Tessoulin, Benoit

Abstract Background: Despite the efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKi) in R/R MCL, patients (pts) ultimately discontinue treatment due to intolerance or development of resistance and disease relapse. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib was safe and effective in the phase 1/2 BRUIN study in pts with R/R B-cell malignancies, including those previously treated with a BTKi. Pirtobrutinib is approved in the EU for adults with R/R MCL after prior treatment with a BTKi (EMA Conditional Approval, Oct 2023), and in the USA for adults with R/R MCL after ≥ 2 lines of systemic therapy, including a BTKi (FDA Accelerated Approval, Jan 2023).Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529), with a follow-up period of up to 5 yrs, focusing on the efficacy and safety of pirtobrutinib in all R/R MCL pts. Methods: Pts with R/R MCL who received ≥1 prior lines of therapy (including BTKi) were eligible for treatment with pirtobrutinib monotherapy. Key endpoints included overall response rate (ORR), duration of response (DOR) and progression-free survival (PFS), all assessed by independent review committee (IRC) per Lugano 2014 criteria (presented here) and investigator, overall survival (OS), and safety. Pts were included across the range of doses evaluated in dose escalation and expansion (25-300 mg/day). A data cutoff on 27 January 2025 was utilized, with a median study follow-up of 17.5 months (range, 0.5-69.6). Results: Among the 166 pts with R/R MCL, 153 (92%) received the pirtobrutinib approved dose of 200 mg/day, 152 (92%) had received prior cBTKi, of which 128 (84.2%) discontinued any prior cBTKi due to progressive disease (PD), and 15 (9.9%) due to toxicity. The cBTKi-pre-treated pts had a median age of 70 yrs (range, 46-88), 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. The median number of prior lines of therapy was 3 (range 1-9), with most pts having received a prior anti-CD20 antibody (96.7%) and chemotherapy (90.1%). Additional prior therapies included hematopoietic stem cell transplantation (21.7%; 19.7% auto and 4.6% allo), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%). As of the data cutoff, 11 (7.2%) pts who received a prior cBTKi and 6 (42.9%) cBTKi naïve pts remained on treatment. The cBTKi pre-treated pts had an ORR of 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (CR) (n=24) and 33.6% partial responses (PR) (n=51). The 75 responding pretreated pts had a median DOR of 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The ORR among 128 pts who had discontinued any prior cBTKi due to PD and 15 pts who discontinued due to toxicity was 43.0% and 93.3%, respectively. The median PFS and OS for cBTKi pre-treated pts were 5.6 months (95% CI, 5.3-9.2) and 23.9 months (95% CI, 17.3-51.5), respectively. Fourteen pts (9.2%) were censored for PFS due to subsequent anticancer therapy without documented PD, including 8 pts who received CAR-T. The cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2), including 50.0% CR (n=7) and 35.7% PR (n=5). The 12 responding naïve pts had a median DOR of 42.7 months (95% CI, 25.8-NE) at a median follow-up of 43 months. The median PFS and OS in the cBTKi naïve pts were 44.6 months (95% CI, 16.7-NE) and not reached (95% CI, 33.5-NE), respectively. Among all R/R MCL pts (n=166), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (31.9%), diarrhea (22.9%), anemia (18.1%), and dyspnea (18.1%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%), and the rate of Grade ≥3 infections was 21.1%. Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. In total, 13 (7.8%) pts had a fatal TEAE, with 4 (2.4%) classified as infections. Overall, 8 pts (4.8%) had treatment-related AE leading to dose reductions, and 6 (3.6%) had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate efficacy in pts with heavily pre-treated R/R MCL including both those who previously received a cBTKi and those who were BTKi-naïve. The safety profile of pirtobrutinib remained favorable with a low-rate of dose reductions/discontinuations due to drug-related toxicity. No new safety signals were identified after up to 5 yrs of follow-up.

