Résumé
Background: In the primary analysis of TRANSCEND FL (NCT04245839), a global, phase 2 study, liso-cel showed an ORR of 97%, CR rate of 94%, and favorable safety in pts with second-line (2L) or later R/R FL. Here, we report results in pts with third-line or later (3L+) and 2L FL with high-risk disease features after approximately 2 y of follow-up.
Methods: Eligible pts with R/R FL included 3L+ and 2L pts with progression of disease ≤ 24 mo (POD24) of diagnosis after treatment with anti-CD20 antibody and an alkylator ≤ 6 mo of FL diagnosis and/or modified Groupe d'Etude des Lymphomes Folliculaires (mGELF) criteria. All pts received ≥ 1 prior combination systemic therapy, including an anti-CD20 antibody and an alkylator. Pts received liso-cel (100 × 106 CAR+ T cells) after lymphodepleting chemotherapy (LDC). Bridging therapy was allowed with reconfirmation of PET-positive disease before LDC. The primary endpoint was ORR per independent review committee (IRC) by PET/CT using Lugano 2014 criteria. Secondary endpoints included CR rate, duration of response (DOR) and PFS by IRC assessment, OS, safety, cellular kinetics, and pt-reported outcomes (PRO). Time to next treatment (TTNT; time from index date to the start date of subsequent systemic treatment or death from any cause, whichever occurred first) and PFS2 (time from index date to the first documented PD, per investigator assessment, or death from any cause after the start date of the subsequent line of therapy) were analyzed post hoc.
Results: At data cutoff (January 10, 2024), 107 3L+ and 23 2L high-risk FL pts had received liso-cel and were evaluable for safety; 103 3L+ and 23 2L pts were efficacy evaluable. In pts with 3L+ FL, median (range) age was 62 y (23-80), 89% had Ann Arbor stage III/IV disease, and 57% were high risk per FLIPI. Forty-three percent of pts had POD24 (per eligibility criteria), 53% met mGELF criteria, and 64% were double refractory to anti-CD20 antibody and an alkylator. In pts with 2L FL, median (range) age was 53 y (34-69), 74% had Ann Arbor stage III/IV disease, 30% were high risk per FLIPI, 52% had POD24, 70% met mGELF criteria, and 48% were double refractory to anti-CD20 antibody and an alkylator.
Median (range) on-study follow-up was 30.0 mo (0.3-39.6) for 3L+ and 29.5 mo (1.0-38.2) for 2L. For 3L+, ORR and CR rate (95% CI) were 97.1% (91.7-99.4) and 94.2% (87.8-97.8), respectively; for 2L, ORR and CR rate were both 95.7% (78.1-99.9). In 3L+ and 2L pts, medians continued to be not reached for all time-to-event analyses. In 3L+ pts, 24-mo (95% CI) DOR was 74.6% (64.8-82.1), PFS was 72.5% (62.7-80.1), OS was 88.2% (80.1-93.1), probability of TTNT was 80.1% (70.8-86.7), and probability of PFS2 was 76.6% (57.7-87.9). In 2L pts, 24-mo (95% CI) DOR was 86.4% (63.4-95.4), PFS was 82.6% (60.1-93.1), OS was 95.7% (72.9-99.4), probability of TTNT was 91.3% (69.5-97.8), and probability of PFS2 was 91.1% (68.8-97.7).
Persistence of liso-cel transgene was observed up to Month 30 in 25% (7/28 pts) and 17% (1/6 pts) for 3L+ and 2L pts, respectively. PRO data showed durable improvements across domains for most pts.
The safety profile with longer median follow-up was manageable and consistent with the primary analysis (18.9-mo median follow-up). As reported in the primary analysis, incidence of grade ≥ 3 cytokine release syndrome (CRS) was 1% (no grade 4/5), grade ≥ 3 neurological events (NEs) were 2% (no grade 4/5), and prolonged cytopenia was 22% (most recovered to grade ≤ 2 by Day 90). There were 9 pts who had second primary malignancies (7%; 7 in the 3L+ cohort and 2 in the 2L cohort), with 5 reported since the primary analysis (malignant melanoma, colorectal cancer, mucoepidermoid carcinoma, myelodysplastic syndrome, and basal cell carcinoma [1 each]). No secondary T-cell malignancies were reported.
In the leukapheresed set, there were 16 on-study deaths, of which 1 occurred before liso-cel infusion and 2 occurred since the primary analysis due to PD, 1 pt each in the 3L and 4L+ cohorts.
In patients who received liso-cel in the outpatient setting (n = 14; 3L+, n = 13; 2L, n = 1), no pts had experienced grade ≥ 3 CRS, NEs, or prolonged cytopenia at data cutoff.
Conclusions: With 2-y follow-up in pts with 3L+ and 2L high-risk R/R FL who received a single administration of liso-cel, ORR and CR rates were above 94%, with sustained high rates of 24-mo DOR, PFS, and OS, and no new safety signals. These data support liso-cel as a highly efficacious and safe treatment option for pts with R/R FL.
