Bristol-Myers Squibb (Italy)

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.

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.

The objective of this study was to assess the cost-effectiveness of mavacamten in combination with the standard of care (SoC), composed of beta-blockers and calcium channel blocker monotherapy, compared to the SoC alone in the treatment of patients with obstructive hypertrophic cardiomyopathy with persistent symptoms, from a French collective perspective. A four state Markov model defined by NYHA classification levels I to III/IV and death was developed to simulate the evolution of disease severity over a lifetime horizon. Clinical inputs and utilities were derived from EXPLORER-HCM trial. According to HAS recommendations, costs, life-years (LYs) and quality-adjusted LYs (QALYs) per patient, incremental costs and LYs/QALYs, incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated. Model uncertainty was assessed through deterministic, probabilistic sensitivity analyses and scenario analyses. Mavacamten in combination with SoC was associated with a QALY gain of 1.52, driven by an improved NYHA distribution of mavacamten patients. Incremental discounted costs were €122,651, owing to increased treatment acquisition costs, partly offset by savings in healthcare resource utilization, resulting in an ICUR of €80,799/QALY. The sensitivity analyses showed the results of the model were relatively robust. The probabilistic sensitivity analysis confirmed base-case ICUR, with 80% probability of mavacamten being cost effective at a willingness-to-pay of €93,750/QALY. The scenario analysis simulating a limited societal perspective highlighted the potential benefit of mavacamten treatment on productivity loss costs. On a public list price basis, mavacamten in combination with SoC is a cost-effective strategy for symptomatic obstructive HCM compared to SoC alone.

TPS8124 Background: Standard treatment for limited-stage small-cell lung cancer (LS-SCLC) has recently changed to add durvalumab consolidation after concurrent chemoradiotherapy. Although durvalumab consolidation increases overall survival (OS; Cheng et al. 2024), other therapeutic agents may be able to provide further improvement. BMS-986489 is a potential first-in-class fixed-dose combination of atigotatug (BMS-986012) and nivolumab. Atigotatug binds to fucosyl-monosialoganglioside-1 (fuc-GM1), which is highly expressed on SCLC cells and is largely absent in normal tissues. This binding results in tumor cell death by antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity. The immune effects initiated by atigotatug may further enhance T cell activation by nivolumab, thereby improving outcomes after chemoradiotherapy. In a randomized phase II study in extensive-stage SCLC, atigotatug improved median OS when added to carboplatin, etoposide, and nivolumab (CE/NIVO): 15.6 months (95% confidence interval [CI]: 11.3-NE) vs 11.4 months (95% CI: 9.3-16.5) with CE/NIVO alone (Kalinka et al. 2024). Methods: TIGOS-LS is an open-label, randomized study to evaluate the safety and efficacy of BMS-986489 as consolidation therapy vs the new standard durvalumab following chemoradiotherapy in LS-SCLC. Approximately 250 participants will be enrolled at 80 sites within the US. Eligible participants will be adults (≥18 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and histologically or cytologically confirmed LS-SCLC. All participants must have completed concurrent chemoradiotherapy for LS-SCLC without progression; prophylactic cranial irradiation (PCI) will be permitted before initiation of study treatment. Confirmation of fuc-GM1 expression will not be required. Participants will be stratified based on disease stage (I/II vs III) and receipt of PCI and will be randomly allocated in a 1:1 ratio to either the BMS-986489 or durvalumab arms. BMS-986489 or durvalumab will be administered intravenously at a fixed dose once every 4 weeks for up to 2 years or until other discontinuation criteria are met. Response will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Survival follow-up will occur every 12 weeks for up to 3 years. The primary endpoint is OS. Key secondary endpoints include progression-free survival, objective response rate, clinical benefit rate, disease control rate, duration of response, and safety parameters. Enrollment is projected to start in April 2025. Clinical trial information: NCT06773910 .

