divarasib (RG6330) / Roche - LARVOL DELTA

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

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=542 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2028 ➔ Aug 2030 | Trial primary completion date: Aug 2027 ➔ Aug 2030

Trial completion date • Trial primary completion date • Colorectal Cancer • Oncology • Solid Tumor

Neoadjuvant divarasib shows manageable safety and promising activity in patients with resectable, early-stage, KRAS G12C+ NSCLC: First results from the NAUTIKA1 KRAS G12C+ cohort (ELCC 2026) - No abstract available

Clinical • Lung Cancer • Non Small Cell Lung Cancer • 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 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

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

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

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

In-Source Fragmentation of Pyrrolidine-Containing KRAS Scaffolds Leads to Enhanced Structure Elucidation and Tandem Mass Spectral Quality. (PubMed, J Am Soc Mass Spectrom) - "We demonstrate the successful application of this optimized workflow to characterize GDC-6036, its synthetic intermediate, and structurally distinct KRAS inhibitors (Adagrasib and MRTX1133) across a chromatographic time scale. This approach offers a universal tool for enhancing the structure elucidation of challenging basic compounds, critical for supporting pharmaceutical process development."

Journal • KRAS

UmbrellaMAX: A Rollover Study for Participants Previously Enrolled in a Genentech and/or F. Hoffman-La Roche Sponsored Study (clinicaltrials.gov) - P3 | N=100 | Recruiting | Sponsor: Hoffmann-La Roche | N=60 ➔ 100

Enrollment change • Oncology

Engineered antibodies that stabilize drug-modified KRASG12C neoantigens enable selective and potent cross-HLA immunotherapy. (PubMed, Nat Commun) - "To address challenges by their low copy number, we develop AETX-R114, a T cell engaging bispecific antibody with picomolar affinity for MHC-restricted sotorasib-modified KRASG12C peptides presented by three HLA-A3 supertype alleles...To broaden the therapeutic potential of creating and targeting synthetic neoantigens, we further develop AETX-R302, which recognizes divarasib-modified KRASG12C peptides presented on alleles from the HLA-A2 and A3 supertypes. Cryo-EM structure determination reveals the molecular basis for breaking HLA supertype restriction. Collectively, our study illustrates how engineered antibodies can transform synthetic neoantigens into actionable cancer immunotherapy targets."

Journal • Oncology • 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

A Study to Evaluate the Pharmacokinetics of Divarasib in Healthy Participants and Participants With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=31 | Completed | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jun 2026 ➔ Nov 2025 | Trial primary completion date: May 2026 ➔ Nov 2025

Trial completion • Trial completion date • Trial primary completion date • Hepatology

A Study to Evaluate the Pharmacokinetics of Divarasib in Healthy Participants and Participants With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology

Krascendo 170: A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Participants With Previously Untreated Advanced or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=320 | Recruiting | Sponsor: Hoffmann-La Roche | N=240 ➔ 320

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

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

NAUTIKA1: A Study of Multiple Therapies in Biomarker-selected Participants With Resectable Stages IB-III Non-small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - P2 | N=99 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Mar 2029 ➔ May 2030 | Trial primary completion date: Dec 2025 ➔ Nov 2026

Biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • KRAS • NTRK1 • NTRK2 • NTRK3 • PD-L1 • RET • ROS1

GO42144: A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation (clinicaltrials.gov) - P1 | N=498 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2026 ➔ Sep 2026 | Trial primary completion date: Feb 2026 ➔ Sep 2026

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

Mutant and Wildtype RAS Crosstalk and Stoichiometric Deficiencies Determine Sensitivity to RAS Pathway Targeted Therapies Free (AACRPanCa 2025) - "Therapies targeting the RAF-MEK-ERK pathway are generally considered to have limited efficacy in KRAS mutant cancers when compared to the FDA approved RAS inhibitors such as sotorasib and adagrasib...Furthermore, we had a patient harboring a KRAS G12R mutation who achieved disease control on Divarasib (RMC-6236) but subsequently became resistant...However, we were able to achieve progression-free survival by utilizing MEK inhibitor plus hydroxychloroquine (MEKi+HCQ). Overall, our work highlights how systems-based approaches in precision medicine can uncover mechanistic insights to guide the identification of PDAC patients most likely to benefit from tailored therapeutic strategies."

Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • NF1

Krascendo 2: A Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Participants With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Hoffmann-La Roche | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Krascendo 170: A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib in Combination With Other Anti-Cancer Therapies in Participants With Previously Untreated Advanced or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=240 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: May 2027 ➔ Jan 2032 | Trial primary completion date: Sep 2025 ➔ Jan 2032

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

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: Aug 2028 ➔ Oct 2026 | Trial primary completion date: Aug 2028 ➔ Oct 2026

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

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 | Recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Sep 2026 ➔ Sep 2027

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