Ratanatharathorn, Voravit

Abstract Introduction: Nivolumab, a fully human IgG4 monoclonal antibody targeting programmed death receptor-1, has recently been FDA approved for classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous stem cell transplantation (ASCT) and post-transplantation brentuximab vedotin (BV). CheckMate 205 (NCT02181738) is a phase 2, international, multicohort study evaluating nivolumab monotherapy in patients with cHL after failure of ASCT. At minimum 6 months' follow-up of Cohort B (205B) which included patients who had received BV after disease recurrence following ASCT, objective response rate (ORR) per independent radiologic review committee (IRRC) was 66% and 6-month progression-free survival (PFS) was 77%, with an acceptable safety profile (Younes et al. Lancet Oncol 2016; Jul 20 [Epub ahead of print]). Here we report outcomes with longer follow-up (minimum 12-month follow-up) in 205B. Primary results from Cohort A, which enrolled patients who relapsed after ASCT but were BV-naïve, will also be presented for the first time as data were not available at time of abstract submission. Methods: CheckMate 205 was designed to evaluate the efficacy and safety of nivolumab monotherapy in patients with cHL who relapsed after ASCT in 3 cohorts: 205A (BV-naive patients; n = 63); 205B (BV after failed ASCT; n = 80); 205C (BV at any time prior to study drug; n = 100). Nivolumab was given at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity in 205A and 205B. The primary endpoint was IRRC-assessed ORR. Results: 80 patients were treated in Cohort 205B; the median age was 37 years (range 18-72). Patients had received a median of 4 prior regimens (range 3-15). At data cut-off (April 2016) with median duration of follow-up of 15.4 months (range 1.9-18.5), 43 patients (54%) still remained on therapy. IRRC-assessed ORR for patients in 205B was 68% (95% confidence interval [CI], 56%, 78%). CR and partial response (PR) rates per IRRC were 8% (3%, 16%) and 60% (48%, 71%), respectively. With longer follow-up, the median duration of response was prolonged to 13.1 months (95% CI, 8.7, not reached; range, 0.0+, 14.2+). The median duration of CR (DOCR) was not reached (95% CI, 4.6, not available [NA]; range, 0.7+, 10.4+) and the median duration of PR was 13.1 months (95% CI, 7.79, NA; range, 0.0+, 13.4+) (Table 1). IRRC median PFS was 14.8 months (95% CI, 11.3 months, NA); 12-month PFS was 54.6% (95% CI, 40.9%, 66.4%), and 12-month overall survival (OS) was 94.9% (median OS not reached). Of 37 patients (46%) who discontinued nivolumab, the most common reasons were disease progression (n = 19 [24%]), allogeneic stem cell transplant (n = 7 [9%]) and adverse events (n = 5 [6%]). Seventy-four patients (93%) had drug-related adverse events (AEs) of any grade. The most common drug-related AEs were fatigue (28%), infusion reaction (20%), arthralgia (15%), and rash (15%). 29% of patients had Grade 3-4 drug-related AEs; the most common were increased lipase (8%), neutropenia (5%), and increased aspartate aminotransferase (4%). The most common serious AEs were pyrexia, pneumonia, tumor progression, arrhythmia, infusion reaction, and meningitis (≤4% each). Conclusions: In this report with extended 12-month follow-up, longer remissions are noted following nivolumab monotherapy in relapsed cHL, including durable PRs in heavily pretreated patients. Nivolumab has an acceptable safety profile, similar to previously reported. Primary results following nivolumab monotherapy in BV-naïve patients with cHL who progressed after ASCT (Cohort 205A) will also be presented at the meeting. Study funding: Study funded by Bristol-Myers Squibb. Professional writing assistance was provided by K. Jesien of Caudex and funded by Bristol-Myers Squibb. Disclosures Timmerman: Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria; Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding. Engert:Takeda, BMS: Consultancy, Honoraria, Research Funding. Armand:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Infinity Pharmaceuticals: Consultancy; Merck: Consultancy, Research Funding; Sequenta Inc: Research Funding. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Kuruvilla:Roche Canada: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Merck: Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Cohen:Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Trneny:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. De Boer:NKI-AVL: Employment. Shipp:Cell Signaling: Honoraria; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Kato:Bristol-Myers Squibb: Employment. Sumbul:Bristol-Myers Squibb: Employment. