector; Personal fees and nonfinancial support from Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Compliment, Asana Bio, and Incyte. H.R., K.B., J.V., Q.W. report no relevant financial disclosures. M.S. reports grands and nonfinancial research support from Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Acerta Pharma, Merck Sharp and Dohme Corp; personal fees and nonfinancial support from Abbvie, Genentech, Astra Zeneca, Sound Biologics, Verastem, ADC therapeutics and Atara Biotherapeutics. B.G.T. reports grants and nonfinancial research support from Mustang Bio and RocheGenentech, and patents/royalties from Mustang Bio. R.C.L. reports grants and nonfinancial research support from Incyte Corporation, TG Therapeutics, Takeda, Juno Therapeutics, Rhizen Pharmaceuticals. A.J.C. reports grants and nonfinancial research support from Janssen, AbbVie, Juno Therapeutics, and Celgene; personal fees and nonfinancial support from Celgene. C.U. reports grants and nonfinancial research support from Pharmacyclics, Abbvie, and Celgene; personal fees and nonfinancial support from Amgen, bayer, Pfizer, Gilead, Astrazeneca, Genentech, Pharmacyclics, Abbvie, and Atara. A.R.S. reports grants and nonfinancial research support from Seattle Genetics, Spectrum Pharmaceuticals, and personal fees and nonfinancial support from Kyowa Hakko Kirin. R.D.C reports grants and nonfinancial research support from Merck Sharp and Dohme Corp., Incyte, Seattle Genetics, Vanda Pharmaceuticals, Amgen, Pfizer, Kite/Gilead; and personal fees and nonfinancial support from Amgen, Pfizer, Jazz, and Adaptive Biotechnologies. Ethics Approval Statement: This study was approved by the Fred Hutchinson Cancer Center- University of Washington Consortium IRB and all patients provided written informed consent to participate in the trial.