Bristol-Myers Squibb (United States)

In the phase 2, double-blind, randomized controlled BEYOND trial (NCT03342404), luspatercept increased hemoglobin levels in patients with non-transfusion-dependent β-thalassemia (NTDT). This study assessed long-term effects of luspatercept on patient-reported outcomes (PROs), using data from BEYOND and patients who continued luspatercept treatment in the phase 3b long-term follow-up (LTFU) study (NCT04064060). In BEYOND, patients received luspatercept or placebo Q3W for ≥ 48 weeks. PRO instruments included NTDT-PRO (BEYOND only), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Survey (SF-36). Mixed-effects models with repeated measures estimated least squares mean changes from baseline in PROs. PROs were evaluable in 144 patients (luspatercept 95, placebo 49) from BEYOND and 58 (luspatercept) from LTFU. Luspatercept improved NTDT-PRO tiredness/weakness and shortness of breath domain, FACIT-F fatigue subscale, and SF-36 vitality scores versus placebo through double-blind treatment (generally maintained through week 96). In LTFU patients, significant, meaningful improvements from baseline in FACIT-F fatigue subscale and SF-36 vitality scores were observed within 12 weeks of treatment initiation and maintained for up to 5 years. Other FACIT-F and SF-36 domains improved or were maintained throughout LTFU. Luspatercept offers rapid and durable benefits by improving anemia-related symptoms and quality of life in patients with NTDT. Trial Registration: ClinicalTrials.gov Identifier: NCT03342404; NCT04064060.

Xanomeline and trospium chloride (X/T) reduced symptoms and was generally well tolerated in two phase 3, 5-week, randomized, double-blind, placebo-controlled trials in adults with schizophrenia. The authors evaluated the long-term safety, tolerability, and efficacy of X/T in an open-label extension of the two phase 3 trials. EMERGENT-4 was a 52-week open-label extension trial of participants who completed the EMERGENT-2 and EMERGENT-3 acute trials. Between February 2021 and October 2023, 152 participants initiated twice-daily oral doses of xanomeline 50 mg/trospium 20 mg and titrated to a maximum dosage of twice-daily oral xanomeline 125 mg/trospium 30 mg. The primary endpoint was the proportion of participants reporting a treatment-emergent adverse event (TEAE). Efficacy measures included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions severity scale (CGI-S). A total of 156 (42.6%) of the 366 participants who completed EMERGENT-2 or EMERGENT-3 enrolled in EMERGENT-4; of these 34 (21.8%) enrolled participants completed the 52-week treatment period. Overall, 81 (53.3%) of 152 treated participants experienced at least one TEAE. Consistent with the acute trials, the most common treatment-related adverse events were gastrointestinal disorders (e.g., nausea, vomiting, dyspepsia, dry mouth) that were mild or moderate in intensity and resolved with continued treatment. No new safety or tolerability issues were observed. X/T was not associated with clinically meaningful motor symptoms, hyperprolactinemia, weight gain, or adverse effects on metabolic parameters. X/T was associated with continued symptom improvement over the trial duration. Mean changes in PANSS total score from acute trial baseline to week 52 were -33.8 and -31.3 in the treatment groups receiving X/T and placebo, respectively, in the acute trials. Similar patterns of continued improvement were observed for scores on the CGI-S, PANSS positive subscale, and PANSS negative subscale. Long-term treatment with X/T over 52 weeks was safe, generally well tolerated, and associated with durable symptom improvement in people with schizophrenia.

B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.