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Abstract Classical Hodgkin lymphomas (cHLs) include infrequent malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive but ineffective inflammatory/immune cell infiltrate. HRS cells exhibit frequent copy number alterations (CNAs) of 9p24.1/CD274 (PD-L1)/PDCD1LG2(PD-L2), ranging from low-level polysomy to relative copy gain and high-level amplification, all associated with increased expression of programmed death receptor-1 (PD-1) ligands on the tumor cell. PD-1 ligands engage the PD-1 receptor on T cells, inhibiting T cell activation and anti-tumor immune responses. cHL patients (pts) with the highest-level 9p24.1 alterations, PD-L1/PD-L2 amplification, have inferior progression-free survival (PFS) after standard primary chemotherapy (Roemer et al. J Clin Oncol 2016). Given the demonstrated responsiveness of cHL to PD-1 blockade, we examined the prevalence and type of 9p24.1 genetic alterations, PD-L1 expression, and association of these alterations with clinical outcome in pts receiving nivolumab (nivo; anti-PD-1) for relapsed/refractory (R/R) cHL. CheckMate205 is a multicenter, multicohort, phase 2 trial of nivo in R/R cHL. This analysis focused on 2 cohorts: pts with recurrent cHL following autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) (cohort B), and pts with R/R cHL following ASCT and BV given pre- or post-ASCT (cohort C). Pts received nivo 3 mg/kg every 2 weeks. Best overall response (BOR) and PFS were assessed by an independent radiological review committee (IRRC). In pts with available tumor biopsies, 9p24.1 genetic alterations were evaluated via fluorescence in situ hybridization (FISH) assay; probes encompassed CD274 (PD-L1, red) or PDCD1LG2 (PD-L2, green)and included a centromeric control (aqua).Dual immunohistochemical staining of PD-L1/PAX5 was performed to delineate PD-L1 expression in PAX5dim+ HRS cells and PAX5- cells in the tumor microenvironment. A modified PD-L1 H-score (range 0-300) was calculated by multiplying the percentage of PAX5+ (malignant) or PAX5- (non-malignant) cells with positive staining (0-100%) and the average intensity of positive staining (1-3+; ≥50 RS cells counted). All p-values are nominal. 96 pts had evaluable baseline tumor biopsy specimens; all 96 had detectable 9p24.1 alterations: polysomy in 10/96 (10%), copy gain in 56/96 (58%), amplification in 28/96 (29%), and presumptive rearrangement (split-apart FISH signal) in 2/96 (2%) (Figure). There was a significant association between PD-L1 protein expression (H-score) and the level of 9p24.1 alterations in HRS cells (p=0.002) (Figure). We next evaluated the association between BOR and defined 9p24.1 alterations and PD-L1 H-scores. The level of 9p24.1 CNAs was significantly associated with BOR (p=0.01); no pts with progressive disease (PD) had genomic amplification and no pts with complete response (CR) had polysomy. Similarly, there was significant association between PD-L1 H-score in HRS cells and BOR (p=0.02); all pts with PD had PD-L1 H-scores in quartiles (Q) 1/2, whereas most pts with CR had PD-L1 H-scores in Q4. We also assessed the association of PFS with 9p24.1 status and PD-L1 H-scores. The level of 9p24.1 alterations was associated with PFS; pts with 9p24.1 amplification had the most favorable PFS with nivo. HRS cell PD-L1 H-score (by quartiles) was also significantly associated with PFS (p=0.048), as pts with PD-L1 H-scores in Q1/Q2 had significantly shorter PFS than those with scores in Q3/Q4 (p=0.01). In contrast, there was no association between PD-L1 expression on non-malignant cells in the tumor microenvironment and PFS (p=0.43). In conclusion, all evaluable pts in this study had genetic alterations of 9p24.1/PD-L1/PD-L2 and copy number-dependent increased expression of PD-L1 in HRS cells. Although high-level alterations of 9p24.1 and increased PD-L1 expression were previously linked with inferior response to standard primary chemotherapy, we now associate these parameters with more favorable outcomes to targeted PD-1 blockade. These analyses also highlight the importance of quantifying and delineating PD-L1 expression in HRS cells and non-malignant cells in the tumor microenvironment in cHL biopsy evaluation. While further research is needed to guide possible use in clinical practice, these data advance understanding of 9p24.1 alterations and PD-L1 expression as prognostic biomarkers in cHL. Disclosures Engert: Takeda, BMS: Consultancy, Honoraria, Research Funding. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Timmerman:Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding; Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Armand:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Research Funding; Sequenta Inc: Research Funding; Roche: Research Funding; Merck: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy. Kuruvilla:BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Cohen:Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Trneny:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Farsaci:Bristol-Myers Squibb: Employment. Kato:Bristol-Myers Squibb: Employment. Sumbul:Bristol-Myers Squibb: Employment. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Shipp:Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding.