divarasib (RG6330)

P1, N=19, Not yet recruiting, Genentech, Inc.

P2/3, N=1000, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P1, N=422, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Apr 2026 --> Nov 2029 | Trial primary completion date: Sep 2025 --> Aug 2027 | Recruiting --> Active, not recruiting

KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

P3, N=320, Recruiting, Hoffmann-La Roche | Trial completion date: Jul 2028 --> Sep 2029

P1/2, N=96, Recruiting, Hoffmann-La Roche | Trial completion date: Sep 2025 --> May 2027

P1, N=422, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P3, N=320, Recruiting, Hoffmann-La Roche | Not yet recruiting --> Recruiting

Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

P3, N=320, Not yet recruiting, Hoffmann-La Roche

P1, N=422, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

Although previously difficult to target, sotorasib and adagrasib are now approved for previously treated NSCLC patients with KRAS G12C mutations...While sotorasib met its primary endpoint in the phase III second line study against docetaxel, the progression-free survival (PFS) benefit was small and no overall survival (OS) benefit was observed...Although most patients reported toxicities, the majority were low-grade and manageable with supportive care. Here we discuss these results in the context of the evolving KRAS G12C landscape.

P2/3, N=1000, Recruiting, Hoffmann-La Roche | Trial completion date: Apr 2024 --> Aug 2028 | Trial primary completion date: Apr 2024 --> Aug 2028

Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation...In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.

P2, N=146, Recruiting, Genentech, Inc. | N=85 --> 146

P2, N=85, Recruiting, Genentech, Inc. | Trial primary completion date: Mar 2024 --> Dec 2025

P1, N=422, Recruiting, Hoffmann-La Roche | Trial completion date: Aug 2026 --> Apr 2026

Divarasib plus cetuximab is well tolerated in patients with KRAS G12C-positive colorectal cancer.

P1 | N=498 | NCT04449874 | Sponsor: Genentech, Inc. | "Consistent with the outcomes of the prior Phase 1 clinical trial, PredicineBEACON showcased remarkable biomarker results in the Phase 1b clinical trial of Divarasib Plus Cetuximab in CRC patients. A decline in KARAS G12C variant allele frequency was associated with treatment response, observed as early as CID15 in responsive patients. Using baseline, on-treatment, and end-of-treatment plasma samples, out of the 14 patients profiled, 13 (92.9%) exhibited at least one acquired genomic alteration linked with treatment resistance. The enhanced antitumor activity observed in this study reinforces the clinical utility of liquid biopsy profiling in evaluating the Phase 1b clinical trial of combined therapy in CRC patients."

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.

P1, N=498, Recruiting, Genentech, Inc. | Phase classification: P1a/1b --> P1

P1/2, N=60, Recruiting, Hoffmann-La Roche | N=96 --> 60

P1/2, N=96, Recruiting, Hoffmann-La Roche | N=60 --> 96

A phase I trial of divarasib, a next-generation KRASG12C inhibitor under study to treat solid tumors, establishes the agent as safe and highlights its improved efficacy when compared with other drugs in its class. Large, randomized trials of the drug as a monotherapy and in combination with other therapies are needed to confirm these results and determine how best to use divarasib in patients with solid tumors.

†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.

We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

"Predicine, Inc...announced a new study published in The New England Journal of Medicine (NEJM), demonstrating the clinical utility of its minimal residual disease (MRD) Liquid Biopsy Assay in support of Genentech's Phase 1 Clinical Trial of Divarasib. This milestone reaffirms Predicine's position as a leader in the field of liquid biopsy diagnostics....These findings underscore the clinical utility of liquid biopsy profiling in the assessment of phase I clinical trial of Divarasib."

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.).

P1, N=340, Recruiting, Hoffmann-La Roche | Trial completion date: Jan 2026 --> Aug 2026

We introduce a robust assay with an average intra-assay coefficient of variation (CV) of 4% and an interassay CV of 6% obtained from seven studies, enabling us to understand the relationship between KRAS G12C target occupancy and the therapeutic PD effect from mouse tumor samples. Further, the data demonstrated that the drug candidate GDC-6036, a KRAS G12C covalent inhibitor, shows dose-dependent target inhibition (KRAS G12C alkylation) and MAPK pathway inhibition, which correlate with high antitumor potency in the MIA PaCa-2 pancreatic xenograft model.

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.

P1a/1b, N=498, Recruiting, Genentech, Inc. | Trial completion date: Aug 2023 --> Nov 2024 | Trial primary completion date: Aug 2023 --> Nov 2024

Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.

To date, a sensitivity of 0.08 fmol/μg of total protein has been achieved for both free and GDC-6036-bound KRAS G12C with as little as 4 μg of total protein extracted from human tumor samples. This sub-fmol/μg level of sensitivity provides a powerful potential approach to assess covalent inhibitor target engagement at the site of action using core needle tumor biopsies from clinical studies.

GDC-6036 demonstrates greater potency and selectivity compared with other KRAS G12C inhibitors in vitro, and complete tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models. We will present the program that led to the discovery and optimization of GDC-6036, which is currently in clinical development.

Conclusions In patients with KRAS G12C mutant CRC, GDC-6036 demonstrated encouraging antitumor activity and early reduction in ctDNA along with acceptable and manageable safety, and PK profile compatible with once daily dosing. Data from additional pts will be presented.

Conclusions GDC-6036 demonstrated an acceptable safety profile, a PK profile compatible with once-daily dosing, and encouraging efficacy in pts with pretreated oST with a KRAS G12C mutation. Data from additional pts will be presented.

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.

P2/3, N=1000, Recruiting, Hoffmann-La Roche | N=700 --> 1000

GDC-6036 demonstrates greater potency and selectivity compared with other KRAS G12C inhibitors in vitro, and complete tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models. We will highlight the research program that led to the discovery and optimization of GDC-6036, which is currently in clinical development.

P1a/1b, N=342, Recruiting, Genentech, Inc. | N=236 --> 342