Lumakras (sotorasib) / Amgen, Roche - LARVOL DELTA

Krascendo 1: efficacy and safety of divarasib (diva) vs sotorasib (soto) or adagrasib (ada) in previously treated locally advanced or metastatic KRAS G12C-mutated NSCLC (ESMO 2026) - No abstract available

Clinical • Late-breaking abstract • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

ATNM-400 Elicits Durable Anti-tumor Responses in KRAS- and ALK-Driven NSCLC Models in a Mutation-Agnostic Manner (EANM 2026) - "Previously, we demonstrated that the ATNM-400 target is overexpressed in EGFR-mutant NSCLC models and exhibits strong efficacy as monotherapy and in combination with osimertinib...In vivo biodistribution and efficacy (monotherapy and combination) were evaluated in xenograft models, including tumors sensitive and resistant to KRAS G12C inhibitors (sotorasib, adagrasib) and ALK inhibitors (crizotinib, ceritinib, alectinib)... ATNM-400 exhibits potent antitumor activity and favorable tolerability across NSCLC models, independent of oncogenic mutation status. Broad baseline and therapy-induced target expression, combined with specific binding and high-linear energy transfer of 225Ac, enhances its efficacy in KRAS-and ALK-driven NSCLC tumors. These findings support ATNM-400 as a mutation-agnostic targeted alpha therapy and justify further translational and clinical development in advanced NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • EML4 • KRAS

KRAS G12C-mutated Metastatic Colorectal Cancer: Current Therapeutic Strategies and Future Directions. (PubMed, J Gastrointest Cancer) - "Clinical results are line- and regimen-dependent: sotorasib plus panitumumab improved progression-free survival compared with standard later-line therapy in the randomized phase 3 CodeBreaK 300 trial, whereas adagrasib plus cetuximab demonstrated clinically meaningful activity in KRYSTAL-1 but did not improve progression-free or overall survival versus chemotherapy in the second-line phase 3 KRYSTAL-10 trial despite a higher objective response rate. Moreover, acquired resistance remains common and frequently polyclonal, involving secondary KRAS alterations, receptor tyrosine kinase bypass, and downstream pathway reactivation. In this review, we summarize the biologic rationale, current clinical evidence, practical guideline-based positioning, toxicity management considerations, resistance mechanisms, and emerging therapeutic strategies for KRAS G12C-mutated mCRC."

Journal • Review • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Multicenter study of the impact of trial eligibility criteria on enrollment to KRAS G12C inhibitor trials in patients with non-small cell lung cancer. (ASCO 2025) - " We extracted EC for Phase I-III trials of six KRAS G12C inhibitors (sotorasib, adagrasib, olomorasib, divarasib, JDQ443 and RMC-6291) that were published or made available by sponsors. Our data indicate substantial differences between the real-world population of patients treated with KRAS G12C inhibitors and those who were trial eligible. Efforts should focus on improving clinical trial generalizability without compromising safety."

Clinical • Lung Cancer • Nephrology • Non Small Cell Lung Cancer • Oncology • Renal Disease • Solid Tumor • KRAS

Nursing Management of KRAS G12C Inhibitor Toxicities in Thoracic Malignancy: A Canadian Perspective (IASLC-WCLC 2026) - "Unlike cell-surface receptor targeting-tyrosine kinase inhibitors (TKIs), such as osimertinib and alectinib, which are familiar to thoracic oncology nurses, KRAS G12C inhibitors act upon an intracellular downstream signaling pathway...While first-in-class inhibitors sotorasib and adagrasib are approved, next-generation agents including divarasib, olomorasib, and calderasib are demonstrating more favourable safety profiles in ongoing trials...As KRAS G12C inhibitors expand beyond NSCLC to broader solid tumour indications, proactive, evidence-informed, and standardized nursing management is essential to optimizing patient outcomes and ensuring equitable access to precision oncology care globally. This requires that nurses be equipped with the education and clinical tools for informed, evidence-based symptom management across geographically diverse healthcare systems."

