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Clinical Trial
. 2025 Oct 20;43(30):3249-3253.
doi: 10.1200/JCO-25-00040. Epub 2025 Jul 9.

Single-Agent Divarasib in Patients With KRAS G12C-Positive Non-Small Cell Lung Cancer: Long-Term Follow-Up of a Phase I Study

Adrian G Sacher  1 , Wilson H Miller Jr  2 , Manish R Patel  3 , Luis Paz-Ares  4 , Armando Santoro  5 , Myung-Ju Ahn  6 , Rafal Dziadziuszko  7 , Pierre Freres  8 , Jia Luo  9 , Samantha Bowyer  10 , Jayesh Desai  11 , Ben Markman  12 , Maria De Miguel  13 , Sanjeev Deva  14 , Alejandro Falcon  15 , Guzman Alonso  16 , João Daniel Guedes  17 , Se Hyun Kim  18 , Matthew G Krebs  19 , Scott A Laurie  20 , Erminia Massarelli  21 , Laura Medina  22 , Hans Prenen  23 , Alessio Amatu  24 , Marloes Van Dongen  25 , Yoonha Choi  26 , Xuefeng Hou  26 , Ting Qi  26 , Mark T Lin  26 , Kalpesh Koli  26 , Mariah C Mayo  26 , Kenneth K Yau  27 , Stephanie Royer-Joo  26 , Julie Chang  26 , Tomi Jun  26 , Neekesh V Dharia  26 , Jennifer L Schutzman  26 , Patricia Lorusso  28 ; GO42144 Investigator Study group; GO42144 Investigator Study Group
Collaborators, Affiliations
Clinical Trial

Single-Agent Divarasib in Patients With KRAS G12C-Positive Non-Small Cell Lung Cancer: Long-Term Follow-Up of a Phase I Study

Adrian G Sacher et al. J Clin Oncol. .

Abstract

Divarasib (GDC-6036), an oral, highly potent and selective next-generation KRAS G12C inhibitor, has demonstrated a manageable safety profile and promising antitumor activity in patients with advanced KRAS G12C-positive non-small cell lung cancer (NSCLC). Here, we report long-term (≥1 year) follow-up of single-agent divarasib from the ongoing, open-label, and multicenter phase I study (ClinicalTrials.gov identifier: NCT04449874). The primary objective was safety, and the other objectives included preliminary antitumor activity. Overall, 65 patients with advanced KRAS G12C-positive NSCLC received single-agent oral divarasib 50-400 mg once daily and 31 patients (48%) were treated beyond 1 year. Divarasib continued to be well tolerated, and the safety profile beyond 1 year was consistent with the overall safety profile. In patients with measurable disease at baseline across all dose levels (n = 63), the confirmed objective response rate was 55.6% (95% CI, 42.5 to 68.1), and the median duration of response was 18.0 months (95% CI, 11.1 to 24.9). The median progression-free survival was 13.8 months (95% CI, 9.8 to 25.4) in the overall population (N = 65) and 15.3 months (95% CI, 12.3 to 26.1) among patients assigned to the 400-mg dose level (n = 44). With extended follow-up, divarasib demonstrated long-term safety and antitumor activity in patients with advanced KRAS G12C-positive NSCLC.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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Figures

FIG 1.
FIG 1.
Preliminary antitumor activity in patients with NSCLC. (A) Waterfall plot of the best percentage change from baseline in the tumor burden (defined as the sum of the longest diameters of all target lesions) in the 63 patients with NSCLC who had measurable disease at baseline and available postbaseline tumor-assessment data. Of the patients with a best response of CR (dark green), one had a confirmed best response of CR and two had a confirmed best response of PR. Patients receiving divarasib 400 mg are highlighted in blue. (B) Kaplan-Meier plot for DOR in the 40 patients with NSCLC who had a CR or PR. (C) Kaplan-Meier plot for PFS among all 65 patients with NSCLC. PFS was defined as the time from first treatment to the first occurrence of disease progression or death from any cause during the study (whichever occurred first). CR, complete response; DOR, duration of response; NSCLC, non–small cell lung cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
See this image and copyright information in PMC

References

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