7049 Background: Odronextamab, an investigational off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy and a generally manageable safety profile in heavily pretreated pts with R/R FL in the primary analysis of the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. Ann Oncol 2024). We present updated efficacy and safety data for odronextamab in pts with R/R FL from ELM-2 after >2 yrs follow-up. Methods: Odronextamab was administered intravenously until disease progression/unacceptable toxicity, with Cycle (C) 1 step-up dosing to help mitigate cytokine release syndrome (CRS) risk, as reported previously. Pts with a complete response (CR) for ≥9 months (mo) switched from maintenance dosing Q2W to Q4W. Primary endpoint: objective response rate (ORR) per Lugano criteria by independent central review (ICR); secondary endpoints: CR rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS). Results: At the updated data cutoff (Aug 15, 2024), 157 pts with centrally confirmed R/R FL Grade (Gr) 1–3a were enrolled. Median no. of treatment cycles: 19.0 (range 0.1–117.3); 96.2% (n = 151) and 82.8% (n = 130) of pts completed C1 and C4, respectively. The global cohort comprised 128 pts evaluable for efficacy. At a median efficacy follow-up of 28.3 mo, ORR was 80.5% (n = 103) by ICR and CR rate was 74.2% (n = 95); 92.2% of responders achieved CR. Responses were durable (median DOR, 26.0 mo; median duration of CR, 32.2 mo). ORR was consistent across high-risk subgroups (Follicular Lymphoma International Prognostic Index score 3–5, 78.4%; progression of disease within 2 yrs of frontline therapy, 81.0%). Median PFS was 23.0 mo (estimated 36-mo PFS rate, 37.5%), and median OS was 54.2 mo (estimated 36-mo OS rate, 62.6%). Median PFS was longer in pts who were minimal residual disease (MRD) negative (42.4 mo) versus MRD positive (21.6 mo) at Week 12. Of 47/128 pts who switched to Q4W dosing, 32 remained in CR. The odronextamab long-term safety profile was consistent with the primary analysis. All 157 pts had TEAEs (Gr ≥3, 86.0%), and 15.3% discontinued treatment due to TEAEs (most common: COVID-19 infection, 2.5%). With 0.7/4/20 mg step-up dosing (n = 89), CRS events were mostly low grade (Gr 1, 46.1%; Gr 2, 13.5%; Gr 3, n = 1; Gr ≥4, n = 0), occurred mostly in C1, and resolved in a median of 8.4 hrs. Immune effector cell-associated neurotoxicity syndrome was reported in one pt (Gr 2). Infections were reported in 79.0% of pts (124/157; Gr ≥3, 42.0%). COVID-19-related infections were reported in 38.2% of pts (Gr 5, 5.7%). Conclusions: With longer follow-up, odronextamab demonstrated durable responses in heavily pretreated pts with R/R FL from ELM-2, with robust efficacy in those with high-risk features, and a generally manageable safety profile. Overall, these compelling results support odronextamab as a potential off-the-shelf treatment option for pts with R/R FL. Clinical trial information: NCT03888105 .

e19057 Background: In ELM-2 (NCT03888105), a Ph 2, single arm, open label trial, odronextamab demonstrated robust efficacy, generally manageable safety, and overall maintenance of patient-reported outcomes (PROs) in R/R FL pts (Villasboas et al. ASH 2023). In FL, pts with disease progression within 2 yrs of frontline chemoimmunotherapy (POD24) are hard to treat with poor clinical outcomes, representing an unmet need. We report PROs by POD24 status in pts with Grade 1–3a R/R FL from ELM-2. Methods: Pts received IV odronextamab in 21-day cycles (C): 80 mg QW in C1–4, with C1 dose step up to mitigate cytokine release syndrome, then 160 mg Q2W (Q4W if complete response ≥9 mo) until progression. PROs were collected at baseline (BL), Wks 2–4, 10, then Q8W in Yr 1, and Q12W in Yr 2. Post-hoc POD24 subgroup analyses were performed on six EORTC QLQ-C30 scales, the EQ-5D-3L VAS, and FACT-Lym LymS. Estimated mean change from BL (CFB) was analyzed using mixed models for repeated measures (MMRM) through Wk 42 (≥10 pts at last assessment). Published meaningful CFB thresholds were used to define deterioration/improvement in responder analyses. Results: By Jan 31, 2023, 140 pts with R/R FL had received odronextamab. Pts with POD24 (n=70) were