Lumakras (sotorasib) / Amgen, Roche - LARVOL DELTA

Recent advance of KRAS-G12C inhibitors for cancer therapy. (PubMed, Eur J Med Chem) - "In 2021, the FDA approved AMG510 (Sotorasib), the first covalent inhibitor targeting the KRAS-G12C mutation...This review provides an overview of contemporary medicinal chemistry approaches in KRAS-G12C inhibitor development. The collective insights from this analysis, combined with existing literature, provide valuable frameworks for designing novel KRAS-G12C targeted therapeutics."

Journal • Oncology • KRAS

Matching-Adjusted Indirect Comparison of Sotorasib Versus Adagrasib in Previously Treated Advanced/Metastatic Non-Small Cell Lung Cancer Harboring KRAS G12C Mutation. (PubMed, Adv Ther) - "In this MAIC, sotorasib and adagrasib showed comparable efficacy in previously treated advanced KRAS G12C-mutated NSCLC. Among patients with baseline brain metastases, PFS point estimates favored sotorasib. Sotorasib also demonstrated a favorable overall safety profile. These findings may help inform payer decisions and clinical practice in the treatment of KRAS G12C-mutated NSCLC."

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

Analysis of Pan-Specific Inhibitors of Oncogenic Mutant Forms of KRAS GTPase. (PubMed, Curr Med Chem) - "The clinical application of covalent KRAS inhibitors (sotorasib, adagrasib) is limited to the treatment of only certain KRASG12C-mediated types of cancer. The consideration of 28 patents included descriptions of the structures of the presented molecules, identification of the most active and selective examples of compounds, as well as results from structure-activity relationship (SAR) analyses for each sample. As a result of this work, some structural features of the most active examples of pan-KRAS inhibitors were identified."

Journal • Oncology • KRAS

Cost-effectiveness analysis of sotorasib plus panitumumab in the treatment of refractory colorectal cancer with mutated KRAS G12C in the USA. (PubMed, Expert Rev Pharmacoecon Outcomes Res) - "The ICER was calculated at 3,551,555554USD/ QALY, suggesting the sotorasib plus panitumumab therapy did not demonstratean economic advantage over standard care therapy for refractory CRC patientswith mutated KRASG12C at the threshold of 150,000 USD/ QALY. Sotorasib plus panitumumab did notdemonstrate an economic advantage compared to standard care in the treatment ofrefractory CRC with mutated KRASG12C in the U.S.A."

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

CodeBreaK 201: A Study of Sotorasib (AMG 510) in Participants With Stage IV NSCLC Whose Tumors Harbor a KRAS p.G12C Mutation in Need of First-line Treatment (clinicaltrials.gov) - P2 | N=42 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1 • STK11

Sotorasib in Combination With Trastuzumab Deruxtecan for the Treatment of Locally Advanced and Metastatic Non-small Cell Lung Cancer With a KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=37 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ERBB3 • KRAS

Quantitative Chiral Separations on KRAS Inhibitor Sotorasib by UHPLC-MS/MS: Method Validation and Enantioselective Pharmacokinetics Assessment in Rat Plasma. (PubMed, Chirality) - "The study provides insights in controlling the enantiomeric impurity in quality control aspects. This research also provides a reference for clinical practice and supports further research in distomer toxicity, enantioselective drug metabolism, and drug interactions."

Journal • PK/PD data • Preclinical • KRAS

Biosurfactant stabilized nanosuspension of KRAS inhibitor - Sotorasib (AMG-510): Systematic optimization using quality by design approach. (PubMed, Colloids Surf B Biointerfaces) - "Storage stability testing revealed that the nanosuspensions and freeze-dried formulations remained stable under accelerated conditions, preserving particle size, PDI, and drug loading over three months. The developed nanocrystalline formulation offers a promising strategy to improve the therapeutic efficacy of poorly soluble drugs like sotorasib, especially in high-dose regimens, enhancing patient convenience and adherence."

Journal • Addiction (Opioid and Alcohol) • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Tumor-agnostic therapies in a high-volume Brazilian center: Real-world challenges and opportunities. (ASCO 2025) - "Forty pts (24%) received TAT: 37% checkpoint inhibitors, 12.5% Trastuzumab deruxtecan, 7.5% trastuzumab plus pertuzumab, crizotinib and sotorasib, 5% dabrafenib plus trametinib and 23% others. In this real-world retrospective analysis of a high-volume Latin American center, CGP enabled the identification of agnostic biomarkers, offering targeted therapeutic options and improved outcomes for select individuals. The analysis was limited by unmatched distribution of tumor types, lacking treatment history and comorbidities among groups. Limited access to TAT may reflect the timing of tests, pre-dating some agnostic approvals, as well as the high cost and restricted availability of these therapies."

