Outcomes of Subsequent Anti-Lymphoma Therapies in Patients (Pts) with Large B-Cell Lymphoma (LBCL) Treated with Axicabtagene Ciloleucel (Axi-Cel) or Standard of Care (SOC) in the Second-Line (2L) ZUMA-7 Study

Background: In the pivotal Phase 3 ZUMA-7 (NCT03391466) trial, axi-cel significantly improved outcomes vs 2L SOC (event-free survival [EFS] hazard ratio, 0.398, P<.0001; Locke, et al. NEJM. 2022). Thus, chimeric antigen receptor (CAR) T-cell therapy has been proposed as the new SOC for 2L treatment for eligible pts (Westin, Sehn. Blood. 2022) and axi-cel was recently approved in the United States for the treatment of adult pts with relapsed/refractory (R/R) LBCL ≤12 mo of first-line (1L) chemotherapy. However, pts may require additional therapy and the question of optimal management after 2L therapy remains. Here, we describe outcomes for pts who received subsequent treatment in ZUMA-7.

Methods: Eligible pts were randomized 1:1 to axi-cel or SOC (2-3 cycles of chemotherapy followed by high-dose therapy with autologous stem cell transplant [HDT-ASCT] for those with partial response [PR] or complete response [CR]). Subsequent therapies and disease assessments after new lymphoma therapy, not defined in the study protocol, were per investigator discretion. Treatment with subsequent third-line (3L) therapy was classified as chemotherapy and cellular immunotherapy (for axi-cel arm, axi-cel retreatment on protocol for pts who initially responded to axi-cel). Kaplan-Meier estimates for progression-free survival (PFS) and overall survival (OS) were calculated from 3L treatment initiation. Pts who did not meet the criteria for a PFS event were censored at fourth-line treatment initiation, if any, or last known alive date. Pts who received subsequent SCT while in a response from 3L axi-cel retreatment were censored at the time of SCT. Best response to subsequent therapy was evaluated.

Results: In the axi-cel arm, 84 of 180 randomized pts required 3L subsequent therapy; 60 and 8 pts received 3L chemotherapy and 3L cellular immunotherapy, respectively. For pts who received 3L chemotherapy, overall median PFS was 1.7 mo (95% CI, 1.4-2.0) and median OS was 8.1 mo (95% CI, 5.8-11.5) since 3L treatment initiation, with an objective response rate (ORR) of 25% (CR rate: 13%). For 34 pts who received 3L chemotherapy after initial response to 2L axi-cel, overall median PFS was 1.7 mo (95% CI, 1.4-2.4) and median OS was 8.1 mo (95% CI, 6.8-11.9), with an ORR of 32% (CR rate: 18%).

Of 60 pts who received 3L chemotherapy, 10 pts received SCT in 3L (9 ASCT, 1 alloSCT) after chemotherapy, but it is unknown how many pts who received 3L therapy were intended for SCT. Median PFS was 11.5 mo (95% CI, 2.4-not evaluable [NE]) vs 1.6 mo (95% CI, 1.2-1.8), and median OS was 17.5 mo (95% CI, 2.4-NE) vs 7.2 mo (95% CI, 4.8-9.1) for those who did vs those who did not reach SCT, respectively. Of 8 pts in the axi-cel arm who received 3L cellular immunotherapy, median PFS was 3.5 mo (95% CI, 1.1-NE); 6 received subsequent SCT (1 ASCT, 5 alloSCT) in any line, 3 (alloSCT) of which immediately followed 3L axi-cel. Of 6 pts who received SCT, 5 remained in CR; 1 pt had a PR after axi-cel retreatment and proceeded to alloSCT with best response of CR, but relapsed 7.3 mo after SCT. All 6 pts who received SCT were alive at the data cutoff date (median follow-up since 3L treatment initiation: 24.4 mo). Of 2 pts who received 3L axi-cel but did not receive SCT, 1 had disease progression after 3L axi-cel and died 8.7 mo after retreatment, and 1 had a CR after 3L axi-cel and was disease-free and alive by data cutoff (8.4 mo after retreatment).

In the SOC arm, 127 of 179 randomized pts required 3L subsequent therapy; of these, 68 pts received 3L cellular immunotherapy. For pts who received 3L cellular immunotherapy, median PFS was 6.3 mo (95% CI, 3.4-16.3) and median OS was 16.3 mo (95% CI, 8.7-NE), compared with median PFS and median OS of 1.9 mo (95% CI, 1.1-2.7) and 9.5 mo (95% CI, 6.6-15.4), respectively, for those who did not receive cellular immunotherapy. Of 68 pts who received 3L cellular immunotherapy and were evaluated for response, ORR was 57% (CR rate: 34%).

Conclusions: In ZUMA-7, subsequent 3L axi-cel retreatment was feasible and outcomes for these pts appeared improved, as pts were able to achieve meaningful responses. While definitive conclusions cannot be made due to the small number of pts, 3L CAR T-cell therapy after initial response in 2L may be a viable option. Outcomes for pts who received subsequent 3L cellular therapy were numerically inferior to those who received 2L cellular therapy. These findings may help inform subsequent treatment choices after failure of 2L therapy for R/R LBCL.

