divarasib (RG6330) / Roche - LARVOL DELTA

Neoadjuvant Divarasib Shows Manageable Safety and Promising Activity in Resectable KRAS G12C+ NSCLC: Updated NAUTIKA1 Data (IASLC-WCLC 2026) - P2 | "Post-resection, patients with programmed death-ligand 1 tumor cell (PD-L1 TC) <1% received either adjuvant chemotherapy followed by up to 3 years of divarasib, up to 3 years of divarasib monotherapy, or standard of care; patients with PD-L1 TC ≥1% received adjuvant chemotherapy followed by atezolizumab, or standard of care. Divarasib also demonstrated manageable safety in the adjuvant setting. Divarasib will be investigated further in early-stage, resectable NSCLC in the phase III Krascendo 3 trial."

Clinical • IO biomarker • Constipation • Gastroenterology • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • KEAP1 • KRAS • PD-L1 • STK11 • TP53

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

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

Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation (AACR 2023) - P1a/1b | "GDC-6036 in combination with cetuximab demonstrated a manageable safety profile and promising clinical activity. These data support that the addition of anti-EGFR therapy to GDC-6036 may lead to robust clinical benefit in patients with KRAS G12C-positive CRC."

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

Divarasib Single-Agent Long-Term Follow-up and Atezolizumab Combination Treatment in Patients with KRAS G12C-Positive NSCLC (IASLC-WCLC 2024) - P1 | "Conclusions : Single-agent divarasib continued to demonstrate encouraging radiographic response rates and durable clinical activity alongside a tolerable safety profile, establishing promising combination potential with other anticancer therapies. Divarasib in combination with atezolizumab demonstrated an acceptable safety profile and preliminary clinical activity in patients with KRAS G12C -positive NSCLC."

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

First-line (1L) divarasib plus pembrolizumab (pembro) in advanced or metastatic KRAS G12C+ non–small cell lung cancer (NSCLC): Results from the Krascendo-170 study. (ASCO 2026) - P1/2, P3 | "In Krascendo 170, divarasib 400 mg once daily plus pembro had a manageable safety profile. Promising efficacy was shown in pts with advanced KRAS G12C+ NSCLC in both PD-L1- positive and -negative cohorts. A global, phase III trial investigating divarasib 400 mg in 1L advanced KRAS G12C+ NSCLC (Krascendo 2; NCT06793215) is currently enrolling."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

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

BFAST: A Study to Evaluate the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Participants With Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - P2/3 | N=1000 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2026 ➔ Jun 2027 | Trial primary completion date: Oct 2026 ➔ Jun 2027

Trial completion date • Trial primary completion date • Tumor mutational burden • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF

SPARK: An International Study of Acquired Resistance to KRAS Inhibitors in KRAS-Driven NSCLC Using Remote Plasma ctDNA and Tissue Profiling (IASLC-WCLC 2026) - P | "These included adagrasib (34.4%), sotorasib (54.2%), divarasib (2.1%), and investigational RAS(ON) inhibitors (8.3%)...This resistance mechanism was effectively overcome by combined KRAS and ALK inhibition (adagrasib plus alectinib) and was also suppressed by the multi-selective RAS(ON) inhibitor RMC-6236 as a single agent. Conclusions : This first analysis of SPARK demonstrates that acquired resistance to KRAS inhibitors in KRAS -driven NSCLC is molecularly heterogeneous but frequently actionable, involving on-target KRAS alterations and bypass pathway activation affecting key MAPK signaling nodes. These findings highlight the value of repeat molecular profiling at progression to identify targetable resistance mechanisms and inform rational combination or next-generation KRAS -directed therapies."

Circulating tumor DNA • IO biomarker • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • BRAF • ERBB3 • KRAS • MAP2K1 • MET • NF1 • NRAS • PTPN11

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

Targeting KRAS-Mutant Lung Cancers. (PubMed, J Natl Compr Canc Netw) - "The first allele-specific inhibitors, sotorasib and adagrasib, validated KRASG12C as a druggable dependency, changing the treatment paradigm for previously treated KRASG12C NSCLC, although primary, acquired, and adaptive resistance remain widespread. Next-generation inhibitors such as divarasib improve potency and tolerability but continue to face resistance through secondary KRAS alterations, bypass receptor tyrosine kinase (RTK) signaling, and adaptive MAPK reactivation...Early clinical results with tricomplex RAS(ON) inhibitors (eg, daraxonrasib) and G12D-selective agents (eg, zoldonrasib) demonstrate promising activity in subsets historically lacking targeted options. In parallel, rational combination strategies aimed at enhancing overall efficacy, such as RTK, SHP2/SOS1, or PD-1/PD-L1 blockade, together with emerging modalities including RAF-MEK clamps, adoptive cell therapies, and KRAS vaccines, are broadening the therapeutic landscape. This review comprehensively..."

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

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. (PubMed, Nat Med) - P1 | "As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874."

Journal • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • KRAS

Krascendo 3: A randomised, phase III trial in progress of divarasib vs immunotherapy or observation in patients with resected, stage II–IIIB, KRAS G12C+ non-small cell lung cancer (ESMO 2026) - No abstract available

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

Long-term follow-up of single-agent divarasib in patients with KRAS G12C-positive solid tumors (ESMO 2024) - P1 | "Single-agent divarasib was well tolerated with few new-onset TRAEs after 1 year and continued to demonstrate durable clinical activity in patients with advanced KRAS G12C-positive solid tumors."