Clinical • Pan tumor • Real-world • Real-world evidence • Tumor mutational burden • Lung Cancer • Microsatellite Instability • Oncology • Solid Tumor • ALK • BRAF • FGFR • HER-2 • KRAS • MSI • NRG1 • NTRK • TMB

Unexplored targets in myeloid neoplasms: Investigating potential areas of clinical actionability using a comprehensive genomic database. (ASCO 2025) - "Our findings identify actionable mutations in MNs (KRAS, EZH2, NF1, BRAF) with FDA-approved targeted therapies (e.g. sotorasib, tazemetostat, selumetinib, vemurafenib). These mutations are underexplored in MNs, though some studies have assessed MEK inhibitors for certain subtypes."

Clinical • Genomic data • Hematological Malignancies • Oncology • Solid Tumor • BRAF • BRCA2 • EGFR • EZH2 • KRAS • NF1 • NRAS • NTRK1 • RET • ROS1

Molecular profiling using NGS in lung cancer patients: Revolutionizing targeted therapy and personalized treatment. (ASCO 2025) - "The hotspot KRAS mutation G12C was detected in 10,3% of cases and it is associated with response to the FDA approved drugs Sotorasib and Adagrasib...Additionally, ALK fusion was detected in 2,2% of patients offering response to on label therapies like Brigatinib and Lorlatinib... The findings described above underline the necessity of a multigene analysis for patients with NSCLC, in order to benefit from the available targeted therapies. PDL-1 testing increases this benefit as it is a positive predictive biomarker for immunotherapy, even for patients harboring no driver mutations."

Clinical • IO biomarker • Next-generation sequencing • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • HER-2 • KRAS • MET • NTRK1 • NTRK2 • NTRK3 • RET • ROS1 • STK11

Outcomes with KRAS G12C inhibitors in metastatic non-small cell cancer: A systematic review and meta-analysis. (ASCO 2025) - "Sotorasib 61% (n=471) and adagrasib 39% (n=301) were used KRAS G12C inhibitors. KRAS G12C inhibitors displayed favorable efficacy with acceptable safety profile in the 2nd of later line of therapies. It is the need of an hour to study this targeted therapy in the first line in mNSCLC patients."

Metastases • Retrospective data • Review • Non Small Cell Lung Cancer • Oncology • KRAS

Efficacy and safety of KRAS p.G12C inhibitors in advanced NSCLC: A systematic review and meta-analysis. (ASCO 2025) - "The KRAS p.G12C inhibitors evaluated were sotorasib, adagrasib, divarasib, and garsorasib. This meta-analysis underscores the favorable safety and efficacy profiles of KRAS p.G12C inhibitors after first-line progression in advanced NSCLC, despite the frequent adverse events, which were considered manageable. Further randomized controlled trials are expected to confirm these results and refine their role in subgroup populations, including STK1 and KEAP1 co-mutations, that confer even poor prognosis."

Metastases • Retrospective data • Review • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKB • CDK7 • KEAP1 • KRAS

Chemotherapy versus targeted therapy in high and low NRF2 lung adenocarcinoma. (ASCO 2025) - "These results show that NRF2 activation impairs the efficacy of sotorasib in LUAD due to transformation to a more aggressive SCC, and to lesser extent NE tumor cells, with high growth rate and invasion. These changes were attenuated post chemotherapy. Further, high growth inhibition was observed with carboplatin treatment in NRF2low and NRF2high LUAD cells compared to sotorasib."

Endocrine Cancer • Lung Adenocarcinoma • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • KRAS • SYP • TP63

Outcomes of KRAS G12C inhibitors in metastatic pancreatic cancer: A systematic review and meta-analysis. (ASCO 2025) - "Platinum-based chemotherapy was the most commonly used regimen (85%, n = 50) followed by gemcitabine (71%, n = 42) and taxanes (68%, n = 40). Sotorasib and Adagrasib exhibited favorable therapeutic activity in KRAS p.G12C-mutated pancreatic cancer patients with tolerable side effects. While the results are promising, the data highlights the need for further investigations to optimize clinical outcomes."

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

Outcomes with KRAS G12C inhibitors in metastatic colorectal cancer: A systematic review and meta-analysis. (ASCO 2025) - "Adagrasib 51% (38% received Adagrasib in combination with cetuximab], Sotorasib 32%, and Divarasib 17% used KRAS G12C inhibitors. The median number of prior therapies was 3 (1-9) and fluoropyrimidines were the most used regimen (98%, n = 323) followed by oxaliplatin (97%, n = 320), and irinotecan (89%, n = 296)... KRAS G12C inhibitors demonstrated promising efficacy in metastatic KRAS G12C mutated CRC with an acceptable toxicity profile. However, large studies with randomization are needed to consolidate these findings."

