A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039)

Abstract

Introduction: Nivolumab (nivo) is a fully human IgG4 monoclonal antibody (mAb) targeting programmed death receptor-1 (PD-1). Nivo has demonstrated clinical activity and an acceptable safety profile in a phase 1b study (NCT01592370; CheckMate 039) in patients (pts) with relapsed/refractory hematologic malignancies. In pts diagnosed with Hodgkin lymphoma (HL), after a median 86 weeks of follow-up, 7/20 responders maintained a response for >1.5 years (Ansell S et al. Blood 2015;126:583), and after a median follow-up of 67 weeks, clinical activity (investigator-assessed objective response rate) was demonstrated in follicular lymphoma (FL; 40%), diffuse large B-cell lymphoma (DLBCL; 36%), mycosis fungoides (15%), and peripheral T-cell lymphoma (PTCL; 40%) (Lesokhin AM et al. J Clin Oncol 2016;34:2698). CheckMate 039 also included a cohort of pts who had received nivo in combination with ipilimumab (ipi), a fully human mAb targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4). Combination of CTLA-4 and PD-1 blockade has shown superior efficacy compared with nivo or ipi alone in preclinical studies and solid tumor malignancies (Wolchok JD et al. N Engl J Med 2013;369:122; Larkin JM et al. N Engl J Med 2015;373:22; Antonia SJ et al. Lancet Oncol 2016;17:883). The aim of this cohort study was to evaluate the safety and efficacy of combined immune checkpoint blockade (nivo+ipi) in pts with the following hematologic malignancies: HL, B-cell non-Hodgkin lymphoma (B-NHL; FL and DLBCL), T-cell NHL (T-NHL; cutaneous T-cell lymphoma [CTCL] and PTCL]), and multiple myeloma (MM). Methods: Nivo+ipi were given at 3 mg/kg IV and 1 mg/kg IV, respectively, every 3 weeks for 4 doses, followed by nivo monotherapy (3 mg/kg) every 2 weeks for up to 2 years. Pts with any of the above histologies, relapsed or refractory disease after ≥2 prior lines of therapy, and adequate organ function were included in the study. Prior systemic therapy may have included chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Prior anti-PD-1 therapy and allogeneic (allo)-HSCT were not permitted. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival (PFS). Results: In total, 65 pts were treated with nivo+ipi (31 HL, 15 B-NHL, 11 T-NHL, 7 MM, and 1 with primary mediastinal B-cell lymphoma [PMBL] who was included in the overall safety cohort only). Median (range) number of prior systemic therapies was 4 (2, 10; HL), 3, (1, 16; B-NHL), 4 (1, 11; T-NHL), and 5 (2, 20; MM). Among patients with HL, only 13% (4/31) had prior auto-HSCT. 2 pts with HL and 1 with T-NHL proceeded to allo-HSCT after stopping study therapy. Across all cohorts, median follow-up was 11.4 months. 5 pts (8%) discontinued due to a drug-related adverse event (AE). The most common drug-related AEs of any grade were fatigue (17 pts [26%]), pyrexia (15 [23%]), and diarrhea (12 [18%]). 19 pts (29%) had a drug-related AE of grade ≥3. 31 pts (48%) had a serious AE. 24 pts (37%) died: HL 2 pts, B-NHL 11, T-NHL 6, MM 4, PMBL 1. Among those pts, 22 (34%) were from disease progression (HL 2 pts, B-NHL 10, T-NHL 5, MM 4, PMBL 1); no deaths were due to an AE. Clinical outcome data are presented (Table). Conclusions: These are the first reported data of combination checkpoint blockade therapy in hematologic malignancies. Overall, the combination of nivo+ipi in these heavily pretreated patients demonstrated a safety and efficacy profile similar to that previously reported for nivo monotherapy in HL, NHL, and MM. Additional follow-up may further clarify the role of ipi in this cohort of patients. In this predominantly transplant-naïve group of patients with HL, the efficacy of nivo+ipi was similar to that seen in patients with relapsed/refractory HL treated with nivo alone. Funding: Bristol-Myers Squibb (BMS). Medical writing: S Addison, Caudex, funded by BMS Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Gutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging; Incyte Corporation: Consultancy; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage. Shipp:Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Moskowitz:Seattle Genetics: Research Funding; Seattle Genetics, Merck: Consultancy. Borello:Bristol-Myers Squibb: Research Funding, Speakers Bureau. Popa-Mckiver:Bristol-Myers Squibb: Employment, Equity Ownership. Farsaci:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Armand:Sequenta Inc: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Roche: Research Funding; Merck: Consultancy, Research Funding.

Diffuse large B‐cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment

“…A phase I clinical trial of nivolumab in RR DLBCL had an ORR of 36% with a median PFS of only 7 weeks . Checkmate 036, the combination of nivolumab plus ipilimumab yielded an ORR of 20% in RR NHL (10/15 with DLBCL), with a median PFS of only 1.5 months . In a recently published multicenter phase II trial of 121 patients with RR DLBCL who had failed or were noneligible for ASCT, ORRs were 10% and 3%, respectively, at 9 and 6 months of the follow‐up .…”

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

“…Across lymphoma entities, anti-PD-1 monotherapy showed the greatest efficacy in R/R cHL. [20][21][22][23]76,[107][108][109][110][111][112][113][114][115] In a phase 1 trial of nivolumab, the objective response rate (ORR) was remarkable (87%). 20 In phase 2 trials, nivolumab and pembrolizumab had similar ORRs (68% and 69%) and OS rates (99%) at 6 months, 22,23 leading to accelerated FDA approval in 2016 for nivolumab and in 2017 for pembrolizumab.…”

“…Nivolumab and ipilimumab combination therapy had ORRs of 74% in HL and 20% in B-NHL in a phase 1 trial. 108 Nivolumab combined with ibrutinib showed clinical activity in a small number of patients with R/R CLL or RT. 111 The combination of pembrolizumab and rituximab showed a high ORR of 80% in relapsed FL.…”

Mature B‐NHL in children, adolescents and young adults: current therapeutic approach and emerging treatment strategies

“…The combination of nivolumab (an anti PD‐1 antibody) and ipilimumab has been investigated in a phase I study that included 15 patients with r/r B‐NHL, with disappointing results. There were no CRs and 3 PRs (15%) (Ansell et al , ). Pembrolizumab has had more encouraging results in phase I studies (Zinzani et al , ) and is currently being investigated in a phase II clinical trial in adult patients with relapsed PMBCL (Zinzani et al , ).…”