Krazati (adagrasib) / ZAI Lab, BMS - LARVOL DELTA

Actionable mutations in pancreatic cancer: where targeted therapies are making a difference. (PubMed, BMJ Open Gastroenterol) - "It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the..."

Journal • Review • Gene Therapies • Microsatellite Instability • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2 • HER-2 • KRAS • MSI • MTAP • NRG1 • NTRK

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

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

Optimizing PICO Scoping in EU HTA: Lessons From a HTA Coordination Group PICO Exercise in Advanced NSCLC to Inform Future Best Practice (ISPOR-EU 2025) - "In this study, we aimed to review consolidated PICOs proposed for adagrasib to integrate developers perspective based on broader clinical evidence base and epidemiological insights from adagrasib HTA submissions and inform future best practices for scoping. We systematically reviewed the consolidated PICOs with respect to i) relevance of the different populations based on the approved indication and the target patient population in the pivotal trial KRYSTAL-1 and KRYSTAL -12 (confirmatory head-to-head trial) and ii) clinical relevance of comparators in each PICO based on precise target population, current national/EU level treatment guidelines, and clinical feedback during HTA assessments within KRAS G12C-mutated NSCLC in the UK/Europe. The clinical relevance of 3 comparators (PICO 2,4,5) was unclear since 98.3% and 100% of patients had received prior IO and PDC in KRYSTAL-1 and KRYSTAL-12 studies respectively... Given the lack of systematic involvement of developers in..."

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

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

Genetic Characteristics and Survival Outcomes between Different Ethnicities with Colon Adenocarcinoma (AMP 2025) - "The findings reveal poorer OS in AAoB populations compared to Whites. Assessment of confounds revealed no effect on OS, indicating a need to investigate other potential mediators of CA prognosis. KRAS mutations were significantly more prevalent in the AAoB patients, implicating the advent and availability of KRAS-targeting treatments like adagrasib as a tool to bridge the survival gap."

Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • KRAS • PDK1

Forecasted Milestones (GlobeNewswire) - "Initiate FIT-001 Phase 1b expansion cohorts of darlifarnib and cabozantinib in patients with advanced RCC in the first half of 2026. Present updated dose-escalation data from the combination of darlifarnib and cabozantinib in patients with advanced RCC in 2026. Present preliminary clinical data from the combination of darlifarnib and adagrasib in patients with KRASG12C-mutated solid tumor indications in 2026."

P1 data • Trial status • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma • Renal Cell Carcinoma

Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1 (clinicaltrials.gov) - P1/2 | N=731 | Active, not recruiting | Sponsor: Mirati Therapeutics Inc. | Recruiting ➔ Active, not recruiting

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

Transcription factors enhancing anti-tumor chemokine expression and lymphocyte infiltration in KRAS G12C inhibitor-resistant non-small cell lung cancer. (AACR-NCI-EORTC 2025) - "Supporting this, early-phase clinical trials combining adagrasib or olomorasib with pembrolizumab have reported improved efficacy, with ORRs ranging from 63–75% (Garassino et al., Ann. These results suggest that G12Ci may stimulate CXCL chemokine expression either by activating transcription or by relieving repression by specific TFs, which may drive lymphocyte recruitment and help convert 'immune cold' tumors into 'hot' microenvironments. The transcription factors we identified may represent new therapeutic targets to potentiate anti-tumor chemokine signaling and improve responses to immunotherapy."

IO biomarker • Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CXCL10 • CXCL11 • CXCL9 • FOXP1 • IRF1 • KRAS • PD-L1 • STING • STK11 • ZNF384

Statin Use in Patients With Cancer: Drug Interaction and Statin Usage. (PubMed, JACC Adv) - "Statin-oncology agent DDIs are relatively common but rarely is statin use contraindicated. Frequency of statins use varies according to cancer type. These findings highlight the importance of individualized risk-benefit assessments that consider prognosis, cardiovascular risk, potential drug interactions, and patient preferences to guide statin use in cancer patients."

Journal • Breast Cancer • Cardiovascular • Dyslipidemia • Lung Cancer • Oncology • Solid Tumor

Adagrasib (Krazati®)-Induced Esophageal Dysmotility in the Treatment of Non-Small Cell Lung Cancer (ACG 2025) - "The patient was started on 6 weeks of chemoradiation with carboplatin/paclitaxel, followed by gamma knife radiation to the occipital lobe lesion. Our case highlights esophageal dysmotility associated with adagrasib therapy in our patient with stage IVB lung adenocarcinoma. Treating the esophageal dysmotility with mealtime and bedtime metoclopramide improved our patient's oral intake, improved mentation and contributed to overall healing of the patient despite grim circumstances of his disease."