younger than pts without POD24 (n=70; median age 57.5 vs 62.0 y), had fewer prior Tx lines (median 2 vs 3), and a higher proportion double refractory to anti-CD20 Ab + alkylator (53% vs 29%). Objective response rate was similar in evaluable pts with (n=63; 79%) and without (n=65; 80%) POD24. PRO questionnaire completion ranged from 52–95% through Wk 42 across groups. Descriptive analyses suggest BL PRO scores were similar by POD24 status, showing good HRQoL/functioning and low symptom burden, and were generally maintained through Wk 42 with minimal between-group differences (overlapping 95% CIs for LS mean CFB [Table]). In both groups, more pts reported PRO maintenance or improvement vs deterioration across visits, except for fatigue at Wk 10 in pts without POD24. Conclusions: In pts with heavily pretreated R/R FL, odronextamab Tx maintained HRQoL, functioning, and symptoms irrespective of POD24 status. Clinical trial information: NCT03888105 . [Table: see text]

Abstract Background: R/R FL is an incurable disease and outcomes worsen with successive relapses. A high unmet need remains for therapies that improve tumor control and extend survival after relapse. Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy, generally manageable safety, and maintenance of pt-reported overall quality of life scores from baseline in an interim analysis of the ELM-2 study (NCT03888105) in heavily pretreated pts with R/R FL (Villasboas et al. ASH 2023). Here, for the first time, we present the primary analysis of R/R FL in ELM-2. Methods: IV odronextamab was administered in 21-day cycles (C) until disease progression/unacceptable toxicity. Steroid prophylaxis and step-up dosing (0.7/4/20 mg) were used in C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg on Days (D) 1, 8, and 15 of C2-4. Maintenance dosing continued at 160 mg Q2W, or Q4W if complete response (CR) was durable for 9 months (mo). Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Primary analysis was performed when 128 pts had ≥52 weeks’ follow-up. Results: At data cutoff (Oct 20, 2023), 128 pts with FL Grade (Gr) 1-3a were evaluable for efficacy and safety: median age 61 yrs (range 22-84); FLIPI risk score 3-5 57.8%; POD24 49.2%; median 3 prior lines of therapy (2-13); 71.9% refractory to last treatment (Tx); 74.2% refractory to an anti-CD20 antibody. The median no. of Tx cycles was 19.4 (0.1-95.9); 95.3% and 85.2% of pts completed C1 and C4, respectively.Median efficacy follow-up was 20.1 mo; ORR was 80.5% and CR rate was 73.4% confirmed by ICR. Responses were durable (median DOR 22.6 mo; median DOCR 25.1 mo). Median PFS was 20.7 mo and 24-mo PFS was 46.1%. Median OS was not reached and 24-mo OS was 70.1%.The odronextamab safety profile was generally manageable and consistent with previous reports. Tx-emergent adverse events (AEs) occurred in all pts (Gr ≥3 85.9%); 15.6% had AEs leading to Tx discontinuation. With 0.7/4/20 mg step up (n=60), CRS events were mostly low grade (Gr 1 45.0%; Gr 2 10.0%; Gr 3 in 1 pt), occurred mostly in C1, and resolved in a median of 2 days; ICANS was reported in 1 pt (Gr 2). Infection rates were consistent with heavily pretreated, immunosuppressed pts (Leonard et al. JCO 2019; Hayne et al. BBMT 2020), occurring in 79.7% (102/128) of pts (Gr 4/5 14.0%; COVID-19 36.7% [Gr 5 6.3%]).Conclusion: Odronextamab demonstrated deep and durable responses in heavily pretreated pts with R/R FL; 91% of responders achieved CR, correlating with favorable PFS and OS at 24 mo. Odronextamab had a generally manageable safety profile and a low incidence of Gr 3 CRS/ICANS. Odronextamab could offer an important off-the-shelf Tx option for pts with heavily pretreated R/R FL. Citation Format: Geoffrey Chong, Michal Taszner, Silvana Novelli, Seok-Goo Cho, Jose C. Villasboas, Ana Jiménez Ubieto, Benoît Tessoulin, Michelle Poon, David Tucker, Jan Walewski, Yuqin Song, Emmanuel Bachy, Stephanie Guidez, Aranzazu Alonso, Deepa Jagadeesh, Stefano Luminari, Laura Magnano Mayer, Elżbieta Iskierka-Jażdżewska, Monica Tani, Jingxian Cai, Amulya Uppala, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Tae Min Kim. Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT243.

Background The class of CD20×CD3 bispecific antibodies (BsAbs) has emerged as an important anti-lymphoma modality for patients (pts) with R/R B-cell non-Hodgkin lymphoma. Odronextamab, a novel, off-the-shelf, CD20×CD3 BsAb, has previously demonstrated compelling efficacy in both R/R diffuse large B-cell lymphoma and R/R FL. In pts with R/R FL, odronextamab monotherapy achieved 75% complete response (CR) rates and encouraging durability of responses, and showed generally manageable safety, in the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. ASH. 2022). Here, we report the results of a second, pre-specified interim analysis of ELM-2. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Optimization of the step-up regimen to further mitigate cytokine release syndrome (CRS) was reported previously (Kim TM, et al. ASH. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1, followed by 80 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 160 mg every 2 weeks until disease progression or unacceptable toxicity. Pts who achieved a durable CR for ≥9 months transitioned to dosing every 4 weeks. A pre-specified interim analysis was performed when 80 pts had completed ≥12 months follow-up. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included CR rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and changes in scores of patient-reported outcomes. Minimal residual disease (MRD) was included as an exploratory endpoint. Results At data cut off (Jan 31, 2023), the global study was fully enrolled and included 140 safety-evaluable pts with FL; 128 pts were efficacy-evaluable and 85 pts had ≥12 months follow-up. The median duration of study follow-up for efficacy was 26.6 months. In the safety-evaluable FL population, median age was 60.5 years (range 22-84), 53% were male, and pts had received a median of 3 (range 2-13) prior lines of therapy. 73% of pts were refractory to their last therapy, 41% were double refractory, and 74% were refractory to an anti-CD20 antibody. 50% of pts had progression of disease within 2 years (POD24) and 29% had a prior autologous hematopoietic stem cell transplant. ORR and CR rate by ICR were 80% (102/128) and 72% (92/128), respectively, and were consistent across pts with high-risk features. Responses were durable, with both median DoR and duration of CR of 21.7 months; the probability of maintaining CR for 24 months was 48%. Median PFS was 20.7 months (95% CI: 16.7-26.5) and median OS was not reached; the probability of survival at 3 years was 63%. Patient-reported overall quality of life (QoL) scores were maintained during the course of treatment. MRD status at 12 weeks was highly predictive of PFS. Safety was generally consistent with previous reports, and no new treatment-related Grade (Gr) 5 events were recorded since the first interim analysis. The most common treatment-emergent AEs (>30% all grades) were CRS (55%), anemia (34%), neutropenia (34%), and pyrexia (33%). With the optimized 0.7/4/20 mg step-up regimen (n=72), 98% of CRS events were Gr 1/2, and only one pt had Gr 3 CRS. All CRS events resolved with supportive measures; 13 pts received tocilizumab for CRS management with the optimized regimen. Only one low-grade ICANS event was reported with the optimized regimen. Gr ≥3 infections occurred in 50 (36%) pts (Gr 5, n=14 [10%]); COVID-19 infections were reported in 46 (35%) pts (Gr 5, n=8 [6%]). Conclusions The results of this pre-specified analysis of the Phase 2 ELM-2 study continue to demonstrate deep and durable responses with odronextamab in heavily pretreated, refractory pts with R/R FL. 90% of responders were complete responders, with a 48% probability of maintaining CR for 2 years. High CR rates appear to translate to favorable, long-term survival outcomes in the setting of incurable disease. The incidence of AEs was consistent with earlier reports, with no new treatment-related Gr 5 events. Importantly, continued treatment with odronextamab had no detrimental effects on overall QoL. These data underscore the promise of odronextamab as a potentially effective agent for the management of R/R FL. Updated data will be presented.

