Evidence of Antitumor Effect With GDC-6036 Monotherapy in KRAS G12C+ NSCLC Revealed at 2022 WCLC

The novel KRAS G12C inhibitor GDC-6036 induced a high response rate in patients with previously treated KRAS G12C mutation–positive non–small cell lung cancer.

Data from a phase 1a trial (NCT04449874) of the KRAS G12C inhibitor GDC-6036 showed promising responses and safety with the monotherapy in patients with previously treated KRAS G12C–mutant non–small cell lung cancer (NSCLC), according to data presented at the 2022 World Conference on Lung Cancer.1

Findings showed that GDC-6036 monotherapy elicited an unconfirmed overall response rate (ORR) of 53% in efficacy-evaluable patients with NSCLC harboring KRAS G12C mutations (n = 57) All 30 responders experienced partial responses (PRs). Additionally, the confirmed ORR was 46%, with 26 confirmed PRs.

The oral, highly potent, and selective KRAS G12C inhibitor irreversibly locks the protein in an inactive state to turn off its oncogenic signaling. Preclinical studies showed that GDC-6036 was more potent and selective in vitro compared with sotorasib (Lumakras) and adagrasib (MRTX849).2

The phase 1 trial investigated GDC-6036 as a single agent and in combination with various agents in patients with KRAS G12C–mutated solid tumors, including NSCLC. During the study, 135 patients with solid tumors received GDC-6036 monotherapy, including 59 with NSCLC.

Eligible patients needed to have locally advanced or metastatic solid tumors, including NSCLC, harboring KRAS G12C mutations. Patients needed to have measurable or evaluable disease per RECIST v1.1 criteria, and they were required to have undergone at least 1 prior treatment or be intolerable to standard therapy. Patients with previously treated brain metastases were permitted to enroll, and no prior treatment with a KRAS G12C inhibitor was permitted.

During the dose-escalation portion of the trial, patients with NSCLC received oral GDC-6036 once per day for 21-day cycles at doses of 50 mg (n = 6), 100 mg (n = 5), 200 mg (n = 10), and 400 mg (n = 6). In the dose-expansion portion of the study, 32 additional patients were administered 400 mg of GDC-6036 per day.

The key end points of the trial were safety, pharmacokinetics, and preliminary antitumor activity.

Among all enrolled patients with NSCLC, the median age was 67 years (range, 43-82), 56% were female, and 93% were current or former smokers. The majority of patients had an ECOG performance status of 1 (64%), received prior checkpoint inhibitor therapy (86%), and received prior platinum-based chemotherapy (90%). Of 58 evaluable patients, the median number of prior therapies in the metastatic setting was 1 (range, 0-5). In 45 evaluable patients, 56% were PD-L1 positive.

At the time of data cutoff, 42% of patients discontinued study treatment. Reasons for discontinuation included progressive disease (25%), adverse effects (AEs; 7%), physician decision (5%), clinical progression (3%), and patient withdrawal (2%).

Regarding safety, 88.1% of patients with NSCLC experienced at least 1 treatment-related AE (TRAE) of any grade, including 16.9% who had at least 1 grade 3 or higher TRAE. The most common any-grade TRAEs included nausea (76.3%), diarrhea (61%), vomiting (54.2%), fatigue (23.7%), decreased appetite (15.3%), increased alanine aminotransferase (13.6%), increased aspartate aminotransferase (10.2%), and dyspepsia (6.8%). The most common grade 3 or higher TRAEs included increased alanine aminotransferase (6.8%), increased aspartate aminotransferase (5.1%), diarrhea (3.4%), and fatigue (1.7%).

In all patients treated with single-agent GDC-6036 (n = 135), any-grade TRAEs occurred in 88.1% of patients, and grade 3 or higher TRAEs were reported in 11.1% of patients. Grade 5 events occurred in 7 patients, though all were related to disease progression and were not treatment related.

No dose-limiting toxicities were reported. In patients with NSCLC, AEs leading to GDC-6036 dose modifications, reductions, or withdrawal occurred in 36%, 19%, and 5% of patients, respectively. Those rates were 23%, 10%, and 2%, respectively, in all patients treated with GDC-6036 monotherapy.

Pharmacokinetics evaluated in all patients with solid tumors showed that following a single dose of GDC-6036, ranging from 50 mg to 400 mg, the mean half-life ranged from 13-17 hours. Most patients who received the expansion dose of 400 mg per day were predicted to achieve exposures corresponding to the maximal covalent target engagement from nonclinical studies.

References

  1. Sacher A, Patel MR, Miller Jr. WH, et al. Phase Ia study to evaluate GDC-6036 monotherapy in patients with non­–small cell lung cancer (NSCLC) with KRAS G12C mutation. Presented at: 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria; Abstract OA03.04
  2. Purkey H. Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers. Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract ND11