The KRASG12C mutation and KRAS mutations in general have been known about for over forty years as oncogenic drivers involved in the cancerous pathway but they had been previously considered untargetable. More recently it was shown that you could potentially irreversibly bind to the GDP portion of the molecule, the KRAS molecule, and inhibit enzyme production. This was actually the very first study that randomised patients to a KRASG12C inhibitor versus the standard of care, docetaxel, in patients who had previously received a Platinol chemotherapy and an IO therapy, setting the stage now for the approval of sotorasib in over fifty countries.

The primary endpoint of the study itself was improvement in progression free survival and it met its primary endpoint doing so. Other secondary endpoints also supported that finding, including duration of response, time to treatment response. It did not, however, meet the overall survival but the study was not powered to do so so that’s still an unanswered question that has been done. As I said, the most recent presentation focussed on patient reported outcomes. While achieving these different positive efficacy endpoints it did not do so at the expense of the patient. In other words, the toxicities favoured sotorasib and patient reported outcomes, which are different than our measures of toxicity, also favoured sotorasib.

How can these results impact the treatment of NSCLC?

They are already impacting the treatment of non-small cell lung cancer. We know that KRAS mutations are seen in perhaps as much as 24-28% of the patients, of whom half of those have specifically the G12C mutation. So, in other words, about 13-14% of all non-small cell lung cancer patients harbour this actionable mutation. Again, you won’t know that if you don’t do next generation sequencing on these patients so I’m going to be an advocate for comprehensive genomic testing in all patients with advanced non-small cell lung cancer.

Once patients have failed the standard of care frontline therapy, which if they don’t have a targetable mutation such as ALK, ROS, EGFR, and are treated instead with usually a Platinol doublet, often with an IO therapy, when they fail that treatment, as the majority of them will, this is a very viable treatment option in the second line. For patients who harbour the G12C I personally think that the results favour using sotorasib as opposed to Taxotere in that clinical setting.

Anything else to add?

This follows up on the presentation of the patient reported outcomes and this is something that is very important. Historically we have looked at toxicity through the lens of the investigators: I will look at the common toxicity criteria, I will grade their diarrhoea, I will grade their fatigue, I may grade their rash or their laboratory findings. But that doesn’t necessarily mean I’m measuring the impact of those toxicities on the patient and their quality of life. The use of patient reported outcomes allows us to look at the results of the trial through the patient lens – how did these side effects impact their quality of life? We’re seeing an increased use of patient reported outcomes, both in clinical trials and even the clinical setting and that’s a very good thing for our clinical trials and I’m highly supportive of that endeavour.