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

Adagrasib with or without cetuximab in patients with KRASG12C-mutated colorectal cancer (CRC): Analysis of tumor biomarkers and genomic alterations (ESMO 2023) - P1/2, P3 | "Conclusions Exploratory analyses suggest diverse mechanisms of acquired resistance in pts treated with ada mono and in combination with cetux, and a greater depth of ctDNA response in pts treated with ada + cetux. Ada + cetux is being investigated in 2L CRC in the phase 3 KRYSTAL-10 trial (NCT04793958)."

Biomarker • Clinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • KRAS

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. (PubMed, N Engl J Med) - P1/2 | "Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.)."

Clinical • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • KRAS

KRYSTAL-1: Pooled phase 1/2 efficacy and safety of adagrasib (MRTX849) in combination with cetuximab in patients with metastatic colorectal cancer (CRC) harboring a KRASG12C mutation (AACR 2024) - P1/2, P3 | "In these pooled registrational Ph1/2 cohorts of heavily pretreated pts with KRASG12C-mutated CRC, ada + cetux was well tolerated with clinically meaningful antitumor activity. Ada + cetux is being investigated for second-line treatment of KRASG12C-mutated CRC in the Ph3 KRYSTAL-10 trial (NCT04793958)."

Clinical • Combination therapy • Metastases • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer. (PubMed, Cancer Discov) - "Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer."

Journal • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • 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

KRYSTAL-1: Updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation (ESMO 2022) - P1/2, P3 | "Both showed clinical activity in heavily pretreated pts with KRAS G12C -mutated CRC, with more sustained responses with the combination. Adagrasib + cetuximab is being investigated in 2L CRC in the Phase 3 KRYSTAL-10 trial (NCT04793958)."

Clinical • Late-breaking abstract • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • 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

Second-line adagrasib plus cetuximab vs chemotherapy in patients with KRASG12C-mutated metastatic colorectal cancer: Results from the KRYSTAL-10 trial (ESMO-GI 2026) - P3 | "Methods Pts with KRAS G12C -mutated mCRC who progressed on first-line fluoropyrimidine-based doublet chemo with oxaliplatin or irinotecan were randomized 1:1 to Ada (600 mg twice daily) + Cetux (500 mg/m 2 every 2 weeks) or chemo (FOLFIRI or mFOLFOX6; ± VEGF/VEGFR inhibitors)...Conclusions In pts with KRAS G12C -mutated mCRC, 2L Ada + Cetux showed antitumor activity, along with manageable safety. While KRYSTAL-10 did not meet its dual primary endpoints vs chemo, these results demonstrated clinical activity as a chemo-free targeted regimen in previously treated pts with KRAS G12C -mutated mCRC."

Clinical • Late-breaking abstract • Metastases • Colorectal Cancer • Gastrointestinal 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

Adagrasib (Ada) + cetuximab (Cetux) for KRASG12C -mutated metastatic colorectal cancer (mCRC): Longer follow-up analysis from KRYSTAL-1. (ASCO-GI 2025) - P1/2, P3 | "In heavily pretreated pts with KRASG12C-mutated mCRC, Ada + Cetux continued to demonstrate clinically meaningful activity and tolerable safety with longer follow-up. These updated results are consistent with those from the primary analysis and constitute the longest duration of follow-up for dual KRASG12C/EGFR blockade in this setting. Efficacy of second-line Ada + Cetux vs chemotherapy in KRASG12C-mutated mCRC is being investigated in the phase 3 KRYSTAL-10 study (NCT04793958)."

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

The KRAS targeting revolution in metastatic pancreatic cancer: insights from the landmark RASolute-302 trial and emerging allele-specific strategies at ASCO 2026. (PubMed, J Hematol Oncol) - "This correspondence highlights how the first-in-class pan-RAS (ON) inhibitor daraxonrasib (RMC-6236) virtually doubled median overall survival (13.2 vs. 6.6 months) and progression-free survival compared to chemotherapy in second-line mPDAC, establishing a new standard of care...These include the selective KRAS G12D inhibitor DN022150 and promising horizontal combinations pairing the G12D inhibitor HRS-4642 with either the anti-PD-L1 antibody adebrelimab or a Nectin-4-targeted antibody-drug conjugate (ADC). Furthermore, we address the KRAS G12C cohort where farnesyl transferase co-inhibition (darlifarnib plus adagrasib) successfully bypasses adaptive resistance. Ultimately, the therapeutic landscape of mPDAC is transitioning toward tailored genomic frameworks. Future success will rely on optimizing the clinical sequencing or combination of pan-RAS and allele-specific agents, guided by real-time liquid biopsies, to permanently dismantle resistance and transform mPDAC into..."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

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

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

Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial. (PubMed, Lancet) - P3 | "Adagrasib demonstrated a statistically significant improvement in progression-free survival over docetaxel in patients with previously treated KRASG12C-mutated NSCLC, without new safety signals."

Clinical • IO biomarker • Journal • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors (AACR 2024) - P1, P2 | "Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes...In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models...Other combination arms may also be considered. The study began accrual in October 2023."

Clinical • Combination therapy • First-in-human • IO biomarker • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS • 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

KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non–small cell lung cancer (NSCLC) harboring a KRASG12C mutation. (ASCO 2022) - P1/2, P3 | "Adagrasib is well tolerated and demonstrates promising efficacy in pretreated patients with NSCLC harboring a KRASG12C mutation. A Phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRASG12C-mutant NSCLC is ongoing (NCT04685135)."

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

Impact of co-mutations and transcriptional signatures in non-small cell lung cancer patients treated with adagrasib in the KRYSTAL-1 trial. (PubMed, Clin Cancer Res) - P1/2 | "KEAP1, STK11 and NRF2 status define KRASG12C-mutant NSCLC patients with markedly distinct outcomes to adagrasib. These results further support the use of genomic features - mutational and non-mutational - for treatment selection of KRASG12C-mutant NSCLC patients."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • STK11

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

Patient-reported outcomes with adagrasib in KRYSTAL-12. (PubMed, Lancet) - No abstract available

Journal

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

Additional practice-informing adverse event patterns and management in the KRYSTAL-1 phase II study of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC (ESMO 2022) - P1/2 | "Conclusions Adagrasib demonstrated a manageable AE profile in pre-treated pts with KRAS G12C -mutated NSCLC. Most TRAEs were low grade, occurred early in treatment, and resolved quickly, resulting in a low (6.9%) discontinuation rate."

Adverse events • Clinical • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

ADEPPT: Adagrasib in Patients With KRASG12C-mutant NSCLC Who Are Elderly or Have Poor Performance Status (clinicaltrials.gov) - P2 | N=68 | Active, not recruiting | Sponsor: ETOP IBCSG Partners Foundation | Trial completion date: Jul 2026 ➔ Dec 2026

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS