PURPOSE: Adagrasib, a KRAS^G12Cinhibitor, has demonstrated clinical activity in patients with KRAS^G12C-mutated non–small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRAS^G12Cmutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRAS^G12Cmutation.METHODS: In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249 ; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRAS^G12C-mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety.RESULTS: As of October 1, 2022, 64 patients with KRAS^G12C-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients.CONCLUSION: Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRAS^G12C-mutated solid tumors.

The mainstay of treatment for advanced hepatocellular carcinoma (HCC) was the tyrosine kinase inhibitor (TKI) sorafenib, which targets vascular endothelial growth factor (VEGF) receptors, among other kinases.¹ Sorafenib showed overall survival (OS) benefit compared with placebo in the SHARP trial and, since then, multiple studies evaluating different agents have failed to show survival benefit until recently, when multiple VEGF TKIs showed survival benefit compared with placebo in the second-line setting^2,3 and noninferiority compared with sorafenib in the untreated population.⁴ On the other hand, although checkpoint inhibitor monotherapy showed promising results in early phase 2 studies, subsequent phase 3 trials showed no improved efficacy compared with sorafenib and placebo in the first- and second-line setting, respectively.^5,6 Most recently, the combination of atezolizumab, a checkpoint inhibitor, and bevacizumab showed—for the first time—an OS benefit compared with sorafenib in advanced treatment-naive patients with HCC.⁷ Therefore, systemic treatment for advanced HCC currently incorporates VEGF inhibitors (VEGFis), checkpoint inhibitors (CPIs), or the combination of both. Because these studies show variable efficacy across lines of therapy, a network meta-analysis (NMA) is helpful to compare different agents across randomized clinical trials (RCTs). This is especially important because current guidelines list the available treatments with no guidance regarding which regimen to be considered first.⁸ In this systematic review and network meta-analysis, we aim to compare the efficacy of different treatment agents for patients with advanced HCC across the lines of therapy.

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2–7.6). Median progression-free survival was 6.9 months (95% CI, 5.7–7.4) and median overall survival was 15.9 months (95% CI, 11.8–18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3–4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. Significance: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897 See co-corresponding author Rona Yaeger discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932606282/f27a6e46f4

FGFR2 rearrangements resulting in dysregulated signaling are drivers of cholangiocarcinoma (CCA) tumorigenesis, and occur almost exclusively in intrahepatic CCA. Pemigatinib, a selective, potent, o...