Bristol-Myers Squibb
  • New York City, United States
Recent publications
Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment. Adaptive immune cell-enriched is intrinsically linked with highly distinct B and T cell clonal selection, diversification, and differentiation. Using TCR data, we see the largest clonal expansions in CD8 effector memory, senescent cells, and highly activated regulatory T cells which are induced within the tumour from naïve cells. We identify pathways that potentially lead to a suppressive microenvironment, including investigational targets TIGIT/PVR and SIRPA/CD47. Analysis of patients from the APACT clinical trial shows that myeloid enrichment had a shorter overall survival compared to those with adaptive cell enrichment. Strategies for rationale therapeutic development in this disease include boosting of B cell responses, targeting immunosuppressive macrophages, and specific Treg cell depletion approaches.
BCMA-targeted CAR T-cells transformed the treatment of relapsed and refractory multiple myeloma (RRMM), yet improvements are needed in manufacturing, toxicity and efficacy. We conducted a phase 1 clinical trial of BMS-986354, an autologous BCMA CAR T manufactured using an optimized NEX-T® process, in participants with triple-class exposed, RRMM. The 65 participants had a median of 5 (range 3–13) prior regimens, 39% had cytogenetic high-risk, 91% triple-class refractory, and 43% extra-medullar disease. Part A (dose-escalation) of the study enrolled participants in cohorts receiving 20 (N = 7), 40 (N = 24), or 80 (N = 11)x 10⁶ CAR + T-cells. In part B (expansion), an additional 23 participants were treated at the recommended phase 2 dose, 40 ×10⁶ CAR + T cells. Across dose levels, cytokine release syndrome (CRS) occurred in 82% (2% grade ≥3), neurotoxicity in 8% (2% grade ≥3), and infections in 32% of participants (5% grade ≥ 3). The response rate was 95%, with 46% achieving complete responses. Median progression-free survival was 12.3 months (95% CI 11.3–16). Compared to orvacabtagene autoleucel (same CAR construct, conventional manufacturing), BMS-986354 had higher proportion of T central memory cells, were less differentiated and had enhanced potency and proliferative capacity, supporting the use of NEX-T® in future CAR T development.
520 Background: In the phase 3 CheckMate 9DW study (NCT04039607), 1L NIVO + IPI demonstrated significant overall survival (OS) benefit vs LEN/SOR, higher objective response rate (ORR) with durable responses, and manageable safety in uHCC. We present efficacy by best overall response (BOR) subgroups and baseline characteristics, and additional safety analyses from the preplanned interim analysis. Methods: Patients (pts) with previously untreated HCC not eligible for curative surgical or locoregional therapies, Child-Pugh score 5 or 6, and ECOG performance status 0 or 1 were randomized 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles), then NIVO 480 mg Q4W or LEN 8 mg or 12 mg QD or SOR 400 mg BID until disease progression or unacceptable toxicity. NIVO was given for a maximum of 2 years. The primary endpoint was OS; secondary endpoints included ORR and duration of response (DOR) per blinded independent central review (BICR) using RECIST v1.1. Results: A total of 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333). At a median follow-up of 35.2 (range 26.8–48.9) months (mo), median OS (95% CI) was 23.7 (18.8–29.4) mo with NIVO + IPI vs 20.6 (17.5–22.5) mo with LEN/SOR (HR 0.79 [95% CI 0.65–0.96]; P = 0.0180). ORR (95% CI) per BICR was significantly higher with NIVO + IPI vs LEN/SOR (36% [31–42] vs 13% [10–17]; P < 0.0001); median DOR (95% CI) was 30.4 (21.2–not estimable [NE]) mo vs 12.9 (10.2–31.2) mo. Survival benefit of NIVO + IPI vs LEN/SOR was observed across BOR subgroups at the 24-week landmark timepoint (Table). In subgroup analyses, ORR (95% CI) per BICR was higher with NIVO + IPI vs LEN/SOR across HCC etiologies (uninfected: 35% [26–44] vs 8% [4–15]; HBV infected: 