divarasib (RG6330) / Roche - LARVOL DELTA

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

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

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

A Study to Evaluate the Pharmacokinetics of Divarasib in Healthy Participants and Participants With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Jan 2027 ➔ Jun 2026 | Trial primary completion date: Oct 2026 ➔ May 2026

Trial completion date • Trial primary completion date • Hepatology

Binding modes of the KRAS(G12C) inhibitors GDC-6036 and LY3537982 revealed by all atom molecular dynamics simulations. (PubMed, Sci Rep) - "While both inhibitors display low activity towards KRAS(WT), LY3537982 maintains high activity against other RAS isoforms with G12C mutation. As the simulation predictions align with the experimental results, our findings indicate that microsecond timescale simulations can be a valuable tool for predicting binding modes."

Journal • 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

RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy. (PubMed, Cancer Res) - "Finally, RIT1M90I drove resistance to the KRASG12C inhibitor, divarasib, and the combination with migoprotafib reverted this phenotype. Together, our data shows that RIT1M90I is a bona fide oncogenic driver of lung cancer and mediator of targeted therapy resistance as a co-occurring mutation and suggests that RIT1-altered cancer patients may benefit from combination treatments with a SHP2 inhibitor."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • RIT1

The complex journey of targeting RAS in oncology. (PubMed, BMC Cancer) - "This breakthrough has led to the development of targeted therapeutics, such as sotorasib and adagrasib, for KRAS G12C-mutated non-small cell lung cancer (NSCLC)...New inhibitors, such as LY3537982 or GDC-6036, are promising, but achieving effective and selective RAS inhibition remains a significant challenge...Challenges such as off-target effects and delivery issues remain significant barriers in the introduction of effective therapies based on RAS inhibitors. This overview highlights the evolving nature of targeting RAS in cancer therapy."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • TP53

Efficacy and safety of KRAS p.G12C inhibitors in advanced NSCLC: A systematic review and meta-analysis. (ASCO 2025) - "The KRAS p.G12C inhibitors evaluated were sotorasib, adagrasib, divarasib, and garsorasib. This meta-analysis underscores the favorable safety and efficacy profiles of KRAS p.G12C inhibitors after first-line progression in advanced NSCLC, despite the frequent adverse events, which were considered manageable. Further randomized controlled trials are expected to confirm these results and refine their role in subgroup populations, including STK1 and KEAP1 co-mutations, that confer even poor prognosis."

Metastases • Retrospective data • Review • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKB • CDK7 • KEAP1 • KRAS

Outcomes with KRAS G12C inhibitors in metastatic colorectal cancer: A systematic review and meta-analysis. (ASCO 2025) - "Adagrasib 51% (38% received Adagrasib in combination with cetuximab], Sotorasib 32%, and Divarasib 17% used KRAS G12C inhibitors. The median number of prior therapies was 3 (1-9) and fluoropyrimidines were the most used regimen (98%, n = 323) followed by oxaliplatin (97%, n = 320), and irinotecan (89%, n = 296)... KRAS G12C inhibitors demonstrated promising efficacy in metastatic KRAS G12C mutated CRC with an acceptable toxicity profile. However, large studies with randomization are needed to consolidate these findings."

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

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

Recent advances in therapeutic targeting of the KRAS pathway in cancer. (PubMed, Pharmacol Ther) - "Agents such as Sotorasib, Adagrasib, and Divarasib exhibit notable efficacy against KRASG12C mutations, particularly in NSCLC, with combination strategies significantly improving outcomes, especially in CRC. However, substantial challenges remain, including optimizing clinical trial designs, particularly in early-phase trials, and integrating pharmacodynamic tools to refine dosing and treatment schedules, thus achieving an optimal balance between efficacy and patient tolerability. This review summarizes recent therapeutic advancements, highlighting the clinical development of KRAS-specific inhibitors, and emphasizes future strategies involving a combination of mutant-specific and broader mutant-independent approaches to overcome resistance, thereby offering promise for more durable cancer control and expanded patient eligibility."

Journal • Review • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • KRAS

The structure of KRASG12C bound to divarasib highlights features of potent switch-II pocket engagement. (PubMed, Small GTPases) - "KRAS is the most frequently mutated oncogene in human cancer. Though it binds in the same allosteric pocket as sotorasib and adagrasib, the switch-II loop in each crystal structure takes on a distinct conformation differing as much as 5.6 Å between the Cα atom of residue 65 with sotorasib. Additionally, we highlight structural features of the drug complex that may guide future medicinal chemistry efforts targeting various KRAS alleles."

Journal • Oncology • KRAS

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 | Not yet recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Feb 2030 ➔ Oct 2030 | Initiation date: May 2025 ➔ Dec 2025 | Trial primary completion date: Apr 2028 ➔ Nov 2028

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