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EGFR Mutated NSCLC
Current and Emerging Therapies for Advanced NSCLC With Uncommon EGFR and EGFR Exon 20 Insertion Mutations

Released: April 14, 2026

Nicolas Girard
Nicolas Girard, MD, PhD
Zofia Piotrowska
Zofia Piotrowska, MD, MHS
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Key Takeaways
  • Response rates to different EGFR TKIs in advanced EGFR-mutated NSCLC vary among specific uncommon EGFR mutations (G719X, S768I, etc).
  • Novel EGFR TKIs, such as enozertinib, furmonertinib, and zipalertinib, are available through clinical trials for patients with advanced NSCLC and uncommon EGFR mutations and/or EGFR exon20 insertion mutations.

Introduction
During the live webinar, “Precision in Progress: Advancing Personalized Care in EGFR Mutation–Positive NSCLC Care” held on March 6, 2026, Nicolas Girard, MD, PhD, and Zofia Piotrowska, MD, MHS, discussed the latest developments in the treatment of patients with non-small-cell lung cancer (NSCLC) and EGFR mutations. Here, they provide their perspectives on the treatment of patients with uncommon EGFR mutations and exon 20 insertion mutations including emerging therapies and strategies on the near horizon.

Heterogeneity in the Treatment Response of NSCLC With Uncommon EGFR Mutations

Nicolas Girard, MD, PhD:
For patients with common EGFR mutations (L858R or exon 19 deletion), we have very clear guidelines. For example, in the 2025 ESMO guidelines, the preferred option for completely resected stage IB-IIIA EGFR-mutated disease is adjuvant osimertinib for up to 3 years after chemotherapy where appropriate. For stage IV NSCLC with common EGFR mutations, the options include amivantamab plus lazertinib, osimertinib plus platinum-based chemotherapy, or single-agent osimertinib or an alternate EGFR TKI if osimertinib is not accessible.

By contrast, advanced NSCLC with uncommon EGFR mutations (S768I [exon 20], L861Q [exon 21], G719X [exon 18]) has fewer options compared with tumors with common EGFR mutations. Afatinib, an irreversible, second-generation EGFR TKI, is the only FDA-approved treatment option for uncommon EGFR mutations.

Zofia Piotrowska, MD, MHS:
Indeed, in a randomized study evaluating first-line use of afatinib compared with platinum doublet chemotherapy in patients with uncommon EGFR mutations, results confirmed the superiority of afatinib in objective response rate and progression-free survival (PFS). Of interest, if you look at the different mutations, the response rate in the patients with G719X mutations (66.7%) was higher than those with L861Q (46.2%), suggesting outcome heterogeneity.

In addition, many healthcare professionals use osimertinib for uncommon EGFR mutations, largely based on retrospective data and clinical experience. For example, among patients with G719X mutations, the response rate was approximately 47% with osimertinib and the median PFS was 8.8 months. For patients with L861Q mutations, activity was higher at 80% with osimertinib and a median PFS of 15.7 months. In some cases, we use osimertinib in an off-label fashion for patients with uncommon EGFR mutations, particularly given some of the toxicity concerns that we see with second-generation EGFR inhibitors, which are associated with higher rates of diarrhea.

Approved Options for Treating Tumors With Exon 20 Insertion Mutations

Zofia Piotrowska, MD, MHS:
The first agent approved for patients with EGFR exon 20 insertions was amivantamab, a bispecific antibody targeting EGFR and MET. In this setting, amivantamab is approved in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations and as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

The phase III PAPILLON trial in treatment-naive patients with EGFR exon 20 insertions showed an improvement in the primary endpoint of PFS of 11.4 months with amivantamab plus chemotherapy compared with 6.7 months with chemotherapy. Even though we do not have final overall survival data from this study, based on these results, this is how we are most often using amivantamab for our patients with EGFR exon 20 insertions.

Sunvozertinib is an oral kinase inhibitor that is important to be aware of based on its accelerated FDA approval in 2025 for the treatment of adults with NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The WU-KONG1 study demonstrated a confirmed overall response rate of 45.9% with the approved 200-mg dose and 47.2% with the 300-mg dose and median duration of response of 11.1 and 13.8 months, respectively. However, because of drug production and distribution issues, it is currently unavailable in the marketplace.

