Treating EGFR Exon 20 Insertions and HER2-Mutant NSCLC

Dr Vamsidhar Velcheti evaluates the use of mobocertinib in patients with EGFR exon 20 insertions, and Drs John V. Heymach and Sandip P. Patel discuss the treatment of HER2-mutant NSCLC.

John V. Heymach, MD, PhD: One of the things that has happened in the last couple of years is that there have been a lot more data about atypical EGFR [epidermal growth factor receptor] mutations that are the drivers. The first place where we’ve seen some progress is in exon 20 insertion non–small cell lung cancer. Vamsi, do you want to talk about mobocertinib?

Vamsidhar Velcheti, MD: Thank you. Certainly, it’s interesting. EGFR mutations are in the exon 20, which were previously thought undruggable by EGFR inhibitors. Mobocertinib, or TAK-788, is an oral first-in-class reversible EGFR TKI [tyrosine kinase inhibitor] that targets EGFR exon 20. We saw some interesting data recently presented at the [International Association for the Study of Lung Cancer] World Conference on Lung Cancer. It’s a fairly large study of 114 patients. About 43% of these patients had prior immunotherapy, and all these patients are heavily pretreated with a platinum doublet and a few of them with TKIs as well.

Overall, the study had a really respectable response rate, a confirmed ORR [overall response rate] of 28% and very good disease control rate of 78%. About 40% of patients had previous brain metastases, which were treated and stable. There was a good duration of response. I think it was 9 months of median duration of response. Overall, the were impressive, and it’s nice to have another alternative treatment option. Now we have 2 drugs FDA approved to use in EGFR exon 20 population.

John V. Heymach, MD, PhD: We’ve got amivantamab and mobocertinib, both FDA approved for exon 20 insertions. Vamsi, any thoughts about how you choose between them? As you said, it’s good to have more than 1 choice in this space.

Vamsidhar Velcheti, MD: Yes, it is. An oral agent is certainly more appealing than going through an IV [intravenous] agent. The other thing I want to highlight is that with amivantamab alone, I’m not so sure there’s much CNS [central nervous system] activity. If patients have brain metastases, then they should definitely consider mobocertinib over amivantamab. Looking at the safety profile, it’s very different. Mobocertinib also has GI [gastrointestinal] toxicity as expected.

John V. Heymach, MD, PhD: I guess there’s the pill-vs-IV issue as well.

We now have data for several drugs targeting HER2 [human epidermal growth factor receptor 2] mutations for non–small cell lung cancer. One of those drugs is poziotinib. This is a drug that our group at [The University of Texas] MD Anderson Cancer Center was involved in identifying as being active. We recently reported a response rate of 27%. It conferred an objective response rate in patients who were refractory to prior therapies, and that’s similar to the early results in the refractory cohort of ZENITH20, an international registration study.

More recently, at ESMO [European Society for Medical Oncology Congress], we saw presentation of the first-line data for poziotinib. The frontline objective response rate was 44%. We see that for first-line therapy, patients were doing very well. Progression-free survival [PFS] was about 5½ months, and the duration of response was a bit longer than that. It’s clearly highly active, although there are some limits on the duration of response and no significant frequency of pneumonitis. Let me pause there. Any thoughts? We have poziotinib or other HER2 tyrosine kinase inhibitors in this space. Stephen?

Stephen Liu, MD: A lot of it comes down to proper management of the toxicities. These drugs are going to have some activity in wild-type EGFR—rash, diarrhea, stomatitis. Clearly, there are going to be fewer adverse effects if the dose is lower. The concern is if you drop the dose to a point where there are no toxicities, will you drop out of your therapeutic window? There needs to be a balance. The key to these drugs moving forward is aggressive management of toxicities, anticipating those, and trying to maintain the dose for as long as you can.

John V. Heymach, MD, PhD: We saw some data with now twice-a-day dosing with poziotinib going to a lower dose but twice a day, which is far better tolerated with far fewer discontinuations. For drugs in this space, for both EGFR exon 20 and drugs like poziotinib, management of wild-type EGFR toxicities, like rash and diarrhea, is certainly limiting. We saw in the poziotinib studies that the majority of patients have required dose modifications. While it’s active, finding better regimens— hopefully the twice-a-day dosing is able to do that—is going to be very important. Sandip, we had another HER2-targeted drug. We had the trastuzumab deruxtecan presented as part of the DESTINY-Lung01 study for HER2-mutant non–small cell lung cancer. Would you like to talk about the results?

Sandip P. Patel, MD: This is a really impressive study. HER2 mutations in non–small cell lung cancer occur in 3% to 4% of patients. It’s a reasonable number, and 1 of the key concepts we’ve heard over and over is if we don’t do appropriate broad-based molecular testing, we’re not going to find these patients. For these 3% to 4% of patients who have this HER2 mutation, it’s a little different from what we see in breast cancer in terms of protein overexpression only, though it’s the same drug. We’ve seen some remarkable results: a 50% objective response rate, a PFS of 9 to 10 months, which is best in class. Thus, it’s an impressive drug in our therapy armamentarium.

As Stephen was mentioning earlier, toxicities are key. The dose used in lung cancer is higher than what’s used in breast cancer. Something to keep in mind is the ILD [interstitial lung disease] risk. In particular, we need to counsel patients and their caregivers about that because early intervention can mean patients benefit from this very promising therapy. It also showed we’re in a bit of renaissance for ADCs, antibody-drug conjugates. We heard a little about patritumab. We’re hearing about trastuzumab deruxtecan. And there’s something with the way the payload is being done, this bystander effect, because even in breast oncology, our colleagues have been using HER2-targeted drugs for a long time.

They compared trastuzumab deruxtecan with T-DM1 [trastuzumab emtansine], which is an excellent antibody-drug conjugate first generation. The P value on the PFS was another 7 times 10-22. It was something you use from your old physics textbooks or chemistry textbooks because of the difference. Not all ADCs are the same. It looks like this is particularly effective, but the key is it’s a different dose. For those of you who see lots of different types of patients, your dose in breast cancer is lower than the dose you’d use in non–small cell lung cancer.

John V. Heymach, MD, PhD: Wonderful. That covers HER2.

Transcript Edited for Clarity

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