Min Vedal

An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d'Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee-assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839 .

Introduction: Pts with R/R indolent NHL (iNHL), particularly those with high-risk features, have poor outcomes. TRANSCEND FL (NCT04245839), a global, phase 2, single-arm, multicohort, pivotal study assessed efficacy and safety of the anti-CD19 CAR T cell therapy liso-cel in pts with R/R iNHL. We report primary analysis results in pts with R/R FL, with safety in all liso-cel–treated pts (i.e., second-line or later [2L+] pts; safety set) and efficacy focused on pts in third line or later (3L+). Methods: Eligible pts with R/R FL included 3L+ pts and second-line (2L) pts with disease progression within 24 mo (POD24) of diagnosis and/or modified Groupe d'Etude des Lymphomes Folliculaires (GELF) 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. Bridging therapy was allowed. 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), PFS, OS, safety, and PK. Pharmacodynamics (PD) were exploratory. Results: At data cutoff (January 27, 2023), of 139 leukapheresed pts, 130 (94%) received liso-cel, 5 received nonconforming product, and 124 (89%) were efficacy evaluable (EE) per IRC. 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 FL International Prognostic Index. Forty-three percent of pts had POD24, 53% met GELF criteria, and 64% were double refractory to anti-CD20 antibody and an alkylator. Median (range) prior lines of therapy was 3 (2–10). Median (range) follow-up was 18.9 mo (0.3–28.2). In EE pts with 3L+ FL (n = 101), the primary endpoint of ORR was met at 97.0% (95% CI, 91.6–99.4; one-sided P < 0.0001; Table). CR rate was 94.1% (95% CI, 87.5–97.8; one-sided P < 0.0001). With a median follow-up of 16.6 mo and 17.5 mo, respectively, median DOR and PFS were not reached; 12-mo DOR and PFS were 81.9% and 80.7%, respectively. ORR, CR rate, DOR, and PFS were similar in EE pts with 2L+ FL. In the safety set (2L+ FL, n = 130), the most common grade (gr) ≥3 treatment-emergent adverse events (TEAE) were cytopenias; neutropenia was most frequent (65%). One TEAE death due to gr 5 macrophage activation syndrome occurred. Cytokine release syndrome (CRS) occurred in 58% of pts (gr 3, 1%; no gr 4–5) and neurological events (NE) in 15% (gr 3, 2%; no gr 4–5; Table). Prolonged cytopenia (gr ≥3 laboratory values at Day 29) occurred in 22% of pts and gr ≥3 infection in 5%. PK/PD data will be presented. Conclusions: In pts with R/R FL, liso-cel demonstrated clinically meaningful benefit, with high response rates that were durable, and a favorable safety profile, with low rates of gr ≥3 TEAEs of CRS/NEs, prolonged cytopenia, and infection. The research was funded by: This study was funded by Celgene, a Bristol-Myers Squibb Company. All authors contributed to and approved the abstract; writing and editorial assistance were provided by Amy Agbonbhase, PhD, CMPP, of The Lockwood Group (Stamford, CT, USA), funded by Bristol Myers Squibb. Keyword: Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract F. Morschhauser Consultant or advisory role Gilead, Novartis, BMS, Roche, Genmab, Abbvie Honoraria: Roche, Chugai Other remuneration: Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Gilead, Astra Zeneca, Abbvie S. Dahiya Other remuneration: Advisory board: BMS M. L. Palomba Consultant or advisory role Novartis, Cellectar, Synthekine, Kite, Seres, Magenta, WindMIL, Rheos, Nektar, Notch, Priothera ,Ceramedix, Lygenesis, Pluto Stock ownership: Juno, Seres Research funding: Seres Other remuneration: Royalties or licenses: Juno, Seres; Patents planned, issued or pending: Juno, Seres A. M. Garcia-Sancho Consultant or advisory role Roche, BMS/Celgene, Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, Gilead/Kite, Incyte, Lilly, Takeda, ADC Therapeutics America, Miltenyi, Ideogen, Abbvie Honoraria: Roche, BMS/Celgene, Janssen, Gilead/Kite, Takeda, Eusa Pharma, Novartis Educational grants: Gilead/Kite, Janssen, Roche, BMS/Celgene Other remuneration: Participation on a Data Safety Monitoring Board or Advisory Board: BMS J. L. Reguera Ortega Honoraria: Kite/Gilead, Novartis, Janssen, Sanofi, Amgen, BMS Educational grants: Kite/Gilead, Janssen J. Kuruvilla Consultant or advisory role Abbvie, Antengene, BMS, Gilead, Karyopharm, Merck, Roche, Seattle Genetics Honoraria: Abbvie, Amgen, Astra Zeneca, BMS, Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, Seattle Genetics Research funding: Roche, Astra Zeneca, Merck Educational grants: Kite Other remuneration: Participation on a Data Safety Monitoring Board or Advisory Board: Karyopharm; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Lymphoma Canada U. Jager Honoraria: BMS, Novartis, Gilead, Miltenyi, Janssen and Roche Other remuneration: supported by the Innovative Medicines Initiative (IMI) T2EVOLVE and receives funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 945393. This Joint Undertaking receives support from the European Union ́;s Horizon 2020 research and innovation program and EFPIA. G. Cartron Consultant or advisory role BMS, Roche, Abbvie, MedXcell, Ownards Therapeutic, MabQi Honoraria: Gilead, Jansen, Novartis, Roche, BMS, Abbvie K. Izutsu Consultant or advisory role Otsuka, Kyowa Kirin, Genmab, Tanabe Mitsubishi Honoraria: Bristol Myers Squibb, AstraZeneca, Eisai Zenyaku, Kyowa Kirin, Takeda, Chugai, Novartis, MSD, SymBio, Nihon Shinyaku, Abbvie, Ono Pharmaceutical, Pfizer, Eli Lilly, Meiji Seika Pharma, Daiichi Sankyo Other remuneration: Grants or contracts from any entity: Chugai, Otsuka (paid to institution) M. Dreyling Honoraria: Astra Zeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, Roche Research funding: Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche Other remuneration: Advisory board: Abbvie, Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche B. Kahl Consultant or advisory role BMS and Kite Pharmaceuticals H. Ghesquieres Consultant or advisory role Gilead, Roche Honoraria: Gilead, Roche, BMS, Abbvie K. Ardeshna Educational grants: Novartis, Gilead, BMS H. Goto Honoraria: BMS, Novartis, Kite, Chugai, Daiichi-Sankyo, Kyowa-Kirin, Symbio, MSD Other remuneration: Grants or contracts from BMS, Symbio, Kyowa-Kirin. J. S. Abramson Consultant or advisory role Celgene, Novartis, Abbvie, Kite, Genetech, EMD Serono, MorphoSys, Alimera Sciences, Karyopharm Therapeutics, BMS, BeiGene, AstraZeneca, Incyte, Bluebird Bio, Kymera, Epizyme, Genmab, MustangBio, Ono Pharmaceutical, Century Therapeutics, Lilly, Caribou Biosciences, Janssen, Takeda, C4 Therapeutics Honoraria: Regeneron, AstraZeneca, Janssen, BMS/Celgene Research funding: Seattle Genetics, AI Therapeutics, BMS/Celgene I. Fleury Consultant or advisory role Abbvie, AstraZeneca, Beigene, Celgene, Incyte, Janssen, Kite-Gilead, Merck, Novartis, Roche, Seagen Honoraria: Abbvie, Beigene, BMS, Incyte, Janssen, Kite-Gilead, Merck, Novartis, Roche, Seagen S. Mielke Honoraria: Celgene/BMS: Novartis: Janssen: Gilead/KITE: JSMO: Pfizer Other remuneration: Participation on a Data Safety Monitoring Board or Advisory Board: Immunicum/Mendes, Miltenyi. Founder/Leadership (via my institution): SWECARNET. Founder (spouse): ScientifyResearch T. Farazi Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb Other remuneration: Patents: Bristol Myers Squibb O. Fasan Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb J. Lymp Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb M. Vedal Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb R. Nishii Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb A. Avilion Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb J. Papuga Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb L. J. Nastoupil Consultant or advisory role Sirpant, Incyte, Abbvie, Regeneron Honoraria: Gilead/Kite Educational grants: Genentech Other remuneration: Participation on a Data Safety Monitoring Board or Advisory Board: DeNovo, MEI, Genentech, Takeda BMS, Caribou Biosciences, Daiichi Sankyo, Gilead, Janssen, Merck, Novartis, Takeda