508 Background: C+N is approved as first-line treatment in aRCC based on the CheckMate 9ER trial, which demonstrated superior progression-free survival (PFS) and overall survival (OS) versus sunitinib in this pt population. In this exploratory, post hoc analysis, we characterized the depth and durability of response with long-term follow-up (based on the final analysis of CheckMate 9ER) in pts receiving C+N. Methods: Pts received C (40 mg) once daily plus N (240 mg) every 2 weeks. Depth of response (DepOR) subgroups were based on best overall response (blinded independent central review [BICR] per RECIST v1.1) and best tumor reduction threshold, as follows: complete response (CR); partial response subdivided by a tumor reduction of ≥80% (PR1), ≥60%–<80% (PR2), or ≥30%–<60% (PR3); stable disease (SD); and progressive disease (PD). PFS (per BICR) and OS were analyzed by DepOR subgroups after a 6-month post-randomization landmark. Results: Of 323 pts randomized to C+N, 293 pts were alive, and 234 pts were alive and progression-free at the 6-month landmark and were categorized by DepOR subgroup. With a median follow-up of 67.6 months (range: 60.2–80.2), pts with a CR exhibited a durable response and prolonged benefit in DOR, PFS, and OS (Table). Pts who experienced a response (CR or any PR) included those with liver metastases (16%– 29%), sarcomatoid features (6%–15%), ≥2 metastatic sites (60%–78%), and poor IMDC risk (7%–17%). Median duration of therapy was 30.4 (CR), 29.9 (PR1), 35.6 (PR2), 23.0 (PR3), 15.3 (SD), and 9.0 (PD) months. Any-grade treatment-related adverse events were generally consistent across DepOR subgroups. Conclusions: This exploratory analysis of CheckMate 9ER revealed durable responses in pts who experienced a CR. Pts who responded to treatment (CR or any PR) included those with poor prognostic characteristics. Clinical trial information: NCT03141177 . Clinical outcomes by DepOR subgroup in pts treated with C+N. DepOR Median DOR a (95% CI), months PFS DepOR pop n=234n (%) 48-month b PFS (95% CI), % Median PFS b (95% CI), months OS DepOR popn=293n (%) 48-month b OS (95% CI), % Median OS b (95% CI), months CR NR(30.5, NE) 45 (19) 54(38, 68) NR(30.4, NE) 45 (15) 84(70, 92) NR(NE, NE) PR1 22.1(15.1, 26.0) 25 (11) 12(3, 28) 18.8(13.3, 32.7) 27 (9) 56(35, 72) 51.6(32.2, NE) PR2 21.7(14.1, 30.4) 36 (15) 24(11, 39) 18.9(13.3, 27.4) 38 (13) 67(50, 80) 63.2(47.0, NE) PR3 10.8(7.0, 17.3) 63 (27) 3(0, 13) 9.4(5.5, 17.0) 70 (24) 42(30, 53) 41.9(33.8, 49.5) SD NA 65 (28) 4(1, 11) 5.9(3.9, 10.0) 98 (33) 29(20, 39) 28.7(17.5, 35.0) PD NA NA NA NA 15 (5) 20(5, 42) 11.0(4.8, 25.1) a Calculated in the OS DepOR response (CR or any PR) pop. b From the 6-month landmark.DOR, duration of response;

The development of allele-specific KRAS inhibitors underscores the importance of understanding the distinct tumor biology associated with common KRAS mutations, G12D and G12C, in genetically engineered mouse models (GEMMs) of non-small cell lung cancer (NSCLC) and patient samples. Lung tumors driven by the most common KRAS mutation, G12C, show delayed onset and slower progression compared with those driven by KRAS G12D in patients and mice. G12C tumors display lower proliferation and increased immune cell engagement, the latter of which is consistent with observations in patient tumors. Allele-specific KRAS G12C/D inhibitors effectively suppress the growth of respective autochthonous lung tumors. However, G12D-driven tumors relapse more rapidly than G12C-driven tumors in autochthonous models, reflecting greater intrinsic aggressiveness. Given this aggressive clinical behavior, we focused on elucidating the mechanism of action and strategies to potentiate KRASG12D inhibition in nonimmunogenic and immunogenic lung cancer models. G12D inhibition enhances tumor antigen presentation, activates T cells, and enables antigen-specific cytotoxicity, leading to efficacy with immune checkpoint blockade combination. This combination induces durable immune memory in immunogenic models but not in nonimmunogenic settings. Our findings underscore key differences between KRAS G12D and G12C mutations in shaping lung cancer biology, reveal distinct resistance dynamics under long-term targeted therapy, and uncover immune-mediated mechanisms specific to KRASG12D inhibition with direct clinical and translational relevance.

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