9p gain predicts outcomes in patients with relapsed/refractory (r/r) diffuse large b-cell lymphoma (dlbcl) treated with r-gemox +/- atezolizumab. argo: a randomised phase ii study

Introduction: Outcomes for transplant ineligible R/R DLBCL pts are poor. Atezolizumab (A), a humanised anti PD-L1 with limited single agent activity in DLBCL, may provide a novel mechanism to improve outcomes from rituximab (R), gemcitabine (Gem) and oxaliplatin (Ox) (R-GemOx) immunochemotherapy. Chemotherapy may reduce regulatory T-cell activity, enhance cross-presentation of tumour antigens and induce PD-L1 expression. This leads to synergistic clinical activity in some solid tumours. Methods: ARGO was an open-label randomised phase II trial with a 3:1 randomisation favouring the experimental arm (Arm B) with no formal planned direct arm comparison. Stratification was by R/R status. R-GemOx was delivered for 6 cycles on a 14-day schedule: R cycle 1 IV 375mg/m2, cycle 2-6 sc 1400mg; Gem 1000mg/m2; Ox 100mg/m2 with GCSF support (Arm A). In Arm B A 840mg IV was added every 14 days from cycle 2 onwards, responding pts continued with A at 840mg every 21 days for 8 cycles. The primary endpoint was 1-year progression free survival (PFS), aiming for ≥40%, to exclude a rate <25%. The study planned to recruit 112 pts but stopped early on the recommendation of the Data Monitoring Committee due to failure to reach the prespecified futility boundary. Results: Between July 2018 and June 2020, 53 transplant ineligible DLBCL pts were enrolled (Arm A n = 12 Arm B n = 41). The median age was 73 years (23-85), median previous lines of therapy was 1 (1-7). 74% had IPI ≥3 at entry, 58% refractory, 42% relapsed. Three pts were double hit, 21 double expressors and 16 ABC. TP53 was mutated in 44%. 72% of pts completed 6 cycles of induction therapy, 10 withdrawals due to progressive disease (PD), 4 subject/investigator withdrawals, 1 death (pneumonia). The overall response rate (ORR) was 38% (CR 13%) in Arm B and 27% (CR 9%) in Arm A. Of 16 pts that started maintenance, 63% (10 pts) prematurely stopped (5 PD, 4 trial cessation and 1 proceeded to high-dose therapy). PFS at 12 months was 15.2% (95%CI 5.8-28.8) in Arm B and 8.3% (95%CI 0.51-31.1) with R-GemOx alone. Overall survival at 12 months: 53.9% (95%CI 37.0-68.1) Arm B, 58.3% (95%CI 27.0-80.1) Arm A. Grade ≥3 toxicity in ≥10% patients was thrombocytopenia (Arm A 25% Arm B 32%) and neutropenia, pneumonia and pyrexia (Arm A 0% Arm B 10% each). In Arm B, ORR, PFS and OS were higher in tumours with gain of PD-L1 locus at 9p by FISH (10/29), median PFS 7.2 months 9p gain vs 3.2 months normal P = 0.037, median OS not reached in gain 9p vs 5 months P = 0.025. This was not reflected in protein expression by immunohistochemistry. There was no difference in outcome by peripheral blood immune effector cell numbers, double expressor status or cell of origin. The research was funded by: F. Hoffmann-La Roche Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract A. Davies Consultant or advisory role: Celgene, Roche, Gilead/Kite Pharma, Takeda, Kayropharma, Incyte, VelosBio Honoraria: Celgene, Roche, Gilead/Kite Pharma, Takeda, Janssen, Acerta Pharma, AstraZeneca, ADC Therapeutics, Incyte, VelosBio Research funding: Celgene, Roche, Gilead/Kite Pharma, Takeda, Janssen, Kayropharma, Acerta Pharma, AstraZeneca, ADC Therapeutics Educational grants: Celgene, Roche P. McKay Consultant or advisory role: TAKEDA, Roche, Celgene, Kite and Beigene Honoraria: TAKEDA, Roche, Celgene, Kite and Beigene W. Osborne Consultant or advisory role: Roche, Takeda, Servier, Kite Gilead, MSD, Novartis, Beigene, Syneos, Autolus Honoraria: Pfizer, Astra Zeneca, Roche, Takeda, Kite Gilead, Novartis, Kyowa Kirin Educational grants: Novartis, Takeda, Pfizer, Roche F. Miall Consultant or advisory role: Roche and Takeda Honoraria: Roche and Takeda G. Griffiths Research funding: Jannsenn-Cilag, AZ, Novartis, Astex, Roche, Heartflow, BMS, BionTech Other remuneration: Celldex C. Burton Consultant or advisory role: Roche P. Johnson Consultant or advisory role: Epizyme, Janssen, Oncimmune, Boehringer Ingelheim Honoraria: Bristol Myers Squibb, Celgene, Genmab, Incyte, Kite Pharma, Kymera, MorphoSys, Novartis, Takeda Research funding: Epizyme