Ghobadi:Amgen: Consultancy, Research Funding; Atara: Consultancy; Wugen Inc: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; CRISPR Therapeutics: Consultancy; Genentech: Research Funding. Munoz:Celgene: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene/Bristol Myers Squibb: Speakers Bureau; Incyte: Research Funding; Physicians' Education Resource: Honoraria; Portola: Research Funding; Millennium: Research Funding; Merck: Research Funding; Verastem: Speakers Bureau; Seagen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech/Roche: Speakers Bureau; AstraZeneca: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau; Servier: Consultancy; Pharmacyclics/AbbVie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; MorphoSys/Incyte: Consultancy; Karyopharm: Consultancy; Juno/Celgene: Consultancy; Janssen: Consultancy, Research Funding; Innovent: Consultancy; Genmab: Consultancy; Gilead: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Fosun Kite: Consultancy; Epizyme: Consultancy; Debiopharm: Consultancy; Bristol Myers Squibb: Consultancy; BeiGene: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; ADC Therapeutics: Consultancy; Targeted Oncology: Honoraria; OncView: Honoraria; Kyowa Kirin: Consultancy, Honoraria, Speakers Bureau; Curio: Honoraria; Pharmacyclics: Research Funding; Genentech: Research Funding. Westin:ADC Therapeutics: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; MonteRosa: Consultancy; Calithera: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy; Iksuda: Consultancy; MorphoSys/Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie/GenMab: Consultancy; SeaGen: Consultancy. Locke:CERo Therapeutics: Research Funding; Takeda: Consultancy; Sana: Consultancy; CAREducation: Other: Education or editorial activity; Clinical Care Options Oncology: Other: Education or editorial activity; Imedex: Other: Education or editorial activity; Society for Immunotherapy of Cancer: Other: Education or editorial activity; ), National Cancer Institute: Research Funding; Leukemia and Lymphoma Society: Research Funding; Aptitude Health: Other: Education or editorial activity; ASH: Other: Education or editorial activity; BioPharm Communications: Other: Education or editorial activity; BMS: Research Funding; Daiichi Sankyo: Consultancy; A2: Consultancy; Celgene: Consultancy; Other: Patents & Royalties: patents, royalties, other intellectual property from several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy.; Wugen: Consultancy; Umoja: Consultancy; Novartis: Consultancy, Research Funding; Legend Biotech: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy; Iovance: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions Gerson Lehrman Group: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Calibr: Consultancy; Cellular Biomedicine Group: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Bluebird Bio: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Amgen: Consultancy. Miklos:Janssen: Consultancy, Honoraria; Fosun Kite: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy; Novartis: Consultancy; Allogene: Research Funding; Adaptive Biotech: Consultancy; Pharmacyclics: Patents & Royalties: cGVHD Ibrutinib patent ; Kite, a Gilead Company: Research Funding. Perales:Omeros: Consultancy; Nektar Therapeutics: Consultancy, Honoraria; Bellicum: Honoraria; Servier: Consultancy; Kite, a Gilead Company: Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria; Medigene: Consultancy; Vor Biopharma: Honoraria; VectivBio AG: Honoraria; DSMB: Other; MorphoSys: Consultancy, Honoraria; Celgene: Honoraria; Novartis: Honoraria; Cidara Therapeutics: Consultancy; Orca Bio: Consultancy; Merck: Consultancy; Takeda: Honoraria; Astellas: Honoraria; Abbvie: Honoraria; Sellas Life Sciences: Consultancy; Incyte: Honoraria, Research Funding; Bristol-Mysers Squibb: Honoraria; Karyopharm: Honoraria. Reagan:Genentech: Research Funding; Seagen: Research Funding; Kite, a Gilead Company: Consultancy; Caribou Biosciences: Consultancy. McGuirk:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Nextar: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Allovir: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Orca Bio: Research Funding; Sana: Honoraria; CRISPR Therapeutics: Consultancy; In8bio, Inc.: Other: IIT Clinical Trial. Jacobson:Clinical Care Options: Speakers Bureau; Ispen: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Instil Bio: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Lonza: Consultancy, Honoraria, Other: Travel Support; Nkarta: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria, Other: Travel Support; ImmPACT Bio: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Precision BioSciences: Consultancy, Honoraria, Other: Travel Support; Axis: Speakers Bureau; Celgene: Other: Travel Support; Pfizer: Other: Travel Support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Support; BMS/Celgene: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Kersten:Takeda: Research Funding; Roche: Consultancy, Honoraria, Other: Travel support , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support ; Miltenyi Biotech: Consultancy, Honoraria, Other: Travel support ; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Adicet Bio: Consultancy, Honoraria; Celgene: Research Funding. Avivi:Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Peng:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Schupp:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. To:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Oluwole:Curio Science: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Kite, a Gilead Company: Research Funding.