The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2–4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.
Context: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but many patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type and C481-mutated BTK with equal low nM potency. Objective: Determine whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naïve MCL. Design: BRUIN MCL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated, BTKi-naïve MCL. Approximately 500 patients will be randomized 1:1. Randomization will be stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Setting: Global; community hospitals, academic medical centers. Patients: Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL who received ≥ 1 prior line of systemic therapy for MCL that did not include a prior BTKi. Patients must have measurable disease per Lugano criteria and must have progressed on or relapsed following the most recent line of therapy prior to study enrollment. Key exclusion criteria include a history of current or prior CNS involvement, significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of randomization, and allogeneic stem cell transplant (SCT), autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. Interventions: Pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy. Main outcome measures: The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee, with the goal of demonstrating the superiority of pirtobrutinib over the investigator's choice of covalent BTKi. Secondary endpoints include overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04662255). Results: Trial in Progress. Conclusions: Trial in Progress.
Context: ASPEN is a randomized, open-label, phase 3 study comparing zanubrutinib, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi, ibrutinib, in Waldenström macroglobulinemia (WM). Data with a median follow-up of 43 months are presented. Design: In cohort 1, patients with MYD88 mutations were randomized 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily; stratifications were CXCR4 mutations and prior lines of therapy. In cohort 2, patients without MYD88 mutations received zanubrutinib 160 mg twice daily. Main outcome measures: The primary endpoint was the proportion of patients with complete response/very good partial response (CR+VGPR). Results: In cohorts 1 and 2, 201 (zanubrutinib=102; ibrutinib=99) and 28 patients were enrolled, respectively. More cohort 1 patients in the zanubrutinib versus ibrutinib arm had CXCR4 mutations (32% [33/98] vs 20% [20/92] with next-generation sequencing data) and were aged >75 years (33% vs 22%). With median treatment durations of 42 (zanubrutinib) and 41 (ibrutinib) months, 67% and 58% remain on treatment, respectively. Investigator-assessed CR+VGPR rate was 36% versus 22% (zanubrutinib vs ibrutinib; P=0.02) and 31% in cohort 2 (1 CR). CR+VGPR rates for wild-type CXCR4 were 45% versus 28% (zanubrutinib vs ibrutinib; P=0.04) and were 21% versus 5% (P=0.15) for mutated CXCR4. Median progression-free survival and overall survival were not yet reached. Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, grade ≥3 infection, and adverse events leading to discontinuation/death were lower for zanubrutinib versus ibrutinib, as were exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension (0.2 vs 0.8 and 0.5 vs 1.0 persons/100 person-months; P<0.05); neutropenia rate was higher. Zanubrutinib safety outcomes were similar between cohorts. Conclusions: ASPEN is the largest phase 3 WM trial with head-to-head BTKi comparison. At a median follow-up of 43 months, zanubrutinib had higher CR+VGPR rates and clinically meaningful advantages in long-term safety/tolerability versus ibrutinib.
Context: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but most patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild-type and C481-mutated BTK with equal low nM potency. Objective: To evaluate pirtobrutinib safety and efficacy in patients with MCL. Design: BRUIN is an ongoing multicenter phase 1/2 study (NCT03740529) of pirtobrutinib monotherapy. Setting: Global; community hospitals, academic medical centers. Patients: Patients with advanced B-cell malignancies. Interventions: Oral pirtobrutinib, phase 1 dose-escalated in a standard 3+3 design, phase 2 continuous therapy, 28-day cycles. Main outcome measures: The primary phase 1 objective was to determine the recommended phase 2 dose (RP2D) and the primary phase 2 objective was overall response rate (ORR); secondary objectives included duration of response, progression-free survival, overall survival, safety/tolerability, and pharmacokinetics. Results: As of 27 September 2020, 323 patients (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL) were treated on 7 dose levels (25-300mg QD). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in >10% of patients. The most common adverse event of grade ≥3 was neutropenia (10%). Five (1%) patients discontinued due to treatment-related adverse events. 52 prior BTKi treated MCL patients were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%]), 11 PD [21%] and 5 [10%] discontinued prior to first response assessment). Median follow-up was 6 months (0.7-18.3+). Responses were observed in 9/14 patients (64%) with prior autologous or allogeneic stem cell transplant, and 2/2 with prior CAR-T cell therapy. Conclusions: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new patients with MCL and an additional 10 months since the prior data-cut will be presented.
Context: Covalent BTK inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but many patients (pts) will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type and C481-mutated BTK with equal low nM potency. Objective: To evaluate the safety and efficacy of pirtobrutinib in previously treated CLL/SLL. Design: BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy. Setting: Global; community hospitals, academic medical centers. Patients: Pts with advanced B-cell malignancies. Intervention: Oral pirtobrutinib, phase 1 dose escalated in a standard 3+3 design, phase 2 continuous monotherapy, 28-day cycles. Main outcome measures: The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D). The primary objective of phase 2 was ORR. Secondary objectives included duration of response, progression-free survival, overall survival, safety and tolerability, and pharmacokinetics. Results: As of 27 September 2020, 323 previously treated pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other) were treated on 7 dose levels (25-300mg QD). No dose limiting toxicities were reported and MTD was not reached (n=323). 200mg QD was selected as RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent TEAEs regardless of attribution or grade seen in >10% pts. Most common AE of grade ≥3 was neutropenia (10%). 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (0.16-17.8+). ORR was 63% (95%CI 55-71) with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%) and 1 PD (1%), and 5 (4%) discontinued prior to first response assessment. Among 121 BTKi pretreated pts, ORR was 62% (95%CI 53-71). Responses deepened over time with an ORR of 86% among pts with >10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other (52%). Of 88 responding pts, all except 5 remained on therapy. Conclusions: Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data from 252 efficacy evaluable BTK pre-treated CLL/SLL patients with a data cutoff date of 16 July 2021 will be presented.
Context: Durable responses with the immunotherapy tafasitamab+lenalidomide were previously reported in ASCT-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in the Phase II L-MIND trial (NCT02399085). Based on L-MIND, tafasitamab+lenalidomide received accelerated approval (US) and conditional approval (EU and other countries) in this setting. Objective: To describe the long-term efficacy and safety of tafasitamab+lenalidomide in L-MIND patients who received treatment for ≥2 years. Methods: Ongoing, multicenter, open-label, single-arm Phase II study. Eligibility: ≥18 years old, histologically confirmed DLBCL, and 1-3 prior systemic therapies for DLBCL, including ≥1 anti-CD20 therapy. Tafasitamab: twelve 28-day cycles (12 mg/kg IV) QW during Cycles 1-3, with a loading dose on Cycle 1 Day 4; Q2W Cycles 4-12. Lenalidomide: 25 mg PO Cycles 1-12 Days 1-21. Cycle 13+ tafasitamab monotherapy Q2W until disease progression. Time-to-event, treatment response, and safety endpoints were assessed. Results: Of 80 patients in the full analysis set, 27 (34%) received treatment for ≥2 years (median: 4.3 years). At data cut-off (February 15, 2022), 23 of 27 patients were confirmed alive, one was lost to follow-up, one died with unknown cause, and two died following adverse events (AEs) unrelated to study treatment. Thirteen patients remained on treatment, including six with treatment ≥5 years. Fourteen patients discontinued tafasitamab after ≥2 years due to progressive disease (n=4), patient/physician's decision (n=8), and non-treatment-related fatal AEs (n=2: one each, COVID-19 and cardiovascular AE). Among the 27 patients who received treatment for ≥2 years, the AE analysis for patients receiving tafasitamab+lenalidomide combination therapy (Cycles 1-12) and tafasitamab monotherapy (Cycles 13-24) by exposure-adjusted incidence revealed lower incidence of AEs during tafasitamab monotherapy compared with combination therapy. The majority of AEs were Grade 1-2. The most common AEs (≥1 event/patient-year) were neutropenia and diarrhea during combination (incidence, all-grade/Grade ≥3 AEs: 3.87/1.91 and 1.04/0.04, respectively) and following monotherapy (incidence, all-grade/Grade ≥3 AEs: 0.87/0.45 and 0.32/0.0, respectively). Conclusions: Tafasitamab+lenalidomide followed by tafasitamab monotherapy provided durable responses, with long-term treatment efficacy in those patients who received tafasitamab for up to 5 years. The adverse event burden decreased as patients transitioned from combination therapy to tafasitamab monotherapy. Funding: MorphoSys AG.
