Nivolumab in Patients (Pts) with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL): Clinical Outcomes from Extended Follow-up of a Phase 1 Study (CA209-039)
Authors: Ansell Stephen , Armand Philippe , Timmerman John M. , Shipp Margaret A. , Bradley Garelik M Brigid , Zhu Lili , Lesokhin Alexander M. 
Published: October 2019

Abstract
Introduction: The programmed death-1 (PD-1) immune checkpoint pathway regulates T-cell-mediated antitumor immune responses in solid tumors and hematologic malignancies. Nivolumab (Bristol-Myers Squibb, Ono Pharmaceutical) is a fully human IgG4 PD-1-blocking monoclonal antibody with demonstrated efficacy in a range of tumors. Results from an independent cohort of 23 pts with R/R cHL in a phase 1 study (CA209-039) showed that nivolumab was well tolerated and yielded an overall response rate (ORR) of 87% (Ansell et al, N Engl J Med, 2015). This raises important questions including the necessary duration of treatment, the relevance of the depth of response (complete response [CR] vs partial response [PR]), the duration of response, and the feasibility of retreatment. Here, we present the clinical course and post-treatment outcomes from extended follow-up of these pts to shed some light on these questions.
Methods: Pts with R/R cHL received nivolumab 3 mg/kg at weeks (wks) 1 and 4, and then every 2 wks for up to 2 years (yrs). Therapy was stopped earlier in pts with intolerance to treatment or progressive disease (PD) without evidence of clinical benefit. Pts who discontinued treatment due to toxicity were followed for up to 120 days after discontinuation; other pts were followed for 1 yr after discontinuation. Responding pts discontinued after confirmed CR or 16 wks after unconfirmed CR, or continued treatment for up to 2 yrs if they had PR or stable disease (SD). Pts who discontinued treatment with ongoing CR, PR, or SD could be retreated for confirmed PD occurring <1 yr after nivolumab discontinuation. Responses were evaluated using the Revised Response Criteria for Malignant Lymphoma (Cheson et al, J Clin Oncol, 2007). The primary endpoint was safety, and the key secondary endpoint was antitumor activity.
Results: A total of 23 pts with R/R cHL were treated. The median follow-up observation time is now 86 wks (range: 32-107 wks). Of 20 responders (14 PR, 6 CR), 10 have had durable responses per protocol assessment; their treatment durations and response characteristics are shown in Table 1. Responses were maintained in 2 pts (#5 and #6) after discontinuing nivolumab for >40 wks and in 1 pt (#7) after stopping due to toxicity. Eight pts with durable responses have received nivolumab for >1 yr, including 7 pts who have been in response for >1.5 yrs. One pt (#2) with an initial CR experienced a relapse 43 wks after treatment was discontinued, and achieved a second response (CR) after retreatment with nivolumab. Of the 10 remaining responders, 4 eventually progressed (time to progression [TTP] range: 21.4-92 wks), 1 discontinued treatment due to toxicity with no PD within the 120-day follow-up period, and 5 discontinued nivolumab to undergo stem cell transplant (SCT; 4 allogeneic, 1 autologous) after achieving remission. Time to CR for all responders ranged from 3-88 wks after starting nivolumab, including 2 pts with initial PRs that converted to CRs with continued treatment. All 5 pts who proceeded to SCT had responded to nivolumab within 16 wks of starting treatment (4 PR, 1 CR). Three pts had a best overall response of SD (1 discontinued due to toxicity without documented PD within the 120-day follow-up period; 2 subsequently discontinued for PD [TTP: 15 and 15.3 wks, respectively]). Overall, 3 pts discontinued nivolumab due to adverse events (AEs; Grade 2 peripheral neuropathy, Grade 3 myelodysplastic syndrome, Grade 3 pancreatitis). Grade 1 or 2 immune-related AEs (IR-AEs) occurred in 4 of 10 pts and resolved without treatment in 2 pts. The incidence of IR-AEs did not increase with time on treatment.
Conclusions: In pts with R/R cHL, nivolumab was well tolerated and produced a high ORR. Responses occurred within 16 wks of nivolumab initiation in 15 of 20 pts. Early responses to nivolumab allowed 5 pts to proceed to SCT and lasted ≥1 yr in 7 of 10 pts who did not pursue SCT. One pt achieved CR again after retreatment with nivolumab when relapse occurred within 1 yr of discontinuing treatment following an initial CR.
Table 1. Treatment and Response Parameters for Pts with Durable Ongoing Responses Pt # Best Response Duration of Response, wks Time to First Response, wks Time on Treatment, wks 1 PR 90.7 3.6 96+ 2 CR 82.1 7.1 91+ 3 PR 73.1 7.6 82.4+ 4 PR 71.4 14.9 88+ 5 CR 71.1 3.1 24.9 6 CR 65.1 7.1 22.9 7 PR 55.9 15.3 70.9 8 CR 48.3 39 87 9 CR 45.3 55 82.9 10 PR 41.7 38.7 82.1+ +Still on treatment

Disclosures
Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding. Timmerman:Valor Biotherapeutics: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees. Bradley Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding.