Targeted Therapies Continue to Push the Field of EGFRm Lung Cancer Forward

Edward B. Garon, MD, MS

Despite its aggressive nature, EGFR-mutated lung cancer is generally treatable, especially with the emergence of new treatment options over recent years. Some of these include targeted therapies called EGFR tyrosine kinase inhibitors (TKIs), including erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), and osimertinib (Tagrisso).

A number of additional treatments are currently in development and showing promise in this patient population, according to Edward B. Garon, MD, MS. Furmonertinib is one of these agents and is already approved in China. Trials in the United States, including the phase 1b FAVOUR study (NCT04858958), have now begun evaluating the agent with the hopes of an approval in the future.

The combination of amivantamab-vmjw (Rybrevant) plus chemotherapy has also produced encouraging results in locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR mutations after disease progression on or after osimertinib. Findings from the phase 3 MARIPOSA-2 study (NCT04988295) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with the combination, leading to a supplemental biologics application to be submitted to the FDA seeking approval for the combination. Experts are hopeful to have this regimen as a treatment option in the future.

In an interview with Targeted Oncology^TM, Edward B. Garon, MD, MS, Garon, professor of medicine, Geffen School of Medicine, Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, discussed the ever-changing treatment landscape for EGFR-mutated lung cancer, as well as the unmet needs and potential next steps for research in this space.

Targeted Oncology: Can you provide an overview of some of the available treatment options for patients with EGFR-mutated lung cancer?

There are multiple approved approaches right now in the frontline, as well as [in] previously treated patients, and some new emerging therapies. In the frontline setting, FDA-approved regimens include first-generation EGFR inhibitors, which are really erlotinib and gefitinib and are effective. Also, second-generation agents, afatinib and dacomitinib, are approved. Afatanib, of note, is also approved for 3 uncommon mutations where it is the sole approval.

The most commonly used agent is single-agent osimertinib. There also is an FDA approval for erlotinib and ramucirumab [Cyramza], an anti-angiogenic, as well as the potential for looking at erlotinib and bevacizumab [Avastin] based on NCCN guidance, and also gefitinib plus chemotherapy. Those would be the current frontline approaches that people are able to incorporate.

What are the treatment options for patients who develop resistance to EGFR TKIs?

For the rare patients who still have gotten a first-generation or second-generation agent as their initial therapy, and have not received osimertinib, osimertinib is approved at the time progression. Lazertinib [YH25448] also has an approval and patients who have developed resistance with the T790M mutation. For the remainder of patients, the established approach would be platinum-based chemotherapy.

In a period in which we get next-generation sequencing in many of our patients, oftentimes, we will find additional mutations that are associated with potential response to dual TKI therapy. The reality though, is although that is something that is often done in an academic practice, we don't really have good data on these approaches. I think that it is a lot to expect that people in the community would be trying to mix and match drugs that aren't approved in settings where our biomarkers are not entirely clear.

lung with cancer cells: © catalin - stock.adobe.com

Can you explain some of the recent and interesting research in this space?

Interestingly, we don't have anything very recent that is practice changing. That's because we don't have any approvals based on some very interesting new data that came out. The 1 that I would say is quite actionable right now is the data related to the FLAURA2 study [NCT04035486]. This is a study of chemotherapy and osimertinib vs osimertinib alone. It did show a very prolonged progression-free survival when chemotherapy was added to osimertinib, although the overall survival didn't not have a particularly strong trend in favor of the combination. This is obviously an intensification of therapy. However, it comes at the cost of some toxicity. A cynic could look at that data and say that without a survival advantage, you're having more of a patient's life where they are receiving chemotherapy and the associated toxicity. Obviously, the survival data will continue to mature. Of the recent advances we've seen, that's probably the only that is clinically actionable. That's because there wouldn't be any impediment right now to using that regimen in the clinic.

Can you discuss furmonertinib and the ongoing research of the agent in the FAVOUR trial?

Furmonertinib is a drug that is approved in China for sensitize EGFR mutations, but there now is a study that is looking at this agent in a randomized approach vs chemotherapy in the subset of patients who have a mutation in the exon 20 insertion in the EGFR gene. This has been a particularly difficult mutation for tyrosine kinase inhibitors. For somewhat technical reasons, it's been somewhat difficult to design drugs that do not have high levels of activity and get wild-type EGFR, so they don't have these sorts of toxicities associated with EGFR inhibition, but are able to effectively treat this mutation. There was 1 that was approved in the United States, mobocertinib [Exkivity], but that study failed in its confirmatory phase 3 study, and that has been withdrawn from the market. This study is looking at [furmonertinib] head-to-head vs chemotherapy in these patients with EGFR exon 20 insertion mutations in non–small cell lung cancer.