25% [17–34] vs 17% [10–25]; HCV infected: 50% [39–61] vs 16% [9–25]) and in pts with Barcelona Clinic Liver Cancer stage ≤B (33% [23–43] vs 13% [6–21]) or stage C (37% [31–44] vs 14% [10–19]). Safety data are shown in the Table. Additional exploratory analyses will be presented. Conclusions: These additional analyses from CheckMate 9DW demonstrate the efficacy and manageable safety of 1L NIVO + IPI in uHCC and further support its use as a potential standard-of-care treatment option in this setting. Clinical trial information: NCT04039607 . OS by BOR at week 24 landmark NIVO + IPI LEN/SOR BOR CR + PR (n = 101) SD a (n = 105) PD (n = 47) CR + PR (n = 28) SD a (n = 212) PD (n = 31) Median OS (95% CI), mo NR (44.4–NE) 30.0(23.5–37.8) 16.0(12.0–18.7) 28.3(20.6–NE) 22.5(20.5–24.8) 13.5(8.7–25.3) All treated pts NIVO + IPI (n = 332) LEN/SOR (n = 325) Any-grade/grade 3–4 TRAEs, n (%) 278 (84)/137 (41) 297 (91)/138 (42) Hepatobiliary 44 (13)/35 (11) 15 (5)/10 (3) Cardiovascular 10 (3)/3 (< 1) 138 (42)/39 (12) Hemorrhagic 2 (< 1)/1 (< 1) 20 (6)/5 (2) a Includes non-CR/non-PD. CR, complete response; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease; TRAE, treatment-related adverse event.
LBA143 Background: The CheckMate 8HW study met its dual primary endpoint with NIVO + IPI demonstrating superior progression-free survival (PFS) by blinded independent central review (BICR) vs chemotherapy (chemo) in patients (pts) with centrally confirmed MSI-H/dMMR mCRC in the first-line (1L) setting (HR 0.21; 95% CI 0.14–0.32; P < 0.0001). We report first results from the other dual primary endpoint of PFS for NIVO + IPI vs NIVO across all lines of therapy in pts with centrally confirmed MSI-H/dMMR mCRC. Methods: Immunotherapy-naive pts with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0 or 1 prior line of therapy were randomized 2:2:1 to (i) NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), (ii) NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), or (iii) chemo ± targeted therapies. Pts who had received ≥ 2 prior lines of therapy were randomized 1:1 to the NIVO + IPI or NIVO arms. Treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). Results: Across all lines of therapy,707 pts were randomized to NIVO + IPI (n = 354) or NIVO (n = 353); 55% and 52% received study treatment in the 1L setting, respectively. Of all randomized pts, 296 in the NIVO + IPI arm and 286 in the NIVO arm had centrally confirmed MSI-H/dMMR status. With 47.0 months (mo) of median follow-up (range, 16.7–60.5), NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS by BICR vs NIVO (HR 0.62; 95% CI 0.48–0.81; P = 0.0003) and higher 12-, 24-, and 36-mo PFS rates vs NIVO (Table). Objective response rate (ORR) by BICR was significantly higher with NIVO + IPI vs NIVO (71% vs 58%; P = 0.0011; Table); best overall response of progressive disease was reported in 10% and 19% of pts, respectively. No new safety concerns were identified (Table). Conclusions: In the first randomized study to compare dual- vs single-agent immunotherapy in MSI-H/dMMR mCRC, NIVO + IPI demonstrated superior PFS vs NIVO across all lines of therapy, with a manageable safety profile. These results establish NIVO + IPI as the potential new standard-of-care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . Efficacy by BICR (all lines; centrally confirmed MSI-H/dMMR by IHC and/or PCR test) NIVO + IPI(n = 296) NIVO(n = 286) Median PFS (95% CI), mo NR (53.8–NE) 39.3 (22.1–NE) HR (95% CI); P value 0.62 (0.48–0.81); 0.0003 PFS rate (12/24/36-mo), % 76/71/68 63/56/51 ORR, n (%); 95% CI, % 209 (71); 65–76 165 (58); 52–64 P value 0.0011 Safety (all lines; all treated), n (%) NIVO + IPI (n = 352) NIVO (n = 351) Any-grade/grade 3–4 TRAEs 285 (81)/78 (22) 249 (71)/50 (14) Any-grade/grade 3–4 TRAEs leading to discontinuation 48 (14)/33 (9) 21 (6)/14 (4) Treatment-related deaths 2 (< 1) 1 (< 1) IHC, immunohistochemistry; NE, not estimable; NR, not reached; PCR, polymerase chain reaction; TRAE, treatment-related adverse event.