Anorexia • Cachexia • Fatigue • Gastrointestinal Disorder • Hypotension • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

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

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

PRC2 inhibition enhances KRAS inhibitor response to delay treatment relapse in KRAS-mutant preclinical lung and colorectal cancer models (AACR-NCI-EORTC 2025) - P1 | "The combination of adagrasib, a KRAS G12C inhibitor, and ORIC-944 resulted in greater antitumor efficacy, more tumor regressions, and significantly smaller tumors, in both CRC and NSCLC models. Combining ORIC-944 with KRAS inhibition significantly improved efficacy and PFS in NSCLC and CRC models, demonstrating that PRC2 inhibition can deepen and extend KRAS inhibitor responses to prevent or delay resistance to KRAS inhibition. ORIC-944 is under clinical evaluation in a global Phase 1b study (NCT05413421)."

Preclinical • Breast Cancer • Colorectal Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • KRAS

KRASG12C mutationand metastatic colorectal cancer: Are we ready for neo-adjuvant? A case report. (AACR-NCI-EORTC 2025) - "Despite this advancement, 5-fluorouracil (5-FU)-based chemotherapy remains the standard in upfront settings, as prior trials with anti-EGFR and anti-VEGF agents have failed to demonstrate significant benefit beyond metastatic disease... This case illustrates the effective use of adagrasib plus cetuximab as neoadjuvant and maintenance therapy in a patient with resectable metastatic KRAS G12C-mutated CRC. It raises the question of whether targeted therapy should be further explored in earlier treatment phases for select patients, especially those with limited response to standard chemotherapy."

Case report • Clinical • Metastases • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • KRAS

Structural determination of small proteins by cryo-EM using a coiled coil module strategy. (PubMed, Sci Rep) - "The kRasG12C structure was bound to the inhibitor drug MRTX849 and GDP, both clearly visible in the density map...Additionally, we investigated several other techniques that can be applied to small proteins, regardless of the presence of a terminal helix. These advancements demonstrate the potential of cryo-EM for detailed structural analysis of a wide range of protein targets, extending cryo-EM application for drug discovery."

Journal • KRAS

Inhibition of ULK1/2-Mediated Autophagy Enhances Responses to RAS Inhibition and Augments Antigen-Specific T Cell Cytotoxicity (AACR-NCI-EORTC 2025) - "Inhibition of ULK1/2 alone resulted in increased tumor CD8+ T cell infiltration in the CMT-167 KRAS G12C KI tumors. ULK1/2 inhibition combined with adagrasib and anti-PD-1 results in significantly greater tumor growth inhibition and survival.ConclusionInhibition of ULK1/2-mediated autophagy enhances responses to RAS inhibition by disabling a rapid mechanism of resistance, restoring neoantigen presentation, and enhancing T cell-mediated cytotoxicity."

IO biomarker • Oncology • CASP3 • CASP7 • CD8 • KRAS

“Users of the Monitored Drug Registries are hereby informed that…it will be possible to use the medicinal product KRAZATI via the monitoring register for the indication eligible for reimbursement. KRAZATI as monotherapy is indicated for the treatment of adult patients with advanced NSCLC with a KRAS G12C mutation and disease progression…prior systemic therapy”. [Google translation] (Italian Medicines Agency)

Reimbursement • Lung Cancer • Non Small Cell Lung Cancer • Oncology

SOS1 inhibitor BMS-986509 and EGFR inhibitor combinations are synergistic with adagrasib in KRAS G12C mutant tumor organoid models (ESMO 2025) - P1/2 | "Conclusions Ultimately, these data may facilitate the identification of novel biomarkers, inform on indication expansion, and identify optimal combination strategies. BMS-986509 is currently being evaluated in a FIH trial as a monotherapy and in combination with adagrasib (NCT05578092) in patients with advanced solid tumors harboring a KRAS G12C mutation."

Oncology • Solid Tumor • KRAS

Adagrasib in the treatment of KRASG12C-mutated non-small cell lung cancer: a cost-effectiveness analysis. (PubMed, Transl Cancer Res) - "Amid rising cancer care costs and growing demand for effective therapies, evaluating new treatments' cost-effectiveness is critical. Policymakers must weigh upfront treatment costs against long-term impacts on patient outcomes and healthcare system sustainability."

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

AXL Inhibitor AB801 Increases the Anti-Tumor Efficacy of KRAS Inhibition (AACR-NCI-EORTC 2025) - P1 | "These results were observed when dosing of both agents was initiated concurrently and when AB801 dosing was initiated after tumor stasis was attained with adagrasib monotherapy.ConclusionAB801 is being evaluated in ARC-27 (NCT06120075), a Phase 1/1b study in patients with advanced solid tumors with plans for an expansion cohort in 2L+ NSCLC. These data support the notion that combining AB801 with (K)RAS inhibition has the potential to overcome the resistance often observed with (K)RAS inhibitor monotherapy, leading to deeper and more durable clinical responses."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GAS6 • KRAS