Metastases • Retrospective data • Review • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Targeting focal adhesion kinase to mitigate hepatotoxicity induced by PD-1 inhibition with or without KRAS G12C suppression. (ASCO 2025) - "FAK inhibition with Ifebe effectively reduces liver toxicity associated with KRAS G12C inhibition and PD-1 antibody therapy, underscoring the need for further clinical investigation."

IO biomarker • Hepatology • Oncology • KRAS

Prediction of sotorasib response duration and identification of clinically actionable resistance mechanisms using an RNA- and machine learning–based patient classifier. (ASCO 2025) - "These findings position krasID as a next-generation biomarker for identifying KRASi responders, predicting treatment duration, and guiding personalized follow-on therapies for KRAS-mutated cancers. Performance of time on sotorasib classifier"

Clinical • Machine learning • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Discovery of potent degraders of pan-KRAS based on a novel KRAS binder. (ASCO 2025) - "Recently, direct KRASG12C inhibitors, such as Sotorasib and Adagrasib have occurred first successes. The innovative linker elongation and branching, coupled with modifications of KRAS binder portion significantly contributed to potent pan-KRAS degraders, which demonstrate excellent pharmacokinetics and exhibit remarkable efficacy both in vitro and in vivo. The IND-enabling studies are being conducted and the regulatory IND filing will be completed in 2025."

Oncology • Targeted Protein Degradation • 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

Impact of standard vs reduced dosing of sotorasib on efficacy and toxicity in KRAS G12C–mutated advanced non-small cell lung cancer: A systematic review and meta-analysis. (ASCO 2025) - "While the standard 960 mg dose of Sotorasib showed a trend toward higher ORR compared to starting at reduced doses, it is associated with significant toxicity, resulting in frequent dose reductions and treatment discontinuation. No significant PFS benefit was observed with starting at 960 mg dose, highlighting the need to optimize dosing strategies that balance efficacy with tolerability. Future studies should include subgroup analyses of efficacy and tolerability for dose reductions to guide optimal dosing regimens, aligning with initiatives like the FDA's Project Optimus to improve patient outcomes."

Metastases • Retrospective data • Review • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • 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

Biomarkers of emergent resistance to sotorasib plus panitumumab in KRAS G12C-mutated metastatic colorectal cancer (mCRC) from the randomized, phase 3 CodeBreaK 300 study. (ASCO 2025) - P3 | "In CodeBreaK 300 trial, the addition of panitumumab (pani; monoclonal anti-EGFR antibody) counters this resistance and significantly improves clinical outcomes compared with standard of care (SoC; trifluridine-tipiracil or regorafenib). Dysregulation of the DNA methylation and RTK pathways and KRAS amplifications may contribute to the development of resistance to soto+pani combination. Further characterization of these acquired alterations, can help inform future therapeutic strategies."

Biomarker • Clinical • Metastases • P3 data • Colorectal Cancer • Oncology • Solid Tumor • ALK • DNMT3A • HER-2 • KMT2D • KRAS • LRP1B • TP53

Long-term safety and efficacy of sotorasib plus panitumumab and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreaK 101 (phase 1b). (ASCO 2025) - P1, P3 | "Discontinuation of sotorasib, panitumumab, or FOLFIRI (5-FU, irinotecan, or leucovorin/levoleucovorin) due to AEs was observed in 1 (2.5%), 1 (2.5%), and 16 (40.0%) patients, respectively... Sotorasib plus panitumumab and FOLFIRI showed promising long-term safety and efficacy in pretreated KRAS G12C-mutated mCRC. AEs were consistent with the safety profile of the drugs administered. The ongoing phase 3 study, CodeBreaK 301 (NCT06252649), aims to evaluate this combination against standard of care in first-line patients with KRAS G12C-mutated mCRC."

Clinical • Metastases • P1 data • Colorectal Cancer • Dental Disorders • Dermatitis • Dermatology • Immunology • Oncology • Solid Tumor • Stomatitis • KRAS

Use of new approach methodology for hepatic safety assessment of covalent inhibitor drug candidates. (PubMed, Toxicol Res (Camb)) - "The calculated hepatotoxicity margin towards plasma exposure of 2.5 for compound 35 was found to be in the same range as for the two KRASG12Cinhibitors adagrasib and sotorasib, with clinically reported treatment-related adverse aminotransferase elevations leading to dose modifications. The safety evaluation reported here suggests no negative discrepancy in liver toxicity for compound 35 versus similar approved TCI's. Finally, the risk associated with detected oxidative metabolites was further mitigated as the pan-CYP450 inhibitor 1-aminobenzotriazole (ABT) had no effect on the cytotoxicity response following incubation of compound 35 in the presence and absence of ABT."

Journal • Hepatology • Liver Failure • KRAS