398 Background: At 4-y follow-up, 1L NIVO + chemo continued to demonstrate clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit vs chemo with acceptable safety in patients (pts) with advanced non-HER2+ GC/GEJC/EAC from CheckMate 649. We report efficacy and safety results of NIVO + chemo vs chemo at 5-y follow-up. Methods: Adults with previously untreated, unresectable, advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. Pts were randomized to NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: Pts were randomized to NIVO + chemo (n = 789) or chemo (n = 792). NIVO + chemo continued to show OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts at 60-month (mo) minimum follow-up (Table). OS rates at 60-mo were higher with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table), and OS benefit with NIVO + chemo continued to be observed in most prespecified subgroups. Objective response rates (ORRs) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table). No new safety signals were identified. Conclusions: These results represent the first report of 5-y follow-up for anti–PD-1 + chemo combination therapy in GC/GEJC/EAC to our knowledge. NIVO + chemo continued to provide sustained long-term survival vs chemo with an acceptable safety profile after 5 y of follow-up. These data continue to support the use of NIVO + chemo as a standard 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116 . Efficacy PD-L1 CPS ≥ 5 PD-L1 CPS ≥ 1 All randomized NIVO + chemo(n = 473) Chemo (n = 482) NIVO + chemo (n = 641) Chemo (n = 656) NIVO + chemo (n = 789) Chemo (n = 792) mOS (95% CI), mo 14.4 (13.1–16.2) 11.1 (10.1–12.1) 13.8 (12.4–14.8) 11.4 (10.7–12.3) 13.7 (12.4–14.5) 11.6 (10.9–12.5) HR (95% CI) 0.71 (0.61–0.81) 0.76 (0.67–0.85) 0.79 (0.71–0.88) 60-mo OS rate (95% CI), % 16 (12–19) 6 (4–9) 13 (11–16) 5 (4–7) 12 (10–14) 6 (4–8) mPFS a (95% CI), mo 8.3 (7.0–9.4) 6.1 (5.6–6.9) 7.5 (7.0–8.5) 6.9 (6.2–7.1) 7.8 (7.1–8.6) 6.9 (6.7–7.2) HR (95% CI) 0.71 (0.61–0.82) 0.77 (0.68–0.87) 0.79 (0.71–0.89) ORR a,b (95% CI), % 60 (55–65) 45 (40–50) 60 (55–64) 46 (42–51) 58 (54–62) 46 (42–50) mDOR a,c (95% CI), mo 9.6 (8.3–12.4) 7.0 (5.7–8.0) 8.6 (7.9–10.5) 6.9 (5.8–7.6) 8.5 (7.7–9.9) 6.9 (5.9–7.6) a Per BICR. b In pts with measurable target lesions at baseline. c In all measurable responders. DOR, duration of response; m, median.
