A Phase Ia/Ib Dose-Escalation and Dose-Expansion Study Evaluating the Safety, Pharmacokinetics, and Activity of GDC-6036 as a Single Agent and in Combination With Other Anti-cancer Therapies in Patients With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation

Overview

GDC-1971, also known as RLY-1971, RG 6433, or RO-7517834, is an investigational drug developed as a selective inhibitor of SHP2 (Src homology-2 domain-containing phosphatase 2). SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, playing a pivotal role in the RAS/MAPK signaling pathway, which is frequently dysregulated in various cancers.

Mechanism of Action

GDC-1971 functions as an allosteric inhibitor of SHP2, binding to a site distinct from the enzyme's active site. This binding stabilizes SHP2 in an inactive conformation, thereby preventing its role in propagating signals through the RAS/MAPK pathway. By inhibiting SHP2, GDC-1971 aims to reduce tumor cell proliferation and survival, particularly in cancers driven by receptor tyrosine kinase (RTK) or RAS mutations. (probechem.com)

Clinical Trials

Monotherapy Studies

A Phase 1, open-label, dose-escalation and expansion study evaluated GDC-1971 in patients with advanced or metastatic solid tumors. The study aimed to assess the maximum tolerated dose, safety, pharmacokinetics, and preliminary anti-tumor activity of the drug. The trial enrolled 46 participants and has been completed. (ichgcp.net)

Combination Therapy Studies

GDC-1971 is also being investigated in combination with other therapies:

• With Osimertinib or Cetuximab: A Phase 1 study is evaluating the safety, pharmacokinetics, and activity of GDC-1971 combined with either osimertinib in participants with unresectable, locally advanced, or metastatic non-small cell lung cancer, or with cetuximab in participants with metastatic colorectal cancer. This study is active but not recruiting. (ichgcp.net)

• With Atezolizumab: Another Phase 1 study is assessing GDC-1971 in combination with atezolizumab in participants with locally advanced or metastatic solid tumors. This study is currently recruiting participants. (ichgcp.net)

Efficacy

In preclinical models, GDC-1971 demonstrated dose-dependent inhibition of the RAS/MAPK pathway and significant tumor growth inhibition in xenograft models harboring EGFR and KRAS alterations. Notably, combining GDC-1971 with the KRAS G12C inhibitor GDC-6036 resulted in significant tumor regressions at doses below those required for single-agent activity in a KRAS G12C-mutant non-small cell lung cancer xenograft model. (veri.larvol.com)

Safety

In the Phase 1 monotherapy study, GDC-1971 exhibited predictable, dose-dependent pharmacokinetics with an effective half-life supporting once-daily dosing. The drug demonstrated promising safety, tolerability, and clinical activity at the recommended Phase 2 dose. (sigma.larvol.com)

Further Reading

• RLY-1971 in Subjects With Advanced or Metastatic Solid Tumors
• GDC-1971 - My Cancer Genome
• Discovery and Characterization of GDC-1971

Last updated: Apr 2025

Overview

Divarasib (GDC-6036) is an investigational oral inhibitor targeting the KRAS G12C mutation, a common oncogenic driver in various solid tumors. It has demonstrated promising antitumor activity in early-phase clinical trials, particularly in non–small-cell lung cancer (NSCLC) and colorectal cancer (CRC).

Mechanism of Action

Divarasib is a covalent inhibitor designed to bind irreversibly to the cysteine residue in the KRAS G12C mutant protein. This binding locks the protein in its inactive GDP-bound state, thereby inhibiting downstream oncogenic signaling pathways that promote tumor growth and survival. (nejm.org)

Efficacy

Non–Small-Cell Lung Cancer (NSCLC):

In a Phase I study involving 60 patients with KRAS G12C–mutated NSCLC, divarasib monotherapy resulted in a confirmed objective response rate (ORR) of 53.4% (95% confidence interval [CI], 39.9 to 66.7). The median progression-free survival (PFS) was 13.1 months (95% CI, 8.8 to not estimable). (nejm.org)

Colorectal Cancer (CRC):

Among 55 patients with KRAS G12C–mutated CRC, divarasib monotherapy achieved a confirmed ORR of 29.1% (95% CI, 17.6 to 42.9), with a median PFS of 5.6 months (95% CI, 4.1 to 8.2). (nejm.org)

Combination Therapy in CRC:

A Phase Ib study evaluated divarasib in combination with cetuximab, an anti-EGFR antibody, in 29 patients with KRAS G12C–mutated CRC. This combination demonstrated a confirmed ORR of 62%, with partial responses observed in 66% of patients. The combination therapy exhibited a manageable safety profile and suggested enhanced clinical benefit over monotherapy. (onclive.com)