Hepatology • Interstitial Lung Disease • Liver Failure • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Thoracic Cancer • KRAS

KRAS-Targeted Therapies in NSCLC: Resistance, Combination Strategies, and Emerging Clinical Paradigms. (PubMed, Med Oncol) - "Sotorasib and adagrasib achieve ORRs of 37-43% and median PFS ~ 6-7 months in previously treated KRAS G12C NSCLC, with improved tolerability over docetaxel. Next-generation inhibitors (olomorasib, divarasib, glecirasib, D-1553, IBI351) demonstrate ORRs 45-55% and, in some studies, PFS exceeding first-generation agents, while emerging KRAS G12D inhibitors show early proof-of-concept activity...KRAS-mutant NSCLC is transitioning from historically untargetable disease to a therapeutically actionable subset. Future progress hinges on resistance-directed combinations, biomarker-guided personalization, expansion to non-G12C mutants, and evaluation in earlier disease settings."

IO biomarker • Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Exploratory Outcomes from a Phase II ctDNA-Guided Consolidation Trial in KRAS G12C-Mutant Locally Advanced NSCLC (ASTRO 2026) - P2 | "We conducted a phase II trial using post-cCRT liquid biopsy to select for KRASi therapy (sotorasib). Progression prior to cycle 3 of durvalumab was the dominant barrier to longitudinal ctDNA assessment, highlighting feasibility challenges for ctDNA-persistence triggered consolidation strategies in high-risk subsets. Although underpowered, higher post-cCRT ctDNA had numerically shorter PFS. Earlier integration of KRASi in KRAS G12C mutated LA-NSCLC warrants further prospective evaluation."

Circulating tumor DNA • IO biomarker • Metastases • P2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

COLOSOTO trial: Sotorasib plus panitumumab and 5-fluorouracil in first-line treatment of frail patients with unresectable KRAS G12C mutated colorectal cancer (ESMO 2026) - No abstract available

Clinical • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Not Every Dilated Duct Needs an ERCP: Sotorasib-Induced Liver Injury Mimicking Biliary Obstruction (ACG 2026) - "Case Description/ A 72-year-old woman with KRAS G12C-mutant NSCLC and prior pembrolizumab therapy developed painless jaundice ten weeks after starting sotorasib, approximately 14 weeks after her last ICI dose. (b) More distal CBD segment near the major papilla, with both ducts visualized entering the papilla. No obstructing mass, stricture, or lymphadenopathy is identified."

IO biomarker • Hepatology • Liver Failure • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • Thrombosis • KRAS

A Disappearing Act: Pembrolizumab-Associated Vanishing Bile Duct Syndrome Mimicking Biliary Obstruction in Metastatic Lung Cancer (ACG 2026) - "Case Description/ A 65-year-old woman with metastatic non-small cell lung cancer involving the thigh and brain, previously treated with radiation, carboplatin, pemetrexed, pembrolizumab, and later sotorasib, presented after a fall with abdominal pain...Prednisone led to partial improvement, but liver tests never normalized...Persistent cholestasis despite endoscopic therapy should prompt this diagnosis and early liver biopsy. This case emphasizes that pembrolizumab-associated ductopenic cholangiopathy can present as refractory cholestasis mimicking obstruction, and timely recognition may prevent chronic cholestasis, biliary cirrhosis, liver failure, and death."

Metastases • Cholangiocarcinoma • Cholestasis • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Primary Biliary Cholangitis • Solid Tumor

Where Does Daraxonrasib Stand? Comparative Efficacy of Pan-RAS and KRAS G12C Inhibitors in Metastatic Pancreatic Cancer: A Systematic Review and Network Meta-Analysis (ACG 2026) - "Five studies comprising 1,194 patients were included in the network meta-analysis. The treatment network consisted of pan-RAS inhibition (daraxonrasib; n=248), KRAS G12C inhibitors (sotorasib/adagrasib; n=59), and standard chemotherapy (n=887). Daraxonrasib demonstrated superior efficacy compared with chemotherapy for overall survival (HR 0.40, 95% CI 0.30-0.53), progression-free survival (HR 0.49, 95% CI 0.38-0.64), and objective response rate (RR 2.82, 95% CI 1.95-4.08)."

