Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation
Open accessAbstract
Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. A total of 137 patients (60 with non–small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to 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.)
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The co-evolution of multiple putative drug-resistance mechanisms within the same tumors mirrors observations in human samples whereby multiple distinct mechanisms have been observed within the same patients.
“The co-evolution of multiple putative drug-resistance mechanisms within the same tumors mirrors observations in human samples whereby multiple distinct mechanisms have been observed within the same patients (14, 18, 19).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [14]
The Biomarkers of Response and Resistance section reports several types of putative resistance mechanisms across patients treated with divarasib. It says 16 patients had at least one such mechanism, but does not establish in the text that multiple distinct mechanisms occurred within the same patient. Figure 3B’s caption (Discussion, p. 718) describes patient-level alterations without explicitly making that finding. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMechanisms of acquired resistance in patients with lung and colorectal cancer treated with KRASG12C inhibitors include mutations in KRAS or other RTK-RAS-MAPK pathway effectors, adaptive signaling alterations, and histologic transformation to drug-resistant cell states.
“We and others have recently described mechanisms of acquired resistance in patients with lung and colorectal cancer (CRC) treated with KRASG12C inhibitors, including mutations in KRAS or other RTK–RAS–MAPK pathway effectors, adaptive signaling alterations, and histologic transformation to drug-resistant cell states (14, 18–24).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [14]
The Biomarkers of Response and Resistance section (page not supplied) reports possible acquired genomic resistance mechanisms in patients with lung and colorectal cancer, including KRAS alterations and changes in RTK and MAPK pathway components. It does not report adaptive signaling alterations or histologic transformation to drug-resistant cell states. (LLM, conf=0.88)
Experimental — accuracy not yet measuredClinical trials of multiple KRASG12C inhibitors have shown promising efficacy in advanced, previously treated NSCLC, leading to FDA accelerated approval of adagrasib and sotorasib.
“Clinical trials of multiple KRASG12C inhibitors have shown promising efficacy in advanced, previously treated non–small cell lung cancer (NSCLC), leading to United States Food and Drug Administration (FDA) accelerated approval of two of these therapies (adagrasib and sotorasib) and many others being investigated in this setting (9–17).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [14]
The Discussion reports responses in NSCLC trials of sotorasib and adagrasib, and the introduction describes antitumor activity in previously treated KRAS G12C-mutated cancer. Our copy does not state that these results led to FDA accelerated approval of either drug. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe safety profile of divarasib plus cetuximab was consistent with those of single-agent divarasib and cetuximab.
“The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [11]
The Safety and Discussion sections describe the safety profile of single-agent divarasib. The Discussion says divarasib was being investigated with cetuximab, but this paper does not report the combination’s safety or compare it with either agent alone. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredUpon disease progression with divarasib plus cetuximab, 92.9% of profiled patients had at least one genomic alteration that may be associated with treatment resistance, higher than 30.2% for patients treated with divarasib or other KRAS G12C inhibitors as single agent.
“Upon disease progression with divarasib plus cetuximab, the majority (92.9%) of patients profiled had at least one genomic alteration that may be associated with treatment resistance similarly to two previous reports26,27, which is higher than that of patients treated with divarasib (30.2%) or other KRAS G12C inhibitors as single agent11,28,29.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [11]
The Biomarkers of Response and Resistance section reports possible resistance-associated genomic alterations in patients receiving single-agent divarasib. It identifies 16 of 29 profiled patients (55.2%), not 30.2%; this single-agent study does not establish the stated 92.9% figure for divarasib plus cetuximab. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Divarasib plus cetuximab combination therapy showed a larger decline in KRAS G12C ctDNA levels compared to single-agent divarasib: 77.3% versus 45.7% of patients with detectable KRAS G12C ctDNA at C1D1 had KRAS G12C VAF decline to below 0.5% at C3D1.
“Of note, divarasib plus cetuximab combination therapy showed a larger decline in KRAS G12C ctDNA levels compared to single-agent divarasib (77.3% versus 45.7% of patients with detectable KRAS G12C ctDNA at C1D1 had KRAS G12C VAF decline to below 0.5% at C3D1)11.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [11]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredctDNA analysis showed that 16 of 29 divarasib-treated patients acquired at least one genetic alteration that may mediate therapeutic resistance.
“ctDNA analysis showed that 16 (3 NSCLC, 9 CRC, and 4 other) of 29 patients (8 NSCLC, 16 CRC, and 5 other) treated with divarasib acquired at least one genetic alteration that may mediate therapeutic resistance [29].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [29]
Single-agent divarasib at 400 mg achieved a confirmed objective response rate of 35.9% in patients with colorectal cancer.
“Single-agent divarasib treatment at 400 mg achieved a confirmed objective response rate (ORR) of 56.4% in patients with non-small cell lung cancer and 35.9% in patients with CRC, with a median progression-free survival (PFS) of 13.1 and 6.9 months, respectively11.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [11]
Single-agent divarasib at 400 mg achieved a median progression-free survival of 6.9 months in patients with colorectal cancer.
“Single-agent divarasib treatment at 400 mg achieved a confirmed objective response rate (ORR) of 56.4% in patients with non-small cell lung cancer and 35.9% in patients with CRC, with a median progression-free survival (PFS) of 13.1 and 6.9 months, respectively11.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [11]
In patients with non-small cell lung cancer, divarasib had a numerically higher ORR (56.4%) than sotorasib (37% in a phase 2 trial and 28% in a phase 3 trial) and adagrasib (43% in a phase 2 trial).
