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

Commentary
Video

Ongoing ctDNA analysis may elucidate outcomes associated with divarasib plus migoprotafib for those with KRAS G12C–positive 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] 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). Abstract presented at: 2025 American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT022.

Recent Videos
Success with the 177Lu-PSMA-617 radioligand therapy would be transformative for the clear cell renal cell carcinoma treatment landscape.
4 experts in this video
4 experts in this video
An ongoing phase 1 trial seeks to prove XmAb819 as an effective treatment and ENPP3 as a plausible target in patients with relapsed or refractory RCC.
“The therapy is designed to prevent both CAR T-cell inactivation and to restore the anti-tumor immunity of the white blood cells that have gotten through the tumor,” said Marasco, MD, PhD.
Ongoing studies aim to combine base immunotherapy regimens with novel agents to potentially improve outcomes among patients with kidney cancer.
Investigators have found a way to reduce liver and biliary toxicity when targeting the molecule CAIX in patients with clear cell renal cell carcinoma.
Neoantigen-targeting vaccines resulted in an absence of recurrence in 9 patients with high-risk kidney cancer, according to David A. Braun, MD, PhD.
The Kidney Cancer Research Consortium may allow collaborators to form more mechanistic and scientifically driven efforts in the field.
Wayne A. Marasco, MD, PhD, stated that by targeting 2 molecules instead of 1, higher levels of tumor cell killing can be achieved in patients with clear cell renal cell carcinoma.
Related Content