作者: Lugthart, Sanne ; Fleury, Isabelle ; Cheah, Chan Y. ; Xu, Yan ; Sevindik, Omur Gokmen ; Kryachok, Iryna ; Yang, Jing ; Pinto, Antonio ; Phillips, Elizabeth ; Li, Fei ; Leng, Siyang ; Jurczak, Wojciech ; Lv, Fangfang

Introduction: Covalent Bruton tyrosine kinase inhibitors (BTKi) have demonstrated monotherapy activity in relapsed/refractory follicular lymphoma (FL), although response rates and progression free survival (PFS) have been limited. Nemtabrutinib is a once daily, potent, noncovalent, reversible BTKi with a distinct kinase profile, inhibiting BTK and other B-cell receptor relevant kinases. Here, we present the safety and efficacy results from the phase 2 BELLWAVE-003 study (NCT04728893) of nemtabrutinib at the recommended phase 2 dose (RP2D) in participants (pts) with relapsed/refractory (R/R) FL.Methods: The multicenter, open-label, single-arm phase 2 BELLWAVE-003 study enrolled pts with R/R CLL/SLL, Richter transformation, mantle cell lymphoma, marginal zone lymphoma, FL, and Waldenstrom's macroglobulinemia. Pts with R/R FL received nemtabrutinib at RP2D of 65 mg once daily until unacceptable toxicity, disease progression, or withdrawal. The primary endpoint was objective response rate by investigator assessment according to Lugano 2014 criteria. Additional endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety and tolerability. The data cut-off date was April 19, 2024.Results: At data cut-off, 36 pts with R/R FL treated at RP2D were enrolled. The median (range) follow-up was 6.1 mo (0.2-13.9). These pts had a median age of 58 years (range 33-78), 18 (50%) were female. At enrollment, 2 (6%) pts had Follicular Lymphoma International Prognostic Index (FLIPI) score of 0-1 (low), 12 (33%) had FLIPI score 2 (intermediate), and 22 (61%) had FLIPI score 3-5 (high); 33 (92%) pts had Lugano stage III/IV disease The median (range) number of prior lines of therapy was 4 (1-11). All pts had prior chemoimmunotherapy, 32 (89%) had prior lenalidomide, and 11 (31%) had prior PI3K inhibitor.The median (range) time on therapy was 2.8 mo (0.03-9.5), with 16 (44%) pts on therapy at data cut-off. Among 29 efficacy evaluable pts, the ORR was 41% (95% CI, 24-61), including 1 (3%) with CR and 11 (38%) with PR; 6 (21%) pts had stable disease. The median (range) DOR was 5.8 mo (1.5-not reached [NR]) with median (range) time to response of 2.8 mo (range 2.6-5.4). Median PFS in the as treated population was 5.5 mo (95% CI, 2.8-NR). Median OS was NR (95% CI, 10.4-NR), with 6-mo OS rate of 100%.Any-grade adverse events (AEs) occurred in 31 (86%) pts, most commonly neutropenia in 10 (28%) pts, decreased platelet count (8 [22%], and anemia (7 [19%]). Grade 3-4 AEs occurred in 13 (36%) pts, with grade 3-4 decreased platelet count in 3 (8%) pts, thrombocytopenia in 3 (8%) pts, neutropenia in 3 (8%) pts, and anemia in 2 (6%) pts. No atrial fibrillation or other arrhythmia was observed. Dose reductions due to an AE occurred in 1 (3%) pt (sepsis), and discontinuation due to an AE in 3 (8%) pts (thrombocytopenia, drug related toxicity, urticaria). There were no deaths due to an AE.Conclusion: Nemtabrutinib demonstrated promising antitumor activity in a heavily refractory population of pts with FL post chemoimmunotherapy and immunomodulatory therapy. Nemtabrutinib was well tolerated, and no new safety signals were identified. Enrollment and follow-up are ongoing.

2024-11-05·Blood

Lisocabtagene Maraleucel (liso-cel) in Patients (pts) with Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Transcend FL 2-Year Follow-up

作者: Kuruvilla, John ; Morschhauser, Franck ; Palomba, Maria Lia ; Izutsu, Koji ; Nishii, Rina ; Vedal, Min ; Kahl, Brad S. ; Kamdar, Manali ; Fleury, Isabelle ; Abramson, Jeremy S. ; Farazi, Thalia ; Viardot, Andreas ; Jaeger, Ulrich ; Goto, Hideki ; Kumar, Jinender ; Cartron, Guillaume ; Kao, Grace Shih Hui ; Barbui, Anna Maria ; Skarbnik, Alan P ; Borchmann, Peter ; Ardeshna, Kirit ; Papuga, Jessica ; Nastoupil, Loretta ; Ghesquieres, Herve ; Karmali, Reem ; Martín García-Sancho, Alejandro ; Reguera, Juan Luis ; Mielke, Stephan ; Dahiya, Saurabh ; Dreyling, Martin

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.

2024-08-01·Nature Medicine

Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study

Article

作者: Ardeshna, Kirit ; Kumar, Jinender ; Fleury, Isabelle ; Farazi, Thalia ; Lymp, James ; Abramson, Jeremy S ; Izutsu, Koji ; Ghesquieres, Hervé ; Cartron, Guillaume ; Palomba, M Lia ; Jäger, Ulrich ; Kuruvilla, John ; Reguera Ortega, Juan Luis ; Borchmann, Peter ; Viardot, Andreas ; Mielke, Stephan ; Papuga, Jessica ; Karmali, Reem ; Vedal, Min ; Skarbnik, Alan ; Fasan, Omotayo ; Morschhauser, Franck ; Martin Garcia-Sancho, Alejandro ; Barbui, Anna Maria ; Avilion, Ariel ; Dahiya, Saurabh ; Nastoupil, Loretta J ; de Vos, Sven ; Kamdar, Manali ; Nishii, Rina ; Dreyling, Martin ; Kahl, Brad ; Goto, Hideki

AbstractAn 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.

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