“This is further supported by a numerically higher ORR seen with divarasib in patients with non-small cell lung cancer (56.4%) compared with sotorasib (37% in a phase 2 trial and 28% in a phase 3 trial) and adagrasib (43% in a phase 2 trial)11,23–25.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [11]
In patients with colorectal cancer who had not received prior KRAS G12C inhibitor treatment, single-agent divarasib achieved a response rate of 35.9%, while the combination of divarasib and cetuximab achieved a response rate of 62.5%.
“In patients with CRC who had not received prior KRAS G12C inhibitor treatment, single-agent divarasib achieved a response rate of 35.9%11, while the combination of divarasib and cetuximab achieved a response rate of 62.5%.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [11]
Sotorasib, adagrasib, and divarasib monotherapies have demonstrated objective response rates ranging from 7.1% to 53.4% and median progression-free survival of 4.0-13.1 months.
“For example, sotorasib, adagrasib, and divarasib monotherapies have demonstrated objective response rates ranging from 7.1% to 53.4% and median progression-free survival of 4.0-13.1 months, 13-20”
From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [20]
The incidence of gastrointestinal adverse effects was generally lower in garsorasib (diarrhea 11.5%, nausea 7.7%, no vomiting) compared with other KRAS G12C inhibitors (diarrhea 31.7-69%, nausea 19-78%, vomiting 7.9-58%).
“In terms of gastrointestinal adverse effects frequently observed in other KRAS G12C inhibitors, 11,12,28 the incidence was generally lower in garsorasib (diarrhea at 11.5%, nausea at 7.7%, and no vomiting reported), compared to those reported of other KRAS G12C inhibitors (diarrhea at 31.7-69%, nausea at 19-78%, and vomiting at 7.9-58%).”
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BackgroundMethodResultInfluentialDivarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial
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“The most common AEs observed in this study were low-grade gastrointestinal AEs and rash, which were consistent with single-agent divarasib and cetuximab safety profiles, respectively 11,22 .”
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“…studies and early clinical trials, including divarasib (GDC6036), olomorasib (LY3537982), garsorasib (D ‐ 1553), opnurasib (JDQ443), and glecirasib (JAB21822) (Table 1) [31 – 33, Identification of a similar SIIP as an inhibitory site also provides a solution for targeting other KRAS mutants.”
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- Authors
- Sacher, A., LoRusso, P., Patel, M. R., Miller, W. H., Garralda, E., Forster, M. D., Santoro, A., Falcon, A., Kim, T. W., Paz-Ares, L., Bowyer, S., de Miguel, M., Han, S.-W., Krebs, M. G., Lee, J.-S., Cheng, M. L., Arbour, K., Massarelli, E., Choi, Y., Shi, Z., Mandlekar, S., Lin, M. T., Royer-Joo, S., Chang, J., Dharia, N. V., Schutzman, J. L., & Desai, J.
- Affiliations
- University Health Network (CA)
- From the Princess Margaret Cancer Centre, University Health Network, and the Departments of Medicine and Immunology, University of Toronto, Toronto (A. Sacher), and the Lady Davis Institute and the Segal Cancer Center, Jewish General Hospital, McGill University, Montreal (W.H.M.); Yale Cancer Center, Yale University, New Haven, CT (P.L.); Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota (M.R.P.); Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona (E.G.), Hospital Universitario Virgen del Rocio, Seville (A.F.), and Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc (L.P.-A.), and START MADRID-CIOCC, Hospital Universitario HM Sanchinarro (M.M.), Madrid — all in Spain; the UCL Cancer Institute, University College London Hospitals NHS Trust, London (M.D.F.), and the Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester and Christie NHS Foundation Trust, Manchest...
- Universidad Complutense de Madrid (ES)
- City Of Hope National Medical Center (US)
- ORCID
- Sacher, Adrian
- LoRusso, Patricia
- Patel, Manish R.
- Miller, Wilson H.
- Garralda, Elena
- Forster, Martin D.
- Santoro, Armando
- Paz-Ares, Luis
- Bowyer, Samantha
- Han, Sae-Won
- Krebs, Matthew G.
- Cheng, Michael L.
- Arbour, Kathryn
- Massarelli, Erminia
- Choi, Yoonha
- Shi, Zhen
- Chang, Julie
- Dharia, Neekesh V.
- Schutzman, Jennifer L.
- Desai, Jayesh
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2023-08-24
- Volume
- 389
- Issue
- 8
- Pages
- 710-721
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W4386116142
- Cited by
- 328
- References
- 24
- Citations by year
- 2026: 88 · 2025: 127 · 2024: 95 · 2023: 18
- FWCI
- 60.16
- Type
- journal article
- Language
- en
- Open access
- green
- discovery.ucl.ac.uk
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ORBi (University of Liège) (submittedVersion, other-oa)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Open Access CRIS of the University of Bern
- Funders
- Genentech
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- divarasib, KRAS G12C mutation, covalent KRAS inhibitor, solid tumors, non-small cell lung cancer, colorectal cancer, oral anticancer therapy, treatment-related adverse events, circulating tumor DNA, variant allele frequency, resistance biomarkers, anticancer activity, progression-free survival
- MeSH terms
- Administration, Oral, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Enzyme Inhibitors, Humans, Lung Neoplasms, Mutation, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras)
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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