Metastases • Retrospective data • Review • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

mSWI/SNF Complex Inhibition Sensitizes KRAS-Mutant Lung Cancers to Targeted Therapies via Epithelial-Mesenchymal Subversion (IASLC-WCLC 2026) - "Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-sensitive and -resistant PDO models and in vivo PDX systems. Conclusions : These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, potentiate duration of response, and mitigate emergence of resistance."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • SMARCA4

Overall Survival Analysis of the Phase III CodeBreaK 300 Study of Sotorasib Plus Panitumumab Versus Investigator's Choice in Chemorefractory KRAS G12C Colorectal Cancer. (PubMed, J Clin Oncol) - "In the phase III CodeBreaK 300 study, sotorasib 960 mg-panitumumab significantly prolonged progression-free survival (PFS) versus investigator's choice (trifluridine/tipiracil or regorafenib) in patients with KRAS G12C-mutated chemorefractory metastatic colorectal cancer (mCRC). No new safety signals were observed. Although not statistically significant, the observed OS HR and ORR along with prior PFS and safety findings support sotorasib 960 mg-panitumumab as a standard of care in patients with chemorefractory KRAS G12C mCRC."

Journal • P3 data • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) treated with sotorasib and panitumumab (pmab) versus trifluridine/tipiracil (T/T) or regorafenib (rego) in CodeBreaK 300. (ASCO-GI 2024) - P3 | "In CodeBreaK 300, both doses of sotorasib resulted in better HRQoL and a trend to decreased risk of deterioration vs the control group. In addition to improved clinical outcomes, these findings provide further evidence on the benefit of soto+pmab in patients with chemorefractory mCRC. Clinical trial information: NCT05198934."

Clinical • HEOR • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

CodeBreaK 100/101: First Report of Safety/Efficacy of Sotorasib in Combination with Pembrolizumab or Atezolizumab in Advanced KRAS p.G12C NSCLC (IASLC-WCLC 2022) - "In this mostly pre-treated NSCLC population, combining sotorasib with IO led to a higher incidence of grade 3-4 TRAEs than previously observed with monotherapy, primarily liver enzyme elevations. Lead-in cohorts demonstrated durable clinical activity with lower rates of grade 3-4 TRAEs compared to concurrent cohorts. Dose expansion is ongoing in treatment-naïve patients using sotorasib lead-in followed by combination of sotorasib with Pembro."

Clinical • Combination therapy • IO biomarker • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • KRAS

Sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreak 300 phase III study (ESMO 2023) - P3 | "Methods In the CodeBreaK 300 (NCT05198934) global, open label study, 160 pts with chemorefractory KRAS G12C-mutated mCRC were randomized 1:1:1 to soto 960 mg daily plus pani 6 mg/kg IV (soto960+pani; n=53), soto 240 mg daily plus pani 6 mg/kg IV (soto240+pani, n=53), or investigator's choice of TAS-102 or regorafenib (n=54). Table: LBA10 Efficacy by BICR Soto960+Pani n=53 Soto240+Pani n=53 SOC n=54 Median PFS, months (95% CI) 5.6 (4.21, 6.31) 3.9 (3.71, 5.75) 2.2 (1.94, 3.91) ORR, % (95% CI) 26.4 (15.3, 40.3) 5.7 (1.2, 15.7) 0 (0.0, 6.6) Number of responders 14 3 0 Median DOR, months (range) 4.4 (1.9+, 6.0+) NR (1.8+, 3.8+) -- DCR, % (95% CI) 71.7 (57.7, 83.2) 67.9 (53.7, 80.1) 46.3 (32.6, 60.4) CI, confidence interval; DCR, disease control rate; DOR, duration of response; NR, not reached; ORR, objective response rate Conclusions In the first phase 3 study for a KRASG12C-inhibitor plus an anti-EGFR antibody in chemorefractory mCRC, the primary endpoint was met..."