222 Background: With improvements in treatment of mCRC, OS maintains its gold standard efficacy measure but takes longer to mature than intermediate endpoints. This study analyzed the association between treatment effects on PFS and OS using aggregate-level data from RCTs in previously untreated mCRC patients. Methods: A systematic literature review identified RCTs in previously untreated mCRC patients published from 2010–2021 reporting hazard ratios on PFS (HR PFS ) and OS (HR OS ). All treatments in comparison to chemotherapy alone or chemotherapy with anti-VEGF (bevacizumab) or anti-EGFR (cetuximab) targeted therapy were considered. Correlation between HR PFS and HR OS was evaluated using bivariate random-effects meta-analysis (BRMA) and weighted linear regression (WLR). Predictive performance of the surrogacy equations from WLR was assessed using leave-one-out cross-validation (LOOCV). Surrogate threshold effects (STE), defined as the minimum PFS benefit that would translate into a statistically significant OS benefit with 95% probability, were also derived to gauge the practical utility of the models. Primary analysis consisted of all included trials. Sensitivity analyses omitted trials that (I) had anti-EGFR medications, (II) had anti-VEGF medications, (III) violated proportional hazards assumptions, and (IV) permitted treatment crossover. Results: In the primary analysis 47 trials were included. The estimated correlation between PFS and OS was 0.67 (95% CI: 0.48–0.80) using BRMA and 0.70 (95% CI: 0.48–0.84) using WLR. The surrogacy equation derived from WLR was log(HR OS ) = −0.03 + 0.56 log(HR PFS ) with a statistically insignificant intercept and significant slope. Estimated STEs corresponding to sample sizes of 200 and 300 patients were 0.55 and 0.62, respectively. Observed HR OS ’s were within their 95% prediction intervals predicted from HR PFS for 93.6% of studies in LOOCV. Sensitivity analyses produced moderate correlations with >90% coverage in LOOCV (Table). Conclusions: Moderate correlations were found between HR PFS and HR OS using both modeling approaches, highlighting the stability of the findings. Cross-validations of surrogacy equations indicated promising predictive value of PFS benefit for OS benefit in previously untreated mCRC. Analysis Set # of Studies Correlation (95% CI) STE LOOCV Coverage Rate BRMA WLR N = 200 N = 300 Sensitivity Analysis I 34 0.75 (0.57, 0.86) 0.78 (0.55, 0.90) 0.55 0.61 94.1 % Sensitivity Analysis II 14 0.44 (-0.08, 0.77) 0.62 (-0.05, 0.90) 0.44 0.52 92.9 % Sensitivity Analysis III 36 0.61 (0.36, 0.77) 0.59 (0.26, 0.80) 0.46 0.55 94.4 % Sensitivity Analysis IV 43 0.68 (0.48, 0.81) 0.67 (0.41, 0.83) 0.52 0.60 93.0 %
131 Background: KRAS G12C mutations occur in 3%–4% of CRC cases and are associated with poor prognosis. In the phase 1/2 KRYSTAL-1 study (NCT03785249), at a median follow-up of 11.9 months (mo), Ada (irreversible inhibitor of KRAS G12C ) in combination with Cetux (anti-EGFR antibody) demonstrated promising clinical activity (objective response rate [ORR] of 34% per blinded independent central review [BICR] and 43% per investigator [INV]) and was well tolerated in patients (pts) with previously treated KRAS G12C -mutated mCRC. Based on these findings, Ada + Cetux was granted accelerated approval in the United States for these pts. Here, we present longer-term follow-up analyses from this study. Methods: Adults with previously treated KRAS G12C -mutated mCRC and ECOG performance status of 0 or 1 were treated with Ada (600 mg BID) in combination with Cetux (400 mg/m ² followed by 250 mg/m ² QW or 500 mg/m ² Q2W) until disease progression, unacceptable toxicity, withdrawal of consent, or death, in separate phase 1 and phase 2 cohorts. Primary endpoints were safety (phase 1) and ORR per BICR (phase 2). Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (phase 2). Results: A total of 94 pts received Ada + Cetux. The median number of prior lines of systemic therapy was 3 (range, 1–9); 23 pts (24%) had received ≥ 4 prior lines of systemic therapy. The most frequent sites of metastases at baseline were the lung (71%) and liver (64%). At a median follow-up of 20.4 mo, ORR per INV was 43% (95% CI 32–53) and all were partial responses; median DOR was 5.9 (95% CI 5.5–7.6) mo. Disease control rate per INV was 86% (95% CI 78–92). Median PFS per INV was 6.9 (95% CI 5.9–7.4) mo; 6- and 12-mo PFS rates were 61% and 19%, respectively. Median OS was 16.0 (95% CI 13.3–18.8) mo; 6- and 12-mo OS rates were 88% and 66%, respectively. Any-grade treatment-related adverse events (TRAEs) were reported in 100% of pts, 28% of which were grade 3/4. TRAEs led to discontinuation in 10% of pts. Efficacy analyses by BICR, subgroup analyses, and additional safety results will be presented. Conclusions: In heavily pretreated pts with KRAS G12C -mutated mCRC, Ada + Cetux continued to demonstrate clinically meaningful activity and tolerable safety with longer follow-up. These updated results are consistent with those from the primary analysis and constitute the longest duration of follow-up for dual KRAS G12C /EGFR blockade in this setting. Efficacy of second-line Ada + Cetux vs chemotherapy in KRAS G12C -mutated mCRC is being investigated in the phase 3 KRYSTAL-10 study (NCT04793958). Clinical trial information: NCT03785249 .