2601 Background: The impact of kidney immune-related adverse events (KirAEs) and their management (mgmt) on clinical outcomes in patients receiving immune checkpoint inhibitors (ICI) has not been fully examined. We aimed to evaluate the association between KirAEs, their mgmt, and progression-free survival (PFS) and overall survival (OS) in ICI-treated cancer patients. Methods: Data were drawn from the Flatiron Health Research Database, an EHR-based database representing 280+ U.S. oncology practices. Adults with advanced non-small cell lung cancer (aNSCLC), advanced melanoma (aMel), or metastatic renal cell carcinoma (mRCC) who initiated ICI between 1/1/16 - 12/31/20 were included and followed from ICI initiation to death, loss to follow-up, or end of the study period (12/31/21). CTCAE Grade 2 or higher KirAEs and mgmt actions (immunosuppression using corticosteroids or other immunosuppressants, ICI-regimen holds, ICI-regimen discontinuations) and hospitalizations were curated from unstructured data. Cox regression was used to evaluate the association between KirAEs, their mgmt (both as time-varying covariates) and PFS and OS adjusting for baseline characteristics such as line of therapy and corticosteroid use. The earliest KirAE per patient was examined in survival analyses. Results: The study included 513 aNSCLC, 463 aMel, and 451 mRCC patients. For aNSCLC, aMel, and mRCC, respectively, 21.1%, 29.6%, and 33.9% experienced at least one KirAE, with a median time to onset of 70, 84, and 128 days. Nephritis ranged from 2.1% of KirAEs in aNSCLC to 4.6% in aMel. Elevated creatinine was the most common KirAE (23.6% in mRCC to 29.1% in aNSCLC), followed by acute kidney injury (20.5% in mRCC to 28.4% in aNSCLC). Immunosuppression was used to treat KirAEs in 67.6%, 80.3%, and 67.3% of aNSCLC, aMel, and mRCC patients with KirAEs. In aNSCLC, aMel, and mRCC, respectively, median OS was 17.1, 58.6, and 33.7 months, median PFS was 7.8, 8.9, and 9.5 months, and patients with KirAEs had longer PFS than those without KirAEs [HR (95%CI): 0.65 (0.51-0.83); 0.74 (0.57-0.97); 0.67 (0.53-0.84)]. In aNSCLC, KirAEs were associated with shorter OS [1.31 (0.98-1.74); P = 0.06]. In all cancers, KirAEs that occurred during hospitalization or led to hospitalization were associated with shorter OS (HR≥2.84; P < 0.02). KirAE mgmt was not associated with OS or PFS. Conclusions: Results suggest that while KirAEs might indicate an intensified immune response, their management and impact on survival vary across cancer types and call for cancer-specific strategies for early identification and management of KirAEs in the ambulatory care setting.

7037 Background: TRANSCEND CLL 004 (NCT03331198) is a phase 1/2, open-label, nonrandomized, multicohort study in adult patients (pt) with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma with liso-cel mono and liso-cel + ibrutinib combo cohorts. Given the study design, we performed PS matching/weighting to adjust for differences in key covariates between cohorts to compare efficacy and safety. Methods: Here, PS is the probability of receiving combo given the covariates and estimated by logistic regression. Covariates were hemoglobin, LDH, number of prior therapies, platelets, prior BTKi + venetoclax exposure, R/R on prior BTKi, and bulky disease for efficacy; and ALC, bulky disease, CRP, ferritin, and number of prior therapies for safety. PS balancing methods were optimal 1:1 matching, average treatment effect for treated pts (ATT) full matching, and ATT inverse probability of treatment weighting (IPTW). Efficacy endpoints were response (CR rate, ORR) and time to event endpoints (DOR, PFS, OS). Safety endpoints were proportions of pts with any-grade (gr)/gr ≥ 3 cytokine release syndrome (CRS) and investigator-identified neurological events (NE). Results: Fifty-one and 88 efficacy-evaluable pts were treated at dose level 2 (100 × 10 6 CAR + T cells) in the combo and mono cohorts, respectively. Before matching/weighting on PS, odds of achieving CR and overall response were statistically significantly higher for combo (Table). DOR did not differ between cohorts. For PFS and OS, HRs were lower with combo vs mono (not statistically significant [NS]). Odds of gr ≥ 3 CRS/NE were lower with combo vs mono (NS). After matching/weighting, odds of CR (except IPTW ATT) and overall response remained statistically significantly higher in combo. HRs for PFS and OS and ORs for gr ≥ 3 CRS/NE were numerically lower with combo vs mono (NS, except IPTW ATT for PFS). HRs for DOR were less but close to HR of 1. Conclusions: The liso-cel + ibrutinib combo demonstrated a trend for better efficacy and safety vs liso-cel mono, with statistically significant differences for CR rate and ORR. Clinical trial information: NCT03331198 . Efficacy and safety outcomes: combo vs mono. No adjustment ATT optimal 1:1 IPTW - ATT CR rate, OR (95% CI) 2.07* (1.01–4.28) 2.40* (1.05–5.66) 2.00(0.89–4.61) ORR, OR (95% CI) 3.96* (1.68–10.51) 3.43* (1.33–9.71) 4.18* (1.63–11.78) DOR, HR (95% CI) 0.98(0.51–1.87) 0.88(0.43–1.78) 0.96(0.50–1.85) PFS, HR (95% CI) 0.62(0.37–1.02) 0.61(0.35–1.05) 0.59* (0.35–0.98) OS, HR (95% CI) 0.70(0.38–1.28) 0.73(0.37–1.43) 0.66(0.36–1.22) CRS, OR (95% CI) 0.63(0.26–1.56) 0.67(0.24–1.84) 0.69(0.24–1.88) Gr ≥ 3 CRS, OR (95% CI) 0.23(0.01–1.35) 0.49(0.02–5.28) 0.26(0.01–1.94) NE, OR (95% CI) 0.84(0.41–1.68) 0.92(0.40–2.08) 1.10(0.48–2.52) Gr ≥ 3 NE, OR (95% CI) 0.56(0.19–1.45) 0.58(0.16–1.89) 0.68(0.19–2.30) *Statistically significant difference at 5% level.

