Lumakras (sotorasib) / Amgen, Roche - LARVOL DELTA

Underexplored mutations in plasma cell myeloma (ASH 2025) - "Many FDA-approved therapies exist in other cancers (such as sotorasib, selumetinib,vemurafenib, enasidenib, midostaurin, ruxolitinib, crizotinib, erlotinib), though these remain largelyunexplored in PCM. CHIP mutation burden in MM / PCM was 40%, Our analysis identified several potentially targetablemutations in pts with PCM, including KRAS, NRAS, BRAF, IDH2, FLT3, JAK2, ALK, and EGFR. Clonalhematopoiesis (CH/CHIP) mutations, such as DNMT3A, TET2, ASXL1, and SRSF2, were also observed.Although the lineage origin of several targetable mutations remains unclear, the likely high plasma cellburden in PCM cases suggests that many may originate within the malignant plasma cell clone. Thishypothesis warrants systematic investigation in future studies."

Tumor mutational burden • Hematological Malignancies • Multiple Myeloma • ALK • ASXL1 • BCOR • BRAF • CALR • CREBBP • CSF3R • DNMT3A • EGFR • FLT3 • GNAS • IDH2 • JAK2 • KRAS • NRAS • PHF6 • PPM1D • PRPF8 • SRSF2 • SUZ12 • TET2 • TMB • TP53

A study of aumolertinib combined with palbociclib in patients with advanced solid tumors harboring KRAS mutations (APEAK) (ESMO Asia 2025) - P1/2 | "Background: Although KRASG12C-specific inhibitors (KRASG12Ci) like sotorasib show efficacy in KRASG12C-mutated NSCLC, therapeutic resistance remains challenging. Clinical Trial Identification. NCT06947811."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Th-Vac platform-selected MHC class II KRAS mRNA cancer vaccine drives potent Th1 immunity and sotorasib-comparable anti-tumor activity (ESMO Asia 2025) - "The Th-Vac® platform enables discovery of Th1-specific MHC class II KRAS epitopes. A multi-epitope KRAS mRNA vaccine induced potent Th1 immunity and reshaped the tumor microenvironment, showing anti-tumor efficacy comparable to Sotorasib. This supports development for off-the-shelf or personalized KRAS-driven vaccines, with humanized mouse studies and IND-enabling work."

Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • KRAS

Flourishing innovation in KRAS targeting: Recent advances in medicinal chemistry strategies and future perspectives. (PubMed, Bioorg Chem) - "The landmark approval of Sotorasib in 2021, the first covalent KRASG12C inhibitor, shattered this dogma, ushering in a new era of targeted therapy for KRAS-mutant cancers, which also has catalyzed an explosion of innovative strategies extending far beyond covalent G12C targeting...Additionally, it encompasses structure-activity relationship (SAR) investigations and activity optimization processes and pharmacokinetic properties studies of representative molecules. Furthermore, we critically evaluate existing challenges in developing small-molecule KRAS modulators while discussing emerging opportunities in overcoming on-target resistance, aiming to offer valuable insights and perspectives for future research in this rapidly evolving field."

Journal • Review • Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • KRAS

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 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Initiation date: Dec 2025 ➔ Aug 2026

Enrollment open • Trial initiation date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ERBB3 • KRAS

Evaluating the efficacy of G12C-inhibitors in conjunction with Gamma Knife Radiosurgery for KRAS-mutant NSCLC brain metastases (SNO 2025) - "Sixteen received G12C inhibitors (adagrasib/sotorasib). The addition of KRAS G12C-inhibitors to GKRS in patients with G12C-mut NSCLC brain metastases was not associated with improved OS and was associated with significantly earlier DBF. These findings suggest that, while KRAS G12C-inhibitors have systemic benefits, their integration with radiosurgical management may not confer CNS-specific advantages and warrants further optimization of treatment sequencing and patient selection."

Clinical • IO biomarker • Surgery • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • KRAS

Unlocking New Treatment Possibilities for Metastatic Endometrial Cancer With KRAS G12C Mutation. (PubMed, Case Rep Oncol Med) - "This case highlights the potential clinical utility of KRAS G12C inhibitors in EC and highlights the importance of molecular profiling in identifying actionable mutations that may guide treatment decisions. This report, contributing to the limited body of evidence that includes three prior cases evaluating the role of sotorasib and adagrasib across several solid malignancies, highlights the clinical and translational relevance of adagrasib in advancing precision-targeted therapy for KRAS G12C-mutated tumors."

Journal • Clear Cell Carcinoma • Colorectal Cancer • Endometrial Cancer • Endometrial Clear Cell Carcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Krascendo 1: A Study Evaluating the Efficacy and Safety of Divarasib Versus Sotorasib or Adagrasib in Participants With Previously Treated KRAS G12C-positive Advanced or Metastatic Non-Small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=320 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Activity of direct KRAS(G12C) inhibitors in preclinical models of pediatric cancer. (PubMed, Mol Cancer Ther) - "Here, we show that sotorasib, adagrasib, and the RAS-ON inhibitor RMC-6291 are effective in a neuroblastoma cell line altered by KRAS(G12C). Importantly, sotorasib also decreased ERK phosphorylation in a NRAS(G12C)-altered cell line xenograft model; however, this treatment did not prolong survival as a single agent. These results suggest that combinations of targeted agents that include sotorasib may be required for clinical benefit in pediatric patients with H- or NRAS(G12C)-altered malignancies in addition to those with KRAS(G12C)-altered malignancies."

Journal • Preclinical • Colorectal Adenocarcinoma • Colorectal Cancer • Hematological Malignancies • Leukemia • Neuroblastoma • Oncology • Pancreatic Cancer • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • KRAS • NRAS

Opportunities for Harmonization of US Food and Drug Administration Regulatory Decisions Exemplified by the Traditional Approval of Sotorasib and Panitumumab for Colorectal Cancer. (PubMed, J Clin Oncol) - No abstract available

FDA event • Harmonization • Journal • Colorectal Cancer • Oncology • Solid Tumor

Breakthroughs in KRAS G12C-mutant advanced colorectal cancer: from mechanisms to clinical practice (PubMed, Zhonghua Wei Chang Wai Ke Za Zhi) - "Recent phase I/II trials of KRAS G12C inhibitors have shown promising results, and the phase III CodeBreaK 300 study confirmed that sotorasib combined with panitumumab significantly improved efficacy compared with standard treatment, establishing a new therapeutic option for KRAS G12C-mutant metastatic CRC. Strategies under investigation include targeting alternative signaling pathways, developing next-generation inhibitors and specific degraders, and exploring multi-mechanism or multi-target combination strategies. This review systematically outlines the development of KRAS G12C inhibitors in mCRC, summarizes resistance mechanisms, and discusses emerging combination regimens, aiming to provide a theoretical basis and future directions for treatment optimization."

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

Evaluating the efficacy of G12C-inhibitors in conjunction with Gamma Knife Radiosurgery for KRAS-mutant NSCLC brain metastases (WFNOS 2025) - "Sixteen received G12C inhibitors (adagrasib/sotorasib). The addition of KRAS G12C-inhibitors to GKRS in patients with G12C-mut NSCLC brain metastases was not associated with improved OS and was associated with significantly earlier DBF. These findings suggest that, while KRAS G12C-inhibitors have systemic benefits, their integration with radiosurgical management may not confer CNS-specific advantages and warrants further optimization of treatment sequencing and patient selection."

Clinical • IO biomarker • Surgery • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • KRAS

Pan-RAS Inhibitor RMC-7977 Overcomes Oncogenic RAS Signaling and Exerts Antileukemic Effects in CMML/AML Cells (ASH 2024) - "FDA-approved KRASG12C inhibitors sotorasib and adagrasib demonstrate significant clinical response for non-small cell lung cancer patients harboring KRAS G12C mutation, and early data suggests that pan-RAS inhibitors are safe and effective in PDAC and NSCLC. Experiments evaluating the effects of RMC-7977 in cell line xenografts and additional patients' primary samples are ongoing and will be presented.Collectively, we have demonstrated that the pan-RAS inhibitor RCM-7977 is highly effective against RAS mutated CMML/AML cell lines arising from chronic myeloid neoplasms including CMML while sparing healthy hematopoietic stem and progenitor cells. This work provides the rationale to continue evaluating RAS inhibitors as a targeted therapy in RAS-mutated myeloid malignancies, which is a significant unmet need in the treatment of these conditions."

