PURPOSE Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). Outcomes after a 3-year follow-up in the pivotal ZUMA-2 study of KTE-X19 in relapsed/refractory MCL are reported, including for subgroups by prior therapy (bendamustine and type of Bruton tyrosine kinase inhibitor [BTKi]) or high-risk characteristics. METHODS Patients with relapsed/refractory MCL (one to five prior therapies, including prior BTKi exposure) received a single infusion of KTE-X19 (2 × 106 CAR T cells/kg). RESULTS After a median follow-up of 35.6 months, the objective response rate among all 68 treated patients was 91% (95% CI, 81.8 to 96.7) with 68% complete responses (95% CI, 55.2 to 78.5); medians for duration of response, progression-free survival, and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 to not estimable), respectively. Post hoc analyses showed that objective response rates and ongoing response rates were consistent among prespecified subgroups by prior BTKi exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis. Late-onset toxicities were infrequent; only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during this longer follow-up period. Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse. CONCLUSION These data, representing the longest follow-up of CAR T-cell therapy in patients with MCL to date, suggest that KTE-X19 induced durable long-term responses with manageable safety in patients with relapsed/refractory MCL and may also benefit those with high-risk characteristics.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have an established role in the treatment of non-small-cell lung cancer (NSCLC). First-generation reversible ATP-competitive EGFR-TKIs are approved for the initial treatment of patients with EGFR mutation-positive advanced NSCLC. Afatinib is an irreversible second-generation EGFR-TKI with potent preclinical activity against EGFR (wild type and mutant), HER2, HER4 and EGFR-mutant NSCLC with acquired resistance to reversible EGFR-TKI. LUX-Lung 3 trial demonstrated superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment-naïve patients with advanced adenocarcinoma of the lung and EGFR mutation. Based on these results, afatinib was recently approved for the first-line treatment of NSCLC patients with EGFR mutation. This article summarizes current status of preclinical and clinical development of afatinib in NSCLC.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of R/R large B-cell lymphoma and follicular lymphoma (FL), both after ≥2 lines of systemic therapy. ZUMA-5 is a Phase 2, multicenter, single-arm study evaluating axi-cel in patients with R/R iNHL (including FL and marginal zone lymphoma [MZL]). In the primary analysis of ZUMA-5 (N=104; 17.5 months median follow-up), the overall response rate (ORR) was 92% (76% complete response [CR] rate), and median peak CAR T-cell levels were numerically greater in patients with FL who were in ongoing response at data cutoff than in those who relapsed (Jacobson et al. ASH 2020. Abstract 700). Here, we report updated clinical and pharmacologic outcomes from ZUMA-5. Methods: Adult patients with R/R FL or MZL after ≥2 lines of therapy (including an anti-CD20 mAb plus an alkylating agent) underwent leukapheresis and conditioning chemotherapy followed by a single axi-cel infusion at 2×10 6 CAR T cells/kg. The primary endpoint was centrally assessed ORR per Lugano classification. The updated efficacy analysis occurred when ≥80 consecutively treated patients with FL had ≥2 years of follow-up post-infusion and included patients with MZL who had ≥4 weeks of follow-up post-infusion. Results: As of March 31, 2021, 149 patients with iNHL (124 FL; 25 MZL) were treated with axi-cel. Of those, 110 patients (86 FL; 24 MZL) were eligible for efficacy analyses. Among eligible patients with FL, median follow-up was 30.9 months (range, 24.7-44.3). Centrally assessed ORR was 94% in patients with FL (79% CR rate). At data cutoff, 57% of eligible patients with FL had ongoing responses; 68% of patients who achieved a CR had ongoing responses. The estimated duration of response (DOR) and progression-free survival (PFS) medians were 38.6 months and 39.6 months in patients with FL, respectively. Among patients with FL who progressed <2 years after initial chemoimmunotherapy (POD24; n=49), median DOR was 38.6 months, while median DOR was not reached for those without POD24 (n=29). Median PFS in patients with FL and POD24 was 39.6 months, whereas median PFS was not reached in those without POD24. Median time to next treatment (TTNT) was 39.6 months in all eligible patients with FL. Median overall survival (OS) was not reached, with an estimated OS rate at 24 months of 81%. Among eligible patients with MZL, median follow-up was 23.8 months (range, 7.4-39.4). The ORR was 83% in patients with MZL (63% CR rate), with 50% of eligible patients in ongoing response and 73% of patients with a CR in ongoing response at data cutoff. Medians for DOR and TTNT were not reached in patients with MZL; 24-month rates were not estimable and 51%, respectively. Median PFS was 17.3 months in patients with MZL and median OS was not reached (70% OS rate at 24 months). Common Grade ≥3 AEs in all treated patients with iNHL were consistent with prior reporting: neutropenia (33%), decreased neutrophil count (28%), and anemia (25%). Grade ≥3 cytopenias present ≥30 days post-infusion were reported in 34% of patients with iNHL (33% FL; 36% MZL). Consistent with previous reports, Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 7% of patients (6% FL; 8% MZL) and 19% of patients (15% FL; 36% MZL), respectively. Most CRS cases (120/121) and NEs (82/87) of any grade resolved by data cutoff. Among patients with FL who had evaluable samples, 76% (65/86) had detectable CAR gene-marked cells at low levels by 12 months post-infusion; 53% (23/43) had detectable cells 24 months post-infusion. Among evaluable patients with MZL, 67% (8/12) had detectable CAR gene-marked cells 12 months post-infusion; 60% (3/5) had detectable cells 24 months post-infusion. B-cell reconstitution was detectable in 59% of evaluable patients with FL (49/83) and 42% of those with MZL (5/12) by 12 months post-infusion. By 24 months, B cells were detectable in 61% of evaluable patients with FL (25/41) and 50% of those with MZL (2/4). Conclusions: With long-term follow-up in ZUMA-5, axi-cel demonstrated substantial and continued benefit in patients with iNHL. In FL, high response rates translated to durability, with a median DOR of 38.6 months and 57% of eligible patients in ongoing response at data cutoff. In MZL, efficacy outcomes appeared to improve with longer follow-up, with the median DOR and OS not yet reached. Axi-cel maintained a manageable safety profile, with no new safety signals . Disclosures Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Chavez: Merk: Research Funding; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; AstraZeneca: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Speakers Bureau. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Munshi: Kite, a Gilead Company, and Incyte: Honoraria; Kite, a Gilead Company, and Incyte: Speakers Bureau. Casulo: Genentech: Research Funding; BMS: Research Funding; Verastem: Research Funding; Gilead: Research Funding. Maloney: Kite, a Gilead Company, Juno, and Celgene: Research Funding; A2 Biotherapeutics: Consultancy; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Juno: Patents & Royalties. Reshef: Bayer: Consultancy; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy; ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Gilead and Novartis: Honoraria. Leslie: Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy. Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Rosenblatt: Synergys: Patents & Royalties; BioGraph 55: Research Funding. Sherman: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Dong: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company; GliaCure/Tufts: Consultancy, Patents & Royalties. Giovanetti: Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Yang: Kite, a Gilead Company: Current Employment. Lui: Gilead Sciences: Other: stock or other ownership; Kite, a Gilead Company: Current Employment, Other: travel support. Bashir: Kite, a Gilead Company: Ended employment in the past 24 months; OmniacPharmConsult Ltd: Other: stock or other ownership. Jung: Amgen, Kura, Gilead, and Turning Point: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau.

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