Context: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. Design: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m2) and rituximab (cycle 1: 375 mg/m2; cycles 2-6: 500 mg/m2); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. Main outcome measures: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. Results: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading to death=11 patients (4.6%) versus 11 patients (4.8%). No sudden deaths occurred. Conclusions: In summary, zanubrutinib significantly improved PFS-IRC versus BR and was well tolerated, supporting the potential utility of frontline zanubrutinib in treatment-naïve CLL/SLL.
Poster: ABCL-073 Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) Versus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) Therapy in Patients With Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results From the Phase III POLARIX Study
Context: CLL/SLL treatment has been transformed with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib. Zanubrutinib, a next-generation BTKi, was designed to maximize BTK occupancy and minimize toxicity. ALPINE (NCT03734016) is a global, randomized, phase 3 study of zanubrutinib versus ibrutinib in patients with R/R CLL/SLL; presented here is a pre-planned interim analysis conducted ~12 months after 415 patients enrolled between November 5, 2018, and December 20, 2019. Design: Patients were randomized 1:1 to zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) arms; stratification factors were age (<65 years vs ≥65 years), geographic region, refractory status, and del(17)p/TP53 mutation. Main outcome measures: Primary endpoint was investigator-assessed overall response rate (ORR) per 2008 IWCLL guidelines or Lugano criteria; the noninferiority of zanubrutinib-to-ibrutinib response ratio was evaluated at the noninferiority margin of 0.8558. If noninferiority was demonstrated, superiority of zanubrutinib versus ibrutinib in ORR was tested. Results: Baseline characteristics (zanubrutinib versus ibrutinib): age ≥65 years: 62.3% versus 61.5%, male sex 68.6% versus 75%; >3 prior therapies: 7.2% versus 10.1%; del(17)p: 11.6% versus 12.5%; TP53 mutation without del(17)p: 8.2% versus 5.8%. With a median follow-up of 15 months, ORR was 78.3% versus 62.5% for zanubrutinib versus ibrutinib, respectively (2-sided P=0.0006, prespecified a=0.0099). ORR was higher for zanubrutinib in patients with del(11)q (83.6% vs 69.1%) and del(17)p (83.3% vs 53.8%); zanubrutinib had higher overall 12-month progression-free survival (PFS; 94.9% vs 84.0%) and overall survival (97.0% vs 92.7%). Significantly fewer patients had atrial fibrillation/flutter (AF) with zanubrutinib versus ibrutinib (2.5% vs 10.1%, 2-sided P=0.0014, prespecified a=0.0099). Zanubrutinib had lower rates of major bleeding (2.9% vs 3.9%), adverse events leading to discontinuation (7.8% vs 13.0%), and death (3.9% vs 5.8%). Zanubrutinib had a higher neutropenia rate (28.4% vs 21.7%) while grade ≥3 infections (12.7% vs 17.9%) were lower. Conclusions: In summary, this interim analysis showed zanubrutinib had a superior ORR, improved PFS, and lower AF rate compared to ibrutinib.
Oral Abstract: ABCL-073 Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) Versus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) Therapy in Patients With Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results From the Phase III POLARIX Study
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