Emerging EGFR TKIs Targeting EGFR Exon 20 Insertion and Uncommon EGFR Mutations

Zofia Piotrowska, MD, MHS:
Zipalertinib is a TKI in development for treating NSCLC with uncommon EGFR mutations exon 20 insertions. In the phase I/II REZILIENT1 trial, zipalertinib was evaluated in patients with EGFR exon 20 insertion–positive NSCLC who had previous therapy, including platinum-based chemotherapy or other exon 20–directed agents, like amivantamab. The ORRs varied depending on whether the patients had received prior amivantamab and other TKIs (14%), prior amivantamab only (30%), or prior chemotherapy only (40%). These are important differences because with the novel TKIs like zipalertinib, we are interested in what their activity is in the postamivantamab setting. The rationale is that for patients in our current practice, most will receive chemotherapy and amivantamab as first-line therapy. In REZILIENT1, the grade ≥3 treatment-related adverse events (AEs) reported included alanine aminotransferase increased (2%), anemia (7%), decreased platelet count (2%), diarrhea (2%), pneumonitis (2.5%), and rash (2.5%). Of interest, in a small, dedicated cohort of patients with intracranial metastases (n = 68), the intracranial response rate to zipalertinib seemed to be similar to the systemic ORR (31%). This result suggests that zipalertinib penetrates the central nervous system, where it has some activity.

Resistance to treatment and drug sequencing after first-line therapy remains a clinical concern in managing patients with EGFR-mutated NSCLC. Silevertinib (or BDTX-1535), an investigational fourth-generation TKI, was suggested by a preclinical report to mitigate resistance to osimertinib. The agent was developed to be mutation selective with activity against uncommon EGFR mutations and some acquired resistance mutations, such as EGFR C797S. Early data show some promising tumor shrinkage and partial responses with the atypical mutations. Treatment-related AEs at all grades with silevertinib included rash (78%), diarrhea (41%), fatigue (15%), decreased appetite (11%), nausea (11%), paronychia (11%), and stomatitis (11%). The only grade 3 AE reported that affected more than 10% of patients was rash (19%).

Another agent in development for treating NSCLC with EGFR mutations is furmonertinib (or firmonertinib) to target both the uncommon mutations and exon 20 insertions. In a clinical trial that enrolled patients with previously untreated NSCLC with uncommon EGFR mutations, 2 different dose levels were tested: 160 mg and 240 mg. The response rates were high—52.2% with the 160-mg dose and 81.8% with the 240-mg dose. The median PFS was 16.0 months and 11.1 months, respectively. The phase III ALPACCA trial will evaluate first-line furmonertinib 240 mg vs investigator’s choice of osimertinib or afatinib in patients with uncommon EGFR mutations (specifically atypical P-loop and αC-helix compression mutations or PACC mutations) who have not received any prior therapy for advanced disease. In a previous trial, grade ≥3 treatment-related AEs were observed among 11% of patients. In addition, treatment-related diarrhea was reported in 5% of patients and rashes were reported in 7% of patients. Furmonertinib is also under investigation for the treatment of EGFR TKI–resistant leptomeningeal metastasis in combination with bevacizumab. Results of these trials could help establish treatment protocols for patients with NSCLC with uncommon EGFR mutations.

Enozertinib is another novel EGFR TKI under investigation in patients with the uncommon EGFR mutations or PACC mutations such as G719A, S768I, or L747P. At 80 mg of enozertinib, the confirmed ORR was 36% in previously treated patients with advanced NSCLC and EGFR PACC mutations. We observed quite a few tumor shrinkages, including patients with brain metastases at study entry. Enozertinib also appeared to be well tolerated. There were some treatment-related AEs, mostly grade 1/2, with the most frequently reported being diarrhea, paronychia, and stomatitis. Enozertinib will likely be tested in phase III trials with follow-up of a potential role as first-line therapy for patients with EGFR exon 20 insertions.

Many of the emerging EGFR TKIs, like zipalertinib, sunvozertinib, and furmonertinib, may have some cross resistance. Even if we have multiple agents available for our patients with EGFR-mutated NSCLC, using them sequentially likely will not be as effective as having one that is extremely effective against the disease. Therefore, although sequencing is the current strategy, I do not think that this is effective long term. Resistance to one agent will likely confer resistance to the others. This is why we keep investigating new approaches and look out on the horizon for new agents.

Your Thoughts
What are your current challenges in the care of your patients with advanced NSCLC with uncommon EGFR mutations or EGFR exon 20 insertion mutations? Let us know in the comments.

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