392 Background: NIVO + chemo demonstrated clinically meaningful survival benefit and an acceptable safety profile vs chemo in previously untreated Chinese pts with advanced GC/GEJC/EAC from CheckMate 649, consistent with the overall study population. 1L NIVO + chemo is currently approved for pts with advanced non-HER2+ GC/GEJC/EAC in China and other countries. We report 5-y results of NIVO + chemo vs chemo in Chinese pts from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO + chemo, NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 61-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). 5-y OS rate was 24% with NIVO + chemo vs 8% with chemo in pts with PD-L1 CPS ≥ 5 and 20% vs 7% in all randomized pts. Objective response rate (ORR) was higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). No new safety signals were identified with longer follow-up. Conclusions: NIVO + chemo continued to demonstrate clinically meaningful long-term survival benefit, more durable responses, and acceptable safety vs chemo in Chinese pts after 5 y of follow-up, consistent with earlier reports and with the overall study population of pts with advanced non-HER2+ GC/GEJC/EAC. These results further support NIVO + chemo as a standard 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . Efficacy PD-L1 CPS ≥ 5 All randomized NIVO + chemo(n = 75) Chemo (n = 81) NIVO + chemo (n = 99) Chemo (n = 109) mOS (95% CI), mo 15.5(11.9–21.1) 9.6(8.0–12.1) 14.3(11.5–16.5) 10.3(8.1–12.1) HR (95% CI) 0.57 (0.40–0.82) 0.63 (0.46–0.85) mPFS a (95% CI), mo 8.5(6.0–14.0) 4.3(4.1–6.5) 8.3(6.2–12.4) 5.6(4.2–6.8) HR (95% CI) 0.51 (0.34–0.76) 0.57 (0.41–0.80) ORR a,b (95% CI), % 68 (56–79) 48 (36–60) 66 (55–76) 45 (35–56) mDOR a,c (95% CI), mo 12.5 (7.2–23.4) 6.9 (3.9–8.5) 12.5 (7.2–17.7) 5.6 (4.4–8.3) a Per BICR. b In pts with measurable target lesions at baseline. c In responders. DOR, duration of response; m, median.
Background The incorporation of machine learning is becoming more prevalent in the clinical setting. By predicting clinical outcomes, machine learning can provide clinicians with a valuable tool for refining precision medicine approaches and improving treatment outcomes. Methods This was a post hoc analysis of pooled patient-level data from the global, real-world ACTION and ASCORE trials in patients with rheumatoid arthritis (RA) initiating abatacept. Patient demographic and disease characteristics were input across 10 machine learning models used to predict 12-month treatment retention. Retention was defined as treatment for > 365 days or ≤ 365 days in patients who achieved remission or major clinical response (based on European Alliance of Associations for Rheumatology response criteria). The pooled dataset was split into a training/validation cohort for model development and a test cohort for an unbiased evaluation of performance. SHapley Additive exPlanation (SHAP) values determined the level of importance and directionality for key patient features predicting abatacept retention. Results The pooled ACTION and ASCORE dataset included 5320 patients with RA (mean [standard deviation] age 57.7 [12.7] years; 79% female). The 12-month abatacept retention rate was 61% (n = 3236) with a discontinuation rate of 39% (n = 2037). In the training set (n = 4218), the gradient-boosting classifier model demonstrated the best performance (testing accuracy: 62%). This model had an area under the receiver operating characteristic curve (95% confidence interval) of 0.620 (0.586, 0.653) and F1 score of 0.659 (0.625, 0.689) in the test set of patients (n = 1055). Using this model, the five most important variables predicting 12-month abatacept retention were low body mass index (BMI), low American College of Rheumatology functional status class, anti-citrullinated protein antibody (ACPA) positivity, low Patient Global Assessment, and younger age. Conclusions The gradient-boosting classifier model identified key patient features predictive of abatacept retention from this large, real-world study population. The SHAP values conveyed the directionality and importance of BMI, functional status, ACPA serostatus, Patient Global Assessment, and age for abatacept retention. Findings are consistent with previous observations and help validate the machine learning approach for predictive modelling in RA treatment, and may help inform clinical decision making. Trial registration NCT02109666 (ACTION), NCT02090556 (ASCORE).
