Davies, A., Mckay, P., Osborne, W., Stanton, L., Tansley‐hancock, O., Lawrence, M., Mercer, K., Allen, A., Pottinger, B., Zhelyazkova, A., Miall, F., Rafferty, J., Sale, B., Cucco, F., Nunn, L., Coleman, A., Griffiths, G., Du, M. Q, Burton, C., Barrons, S. and Johnson, P. (2021) 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. Hematological Oncology, 39 (S2), 155 - 156. (doi:10.1002/hon.11_2880).
Abstract
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.
Conclusions: the efficacy of R-GemOx was disappointing and not improved by the addition of A. Further evaluation in pts with PD-L1 gain at 9p is warranted. Funding support from Roche, endorsed by CRUK (CRUKE/16/028). A UK National Cancer Research Institute Lymphoma Group study.
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