ABSTRACT: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB chimeric antigen receptor (CAR) T-cell product approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We present the OUTREACH primary analysis, evaluating the safety and efficacy of outpatient monitoring after liso-cel treatment at community sites in the United States. Adults with R/R LBCL after ≥2 prior lines of therapy received liso-cel. Outpatient vs inpatient monitoring was per investigator discretion. The primary end points were incidences of grade ≥3 cytokine release syndrome (CRS), neurological events (NEs), prolonged cytopenia, and infections. Efficacy was a secondary end point. Eighty-two patients received liso-cel (outpatient monitored, 70%; inpatient monitored, 30%). The median follow-up was 10.6 months (range, 1.0-24.5). In outpatients and inpatients, grade ≥3 CRS occurred in 0% and 0%, NEs in 12% and 4%, infections in 12% and 8%, and prolonged cytopenia in 33% and 32%, respectively. Among outpatients, 25% were never hospitalized after infusion, and 32% were hospitalized ≤72 hours after the day of infusion; the median time to hospitalization was 5.0 days (range, 2-310). The median initial hospitalization duration after liso-cel was 6.0 days (range, 1-28) for outpatients and 15.0 days (range, 3-31) for inpatients. Objective response rate was 80%, complete response rate was 54%, and the median duration of response was 14.75 months (95% confidence interval, 5.0 to not reached). OUTREACH is, to our knowledge, the first and largest study to prospectively assess CAR T-cell therapy with outpatient monitoring in community-based medical centers. Liso-cel demonstrated meaningful efficacy with favorable safety in patients with R/R LBCL. Data support the feasibility of liso-cel administration at community sites with outpatient monitoring. This trial was registered at www.ClinicalTrials.gov as #NCT03744676.