PURPOSE Approximately 50% of patients with advanced Merkel cell carcinoma (MCC) have primary or acquired resistance to PD-(L)1 blockade, which may be overcome using combination immune checkpoint inhibition (ICI) with anti–cytotoxic T lymphocyte antigen-4 antibody. We present results from the recurrent/metastatic MCC cohort in CheckMate 358, a nonrandomized, multicohort, phase I/II study of nivolumab (NIVO) with or without ipilimumab (IPI) in virus-associated cancers (ClinicalTrials.gov identifier: NCT02488759 ). METHODS ICI-naïve patients with recurrent/metastatic MCC and 0-2 previous systemic therapies were administered NIVO monotherapy at 240 mg once every 2 weeks or combination therapy with NIVO 3 mg/kg once every 2 weeks + IPI 1 mg/kg once every 6 weeks. The primary end point was objective response. Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS Sixty-eight patients received NIVO (n = 25) or NIVO + IPI (n = 43). The objective response rate (95% CI) and median DOR (95% CI), respectively, were 60% (38.7 to 78.9) and 60.6 months (16.7 to not applicable [NA]) with NIVO and 58% (42.1 to 73) and 25.9 months (10.4 to NA) with NIVO + IPI. The median PFS (95% CI) and OS (95% CI), respectively, were 21.3 (9.2 to 62.5) and 80.7 (23.3 to NA) months with NIVO and 8.4 (3.7 to 24.3) and 29.8 (8.5 to 48.3) months with NIVO + IPI. The incidence of grade 3/4 treatment-related adverse events was 28% with NIVO and 47% with the combination. CONCLUSION This nonrandomized study showed frequent and durable responses with both NIVO and NIVO + IPI in patients with ICI-naïve advanced MCC. However, it did not show improvement in efficacy with the combination, thus contradicting previous study reports that had suggested clinical benefit with combination ICI. A randomized trial of NIVO + IPI versus NIVO monotherapy is warranted.
Atrial fibrillation (AF), a common heart rhythm abnormality, is linked to a higher risk of stroke. Traditionally, warfarin has been the primary anticoagulation treatment for reducing the stroke risk. The new standard of treatment by direct oral anticoagulants (DOACs) offers greater benefits including improved efficacy and fewer adverse effects with reduced monitoring. This study aims to evaluate the risk of stroke/systemic embolism (SE) and major bleeding (MB) among patients with AF who switched from warfarin to DOACs. This study utilized Medicare data to conduct a retrospective analysis of patients with non-valvular atrial fibrillation (NVAF) who switched from warfarin to DOACs between January 1, 2012, and December 31, 2019. Patients with NVAF aged 65 and older who switched from warfarin and had continuous health plan enrollment were included. Descriptive statistics, propensity score matching (PSM), and Cox proportional hazard (PH) models were utilized to compare the outcomes and assess risks of SE and MB across the DOAC cohorts. Among 1,843,495 patients with NVAF on warfarin, 171,700 switched to DOACs within 90 days of discontinuation (apixaban: 90,850; rivaroxaban: 67,698; dabigatran: 12,900). The mean follow-up period across DOAC cohorts ranged from 552 to 628 days. After PSM, apixaban showed significantly lower rates of stroke/SE compared to dabigatran (2.99% vs. 3.98%, p < 0.0001) and rivaroxaban (3.08% vs. 3.80%, p < 0.0001). MB rates were also lower with apixaban versus dabigatran (4.29% vs. 5.57%, p < 0.0001) and rivaroxaban (4.07% vs. 6.35%, p < 0.0001). Cox PH models confirmed these findings, with apixaban demonstrating lower risks of stroke/SE [hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.72–0.96 vs. dabigatran; HR 0.91, 95% CI 0.85–0.96 vs. rivaroxaban] and MB (HR 0.79, 95% CI 0.71–0.89 vs. dabigatran; HR 0.68, 95% CI 0.65–0.72 vs. rivaroxaban). The risk of stroke/SE and MB varies significantly among patients with NVAF switching from warfarin to different DOACs, with apixaban presenting the lowest risk compared to dabigatran and rivaroxaban.