Late-breaking abstract • Metastases • P3 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Divarasib Versus Adagrasib or Sotorasib in Pretreated KRAS G12C+ Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (IASLC-WCLC 2024) - "The primary endpoint is PFS per RECIST v1.1. Secondary endpoints include: overall survival; patient-reported outcomes (time to confirmed deterioration of cough [EORTC QLQ-LC13], dyspnea, or physical functioning [both EORTC QLQ-C30]); ORR and duration of response per RECIST v1.1; and safety."

IO biomarker • Metastases • Cough • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • KRAS

Theoretical study of KRAS G12C secondary mutations influencing inhibitor resistance. (PubMed, Biophys Physicobiol) - "In this study, we investigated the impact of secondary mutations (Y96D, Y96S, G13D, and Q99L) on the binding efficacy of sotorasib, adagrasib, and the next-generation inhibitor (MK-1084) using molecular dynamics simulations, binding free energy calculations, and dynamic protein-ligand interaction analysis. Our analyses revealed that Y96 mutations directly disrupt inhibitor binding, conferring high resistance to all three inhibitors, whereas G13D and Q99L indirectly alter the binding environment by influencing other residues, resulting in variable resistance profiles. This study provides detailed molecular insights into resistance mechanisms to support the rational design of more robust KRAS G12C-targeted therapies."

Journal • Oncology • KRAS

RAMP 202: A phase 2 study of avutometinib (VS-6766) ± defactinib, in patients with advanced KRAS G12V mutant non–small cell lung cancer (NSCLC). (ASCO 2023) - P2 | "Patients received up to 5 lines of prior systemic therapy (median 2), including prior platinum-based chemotherapy, ICIs, and bevacizumab. In this heavily pretreated population of patients with KRAS G12V mt NSCLC, limited clinical activity was observed with combination therapy. While no new safety signals were identified, criteria to proceed to part B were not met, and further evaluation of avutometinib ± defactinib in KRAS G12V mt NSCLC will not be pursued. Additional trials evaluating rational avutometinib combinations (sotorasib, adagrasib, everolimus) are ongoing in patients with KRAS mt NSCLC."

Clinical • IO biomarker • Metastases • P2 data • Anemia • Hematological Disorders • Immune Modulation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Pan-HER Inhibition Overcomes Feedback Adaptation Resistance to KRAS G12C Inhibition in KRAS G12C Mutant Non-Small Cell Lung Cancer (LUNG-SPORE 2024) - "KRAS G12C inhibitors sotorasib and adagrasib are FDA approved for advanced/metastatic KRAS G12C-positive NSCLC, although the duration of benefit from these drugs is relatively modest and therapeutic resistance typically emerges relatively quickly to these drugs...We observed that in combination with KRAS G12C inhibitors pan-HER TKIs such as poziotinib yielded a synergistic effect compared to HER2 TKI treatment...The combination of pan-HER TKIs with KRAS G12C inhibitor suppressed tumor growth significantly as compared to KRAS G12C inhibitor alone with a tolerable toxicity profile in KRAS G12C mutant patients derived xenograft models. Collectively, our findings indicate that the adaptive feedback activation of HER family members, including not only EGFR but also HER2 and HER3, diminishes the efficacy of KRAS G12C inhibitors against KRAS G12C-positive NSCLC tumor cells, and that the combination of pan-HER TKIs with KRAS G12C inhibitors may be more effective than KRAS G12C..."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ERBB3 • KRAS

