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Background: Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations. Patients and Methods: Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups. Results: One hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P =.042), squamous cell histology (P =.008), poor ECOG performance status (PS) (P <.001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P =.015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P =.004) and KEAP1MUT/STK11MUT (P =.009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P =.2) and OS (P =.053). Conclusions: We define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies. This study aimed to define the clinical outcomes of first-line chemo-immunotherapy in patients with non-small cell lung cancer with KRASG12C mutations and to examine the significance of PD-L1 tumor proportion score and comutation status (KEAP1 and STK11) on outcomes. [ABSTRACT FROM AUTHOR]

Purpose: KRAS variants are associated with poor outcomes in biliary tract cancers (BTCs). This study assesses the prevalence of KRAS variants and their association with survival and recurrence in patients with intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC), and gallbladder adenocarcinoma (GB)., Methods: In this cross-sectional, single-institution study at Memorial Sloan Kettering, tumors from 985 patients treated between 2004 and 2022 with IHC, EHC, and GB who underwent either curative-intent resection or were treated with chemotherapy for unresectable disease were used for targeted sequencing., Results: Of the 985 patients sequenced, 15% had a KRAS mutation. Five hundred and seventy-two had unresectable disease (n = 395 IHC, n = 71 EHC, n = 106 GB) and 413 were treated with curative-intent resection (n = 175 IHC, n = 119 EHC, and n = 119 GB). Median follow-up time was 18 months (IQR, 11-31). KRAS G12D mutations were most common in IHC (38%) and EHC (37%) tumors. Mutations in SF3B1 co-occurred with mutant KRAS in IHC and EHC, with comutant resectable patients having worse survival after adjusting for tumor type (hazard ratio [HR], 4.04 [95% CI, 1.45 to 11.2]; P = .007). KRAS G12 mutations were associated with worse survival in patients with IHC compared with wild-type (WT) or other KRAS mutations, regardless of resection status (unresectable P < .001, resectable P = .011). After adjusting for clinical covariates, KRAS G12 mutations remained a prognostic indicator for patients with IHC compared with WT (HR, 1.99 [95% CI, 1.41 to 2.80]; P < .001)., Conclusion: The adverse impact of KRAS mutations in BTC is driven by G12 alterations in patients with IHC regardless of resection status, which was not observed in GB or EHC. There are unique comutational partners in distinct BTC subsets. These differences have important clinical implications in the era of KRAS-targeted therapeutics.

Background and Objectives: Prospective data on presentation and outcomes of colorectal cancer (CRC) in Nigeria are limited; however, emergency presentation with advanced disease is thought common., Methods: Consecutive CRC patients presenting at six sites over 6 years were included. Risk factors for emergency presentation were evaluated using logistic regression methods. Overall survival (OS) was compared between emergent and elective patients using Kaplan-Meier methods and the log-rank test., Results: Of 535 patients, 30.7% presented emergently. Median age was 56 years, 55% were men, and 5.0% reported a cancer family history. Emergency patients had more proximal cancers (42.1% vs. 24.0%), Stage IV disease (61.6% vs. 40.2%; p < 0.001), lower household income (₦35 000/month vs. ₦50 000/month), lower education levels (p = 0.008) and accessed care with nonmotorized transport (50.6% vs. 37.2%; p = 0.005). Median OS was shorter in the emergency group (6.4 vs. 17.4 months; p < 0.001). Across clinical stages, emergency presentation was associated with worse OS (Stage IV median OS 4.8 vs. 9.4 months; p = 0.002). Surgery improved survival in both groups, although emergency patients had higher 30-day postoperative mortality (23.2% vs. 9.1%; p < 0.001)., Conclusions: Emergent Nigerian CRC patients have worse OS than elective patients. Cancer control efforts should focus on faster cancer detection, early presentation, diagnosis, and treatment., (© 2024 Wiley Periodicals LLC.)

Purpose: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported., Patients and Methods: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel., Results: Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months., Conclusions: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response., (©2024 American Association for Cancer Research.)