Mavacamten is a cardiac myosin inhibitor for adults with obstructive hypertrophic cardiomyopathy (HCM). Dose optimization is performed 4 weeks after starting mavacamten, guided by periodic echo measurements of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Previously, a population pharmacokinetic (PPK) model was developed and exposure‐response (E‐R) of VLVOTg (efficacy) and LVEF (safety) was used to identify the mavacamten titration regimen with the optimal benefit/risk ratio, now included in the US prescribing information. Mavacamten is metabolized primarily by cytochrome P450 2C19 (CYP2C19) (74%), a highly polymorphic enzyme. China has a higher prevalence of poor CYP2C19 metabolizer phenotype compared with the global population; therefore, a previous model was adapted to include Chinese patients with obstructive HCM to identify the optimal dosing regimen for this population. Data from a phase I (healthy Chinese volunteers) and a phase III (EXPLORER‐CN, NCT05174416; Chinese patients with obstructive HCM) trial of mavacamten were added to the previous PPK and E‐R models, and the observed VLVOTg and LVEF from EXPLORER‐CN were successfully simulated. Next, five echocardiography‐guided titration regimens (plus the EXPLORER‐CN regimen) using representative or equal CYP2C19 phenotypes were simulated. The final simulated regimen recommended with an optimal benefit/risk profile across CYP2C19 phenotypes included: down‐titration at Week 4 (if VLVOTg < 20 mmHg), restart at Week 12, and up‐titration at Week 12 (for VLVOTg ≥ 30 mmHg and LVEF ≥ 55%), and every 12 weeks thereafter. This supports the previously recommended regimen for Chinese patients with obstructive HCM, now approved by the National Medicinal Products Administration.
Background The combination of conventional chemotherapy and immune checkpoint inhibitors (ICIs) has been unsuccessful for pancreatic ductal adenocarcinoma (PDAC). Administration of maximum tolerated dose of chemotherapy drugs may have immunosuppressive effects. Methods We thus tested, by using the preclinical model of PDACs including the genetically engineered mouse KPC spontaneous pancreatic tumor model and the pancreatic KPC tumor orthotopic implant model, the combinations of synthetic innate immune agonists including STING and NLRP3 agonist, respectively, and ICIs with or without chemotherapy. Results We found that innate agonists potentiate the role of chemotherapy in inducing effector T cells and subsequently to prime the tumor microenvironment (TME) better for ICI treatments. Triple combination of chemotherapy, innate agonists, and ICIs is superior to single modalities or double modalities in antitumor efficacies. Adding chemotherapy to innate agonists enhances the infiltration of overall CD8⁺ T cells and the memory cytotoxic subtype. NLRP3 agonist has a less effect than STING agonist on driving the T cell exhaustion. Adding chemotherapy to innate agonists enhances the infiltration of dendritic cells (DCs) in the tumors and CD86⁺ mature DCs in tumor draining lymph nodes. RNA sequencing analysis of the pancreatic tumors demonstrates the role of the combination of STING/NLRP3 agonist and chemotherapy, but not either treatment modality alone, in upregulating the T cell activation signaling. The NLRP3 agonist-mediated T cell activation is likely through regulating the nitrogen metabolism pathways. Conclusion This study supports the clinical testing of both STING and NLRP3 agonists, respectively, in combination with chemotherapy to sensitize PDAC patients for ICI treatments.
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1,493 members
Kuan-Hsiang Gary Huang
  • Innovative Medicines Development
Akintunde Bello
  • Clinical Pharmacology Pharmacometrics& Bioanalysis
Puneet Chopra
  • Lead Development and Optimization
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