Evolving Treatment Landscape of EGFR-Mutated Advanced and Metastatic NSCLC: Answers to Frequently Asked Questions

Key Takeaways

• For previously untreated EGFR exon 19 or L858R-mutated non-small-cell lung cancer, osimertinib monotherapy remains the first choice among experts.
• Experts may consider escalation with combination therapy consisting of osimertinib plus chemotherapy or amivantamab with lazertinib―in the context of a clinical trial―for aggressive, later-stage disease, and including those with brain metastases.
• In patients with atypical EGFR mutation (eg, S768I, L861Q, and/or G719X), afatinib and osimertinib are available with amivantamab and lazertinib potentially becoming an option based on data from the phase III MARIPOSA trial presented at ASCO 2024.

The management of patients with EGFR-mutated non-small-cell lung cancer (NSCLC) is constantly evolving, with a growing need for clinical oncologists, pulmonologist, and other members of the care team to remain up-to-date on the growing list of available and emerging new treatments for EGFR-mutated NSCLC. In this commentary, experts provide answers to frequently asked questions posed during a symposium on EGFR-mutated NSCLC held on May 31, 2024, during the American Society of Clinical Oncology (ASCO) Annual Meeting.

What is the current preferred first-line treatment option in patients with EGFR exon 19 deletion or L858R mutation in NSCLC?

Karen Reckamp, MD, MS:

Based on data from the phase III FLAURA of osimertinib vs standard of care EGFR tyrosine kinase inhibitor (TKI) in patients with previously untreated NSCLC with EGFR ex19del or L858R-mutated NSCLC, osimertinib remains the National Comprehensive Cancer Network guidelines’ preferred first-line treatment recommendation for these patients. Other first-line options include the combination of osimertinib with pemetrexed-based chemotherapy for nonsquamous histology supported by the phase III FLAURA2 trial, as well as the first-generation EGFR TKIs erlotinib and gefitinib, second-generation afatinib and dacomitinib, and the combination of erlotinib and either ramucirumab or bevacizumab, all of which have shown improvement in progression-free survival (PFS) for these patients. Recent data from the global, randomized, phase III MARIPOSA trial of amivantamab plus lazertinib vs osimertinib as first-line therapy in patients with metastatic EGFR mutated ex19del or L858R NSCLC also showed PFS improvement in this population. Results from the MARIPOSA study showed prolonged median PFS by blinded independent central review of 23.7 vs 16.6 months (P <.001), including for those with brain metastases (median PFS: 18.3 vs 13.0; HR: 0.69).

What is the current preferred therapy for patients with atypical EGFR mutations (eg, S678I, L681Q, or the G719)?

Karen Reckamp, MD, MS:

Patients with atypical EGFR alterations have often been excluded from most clinical trials. A pooled analysis of phase II LUX-Lung 2, and phase III LUX-Lung 3 and Lux-Lung 6 trials looked at patients with EGFR S768I, L861Q, and/or G719X NSCLC. These were among the first studies that included patients with these atypical mutations and analyzed this data retrospectively. In patients with EGFR G719X-mutated NSCLC, the study showed encouraging activity for afatinib with an overall response rate (ORR), median PFS, and median overall survival (OS) of 78%, 13.8 months, and 26.9 months, respectively. These results led to FDA approval of afatinib for uncommon EGFR mutations, including S768I, L861Q, and/or G719X. Activity in patients with EGFR G719X NSCLC has also been demonstrated with osimertinib in 2 prospective multicenter trials (KCSG-LU15-09 and UNICORN) where the ORR, median PFS, and median OS were 53%, 8.6 months, and 18.4 months, respectively. Thus, osimertinib is also an option for these patients with atypical EGFR mutations. At ASCO 2024, data were presented at the rapid abstract session by Dr Cho and colleagues for the phase I CHRYSALIS-2 study of amivantamab plus lazertinib also in patients with atypical ?EGFR mutations, and there we saw responses from 51% to 55%, median PFS of 19.5 months, and duration of response of ≥6 months including patients without previous therapy or who had progressed on afatinib. Thus, potentially, amivantamab plus lazertinib combination may become an option in this patient population.

Nicolas Girard, MD, PhD:

It was interesting to see the combination of amivantamab plus lazertinib in this cohort of patients with uncommon mutations, excluding EGFR exon 20 insertion mutations. I think the response rate achieved was remarkable. These results extend the MARIPOSA regimen to those patients with uncommon EGFR mutations as well.?

Natasha Leighl, MD, MMSc, FRCPC, FASCO:

I find this data very interesting, but I think one of the challenges of combination therapy is toxicity. Moreover, and as we all know, treatment with afatinib can be challenging due to toxicities, leading many of us to prefer osimertinib, even for the EGFR G719X subset. By contrast, regarding increased efficacy, I think people are willing to consider prophylaxis for the treatment of rash with amivantamab plus lazertinib. At ASCO 2024, I presented data from the global, randomized, phase III PALOMA-3 trial evaluating subcutaneous amivantamab plus lazertinib vs intravenous amivantamab plus lazertinib in patients with locally advanced or metastatic EGFR ex19del or L858R-mutant NSCLC who had progression on or after osimertinib and platinum-based chemotherapy. In that study, we showed that subcutaneous amivantamab treatment substantially reduced amivantamab-related toxicity, reducing administration time, while maintaining efficacy. I think subcutaneous amivantamab is a great new potential option that might make life easier for patients and for physicians alike.

For patients with EGFR exon 21 mutations, aberrant TP53 status, and brain metastases, would you consider the combination of osimertinib and chemotherapy (FLAURA2) or amivantamab plus lazertinib (MARIPOSA)?

Nicolas Girard, MD, PhD:

As you know, aberrant TP53 and brain metastases portend poor outcomes in patients with EGFR-mutant NSCLC. I think we see a similar benefit with the combination of either chemotherapy plus osimertinib or amivantamab plus lazertinib vs osimertinib alone. It is risk factors like those that lead me to escalate and prefer a combination regimen vs osimertinib monotherapy.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:

I agree. Another thing that may inform my decision is circulating tumor DNA (ctDNA). Data reported at the American Association for Cancer Research suggest that patients with ctDNA might be another subset who could benefit from combination therapy. But you have to have a conversation with the patient about this. Some of my patients, even those traveling to the United States for a second opinion, came back and said: ‘let’s go ahead and start the osimertinib.’ I think this is interesting. We discuss with our patients what the data are—it is so important that we do this—and there are those that decide to pursue intensified treatment and others that say, ‘let's just take things one step at a time’.

Nicolas Girard, MD, PhD:

In addition, we do not yet know how to stratify the patients for one combination strategy or another [Editor’s note: as of the date of the live program]. I will guess also it is a matter of sequencing—sequencing chemotherapy, sequencing the tyrosine kinase inhibitor and amivantamab, and future options as well.?

Natasha Leighl, MD, MMSc, FRCPC, FASCO:

Another consideration is whether to use the targeted therapies first and save chemotherapy for later. But should we be thinking like that still, this concept of saving for later, or just give everything upfront?

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Your Thoughts?

What are your thoughts or questions on the rapidly evolving treatment landscape for patients with EGFR-mutated NSCLC? Join the conversation by leaving a comment. Also, feel free to visit the overall program page to view the on-demand webcast from the live event and access downloadable slides on this topic.