Citations

Abstract Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL patients, most of whom had prior treatment with a covalent BTKi (Mato et al. Lancet 2021;397,10277:892-901). The purpose of this randomized study is to demonstrate the superiority of pirtobrutinib compared to investigator's choice of covalent BTKi in patients with previously treated MCL. Study Design and Methods: 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). Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL (cyclin D1 overexpression, and ≥ 1 B-cell marker) who have 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. The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee (IRC), with the goal of demonstrating superiority of pirtobrutinib over investigator's choice of covalent BTKi. Secondary endpoints include overall response rate (ORR), duration of response (DoR), investigator-assessed PFS per Lugano criteria, overall survival (OS), event-free survival (EFS), time to treatment failure (TTF), time to next treatment (TTNT), time from randomization to disease progression on next line of treatment or death from any cause (PFS2), safety and tolerability, and patient reported outcomes. This global study is currently enrolling patients (NCT04662255). Disclosures Eyre: Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Janssen: Honoraria; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; Roche: Consultancy, Honoraria; AstraZeneca: Honoraria, Research Funding; Beigene: Honoraria, Research Funding; Secura Bio: Consultancy, Honoraria. Shah: Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Epizyme: Consultancy; Umoja: Consultancy; Legend: Consultancy; Incyte: Consultancy; Lily: Consultancy, Honoraria, Research Funding. Dreyling: Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Incyte: Consultancy, Speakers Bureau. Vandenberghe: Jansnens: Honoraria; Abbvie: Honoraria. Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Wang: Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Cheah: Loxo/Lilly: Consultancy, Honoraria, Other: advisory; Janssen: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; Celgene: Research Funding; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding. Gandhi: Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Sharman: AstraZeneca: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; BMS: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Yin: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Balbas: Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Kherani: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Wang: AstraZeneca, Bayer Healthcare, BeiGene, CSTone, DTRM Biopharma (Cayman) Limited, Epizyme, Genentech, InnoCare, Janssen, Juno, Kite Pharma, Loxo Oncology, Miltenyi Biomedicine GmbH, Oncternal, Pharmacyclics, VelosBio: Consultancy; Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Innocare, Janssen, Juno, Kite, Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, VelosBio: Research Funding; Acerta Pharma, Anticancer Association, AstraZeneca, BeiGene, CAHON, Chinese Medical Association, Clinical Care Options, Dava Oncology, Epizyme, Hebei Cancer Prevention Federation, Imbruvica, Imedex, Janssen, Kite Pharma, Miltenyi Biomedicine GmbH, Moffit : Honoraria.

Abstract Background: Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide combined with rituximab (R 2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with iNHL (RELEVANCE : N Engl J Med 2018;379:934 and AUGMENT: J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase 3b trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. In the induction phase, lenalidomide 20 mg PO on days 1-21 of a 28-day cycle + rituximab IV at 375 mg/m 2/week cycle 1 and then every 8 weeks starting with cycle 3 (R 2) are administered for 12 cycles. Patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) were randomized 1:1 to R 2 vs rituximab maintenance for 18 months. Data presented here are the complete analysis from the induction phase in efficacy-evaluable patients with FL grades 1-3a or MZL (FL grade 3b, tFL, and MCL not included). The focus of this interim analysis was overall response rate (ORR) by 1999 IWG criteria in the induction intention-to-treat population. Results: As of March 5, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. The median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% (n = 279) with 42% (n = 164) CR/CRu (Table). All patients have completed R 2 induction (n = 232, 59%) or discontinued study treatment (n = 162, 41%). 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs) (n = 54, 14%) or progressive disease (n = 42, 11%). The majority of patients who have completed induction have been randomized and entered maintenance (n = 217). Median duration of response in the induction period was not reached (95% CI, 43.9 mo-NR), and median progression-free survival in the induction safety population (n = 393) was 50.5 mo (95% CI, 39.5-NR). Efficacy results are reported in the table by histology subgroups (FL vs MZL), and rituximab-refractory, double-refractory, and early relapse statuses. Most common all-grade AEs were 47% fatigue, 43% neutropenia, 37% diarrhea, 30% nausea, and 30% constipation. Grade 3/4 AEs occurring in ≥ 5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, and 5% fatigue. Conclusions: These data represent complete analysis of all patients in the induction phase of MAGNIFY which continue to support that R 2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients. Figure 1 Figure 1. Disclosures Lansigan: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Coleman: immunomedics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Abbvie: Research Funding; Bristol Myers: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; BeiGene: Research Funding; Innocare: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning: Sanofi: Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Nowakowski: Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Curis: Consultancy; Selvita: Consultancy; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Karyopharm Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Kyte Pharma: Consultancy; Roche: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys: Consultancy. Gharibo: BMS: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ahn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; ADC therapeutics: Current equity holder in publicly-traded company. Li: BMS: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Sharman: BeiGene: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; AbbVie: Consultancy.

Abstract The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.

PURPOSE Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years). MATERIALS AND METHODS Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non–cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered. RESULTS Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% v 80%, P < .01), similar T stage (% T1-3/T4: 76/24 v 77/23, P = .97), higher N2 disease rate (24% v 22%, P < .01), more likely to complete the planned treatment duration (83.2% v 78.2%, P < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% v 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; P value < .001) and higher 5-year cancer-specific mortality rate (24% v 20%; HR 1.21; 95% CI, 1.00 to 1.47; P value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% v 56%; HR 0.97; 95% CI, 0.73 to 1.29; P value = .85). CONCLUSION Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology.

Study Design This study is a retrospective case control. Objectives This study aims to determine whether cervical degenerative spondylolisthesis (DS) is associated with increased baseline neck/arm pain and inferior health quality states compared to a similar population without DS. Methods Patient demographics, pre-operative radiographs, and baseline PROMs were reviewed for 315 patients undergoing anterior cervical decompression and fusion (ACDF) with at least 1 year of follow-up. Patients were categorized based on the presence (S) or absence of a spondylolisthesis (NS). Statistically significant variables were further explored using multiple linear regression analysis. Results 49/242 (20%) patients were diagnosed with DS, most commonly at the C4–5 level (27/49). The S group was significantly older than the NS group (58.0 ± 10.7 vs 51.9 ± 9.81, P = .001), but otherwise, no demographic differences were identified. Although a higher degree of C2 slope was found among the S cohort (22.5 ± 8.63 vs 19.8 ± 7.78, P = .044), no differences were identified in terms of preoperative visual analogue scale (VAS) neck pain or NDI. In the univariate analysis, the NS group had significantly increased VAS arm pain relative to the S group (4.93 ± 3.16 vs 3.86 ± 3.30, P = .045), which was no longer significant in the multivariate analysis. Conclusions Although previous reports have suggested an association between cervical DS and neck pain, we could not associate the presence of DS with increased baseline neck or arm pain. Instead, DS appears to be a relatively frequent (20% in this series) age-related condition reflecting radiographic, rather than necessarily clinical, disease.