Multiple FGFR inhibitors have demonstrated significant activity in pretreated advanced FGFR2 fusion–positive intrahepatic cholangiocarcinoma. The irreversible pan-FGFR inhibitor futibatinib has the potential to overcome acquired resistance to ATP-competitive FGFR inhibitors in a subset of patients. We present a case of prolonged clinical benefit using FGFR inhibitors sequentially, initially an ATP-competitive inhibitor followed by futibatinib upon progression, for a total of 36 months of FGFR-targeting therapy. This case supports sequential FGFR-targeting therapies for FGFR2 fusion–positive cholangiocarcinoma, with futibatinib acting as rescue therapy after failure of ATP-competitive inhibitors.

Direct inhibitors of KRASG12C are now used as standard-of-care therapy in KRASG12C-mutant non–small cell lung cancer (NSCLC), but less is understood about the molecular mechanisms and consequent treatment vulnerabilities of KRAS codon 13 mutations in this setting. In this study, we characterized the tumorigenic properties of NSCLC harboring KRASG13X in a large multinational cohort of patients with NSCLC and in preclinical models of KRASG13X NSCLC. Induction of KRASG13C or KRASG13D expression confers reduced oncopotency compared with allele-specific controls affecting KRAS codon 12, particularly KRASG13C. We identified functionally relevant comutations in KRASG13X NSCLC, including KEAP1, STK11, BRAF, and NF1. The novel RAS(ON) G13C-selective inhibitor, RMC-8839, reduces viability in a panel of KRASG13C NSCLC cell models. To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust antiproliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo. Significance: We characterize the second most common KRAS mutational hotspot in NSCLC after codon 12, KRASG13X, from tumor initiation to advanced disease. KRASG13C is a novel, directly targetable subset of NSCLC, with vulnerability to the combination of chemotherapeutics and the mutant-selective RAS(ON) inhibitor RMC-8839, a finding immediately relevant to patient care. See related commentary by Araujo and Skoulidi, p. 2206 See related article by Seamon et al., p. 2256

Background: Neurological immune related adverse events (N-irAEs) following immune checkpoint inhibitor (ICI) therapy are associated with significant morbidity and mortality. The early involvement of neurological services is therefore recommended to assist diagnosis and guide management. However, the practical experience of specialist neurology involvement is poorly understood. Methods: A multi-centre, retrospective case note review was performed in a unified healthcare setting in the United Kingdom via predetermined proforma to investigate the involvement and impact of neurology services in this setting. Results: One hundred and nine patients with N-irAE were identified with a median time from ICI treatment to symptom onset of 52 days. Neurology service models, reasons for referral and referral rates varied by centre. Overall, eighty-seven (79.8%) patients (range 52.9–100% by centre) had neurology involvement. Neurology input was associated with younger age (median 67.2 vs. 72.8 years), anatomical location (Central > Peripheral) and severity of neurotoxicity (p < 0.001, q < 0.004). Patients with neurology involvement were more likely to undergo specialist investigations: MR imaging (p = 0.041, q = 0.043), lumbar puncture (p < 0.001, q < 0.004), and neurophysiology (p = 0.005, q = 0.007) resulting in a broader range of specific N-irAE diagnoses. Steroids were appropriately prescribed, with second line treatment (Intravenous immunoglobulins/Plasma exchange) associated with neurology involvement. At lower grades (CTCAE ≤ 2), resolution rates were similar in those with or without neurology involvement. At grades 3–4, one-third of patients with neurology involvement had resolution. In a centre with a model of early neurology involvement for all possible N-irAEs the aetiology of the neurological presentation was changed in 63.7%. Conclusions: This study highlights the potential to improve diagnosis and treatment algorithms and therefore patient outcomes through development of uniform N-irAE models of care to support this area of growing clinical need.

Immune checkpoint inhibitors (ICI) frequently trigger ICI-colitis, commonly leading to ICI discontinuation. With expanding ICI use, ICI-colitis is emerging as a significant clinical challenge. Cytomegalovirus (CMV) infection is known to occur in ICI-colitis, but its prevalence, risk factors and clinical impact are poorly defined. This study aimed to characterise the clinical trajectory of ICI-colitis patients with concurrent colonic CMV infection as compared to a CMV-negative colitis group. We retrospectively analysed consecutive ICI-treated patients with endoscopically and/or histologically confirmed ICI-colitis at two UK hospitals between 2015 and 2024. Clinical, endoscopic (Mayo Endoscopic Score, MES), treatment and oncologic outcome data were collected. CMV was identified by immunohistochemistry (IHC) on colonic biopsies. CMV-positive colitis cases were compared with CMV-negative colitis using chi- squared, Mann-Whitney U, and multivariable regression analyses. Among 249 ICI-colitis patients, IHC proven CMV-positive colitis was detected in 21 (8.4%). CMV-positive colitis was associated with dual ICI therapy (OR 2.8, CI 1.06-7.15), prior infliximab exposure (OR 6.4, CI 2.56-16.7), bloody stool (OR 2.7, CI 1.05-6.69), and higher endoscopic severity (MES 2-3; OR 4.1, CI 1.60-10.38), despite similar CTCAE diarrhoea grades between groups. They also had a higher likelihood of requiring escalation to advanced therapy (80% vs 41.5%; OR 5.6, CI 1.96-15.74), with this association remaining significant after adjusting for endoscopic severity (p = 0.049). Colectomy rates were higher albeit low overall. Antiviral therapy did not significantly affect corticosteroid duration or recurrence, and CMV tissue status did not influence overall or progression-free survival. Concurrent CMV-positive colitis occurs in a notable subset of ICI-colitis patients and may worsen disease severity, highlighting the importance of endoscopic biopsy, especially in steroid-refractory cases.

Supplementary Table 1 - Baseline characteristics of RAS-PM patients. Supplementary Table 2 - Treatment information for RAS-PM patients. Supplementary Table 3 - Number of patients tested for each co-mutation within RAS-PM, independently of treatment regimen. Supplementary Table 4 – Antibodies.