IO biomarker • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • CD34 • FLT3 • HRAS • IDH1 • IDH2 • JAK2 • KIT • KRAS • NRAS

Phenotypic Hit Identification and Optimization of Novel Pan-TEAD and Subtype-Selective Inhibitors. (PubMed, J Med Chem) - "In lung cancer xenograft studies, representatives from both substance classes demonstrated monotherapeutic antitumor activity. For one selected example, the combination effect with the KRASG12C inhibitor sotorasib was demonstrated in vivo."

Journal • Lung Cancer • Oncology • Solid Tumor • KRAS • TEAD2 • TEAD3

A novel anticancer natural product SP09 selectively targets KRAS-mutant NSCLC through LKB1/AMPK/mTOR modulation: implications for novel therapeutic development. (PubMed, Anticancer Drugs) - "Although covalent KRAS^G12C inhibitorsi such as sotorasib and adagrasib have demonstrated clinical activity, pooled analyses indicate only modest response rates and short progression-free survival, with no effective options for non-G12C subtypes...Cell viability, colony formation, and cell cycle distribution were assessed, and the involvement of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling axis was examined by western blot...SP09 exerts potent and selective antiproliferative effects in KRAS-mutant NSCLC through dual regulation of cell cycle and metabolic signaling pathways. Given the restricted efficacy and rapid resistance associated with current KRAS-targeted therapies, our data highlight SP09 as a promising candidate for further preclinical development with potential translational value in KRAS-driven NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AMPK • CCNB1 • CDKN1A • EGFR • KRAS • mTOR • STK11

Oncology (Amgen Press Release) - "Vectibix (panitumumab) sales increased 1% year-over-year to $284 million in the third quarter; KYPROLIS (carfilzomib) sales decreased 5% year-over-year to $359 million in the third quarter, driven by lower volume; LUMAKRAS /LUMYKRAS (sotorasib) sales decreased 2% year-over-year to $96 million in the third quarter; XGEVA (denosumab) sales were flat year-over-year at $539 million in the third quarter...Nplate (romiplostim) sales were flat year-over-year at $457 million in the third quarter. U.S. government orders were $90 million in Q3'25 compared to $128 million in Q3'24...IMDELLTRA (tarlatamab-dlle)/IMDYLLTRA (tarlatamab) generated $178 million of sales in the third quarter. Sales increased 33% quarter-over-quarter, primarily driven by volume growth; MVASI (bevacizumab-awwb) sales increased 9% year-over-year to $213 million in the third quarter, driven by favorable changes to estimated sales deductions."

Sales • Cervical Cancer • Colorectal Cancer • Glioblastoma • Lung Non-Squamous Non-Small Cell Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Ovarian Cancer • Renal Cell Carcinoma • Small Cell Lung Cancer

TRIM7 Inhibition Blocks RTK/RAS Pathway Driven Tumor Cell Proliferation Independent of Mutation and Restores Tumor-Intrinsic IFN Responsiveness (SITC 2025) - "Degradation of RACO-1 resulted in significant TGI in both EGFR/KRAS wild-type and mutant tumor cell lines, and outperformed other KRAS pathway inhibitors like Sotorasib and Zoldonrasib, without selectivity to specific KRAS mutations...TRIM7 inhibition reduced tumor growth in vitro and in vivo and outperformed multiple KRAS inhibitors as monotherapy. Lead TRIM7 inhibitors warrant further development to address the unmet need in cancers that evolve with various resistance mechanisms, including aberrant RTK/RAS/RAF signaling.Ethics Approval Animal studies were approved by an Institutional Animal Care and Use Committee (IACUC); and a licensed veterinarian."

IO biomarker • Tumor cell • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1 • CXCL1 • EGFR • IDO1 • IFIT2 • KRAS • MAP2K2 • RASA1 • STAT1 • STAT3 • TRIM4 • TRIM7

PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs in Japan; durvalumab, cemiplimab, zongertinib, and taletrectinib for lung cancer, pirtobrutinib and atezolizumab for lymphoma, durvalumab for bladder cancer, panitumumab plus sotorasib for colorectal cancer, and vorasidenib for glioma. (PubMed, Int J Clin Oncol) - No abstract available

Japanese regulatory • Journal • Bladder Cancer • Brain Cancer • Colorectal Cancer • Genito-urinary Cancer • Glioma • Hematological Malignancies • Lung Cancer • Lymphoma • Oncology • Solid Tumor

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=610 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting | N=1200 ➔ 610 | Trial primary completion date: Jun 2026 ➔ Dec 2026

