Treating ALK-Mutant and KRAS G12C–Mutant NSCLC

John V. Heymach, MD, PhD: One other disease space where we’ve had spectacular successes recently in terms of wonderful drugs that have come along—very active drugs—has been ALK [anaplastic lymphoma kinase inhibitors]. We’ve got a lot of fantastic choices. One choice that’s recently been approved is lorlatinib in the first-line setting. Stephen, do you want to talk about the presentation regarding lorlatinib and CNS [central nervous system] adverse events that was presented?

Stephen Liu, MD: This was pretty timely. As you mentioned, the CROWN study showed lorlatinib was superior to crizotinib. We don’t talk about it much, but the hazard ratio there of 0.28 was quite a bit lower than we saw with alectinib in ALEX and brigatinib in ALTA-1L. Yet lorlatinib use in the frontline setting doesn’t seem to have overtaken the world. Part of it is this hesitancy about toxicity, and this abstract presented by our colleague Ben Solomon looked at CNS adverse events. That’s the main concern. While you can see weight gain, you can’t see cholesterol. Thus, the CNS, the neurocognitive, events specifically give us pause.

They noted that they saw these CNS events in about 35%, and they run the gamut from mild memory changes and lack of attention and concentration to confusing, depression, seizures, and serious toxicities. This abstract noted that most of these are low grade, and nearly all resolved with some dose reduction. This is a toxicity that’s concerning because it’s something different for us. Some subtle changes aren’t so easily picked up in a 5- or 10-minute clinic visit, so the key is that lorlatinib is a very effective drug. It’s going to play a role for a lot of our patients. We need to educate patients, maybe more important patient families and caregivers, on what to look for so we can identify these early and drop the doses as appropriate.

John V. Heymach, MD, PhD: You mentioned it because sometimes the CNS effects are subtle. For 1 patient recently, I asked how things were going, and she said fine. Then I said, “Have you noticed any differences recently?” Still nothing. Then I said, “Do you seem giddier, or do you seem like you might be tipsy?” Then it just opened a box. They kept talking about all the ways these things had been happening, and they hadn’t attributed it to the drug necessarily. It’s interesting, but it’s encouraging that it’s reversible and manageable probably from the TRK inhibition that happens.

Vamsi, there are some additional data about brigatinib as well in the real world, another first-line choice for ALK. Do you want to briefly tell us about that?

Vamsidhar Velcheti, MD: Yes, it was a retrospective study. But John, the point you bring up is important. Patients often underreport, especially patients with ALK. I have the same experience, with patients who hesitate to bring up these issues with the physicians when they meet them because they’re worried that they’re going to stop the drug. These CNS cognitive issues are real, at least in the few patients I’ve treated, and we don’t use lorlatinib in the frontline setting, especially given that we see activity after other TKIs [tyrosine kinase inhibitors].

BrigALK2 is a real-world study looking at brigatinib use in the EAP [expanded access program] and at subsequent treatment patterns of response to other ALK inhibitors, including lorlatinib. The majority of them were treated with lorlatinib after progressing on brigatinib. They seemed to be responding. It’s not a surprise. We knew that there were certain mutations that negate resistance to 1 of these TKIs. The study doesn’t go into details on the patterns of resistance very much after brigatinib, but nevertheless the point that was highlighted in the study was that you could still respond to lorlatinib in the second line after brigatinib.

John V. Heymach, MD, PhD: It’s wonderful to hear that. Last topic we’re going to cover in this section is an important emerging area. We could spend hours just talking about KRAS. KRAS is our most common oncogenic driver. It’s about a quarter of patients. About half have G12C. Ani, why don’t you talk about the sotorasib data that we got the update on?

Ani Balmanoukian, MD: This is an exciting area, especially now that we have some agents that we can use in this setting. We had none until this year. As we know, sotorasib is approved for the treatment of KRAS G12C–mutant non–small cell lung cancer. This is based on the CODEBreaK 100 study that enrolled patients with non–small cell lung cancer with 3 prior lines of therapy. What they saw was an overall response rate of 36%, which was pretty impressive, with a complete response rate of 2% and a partial response rate of 35%. Disease control rate was 81%. This creates a very exciting option for patients with this mutation.

I should also mention another agent that’s available with KRYSTAL-1 data using the agent adagrasib. That’s also being discussed. It shows an overall response rate of 43%. We have options for patients with regard to patients with KRAS G12C, so that’s exciting. Of course, 1 key discussion point is what do we do after progression in these patients?

There was a good paper by Mark Awad, et al, in New England Journal of Medicine published this year looking into mechanisms of resistance in these patients after treatment with a KRAS G12C–targeted therapy. What they saw in that paper is that there was no consistent mutation noticed. There was no real consistent mechanism of resistance. They saw acquired KRAS alterations: KRAS G12D, RVD. They saw some acquired bypass mechanisms of resistance, including MET amplification and activating mutations such as NRAS [Neuroblastoma-RAS] and BRAF.

What was interesting in the study is that they also saw two histologic transformations, 2 patients with squamous cell transformation on repeat biopsy, which was also very interesting. A lot is still to be deciphered in this area, with a lot of further development to be done, but it’s an exciting time in the development for drug therapy in this setting.

John V. Heymach, MD, PhD: Absolutely. Not only that, but we have new KRAS inhibitors, G12D inhibitors and others coming. In the same way we just had a whole section talking about EGFR [epidermal growth factor receptor] inhibitor resistance, I’m sure in the future we’ll be talking about treatment of KRAS inhibitor resistance as well.

Transcript Edited for Clarity