Divarasib Combo Appears “Promising” in Pretreated KRAS G12C+ NSCLC

In a conversation with CancerNetwork® at the 2025 American Association for Cancer Research Annual Meeting, Jia Luo, MD, spoke about her phase 1 study (NCT04449874) assessing the novel KRAS G12C inhibitor divarasib (GDC-6036) in combination with the SHP2 inhibitor migoprotafib (GDC-1971) for patients with KRAS G12C–positive non–small cell lung cancer (NSCLC).

According to Luo, a thoracic oncologist at Dana-Farber Cancer Institute and an instructor in Medicine at Harvard Medical School, the divarasib combination particularly demonstrated “promising” activity in a cohort of patients who received prior KRAS G12C inhibitors vs those who had no previous exposure to these agents. Additionally, future research will focus on the biomarkers associated with the pretreated cohort to further elucidate the outcomes of patients who respond to divarasib/migoprotafib.

Transcript:

In terms of safety, we did see that the SHP2 inhibitor, even though it had better preclinical properties, still had some challenges with tolerability. We reported the 400 mg of divarasib, which is the dose carried forward for the pivotal study, and various doses of the SHP2 inhibitor: 20 mg and 40 mg. The 40 mg [dose] was a little more difficult to handle, and there were some dose holds, decreases, and pauses with that drug in terms of efficacy. There were 2 cohorts. There were individuals who’d never seen a KRAS G12C inhibitor and had [NSCLC]. [They] received first-line treatment, progressed, and then were assigned to this arm of the trial. Then there was another cohort where individuals had prior [treatment with] mostly sotorasib [Lumakras], adagrasib [Krazati], [JDQ443], as well as divarasib. [These were] prior KRAS G12C inhibitor-experienced patients.

In the cohort of individuals who’d never seen a KRAS G12C inhibitor, the initial objective response rate was around the same as what we see for divarasib [monotherapy]. It was less clear, in this early look at 40-some patients, that there was an obvious signal to move this forward. However, in the individuals who had a prior KRAS G12C inhibitor, we did see some interesting responses. It’s early to say what the contribution of components is, but it is promising that, even though they had a prior KRAS G12C inhibitor and have progressed before being assigned to this clinical trial, we see some activity in this combination.

Future work will be interrogating the biomarkers of these patients who had experienced KRAS G12C inhibitors in the past and are now responding to this combination. We have some early circulating tumor DNA [ctDNA] data that suggest good outcomes, but [there is] very much more to come. All patients had samples, including ctDNA, that were sent for a large panel that remains to be analyzed.

Reference

Luo J, Sacher A, Santoro A, et al. Divarasib plus migoprotafib combination treatment in patients with KRAS G12C-positive non-small cell lung cancer (NSCLC). Presented at the 2025 American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT022.