Background: Results with CD19-directed CAR T cell therapy in patients (pts) with second-line (2L) R/R follicular lymphoma (FL) and high-risk features, such as progression of disease within 24 months (POD24) from diagnosis or double refractory to anti-CD20 antibody plus alkylator, have not been previously reported. TRANSCEND FL (NCT04245839), a global, phase 2, open-label, single-arm, multicohort, pivotal study, assessed efficacy and safety of the anti-CD19 CAR T cell therapy lisocabtagene maraleucel (liso-cel) in pts with second line or later (2L+) R/R indolent NHL. Some data from the primary analysis were previously reported, including safety in 2L+ R/R FL, and focused on efficacy in third line or later R/R FL (Morschhauser F, et al. Hematol Oncol 2023;41[S2]:877‒880). Here, we report primary analysis results in the cohort of pts with 2L high-risk R/R FL. Methods: Eligible pts in the 2L R/R FL cohort had biopsy-confirmed FL before enrollment and must have had POD24 with treatment ≤ 6 months from original FL diagnosis and/or must have had high tumor burden as defined by modified Groupe d'Etude des Lymphomes Folliculaires (mGELF) criteria. All pts received 1 prior combination systemic therapy with an anti-CD20 antibody and alkylator. Eligible pts received liso-cel (100 × 10 6 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), PFS, OS, safety, and cellular kinetics. Pharmacodynamic endpoints were exploratory. Results: At data cutoff (January 27, 2023), 23 of 25 leukapheresed pts received liso-cel and were evaluable for safety and efficacy per IRC; 1 received nonconforming product and 1 reached CR after bridging therapy and no longer met eligibility criteria. Median (range) age was 53 y (34-69), 74% had stage III/IV disease, and 35% were high-risk per FL International Prognostic Index (FLIPI). Sixty-five percent of pts had POD24 from initiation of first-line combination chemoimmunotherapy (52% had POD24 from diagnosis), 70% met mGELF criteria (mGELF only, 48%; mGELF and POD24 from diagnosis, 22%), and 48% were double refractory to anti-CD20 antibody plus alkylator. Median (range) on-study follow-up was 18.1 months (1.0-26.8). In efficacy-evaluable pts, the ORR and CR rate were both 95.7% (95% CI, 78.1-99.9; 1-sided P &amp;lt; 0.0001; Table). With a median follow-up of 16.8 months and 17.8 months, respectively, median DOR and PFS were not reached; 12-month DOR and PFS were 89.8% and 91.3%, respectively. The most common grade (gr) ≥ 3 treatment-emergent AEs (TEAE) were cytopenias; neutropenia was most frequent (52%). Cytokine release syndrome (CRS) occurred in 12 (52%) pts (no gr ≥ 3). Median (range) time to onset and resolution of CRS was 6 days (2-9) and 3 days (2-7), respectively. Neurological events (NE) occurred in 4 (17%) pts, with 1 (4%) gr 3 and no gr 4-5 (Table). Median (range) time to onset and resolution of NEs was 8.5 days (6-11) and 2.5 days (1-4), respectively. Three (13%) pts received tocilizumab/steroids for CRS/NEs. Prolonged cytopenia (gr ≥ 3 laboratory values at Day 29) occurred in 3 (13%) pts; all recovered to gr ≤ 2 by Day 90. No gr ≥ 3 infections were reported. One TEAE death occurred in the context of IRC-assessed disease progression due to gr 5 macrophage activation syndrome (MAS). Liso-cel showed rapid expansion with median (range) time to maximum transgene levels of 10 days (7-11). Persistence of liso-cel transgene was detected up to Month 12 in 5 of 18 (28%) pts. B-cell aplasia (&amp;lt; 3% CD19 + B cells in peripheral blood lymphocytes) after liso-cel infusion was rapid and maintained in ≥ 95% of pts through Month 2. Conclusions: This is the first report of outcomes in 2L high-risk R/R FL with CD19-directed CAR T cell therapy. In this population, liso-cel achieved very high CR rates (22 of 23 pts); deep and durable remissions, with follow-up ongoing; and a favorable safety profile with low rates of severe (gr ≥ 3) CRS, NEs, and prolonged cytopenia, and no severe infections. These data support liso-cel as a potential new treatment option in pts with 2L R/R FL at high-risk for treatment failure.

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.