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

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) - P2 | "In the adjuvant setting, pts whose tumours had <1% programmed death-ligand 1 (PD-L1) had the option of chemotherapy plus up to 3 yrs of divarasib or up to 3 yrs of divarasib alone; pts whose tumours had ≥1% PD-L1 received chemotherapy plus atezolizumab or chemotherapy alone (current standard of care). Conclusions Neoadjuvant divarasib has manageable safety and promising pathological regression and radiographic ORR in pts with resectable, early-stage, KRAS G12C+ NSCLC. No impact on surgical outcomes was observed."

Clinical • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • 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) (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

CO45042: 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 (clinicaltrialsregister.eu) - P2/3 | N=282 | Recruiting | Sponsor: F. Hoffmann-La Roche AG

New P2/3 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • KRAS

FMC-242, a highly potent and selective covalent inhibitor of the PI3Kα -RAS interaction, demonstrates robust anti-tumor activity as monotherapy and in combination with targeted therapies (AACR 2026) - "Combination of FMC-242 with targeted therapies including EGFR inhibitors, KRASG12C inhibitors such as FMC-376, divarasib, olomorasib, or pan-RAS/KRAS agents results in enhanced efficacy and tumor regressions in vivo. Together, these data demonstrate the potential of FMC-242, a selective covalent inhibitor of PI3Kα -RAS interaction, to deliver improved outcomes for patients as monotherapy and in combination with targeted therapies in the clinic."

Combination therapy • Monotherapy • Oncology • HER-2 • KRAS • PIK3CA

The selective YAP/TEAD inhibitor TY-1054 enhances the efficacy of KRAS inhibitors or Trop2-ADC in multiple solid tumors (AACR 2026) - "TY-1054 not only enhanced the efficacy of KRAS G12Di RMC-9805 in SU.86.86 (PDAC, KRAS G12D) in vitro and in vivo, but also enhanced the efficacy of pan-KRASi Daraxonrasib in SU.86.86 in vitro and in vivo...TY-1054 enhances cetuximab efficacy in head and neck squamous cell carcinoma (HNSCC) Cal33 cells...TY-1054 enhances the efficacy of Trop2-ADC (SKB264/Sac-TMT) in triple-negative breast cancer (TNBC) (MDA-MB 231 and HCC1806), NSCLC (H1975 and HCC827), and trastuzumab-resistant breast cancer (JIMT-1) cells... 1. TY-1054 not only enhanced the efficacy of FDA-approved KRAS G12C inhibitors, Adagrasib and Sotorasib, in Non-Small Cell Lung Cancer (NSCLC) H1373 and H2122 cells, but also enhanced the efficacy of Divarasib (GDC-6036) and pan-KRASi Daroxonrasib (RMC-6236) in NSCLC H1972 and H2122 cells. 2."

ADC • Clinical • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • KRAS

The EGFR-PROTAC molecule TY-2719 attenuates acquired resistance to 3rd-generation EGFR TKIs and augments the efficacy of KRAS mutant inhibitors in solid tumors (AACR 2026) - "TY-2719 overcame osimertinib resistance in BaF3 L858R/C797S and BaF3 del19/C797S CDX mouse models and enhanced the efficacy of Divarasib (GDC-6036) and pan-KRASi Daroxonrasib (RMC-6236) in NSCLC H1972 and H2122 cells, as well as Daroxonrasib in MiaPaca 2 (PDAC, KRAS G12D), AsPC-1, SU.86.86, PANC-1 (PDAC, KRAS G12D), and Capan-1 (PDAC KRAS G12V). TY-2719 effectively degraded EGFR with the L858R mutation in NSCLC H3255 cells and the L858R/T790M/C797S and 19del/C797S mutations in BaF3 cells. However, it did not degrade EGFR in cells expressing wild-type EGFR, such as A549 and H358 cells. It demonstrated excellent antiproliferative activity against EGFR mutants but did not inhibit the growth of normal cells, including NHEK, MCF-10A, IOSE-80, and FHC cells."

Clinical • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

USP7 inhibitor synergistically enhanced the anticancer effect of the KRAS G12C inhibitor by effectively countering feedback signaling pathways (AACR 2026) - "KRAS G12C-mutant NSCLC cells and in vivo xenograft models were treated with KRAS G12C specific inhibitor (GDC-6036) and USP7 inhibitor (P5091), either alone or in combination, to evaluate the combinatorial antitumor effects. The combination of KRAS G12C and USP7 inhibitors significantly enhances the anticancer effect by suppressing KRAS feedback signaling, modulating multiple oncogenic and metabolic pathways, and promoting apoptosis in cancer cells, representing a promising novel approach to achieve durable therapeutic benefits of KRAS blockade in NSCLC, warranting further investigation."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • KRAS • USP7

Characterization of intrinsic and acquired resistance to KRASG12C inhibitors across a broad collection of cancer cell line models (AACR 2026) - "Although PTEN loss was restricted to OV56, both OV56 and SW1573 were resistant to inhibitors of various MAPK pathway components, including RAF (tovorafenib, belvarafenib), MEK (trametinib), and ERK (ulixertinib), suggesting MAPK pathway independence. Cross-resistance to adagrasib, sotorasib and divarasib was also observed in the acquired resistant models.Intrinsically KRASG12C inhibitor-resistant cell lines, along with acquired resistant models, represent valuable systems for evaluating next-generation KRAS inhibitors and identifying new drug combinations to optimize therapeutic benefit of KRASG12C inhibitors in patients."