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

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. (PubMed, N Engl J Med) - P1a/1b | "Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.)."

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

Single-Agent Divarasib in Patients With KRAS G12C-Positive Non-Small Cell Lung Cancer: Long-Term Follow-Up of a Phase I Study. (PubMed, J Clin Oncol) - P1 | "The median progression-free survival was 13.8 months (95% CI, 9.8 to 25.4) in the overall population (N = 65) and 15.3 months (95% CI, 12.3 to 26.1) among patients assigned to the 400-mg dose level (n = 44). With extended follow-up, divarasib demonstrated long-term safety and antitumor activity in patients with advanced KRAS G12C-positive NSCLC."

Journal • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Single-agent divarasib experience in patients with KRAS G12C-positive pancreatic adenocarcinoma (panc), cholangiocarcinoma (cholangio), and other solid tumors (ESMO 2025) - P1, P2 | "Conclusions Divarasib is safe and active in previously treated KRAS G12C- positive panc, cholangio, and OST. Updated data with additional solid tumor pts from the TAPISTRY study (n=15, for a total of N=47) will be included."

Clinical • Biliary Cancer • Carcinosarcoma • Cholangiocarcinoma • Colorectal Cancer • Gastric Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Sarcoma • Solid Tumor • KRAS

Phase I A Study to Evaluate GDC-6036 Monotherapy in Patients with Non-small Cell Lung Cancer (NSCLC) with KRAS G12C Mutation (IASLC-WCLC 2022) - P1a/1b | "GDC-6036 exhibits encouraging clinical activity and high target engagement levels across dose levels in NSCLC with a KRAS G12C mutation. This study has also demonstrated a wide therapeutic range for GDC-6036 (50- 400 mg), an acceptable safety profile with manageable and reversible AEs, and a PK profile compatible with once-daily dosing. Data from an expanded cohort will be presented at the conference."

Clinical • Monotherapy • P1 data • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Krascendo-170 Lung: a phase Ib/II study of divarasib + pembrolizumab _ platinum-based chemotherapy and pemetrexed in untreated KRAS G12C+ advanced non-small cell lung cancer (NSCLC) (ESMO-IO 2023) - P1/2 | "†Dose expansion will depend on pre-specified safety parameters during the dose-finding stage; ‡CT: 4 cycles of carboplatin (intravenously, every 3 weeks, AUC5) or cisplatin (intravenously, every 3 weeks, 75 mg/m2) per investigator's choice. Drug administration schedule: Divarasib: orally once daily; Pemetrexed: 500 mg/m2 intravenously every 3 weeks; Pembrolizumab: 200 mg intravenously every 3 weeks."

IO biomarker • Metastases • P1/2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

Krascendo-170 Lung: A phase Ib/II study of divarasib + pembrolizumab ± platinum-based chemotherapy and pemetrexed in untreated KRAS G12C+ advanced non-small cell lung cancer (NSCLC). (ASCO 2024) - P1/2 | "Key secondary endpoints include objective response rate, progression-free survival and duration of response (all investigator assessed per RECIST v1.1). Enrollment into the combination dose finding stage of Cohort A has been completed without dose-limiting toxicities and enrollment into the dose expansion stage is continuing."

IO biomarker • Metastases • P1/2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

Krascendo 2: A phase III study of divarasib and pembrolizumab vs pembrolizumab and chemotherapy in patients with previously untreated, advanced or metastatic, KRAS G12C-mutated non-small cell lung cancer (NSCLC). (ASCO 2025) - P3 | " Krascendo 2 (CO45042; NCT06793215) is a randomized, open-label, multicenter, global, phase III study, evaluating the efficacy and safety of first-line treatment with divarasib and pembro vs pembro and chemo (pemetrexed + carboplatin/cisplatin), in pts with advanced or metastatic KRAS G12C+ NSCLC. Secondary endpoints include confirmed objective response rate and duration of response by BICR, changes in patient-reported symptoms and functioning from baseline to Cycle 5 assessed via questionnaires, and safety. Tumor assessments will occur at screening, every 6 weeks (±7 days) for the first 72 weeks after randomization, and then every 9 weeks (±7 days)."

Clinical • IO biomarker • Metastases • P3 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

Krascendo 2: A phase III study of divarasib and pembrolizumab vs pembrolizumab and chemotherapy in patients with previously untreated, advanced or metastatic, KRAS G12C-mutated non-small cell lung cancer (NSCLC) (BTOG 2026) - "Evidence suggests that KRAS G12C inhibitors and pembrolizumab combinations have promising anti-tumor activities with manageable safety profiles. Divarasib plus pembrolizumab may be an effective and well tolerated first-line chemotherapy-free treatment in advanced/metastatic KRAS G12C+ NSCLC pts."

Clinical • IO biomarker • Metastases • P3 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

An Expanded Access Program to Provide Divarasib to Participants With Previously Treated KRAS G12c-Positive Advanced or Metastatic Non-Small Cell Lung Cancer (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Genentech, Inc.

New trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Highly Atroposelective Negishi Coupling Enables the Commercial Manufacturing Process of Divarasib. (PubMed, Chimia (Aarau)) - "The implementation of a continuous process for the metalation steps of the atroposelective Negishi coupling allowed for the elimination of the cryogenic reaction conditions from the manufacturing process. Furthermore, we detail improvements for the other chemical steps resulting in an impressive yield increase (factor of 6) and process mass intensity (PMI) reduction (factor of 39) for this sequence."

Journal • KRAS