S1900E: A phase II study examining impact of co-mutations on sotorasib for previously treated stage IV/recurrent KRAS G12C mutated (MUT) non-squamous (Non-sq) non-small cell lung cancer (NSCLC) (ECOG-ACRIN led Lung-MAP Sub-study). (ASCO 2025) - P2 | "Funded by NIH/NCI/NCTN grants U10CA180888, U10CA180819 Clinical Trial Registration Number: NCT04625647 Background: In previously treated KRAS G12C MUT NSCLC, the allosteric KRAS G12C inhibitor sotorasib had superior outcomes compared to docetaxel (ORR 28% vs 13%). TP53 CO-MUT cohort met its primary endpoint, while the STK11 CO-MUT cohort did not, suggesting that STK11 CO-MUT have detrimental effect on sotorasib in KRAS G12C NSCLC. S1900E Cohort 3, which may include KEAP1/NFE2L2 and other CO-MUT, will be reported later, as will resistance patterns identified through ctDNA analysis."

IO biomarker • Metastases • P2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • KRAS • STK11 • TP53

Navigating the Nuancesof Therapyin NSCLC: Real-World Insights Into Outcomes and Costs of KRAS G12C Inhibitorsanddocetaxel (IASLC-WCLC 2026) - "We identified adult patients with advanced NSCLC who received KRAS G12C inhibitors (sotorasib and/or adagrasib; n = 53) or docetaxel (n = 151). While adverse event profiles differed, with chemotherapy-related toxicities appearing more frequently with docetaxel, the observed differences in patient characteristics and sample size for KRAS G12C inhibitors preclude direct comparisons of treatment effectiveness. These findings underscore the complexities of evaluating emerging targeted therapies in real-world settings, highlighting the need for careful consideration of patient selection, disease characteristics, and comprehensive outcome measures beyond median survival, such as 2 or 3-year survival rates, in future studies."

Clinical • Real-world • Real-world evidence • Infectious Disease • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Septic Shock • Solid Tumor • KRAS

CodeBreaK 101: Safety and Efficacy of Sotorasib with Carboplatin and Pemetrexed in KRAS G12C-Mutated Advanced NSCLC. (IASLC-WCLC 2023) - "Introduction: Sotorasib is the first oral, irreversible KRASG12C inhibitor to show improved progression-free survival (PFS) over docetaxel (HR=0.66; p=0.0017) in pretreated KRAS G12C-mutated advanced NSCLC. The combination of sotorasib, pemetrexed and carboplatin showed promising clinical activity in KRAS G12C-mutated advanced NSCLC in both the 1L and 2L setting. This combination was safe and tolerable, with incidences of grade 3-4 TRAEs largely consistent with other platinum doublet-based approaches."

Clinical • IO biomarker • Metastases • Anemia • Hematological Disorders • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia • KRAS

Intracranial efficacy of sotorasib versus docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC): Practice-informing data from a global, phase 3, randomized, controlled trial (RCT). (ASCO 2023) - P3 | "In the first randomized evaluation of IC activity of any KRASG12C inhibitor, sotorasib demonstrated a reduced risk of progression and trend towards delayed time to CNS recurrence versus docetaxel in patients with pretreated KRAS G12C-mutated advanced NSCLC who had treated, stable brain metastases. These results suggest IC activity with sotorasib to complement the overall PFS benefit observed with sotorasib versus docetaxel. Clinical trial information: NCT04303780."

Clinical • Late-breaking abstract • Metastases • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Real-world effectiveness and tolerability of sotorasib in patients with KRAS G12C-mutated metastatic non-small cell lung cancer: The IFCT-2102 Lung KG12Ci study. (PubMed, Eur J Cancer) - "This study gave insights into effectiveness and safety of sotorasib in a real-world setting, in advanced or metastatic KRAS G12C-mutated non-squamous NSCLC."

IO biomarker • Journal • Real-world evidence • Hepatology • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1