Enrollment change • Enrollment closed • Monotherapy • Trial primary completion date • Brain Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Ficerafusp alfa-driven tumor penetration via EMT and FMT inhibition in the tumor microenvironment (ESMO 2025) - P1 | "The combination of FICERA with pembro in HPV-neg HNSCC paired biopsies from a Ph1b clinical trial or in combination with sotorasib in a preclinical model of resistant lung cancer reveals down-regulation of EMT and enhanced IFN-γ signaling...T-cell responses observed with FICERA alone or in combination are consistent with enhanced immune cell tumor penetration. Orthogonal approaches highlight and support the proposed mechanism of action of the TGF-β arm of FICERA within the TME."

Biomarker • Tumor microenvironment • Head and Neck Cancer • Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CAFs • IFNG • TGFB1

Comparative Efficacy and Safety of KRAS G12C-Targeted Therapies in Metastatic Colorectal Cancer: A Systematic Review and Network Meta-Analysis (ACG 2025) - "A total of 1,923 records were identified, and after removing duplicates and screening, 14 studies met the inclusion criteria for analysis. A total of 574 patients were included across multiple treatment arms, comprising Sotorasib 960 mg (62), Sotorasib 960 mg + Panitumumab (93), Adagrasib 1200 mg (44), Divarasib + Cetuximab (29), Olomarasib + Cetuximab (49), Sotorasib 960 mg + Panitumumab + FOLFIRI (31), Adagrasib 1200 mg + Cetuximab (94), Sotorasib alone (42), Sotorasib + Panitumumab (39), Adagrasib alone (4), Divarasib alone (55), and Olomarasib alone (32) treatment cohorts. The highest mean ORR was observed in the Sotorasib 960mg + Panitumumab + FOLFIRI group (58.1%, 95% CI: 51.7%–64.5%), while the lowest mean ORR was consistently seen in the Placebo groups (1%, 95% CI: not estimable due to sample size)."

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

FMC-376, a dual inhibitor of ON + OFF states of KRAS G12C, is active in sotorasibresistant PDX models (AACR-NCI-EORTC 2025) - P1/2 | "In models derived from colorectal cancer patients following disease progression with sotorasib or sotorasib in combination with trametinib, FMC-376 demonstrated robust single agent anti-tumor activity. Further, synergistic anti-tumor activity was observed when FMC-376 was combined with Cetuximab...FMC-376 is a clinical stage dual inhibitor of ON and OFF state KRAS G12C that has the potential to overcome limitations of OFF state inhibitors. A Phase 1/2 study of FMC-376 in patients with locally advanced unresectable or metastatic solid tumors harboring KRAS G12Cmutation is currently on-going (NCT06244771)."

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

Development of Patient-Derived Xenograft (PDX) Model with Acquired Resistance to KRASG12C Inhibitors (AACR-NCI-EORTC 2025) - "Then LU22002 was established from tumors of the same patient that progressed under combined treatment of MRTX849 and a SHP2 inhibitor, TNO155...Noticeably, all 6 mice treated with combined treatment of crizotinib and AMG510 showed complete tumor regression after 17 days of treatment. ConclusionWe have successfully developed KRASG12C inhibitor resistant NSCLC PDX models derived from one patient with acquired resistance to AMG510 and MRTX849 treatments, and in vivo induced KRASG12C inhibitor resistant PDX model. EGFR or MET gene amplification was observed in these resistant models, which can be used to evaluate innovative combination strategies."

Clinical • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS

Sex differences in the tolerability to novel targeted therapies: Insights from a French lung cancer data system (ESMO 2025) - "The most used TTs were Osimertinib (71.5%), Alectinib (15.1%), Lorlatinib (5.4%), Brigatinib (3.9%), Dabrafenib+Trametinib (6.3%), Sotorasib (1.7%), Trastuzumab and Amivantamab (0.6% each), others comprising 1.5%. Our study underscore the need for sex-informed supportive care strategies and inclusive toxicity reporting in clinical trials of TTs. Legal entity responsible for the study Gustave Roussy."

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

Potential alternative dosage strategies for patent-protected oral cancer drugs. (PubMed, Eur J Cancer) - "Over half of patent-protected oral oncology drugs have potential alternative dosage strategies that may reduce costs for payors and side effects for patients. Public payors and closed healthcare systems should consider post-marketing dosage optimization trials to evaluate these strategies."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor