Introduction: Nivolumab (nivo) is an anti-PD-1 antibody that restores effective anti-tumor immune responses and is tolerable and effective in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL). Nivo combined with brentuximab vedotin (BV) as first salvage therapy (tx) yields high response rates and favorable progression-free survival (PFS) as a bridge to autologous stem cell transplantation (ASCT) in pts with RR HL. With the frontline approval of BV, it is necessary to evaluate the role of nivo as salvage tx separate from BV. We report interim results of a phase 2 trial evaluating PET-adapted nivo or nivo + ICE (NICE) chemotherapy as first salvage tx in RR HL.
Methods: In this prospective, multicenter trial, pts with biopsy-proven RR HL after frontline tx received 3 mg/kg nivo every 2 weeks for up to 6 cycles (C). PET-CT was performed after C3 and C6. After C6, pts in CR proceeded to ASCT while pts not in CR received NICE for 2 cycles. The primary endpoint was complete response rate according to 2014 Lugano classification. PFS and overall survival (OS) were calculated using the Kaplan Meier method.
Results: 39 pts were evaluable for toxicity; 37 were evaluable for response. Baseline characteristics are shown in Table 1. 32 pts received nivo alone and 7 pts received nivo/NICE. 32 pts completed study tx, 2 pts continue on protocol tx, 1 pt discontinued early in CR to undergo ASCT, 2 pts discontinued nivo early due to nivo-related adverse events (AE, 1 pt = Gr 4 altered mental status, 1 pt = Gr 2 pneumonitis), 1 pt discontinued due to unrelated death during nivo (Gr 5 sepsis due to untreated dental abscess), 1 pt withdrew due to refusal to receive NICE following nivo.
After C3 of nivo, the overall response rate (ORR) was 89% (33/37), with a CR rate of 59% (22/37), partial response (PR) rate of 30% (11/37), and 2 pts each had stable disease (SD) and PD. After C6 of nivo (n=31), the ORR was 90%, with 24 CR (77%), 4 PR (13%), and 3 PD. Thus, including pts who stopped nivo early (due to toxicity or insufficient response and switch to NICE), at the end of nivo (n=37, not including 2 pts with ongoing tx) the ORR was 78%, with 26 CR (70%), 3 PR (8%), 1 pt with SD and 5 with PD. 7 pts were treated with NICE and all responded (100% ORR) with 6 CR (86%) and 1 PR (14%). At the end of protocol tx (nivo or nivo/NICE) including all pts (n=37) except the 2 who remain on ongoing tx, the ORR was 89% with 32 CR (86%) and 1 PR (3%). Among 35 evaluable pts, the ORR was 94% and CR rate was 91% (Figure).
27 pts proceeded to ASCT directly after protocol tx, 1 pt is awaiting ASCT, and 4 pts in CR refused ASCT. One pt with PR after NICE responded to subsequent salvage tx and underwent ASCT. In pts who had ASCT, a median of 2 (range 1-4) stem cell collections were required, a median of 4.7x106 CD34+ cells/kg (range 3.12 - 16.23) were collected, and the median time to neutrophil and platelet engraftment were 11 and 12 days, respectively. The median follow-up time in all pts (n=39) was 10.5 months (range 1.6-24.5 mo). The 1-year PFS was 79% (95 CI, 63-98%) and 1-year OS was 97% (95 CI, 92-100%). Two PD events occurred in pts who had CR but refused ASCT. There were 2 PD events in pts who completed therapy and proceeded to ASCT - both were in pts who required NICE.
The most common AEs related to nivo alone (n=39) were fatigue (28%), rash (18%), fever (15%), thrombocytopenia (10%), and dyspnea (10%), and all were grade (gr) 1-2. Only 2 pts had gr 3-4 nivo-related AE, 1 pt had gr 3 thrombocytopenia and another pt had gr 4 altered mental status and gr 3 tumor lysis syndrome. Among 7 pts who received NICE, the most common AEs were nausea (71%), vomiting (57%), anemia (43%), fatigue (43%), hypertension (43%), and hyponatremia (29%) - all were gr 1-2. The only Gr 3-4 NICE-related AE was gr 4 neutropenia in 1 pt.
Conclusion: PET-adapted nivo followed by NICE in patients without CR is a well-tolerated and effective first salvage approach in pts with RR HL. In our cohort, nivo alone was an effective bridge to ASCT in a majority of pts, sparing them the toxicity of traditional salvage chemotherapy. Pts who did not achieve CR with nivo were effectively salvaged by NIVO+ICE
Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. Chen:Autolus Therapeutics: Employment. Palmer:Gilead Sciences: Consultancy. Mei:Seattle Genetics, Inc.: Research Funding. Popplewell:City of Hope: Employment. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion, Inc.: Consultancy; Celltrion Healthcare: Consultancy. Lee:Seattle Genetics, Inc.: Research Funding.
Asterisk with author names denotes non-ASH members.