Nastoupil:Caribou Biosciences: Honoraria, Research Funding; Denovo Biopharma: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ADC Therapeutics: Honoraria; AbbVie: Honoraria; Genmab: Honoraria, Research Funding; Gilead Sciences/Kite Pharma: Honoraria, Research Funding; Incyte Corporation: Honoraria; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Abbvie, BMS, Caribou Biosciences, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Regeneron, Takeda: Consultancy; BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Takeda: Research Funding; Abbvie, BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Novartis, Takeda: Honoraria. Dahiya:Bristol Myers Squibb: Consultancy; Adaptive Biotechnologies: Consultancy; Kite: Consultancy, Research Funding; Kite-Pharma-Gilead: Consultancy, Research Funding. Palomba:Synthekine: Consultancy; Novartis: Consultancy; Bristo Meyer Squibb: Consultancy; Cellectar: Consultancy. Martín García-Sancho:Miltenyi Biotec: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel and Accommodation Support; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Honoraria; Roche: Honoraria, Other: Travel and Accommodation Support; Incyte: Consultancy, Honoraria; IDEOGEN: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria, Other: Travel and Accommodation Support; EUSA Pharma: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel and Accommodation Support; BeiGene: Consultancy, Honoraria. Reguera:Kite/Gilead: Consultancy; Amgen: Speakers Bureau; Incyte: Speakers Bureau. Kuruvilla:F. Hoffmann-La Roche Ltd, AstraZeneca, Merck, Novartis: Research Funding; DSMB Karyopharm: Other; AbbVie, Amgen, AstraZeneca, BMS, Genmab, Gilead, Incyte, Janssen, Merck, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Seattle Genetics: Honoraria; AbbVie, BMS, Gilead, Merck, F. Hoffmann-La Roche Ltd, Seattle Genetics: Consultancy. Jaeger:Gilead: Consultancy, Honoraria; BMS, Novartis, Janssen: Honoraria. Cartron:Takeda: Honoraria; Novartis: Honoraria; MAbQi: Consultancy; Gilead: Honoraria; BMS: Consultancy, Honoraria; Ownards therapeutics: Consultancy; Beigene: Consultancy, Honoraria; MedXcell: Consultancy; Abbvie: Consultancy, Honoraria; Janssen: Honoraria; Roche, BMS, AbbVie, Ownards therapeutics, MAbQi, MedXcell, BeiGene: Consultancy; Roche, BMS, Gilead, Novartis, Takeda, Beigen, Janssen, AbbVie: Honoraria; Roche: Consultancy, Honoraria. Izutsu:MSD, AstraZeneca, Genmab, Chugai, BMS, Kyowa Kirin, Novartis, AbbVie: Consultancy, Honoraria, Research Funding; Beigene, Yakult, Otsuka: Consultancy, Research Funding; Ono Pharma, Symbio, Takeda: Consultancy, Honoraria; Incyte, Bayer, O Oncology, Regeneron: Research Funding; Pfizer, Janssen, Gilead, Daiichi Sankyo: Honoraria, Research Funding; AstraZeneca, Eli Lily, Astellas, Ono Pharmaceuticals, Eisai, Chugai, Janssen, Symbio, Bristol Myers Squibb, Daiichi Sankyo, Otsuka, Abbvie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, MeijiSeika Pharma, Novartis, Nihon Kayaku, Gilead,: Honoraria; MSD, AstraZeneca, Abbvie, Incyte, Bristol Myers Squibb, Novartis, Bayer, Pfizer, Janssen, Yakult, Kyowa Kirin, Daiichi Sankyo, Chugai, Beigene, Genmab, LOXO Oncology, Otsuka, Regeneron, Gilead: Research Funding; AstraZeneca, Zenyaku, Ono Pharmaceuticals, Mitsubishi Tanabe Pharma, Eisai, Chugai, Bristol Myers Squibb, Takeda, Otsuka, Abbvie, Zenyaku, Kyowa Kirin, MSD, Carna Biosciences, Novartis, Yakult, Nihon Shinyaku, Abe Pharma, Eisai,Beigene: Consultancy. Dreyling:AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd.: Honoraria; AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding; AbbVie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees. Kahl:Kite: Consultancy; ADCT: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy; Lilly: Consultancy; BeiGene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Roche: Consultancy, Research Funding; Genentech: Consultancy; Merck: Consultancy; Novartis: Consultancy. Ghesquieres:Gilead, Roche, BMS, Abbvie, Takeda: Honoraria; Roche, BMS, Takeda: Consultancy. Ardeshna:Novartis, Gilead, Bristol Myers Squibb: Other: travel support. Goto:Chugai: Honoraria; Kyowa Kirin: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; SymBio: Research Funding. Barbui:Roche: Honoraria; Pierre Fabre: Honoraria, Other: transport and accomodation to EHA 2024, Speakers Bureau; Incyte: Speakers Bureau. Abramson:Mustang Bio: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Cellectis: Research Funding; Merck: Research Funding; BeiGene Ltd: Consultancy; Seagen Inc.: Research Funding; Interius BioTh: Consultancy; Incyte Corporation: Consul