Sotorasib for KRAS G12C-Mutated Lung Cancer

PracticeUpdate: One of the important presentations this year at ASCO provides data on targeted therapy for KRAS G12C-mutated lung cancer. How is this novel agent designed to work?

Dr. Goldberg: This is a really interesting and exciting compound. There's a couple of them now in development and being studied. Sotorasib is an Amgen KRAS G12C inhibitor, and it's a drug that's designed to covalently bind to the mutant form of KRAS G12C, specifically.

That is really important when you think about who this drug may work in, because it's specifically for the KRAS G12C mutant form, and so that's the patient population that we're looking at with this drug.

PracticeUpdate: What is the scope of the KRAS-mutated lung cancer?

Dr. Goldberg: KRAS is really common in patients with non-small cell lung cancer. KRAS, in general, makes up about a quarter or so of the non-small cell lung cancer population. If you look specifically at the subtypes of KRAS mutations, G12C is about half of all KRAS.

If you look overall, it's something about 12% or 13% of all non-small cell lung cancer patients will have a KRAS G12C mutation. That's a quite sizable percentage of all lung cancer patients.

We're not so used to looking at the specific KRAS subtypes because it wasn't really relevant until now, but now that we have a class of drugs that are inhibitors of the G12C mutation, now it's become very important to look at the different subtypes. Fortunately, the G12C mutation is the most common KRAS mutation that we find in lung cancer.

Interestingly, in KRAS-mutant lung cancer, there are co-mutations. This occurs in other oncogene-driven cancers as well, where there are additional mutations present, but in KRAS-mutant lung cancer, it has become very relevant because it seems that there are different outcomes with various drugs, depending on the co-mutation present along with the KRAS mutation.

This has been seen in patients treated with immune therapy, where some of the co-mutations, specifically STK11, seem to have resulted in a reduction in the benefit with immune therapy. Interestingly, we're starting to now see some data with sotorasib, the KRAS G12C inhibitor, that maybe there are some subsets of patients with these co-mutations that might have either more or less benefit depending on which mutation is present along with the KRAS G12C mutation.

This is still very early days for this. We're just starting to see this data emerge, and it's fairly small numbers so far, but I think it's something to keep an eye on that the specific co-mutation, along with KRAS, might be relevant when you think about outcomes in patients with this class of drugs.

PracticeUpdate: What was previously demonstrated about the activity of sotorasib in this patient population?

Dr. Goldberg: We've known for now a couple of years that this drug, sotorasib, seems to have activity in patients with non-small cell lung cancer, where the tumor has this KRAS G12C mutation. We knew that there were some patients who responded. I think now we're starting to see larger patient numbers, so we get a better sense of the actual response rate and what we can expect in the clinic and then also the durability of response.

What we saw at ASCO is that the response rate with sotorasib was about 37%. I think also really important to see is the disease control rate, so basically, all the patients who had either a response or stable disease. And that was more than 80%, so most patients were having some degree of tumor control, either response or stable disease. The duration of response was about 11 months. For patients who are responding, that response can be quite durable.

I think we're starting to really see that this drug does have good activity in a subset of patients. Not all patients respond, but a good proportion either respond or have stable disease, and in some of those cases, it is very durable, although not all. Some patients have a shorter duration of response.

I think that's really where these co-mutations are going to be important to understand better, to see if that has implications in larger data sets, and also when we start to think about combinations of drugs, whether that might overcome some of the resistance that we're seeing develop to this drug.

I think now we are starting to see some larger volumes of patients being treated, and starting to get a sense of the durability of this drug.

I think we are now seeing that this drug has good activity in a subset of patients with KRAS G12C-mutant non-small cell lung cancer. Now that it has been FDA approved, it is available, or will be available very soon, for our patients even off of a clinical trial.

This is incredibly exciting. I think it is practice-changing.

The way it was FDA approved is for use after prior treatment. I think still we are using our kind of now standard chemo and immune therapy or immune therapy alone, however you want to think about first-line treatment for these patients. But this is, I think, a fantastic option for second-line treatment or beyond for patients with KRAS G12C mutations. Absolutely practice changing.

There's more data to come in future ASCOs and future meetings and reports where we, hopefully, will understand better the different subsets of KRAS-mutant lung cancer and who will be most likely to benefit. At some point it might move into first line, but I don't think we're quite there yet.

I think the studies are now looking at combinations of treatment and who might benefit most from a combination is also to be determined. I think for now we know that there is activity in a subset of patients, and I think it's a great option to think about after first-line treatment for these patients.