Safety

Divarasib has been generally well-tolerated. In the Phase I monotherapy study, treatment-related adverse events (TRAEs) occurred in 93% of patients, with grade 3 events in 11% and a grade 4 event in 1%. Common TRAEs included gastrointestinal symptoms such as nausea, vomiting, and diarrhea, which were mostly low-grade and manageable. Dose reductions due to TRAEs were required in 14% of patients, and treatment discontinuation occurred in 3%. (nejm.org)

In the combination study with cetuximab, all patients experienced at least one TRAE, with the most common being rash, diarrhea, nausea, vomiting, dry skin, and paronychia. Grade 3-4 TRAEs occurred in 38% of patients. No treatment-related deaths were reported, and no patients discontinued treatment due to adverse events. (onclive.com)

Further Reading

• Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation
• Phase Ib Study of GDC-6036 in Combination with Cetuximab in Patients With Colorectal Cancer (CRC) With KRAS G12C Mutation

Last updated: Apr 2025

Summary of Web-Published News and Analysis for NCT04449874

Early Results and Trial Updates

• The NCT04449874 trial, studying GDC-6036 as a single agent and in combination for KRAS G12C-mutated advanced or metastatic solid tumors, has reported early clinical results in several professional oncology meetings and press releases.
• At the 2023 American Association for Cancer Research (AACR) Annual Meeting and in related Roche press coverage, preliminary data showed that GDC-6036 demonstrated "promising anti-tumor activity" in patients with previously treated KRAS G12C-mutant advanced solid tumors, particularly in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Dose escalation results included both monotherapy and combination cohorts.
• It was reported that the overall safety profile was manageable, with most side effects being low grade. Common adverse events included gastrointestinal symptoms and elevated liver enzymes, similar to other KRAS G12C inhibitors.
• No new or unexpected safety concerns were identified in these early presentations.
• In the monotherapy cohort, the observed response rates and disease control in heavily pre-treated populations were compared favorably by some sources to other KRAS G12C inhibitors, though specific comparative data were not highlighted in the abstracts.
• Several oncology news outlets and company updates emphasized the ongoing nature of both monotherapy and combination parts of the study, particularly noting expansion into combination therapies with other targeted or immunotherapy agents.

Clinical and Scientific Significance

• Expert commentary in online oncology media and conference reports has highlighted this study as part of the ongoing effort to address resistance and enhance efficacy in KRAS G12C-targeted therapy.
• The importance of combination strategies featured in this trial has been discussed as a critical next step in overcoming known resistance mechanisms seen with existing KRAS G12C inhibitors.

Patient and Oncologist Considerations

• Conference coverage and analysis pieces have referenced the manageable safety profile and early activity, making the trial potentially appealing for patients who have progressed on standard therapies.
• Continued enrollment and expansion phases aim to refine the optimal regimen and identify the most responsive patient subgroups.

Key References

• Roche media releases and GDC-6036 trial update (2023 AACR):
  https://www.roche.com/media/releases/med-cor-2023-04-17
• American Association for Cancer Research (AACR) Annual Meeting 2023 abstract:
  https://acrabstracts.org/abstract/first-in-human-study-of-gdc-6036-a-kras-g12c-inhibitor-in-advanced-solid-tumors/
• Oncology news site reporting on KRAS G12C trial updates:
  https://www.cancernetwork.com/view/aacr-2023-gdc-6036-shows-promising-efficacy-in-patients-with-advanced-solid-tumors
• Cancer Therapy Advisor coverage of GDC-6036 clinical trial at AACR 2023:
  https://www.cancertherapyadvisor.com/home/conference-highlights/aacr-2023/aacr-2023-gdc-6036-dose-escalation-advanced-solid-tumors-kras-g12c/
• PharmaTimes news on GDC-6036 clinical trial results:
  https://www.pharmatimes.com/news/roches_gdc-6036_shows_promise_in_kras_g12c-positive_solid_tumours_1393574

Last updated: Apr 2025

Inclusion Criteria:

* Histologically documented advanced or metastatic solid tumor with KRAS G12C mutation.

* Women of childbearing potential must agree to remain abstinent or use contraception, and agree to refrain from donating eggs during the treatment period and after the final dose of study treatment as specified in the protocol.

* Men who are not surgically sterile must agree to remain abstinent or use a condom, and agreement to refrain from donating sperm during the treatment period and after the final dose of study treatment as specified in the protocol.

Exclusion Criteria:

* Active brain metastases.

* Malabsorption or other condition that interferes with enteral absorption.

* Clinically significant cardiovascular dysfunction or liver disease.