Preclinical • Oncology • KRAS • PTEN

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 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Apr 2024 ➔ Aug 2028 | Trial primary completion date: Apr 2024 ➔ Aug 2028

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

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=580 | Recruiting | Sponsor: Hoffmann-La Roche | Not yet recruiting ➔ Recruiting

Enrollment open • IO Companion diagnostic • PD(L)-1 companion diagnostic • Tumor mutational burden • Lung Non-Small Cell Squamous Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • BRAF

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=580 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jan 2022 ➔ Sep 2020

IO Companion diagnostic • PD(L)-1 companion diagnostic • Trial 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 • Thoracic Cancer • BRAF

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=580 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Sep 2020 ➔ Mar 2020

IO Companion diagnostic • PD(L)-1 companion diagnostic • Trial 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 • Thoracic Cancer • BRAF

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=580 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Mar 2020 ➔ Sep 2020

IO Companion diagnostic • PD(L)-1 companion diagnostic • Trial 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 • Thoracic Cancer • BRAF

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=660 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Sep 2020 ➔ Sep 2021 | Trial primary completion date: Sep 2020 ➔ Sep 2021

IO Companion diagnostic • PD(L)-1 companion diagnostic • 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 • Thoracic Cancer • BRAF

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 | Recruiting | Sponsor: Hoffmann-La Roche | N=700 ➔ 1000

Enrollment change • 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

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=580 | Not yet recruiting | Sponsor: Hoffmann-La Roche

IO Companion diagnostic • New P2/3 trial • PD(L)-1 companion diagnostic • Tumor mutational burden • Lung Non-Small Cell Squamous Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • BRAF

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=700 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Sep 2021 ➔ Apr 2024 | Trial primary completion date: Sep 2021 ➔ Apr 2024

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

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 | Recruiting ➔ Active, not recruiting

Enrollment closed • 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

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=580 | Recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Feb 2020 ➔ Jun 2019

IO Companion diagnostic • PD(L)-1 companion diagnostic • 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 • Thoracic Cancer • BRAF

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=580 | Recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Jun 2019 ➔ Sep 2020

IO Companion diagnostic • PD(L)-1 companion diagnostic • 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 • Thoracic Cancer • BRAF

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

A Systematic Review of the Efficacy of KRAS p.G12C Inhibitors in Metastatic Colorectal Cancer: The Current State of Science. (PubMed, Cancer Invest) - "Adagrasib monotherapy yielded a median PFS of 4.4-5.6 months, an OS of 10-19.8 months, and an ORR of 19-23%, while its combination with cetuximab reported a PFS of 6.9 months, an OS of 13.4-15.9 months and an ORR of 34-46%...When combined with panitumumab, 960 mg sotorasib demonstrated better results with a PFS of 5.6-5.7 months, OS of 15.2 months and an ORR of 12.5-30%. Similarly, divarasib monotherapy led to a PFS of 5.6-6.9 months and an ORR of 20%, while its combination with cetuximab resulted in a PFS of 8.1 months and an ORR of 62.5%. Combination therapy of olomorasib and MK-1084, which are new-generation KRAS p.G12C (c.34G > T) inhibitors, with cetuximab also demonstrated highly promising efficacy with ORR of 38-44% and 50%, respectively...Initial results of KRAS-G12C inhibitors appear highly promising when they are combined with anti-EGFR therapy compared to historical therapeutic agents indicated for patients with chemotherapy-refractory CRC. Encouraging..."

Journal • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C. (PubMed, J Med Chem) - "Herein, we report the discovery and development of a brain-penetrant inhibitor of KRAS G12C using divarasib as a starting point. Optimization efforts focused on reducing molecular weight and topological polar surface area as well as shielding of hydrogen bond donors. In this manner, active transport by both P-gp and breast cancer resistance protein (BCRP) was attenuated, and high exposure in rodent brain tissue was achieved."

Journal • Brain Cancer • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C. (PubMed, J Med Chem) - "We demonstrate a significant noncovalent binding component of divarasib that contributes to its potency and rapid kinetics. Divarasib has greater potency and kinetics of alkylation compared with other KRAS G12C inhibitors in vitro and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines."

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