Targeted Agent Bests Chemo in Second-Line for KRAS-Mutant NSCLC

Targeted therapy with sotorasib (Lumakras) in previously treated non-small cell lung cancer (NSCLC) patients harboring KRAS-G12C mutations reduced the risk of disease progression or death by 34% compared with standard second-line chemotherapy, according to a phase III trial presented at the annual congress of the European Society for Medical Oncology (ESMO).

In this exclusive MedPage Today video, investigator Roy S. Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut, explains why although this is good progress, it does not move the needle on second-line standard treatment just yet.

Following is a transcript of his remarks:

It’s historic what we’ve seen with targeting KRAS — the chemistry of these drugs works in KRAS-G12C. However, it’s unfortunately not a home run. I think what we have is in the randomized trial, the drug did a little bit worse than it did in the phase II experience. And while PFS [progression-free survival] was significant and positive, and it met its primary endpoint, I think that the magnitude of that benefit was a bit less than one normally sees with a targeted therapy.

A PFS median of less than 6 months usually is pretty low for targeted therapy. The response rates in the 20-30% range are a little bit low [28% with sotorasib vs 13% with docetaxel], but I just thought it was just not as good as it could be.

And the survival, while it wasn’t powered for survival, clearly there’s no trend for survival at all. And this is in a refractory setting — granted some patients crossed over.

But my sense is — as has always been my sense having done this for 25 years — we’re still not done. We’ll never be done with targeted therapies. We know resistance will always develop and why wouldn’t KRAS resistance develop more than anything else? Because it’s on top of so many different pathways.

So I think this is good progress. But clearly, combinations are going to be necessary to move this to the front line. Even in the second line I would predict we’re gonna need some combinations.

It’s clearly … 10, 15 years ago if you had told me we would’ve had something with targeted KRAS that would beat chemotherapy in PFS, I would’ve told you, “Really? That’s, that’s a big leap.”

So, big progress, but more to come. But that’s true for everything we’re talking about today.