Adagrasib in advanced/metastatic NSCLC with KRAS G12C mutation

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Published: 4 Nov 2020
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Dr Pasi Janne - Dana Farber Cancer Institute, Boston, USA

Dr Passi Janne speaks to ecancer about the activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harbouring KRAS G12C mutation at the 2020 ENA virtual congress.

In this interview he explains the rationale behind using adagrasib for this type of lung cancer and then talks about what end-points were evaluated in this trial.

He goes on to explain the methodology and results of this study and says that this drug is a great break through in trying to target the KRAS pathway which for 30 years researchers have been trying to target.

Dr Janne says this is an important addition to the world of targeted therapies and winds it up by speaking how adagrasib can change the way NSCLC which is KRAS G12C positive can be treated.

Adagrasib, formerly known as MRTX849 is a selective covalent inhibitor of KRASG12C and in preclinical models in lung cancer models it had shown a high degree of activity in those patient derived xenograft models when used as a single agent. This was then the basis for evaluating this drug in patients with KRASG12C mutations. This is a population of patients for whom there are no approved targeted therapies, just chemotherapy and immune therapy, and as such, is a population that needs new therapeutic options. So that was the basis for testing the agent specifically in this patient population.

This is a phase I/II study so the early endpoints of the trial are evaluating safety and toxicity in the phase I escalation portion. Then in the phase II expansion portion the endpoint is to really evaluate the response rate. Once we figured out the dose, which is a 600mg twice daily dose, the next question is if we now treat a larger population of patients with KRASG12C mutations what is the response rate to the agent and how well do people tolerate it and how long do they stay on the study.

What methodology did you use?

This is a standard clinical trial and so patients were enrolled in the trial. They were treated with adagrasib daily, twice daily, at the 600mg twice daily dose. They were evaluated for side effects in clinic and by laboratory evaluations as well. They were evaluated by CAT scans to compare to their baseline pre-treatment scan to see what degree of activity was observed using standard radiographic assessments for response.

What were the key results observed?

In terms of this presentation which really evaluated more the efficacy and the larger safety, there were a couple of things. One is that we observed in the 51 patients of the 79 that were studied in whom we were able to evaluate a scan result we were able to see that 45% of them had what was termed a response, a partial response. So this was a relatively high degree of clinical activity; we’re excited to see this. There were responses in patients that have been previously treated with multiple therapies, as I mentioned. There was a response in a patient that had a brain lesion that had not previously been treated so we’re excited about that possibility as well.

In addition, the agent was in general very well tolerated – less than10% of patients discontinued the medication due to treatment related adverse events. There were some GI toxicities as the main adverse event but for the most part it was well tolerated.

I will say a second part of the efficacy was that, as I mentioned, 45% of the patients had a response. Then as an exploratory analysis we studied to try to evaluate are there specific subsets of individuals among the KRAS mutant patients that had a greater response than others. Intriguingly, we saw that the patients that have a KRASG12C mutation and a mutation in a gene called STK11 or LKB1 had a higher response rate than if you didn’t have this co-mutation present. So that’s an exciting signal for us; it’s an exciting observation. This population of patients that have KRAS mutations and have this STK11 mutation are ones that tend not to respond to immune checkpoint inhibitors either given as a single agent or in combination with chemotherapy. The fact that we’re seeing a higher response rate in that patient population when treated with adagrasib is an exciting observation and something that we want to continue to pursue.

How can these results change the treatment of NSCLC?

KRAS mutations are a big population of non-small cell lung cancer. About 25% of lung adenocarcinomas have KRAS mutations and about half of them are the KRASG12C mutation. We have multiple other subsets of lung adenocarcinoma where we have targeted therapies – EGFR mutant lung cancer, ALK rearranged lung cancer. In those subsets that targeted therapy approach has fundamentally changed the treatment strategy and the outcome for that patient population.

We’re hoping that the same will be true here now for the G12C patients now that we have agents like adagrasib in the clinic and continue to develop that. As I mentioned, this is a population of patients for whom we don’t have any approved targeted therapies, there is only chemotherapy and immune therapy. This opens up a completely new avenue of treatment for this group of patients and hopefully as a result will allow a new therapeutic approach and allow ultimately to improve the outcome for this subset of patients.

KRAS mutations are genetic alterations that we’ve known about for thirty years and we as a community have had a difficult time developing therapies for this subset of patients. The fact that we now have potential therapies that have activity and have responses is just really exciting. It’s an exciting time, it’s an exciting time for patients. It opens up a new therapeutic avenue and I look forward to seeing how this field develops and how these therapies will ultimately be incorporated into the clinic moving forward.