Background: Goals of patient-centered care for management of relapsed or refractory follicular lymphoma (R/R FL) are to improve clinical outcomes while maintaining or improving health-related quality of life (HRQoL). In ELM-2 (NCT03888105), a Phase 2, open-label, multicohort, multicenter study, odronextamab monotherapy demonstrated high and durable complete response rates and generally manageable safety in patients with R/R FL. We report here, for the first time, patient-reported outcome (PRO) results from ELM-2 in patients with R/R FL. Methods: Patients with R/R FL Grade 1-3a received odronextamab IV at 80 mg weekly in 21-day cycles in Cycles (C) 1-4. Optimization of the step-up regimen to mitigate cytokine release syndrome (CRS) was reported previously. Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg in C1, then 80 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance continued at 160 mg every 2 weeks until disease progression or unacceptable toxicity. Patients with durable complete response (≥9 months) switched to dosing every 4 weeks. Patients completed EORTC QLQ-C30, FACT-Lym, and EQ-5D-3L questionnaires at Weeks 1 (baseline), 2, 3, 4, and 10, then every 8 weeks for the remainder of the first year and every 12 weeks in the second year. Results here focus on six key PRO scales: EORTC QLQ-C30 Global Health Status/Quality of Life (GHS/QOL), physical functioning (PF), role functioning (RF), and fatigue; FACT-Lym lymphoma subscale (LymS); and EQ-5D-3L visual analog score (VAS). Longitudinal analyses using mixed models for repeated measures (MMRM) were conducted through Week 50 (the last visit with ≥10 patients with PRO data). Changes from baseline were considered statistically significant if the 95% confidence interval did not contain zero. No adjustment for multiplicity was performed, hence all statistical significance is nominal. Published ranges for minimum important difference (MID) to define clinically meaningful changes are: EORTC QLQ-C30 scales, 10 points; FACT-Lym LymS, 2.9-5.4 points; and EQ-5D-3L VAS, 7-12 points. For responder and time to definitive deterioration (TTDD) analyses, the upper end of these published MID ranges was used to define deterioration or improvement. Results: At the ELM-2 interim data cutoff on 31-Jan-2023, 140 patients with R/R FL Grade 1-3a had received at least 1 dose of odronextamab. Median age was 60.5 years (range: 22-84), with 38.6% ≥65 years, 52.9% male, 57.1% White, 32.1% Asian, 52.2% ECOG=0, and 47.1% ECOG=1. Median duration of follow-up was 26.6 months (range: 6.2-37.5). PRO completion rates for EORTC-QLQ-C30, FACT-Lym, and EQ-5D-3L were high at baseline and remained high for all assessments through Week 50. At baseline, moderate levels of general health (GHS/QoL) and high levels of functioning (PF and RF) were observed that were higher (better) than reference values for general cancer or non-Hodgkin's Lymphoma (NHL). Fatigue scores at baseline were lower (less symptoms) than reference values for general cancer or NHL. EORTC QLQ-C30 GHS/QOL, PF, RF, and fatigue scores were maintained from baseline through Week 50 (Table). For EQ-5D-3L VAS, the overall estimated mean changes from baseline improved statistically significantly but did not reach MID thresholds (Table). For FACT-Lym LymS, overall estimated mean change from baseline statistically significantly improved, and scores improved statistically significantly from Weeks 10 to 42 (except Week 34), with clinically meaningful improvements at Weeks 26 and 42 (Figure). The proportion of patients reporting meaningful improvement or stability across the six scales was higher than the proportion reporting meaningful worsening through Week 50 (Table). The median TTDD for EORTC-QLQ-C30 GHS/QoL was 22.41 (95% CI: 14.59 to not yet reached) months, corresponding to the median PFS. Median TTDD was not reached for EORTC QLQ-C30 PF, FACT-Lym LymS, and EQ-5D-3L VAS scales. Conclusions: For patients with R/R FL, patient-reported HRQoL results were favorable during odronextamab treatment until disease progression, with no detriments on patient-reported symptoms, functioning, and overall quality of life. These results complement encouraging clinical efficacy, durability of responses, and tolerability observed in this highly refractory patient population and support the future role of odronextamab in the management of patients with R/R FL.

Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.

PURPOSE Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis. METHODS Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529 ). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety. RESULTS The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event. CONCLUSION Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.