divarasib (RG6330)

P1, N=18, Completed, Genentech, Inc. | Trial completion date: Jul 2025 --> Feb 2025 | Trial primary completion date: Jul 2025 --> Feb 2025 | Active, not recruiting --> Completed

When sotorasib was used alone, the objective response rate (ORR) ranged from 7.1 to 9.7%, with disease control (DC) rates of 73.8 to 82.3% and a median progression-free survival (PFS) spanning 4-5.6 months...Meanwhile, pairing adagrasib with cetuximab led to a 42% ORR and a median PFS of 6.9 months, surpassing the 19% ORR observed with adagrasib alone. Divarasib monotherapy produced a 36% ORR and an 85.5% DC rate, with a PFS of 5.6 months; in tandem with cetuximab, those numbers climbed to a 62.5% ORR and a PFS of 8.1 months...Overall, KRAS G12C inhibitors appear to offer meaningful benefits for CRC patients, particularly when used alongside EGFR inhibitors like cetuximab or panitumumab. However, further large-scale, randomized trials are needed to refine dosing strategies and gain a clearer picture of both efficacy and potential risks.

P1, N=18, Active, not recruiting, Genentech, Inc. | Not yet recruiting --> Active, not recruiting

P1, N=18, Not yet recruiting, Genentech, Inc.

P1, N=498, Recruiting, Genentech, Inc. | Trial primary completion date: Mar 2025 --> Feb 2026

P1, N=542, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2029 --> Nov 2028

Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRASG12Ci detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations.

P1, N=40, Recruiting, Genentech, Inc. | Not yet recruiting --> Recruiting | Trial primary completion date: May 2026 --> Oct 2026

P1, N=18, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting

P3, N=600, Not yet recruiting, Hoffmann-La Roche

P1/2, N=240, Recruiting, Hoffmann-La Roche | N=96 --> 240

P1, N=19, Completed, Genentech, Inc. | Active, not recruiting --> Completed

P1/2, N=240, Recruiting, Hoffmann-La Roche | N=96 --> 240

P1, N=542, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P1, N=18, Recruiting, Genentech, Inc. | Not yet recruiting --> Recruiting | Trial completion date: Jan 2025 --> Jul 2025 | Trial primary completion date: Jan 2025 --> Jul 2025

P1, N=40, Not yet recruiting, Genentech, Inc.

P1, N=498, Recruiting, Genentech, Inc. | Trial completion date: Nov 2024 --> Mar 2026 | Trial primary completion date: Nov 2024 --> Mar 2025

P1, N=19, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting

P1, N=19, Recruiting, Genentech, Inc. | Not yet recruiting --> Recruiting

P1, N=18, Not yet recruiting, Genentech, Inc.

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