If positive, how may this study of furmonertinib impact this patient population?

If the study were positive, they would have basically a non-chemotherapy approach that would be available and presumably superior to chemotherapy. I think there is a fair question as to what the uptake would be. The issue is that my colleague Jonathan Goldman, MD, and others, recently reported results in the Journal of Medicine for the PAPILLON study [NCT04538664], which was looking at the combination of chemotherapy and amivantamab in patients with EGFR exon 20 insertion non–small cell lung cancer, showing a significant improvement in progression-free survival when amivantamab was added to chemotherapy in that setting.

In your own practice, how do you manage patients with brain metastases?

In my practice, patients with brain metastases, at least in their initial therapy, often are treated the same. Osimertinib for instance, is a very active agent in the central nervous system. I don't necessarily radiate patients with asymptomatic brain metastases at baseline. This does become a bigger problem at the time of progression. There is some efficacy of chemotherapy in the brain. However, oftentimes, these patients will require radiation. After they've progressed on osimertinib. There's some practitioners that do routinely keep the osimertinib going and there are clinical trials that will evaluate whether or not that is sort of an appropriate approach.

What is the current unmet need in this space?

I think the current unmet need in the frontline therapy of EGFR mutation-positive disease is that all of our therapies that we use are eventually going to breed resistance. It is gratifying to see the progression-free survival and overall survival data push out further over the years. The FLAURA study of osimertinib showed an overall survival that was over 3 and a half years. When I started my career in this field and we were quoting an overall survival of 10 months, that's quite good. On the other hand, if you're in your mid 30s, that's not that exciting. I think that there is a significant yearning among these patients with EGFR mutations, particularly the younger ones, for a sort of approach that isn't going to be something that you're giving for a while and hoping it takes a while for them to develop resistance.

There's a potential approval of amivantamab and chemotherapy next year. How may this approval change the landscape in the future?

There were recently 2 studies that were presented using amivantamab in EGFR mutation-positive disease. There is data to indicate that this is beneficial in patients with the rare exon 20 insertion and there actually is an approval of amivantamab. One of the studies looked at amivantamab and lazertinib—lazertinib is another third-generation EGFR TKI—compared with osimertinib and again, a substantial improvement in progression-free survival.

The overall survival data on that study is immature, although trending in favor of the amivantamab, but I think it's important to note that unlike the FLAURA2 study where everybody would be able to cross over to chemotherapy, they progressed on osimertinib monotherapy, amivantamab was not available for patients who progressed on osimertinib as part of that study.

The other study there was in previously treated patients and that was taking the group of patients for whom standard therapy would be chemotherapy and randomizing them to chemotherapy or 1 of 2 other arms of either the combination amivantamab, lazertinib, and chemotherapy or simply amivantamab and chemotherapy. Both of the amivantamab-containing arms did look better than the chemotherapy alone arm, although there were some differences. They were similar with respect to progression-free survival, maybe a slight amount better, at least numerically, with the 4-drug regimen. When we looked at overall survival, that looked similar to chemotherapy, whereas it did look more suggestive of a benefit in patients who were receiving amivantamab plus chemotherapy, but not the lazertinib. I think we will await more mature data regarding that.

What would you like new and emerging therapies in the exon 20 space to demonstrate?

I think that for exon 20 insertions, despite the fact that we do have 1 approval, still suffers from suboptimal efficacy and suboptimal tolerability. Although it is exciting that we do have an agent that is approved in this setting, I think that it also underscores that there is still work to do because we still aren't seeing the efficacy or the tolerability for that we see with EGFR mutations and in patients with the traditionally sensitizing mutations.

Are there any new therapies that you're particularly excited about?

I think it will be exciting for patients to have the potential for incorporating amivantamab. When one takes the data in totality, there's reason to believe that it will improve patient outcomes. I think the other thing that is leading to some enthusiasm is antibody-drug conjugates. We have seen sort of phase 2 data and phase 1 data indicating that these may be particularly exciting approaches in patients with EGFR mutations. There also was some data presented at [the European Society for Medical Oncology 2023 Annual Congress] by Aaron Lisberg, MD, looking at a study of datopotamab deruxtecan drugs, and the results did look certainly promising in patients with EGFR mutations.