Adagrasib pembrolizumab combo shows promise for KRASG12C-positive NSCLC

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Published: 21 Oct 2023
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Dr Pasi Janne - Dana-Farber Cancer Institute, Boston, USA

Dr Janne speaks to ecancer about the phase II KRYSTAL-7 trial which reviewed the efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer harbouring a KRASG12C mutation.

The trial was presented during the ESMO Congress 2023, held in Madrid, Spain.

The study found adding adagrasib to pembrolizumab in patients with advanced, unresectable, or metastatic NSCLC with KRASG12C mutation showed “encouraging preliminary activity” especially in patients with high PD-L1 expression, and the team are looking towards a phase III study next.

Adagrasib pembrolizumab combo shows promise for KRASG12C-positive NSCLC

Dr Pasi Janne – Dana-Farber Cancer Institute, Boston, USA

The KRYSTAL-7 study evaluated the combination of adagrasib, a KRASG12C inhibitor, with pembrolizumab as a first-line treatment for patients with advanced KRASG12C-mutant non-small cell lung cancer. The study demonstrated a few important points: one, that you can combine pembrolizumab with adagrasib without undue toxicity. Previous efforts in the space, notably with combining with sotorasib, an immune checkpoint inhibition, had been difficult due to hepatotoxicity, and although some hepatotoxicity was observed in this trial, the incidence was no greater than is typically seen with adagrasib by itself.

In general the combination was well-tolerated. It led to a high response rate of over 60% with a median PFS and durability of response not reached yet. I think it’s an opportunity and offers the possibility of getting KRAS-targeted therapies into the first line space. Right now KRASG12C inhibitors are approved for patients after prior chemotherapy or chemotherapy and immune checkpoint inhibition, and they’re not approved as initial treatment, but hereby combining adagrasib with pembrolizumab, this will allow hopefully movement of this combination as an initial treatment for patients with advanced KRASG12C-mutant non-small cell lung cancer. There is a trial that is addressing that, a phase III trial, that will pursue that approach.

What are the potential clinical implications of these findings?

The impact would be hopefully that the combination would be better than what would be normally used in this situation, in the front line setting, which would be either single agent pembrolizumab which is what the future study will compare it to, or chemotherapy and pembrolizumab. In general for patients with oncogenic alterations in lung cancer, we like to use targeted therapies, if effective, as first line therapies and not save them for later. Hereby combining adagrasib with pembrolizumab, we’ll hopefully be able to achieve that.