Aims CheckMate-77T demonstrated the clinical benefit of perioperative nivolumab plus neoadjuvant platinum-doublet chemotherapy (periNivo + neoCT). This study assessed the cost-effectiveness of periNivo + neoCT as treatment for non-metastatic (Stage IIA-IIIB), resectable non-small cell lung cancer (NSCLC) vs. relevant comparators in the US. Materials and methods Following the natural history of non-metastatic NSCLC, a four-state Markov model was developed. Modeled health states were event-free survival, locoregional recurrence, distant metastasis, and death. CheckMate-77T informed time to progression estimates for periNivo + neoCT and neoCT; mortality estimates leveraged longer-term follow-up available from CheckMate-816. Indirect treatment comparison informed efficacy of comparator treatments not considered in CheckMate-77T. Comparators were neoadjuvant treatment strategies (neoadjuvant nivolumab + chemotherapy [neoNivo + CT], neoadjuvant chemotherapy [neoCT], and neoadjuvant chemoradiotherapy [neoCRT]), adjuvant chemotherapy (adjCT), and perioperative immuno-therapy (IO) strategies (perioperative durvalumab + neoadjuvant chemotherapy [periDurva + neoCT] and perioperative pembrolizumab + neoadjuvant chemotherapy [periPembro + neoCT]). Cost inputs were obtained from published literature and standard US sources and expressed in 2024 USD. The base-case analysis adopted the perspective of a commercial payer with a lifetime time horizon and discounted cost and health outcomes by 3% annually. Results Model results showed that periNivo + neoCT is more effective and costly than comparators. Deterministic incremental cost-effectiveness ratios were $84,921, $153,557, $77,976, $60,826, $74,252, $32,069, and $21,974 vs. neoCT, neoNivo + CT, neoCRT, adjCT, surgery, periPembro + neoCT, and periDurva + neoCT, respectively. In probabilistic sensitivity analysis, periNivo + neoCT resulted in an ICER below $150,000/QALY in 93.3%, 58.2%, 82.4%, 95.1%, 98.3%, 69.9%, and 82.1% of iterations vs. neoCT, neoNivo + CT, neoCRT, adjCT, surgery only, periPembro + neoCT, and periDurva + neoCT, respectively. Limitations Uncertainty in the survival extrapolations reflected the limited body of evidence informing the indirect treatment comparison. ICERs vs. perioperative IO treatment strategies were sensitive to small changes in predicted costs and QALYs, given low incremental base case costs and QALYs. Conclusion PeriNivo + neoCT is a cost-effective treatment option for patients with resectable, non-metastatic NSCLC.

Oral azacitidine (Oral-AZA) is recommended as maintenance therapy for patients with newly diagnosed acute myeloid leukemia (ND AML) achieving remission with intensive chemotherapy (IC) but not transplant candidates; venetoclax plus injectable azacitidine (VEN-AZA) is recommended for patients ineligible for IC. Some patients may be considered candidates for either regimen. This retrospective study used Flatiron Health’s database to compare treatment patterns and clinical outcomes with Oral-AZA maintenance after IC (IC🡪Oral-AZA) versus frontline VEN-AZA. Relapse-free survival (RFS) and overall survival (OS) were analyzed at 4 different time points, including from Oral-AZA initiation (IC🡪Oral-AZA cohort) or from remission (VEN-AZA cohort) in the Core Analysis. Median RFS was 14.9 and 8.1 months for IC🡪Oral-AZA and VEN-AZA propensity score-matched cohorts, in the Core Analysis (n = 32 in each; p = 0.027); median OS was 18.7 and 15.2 months (p = 0.034). In patients with AML, IC🡪Oral-AZA significantly improved RFS and OS compared with VEN-AZA.