Advancements in clinical trials for EGFR exon 20 insertion lung cancer

The results of the Phase 3 trial for zipalertinib and the long-term follow-up for Rybrevant have been unveiled

Sunvozertinib is added...treatment landscape becomes a "three-way race"

Competition for the first-line treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations is intensifying.

In a Phase 3 trial, the oral EGFR TKI zipalertinib combined with chemotherapy improved progression-free survival (PFS). Final overall survival (OS) results for Rybrevant were also presented from more than four years of long-term follow-up, bolstering the evidence for its long-term use.

In addition to the previously reported positive Phase 3 results for sunvozertinib, the first-line treatment landscape for EGFR exon 20 insertion-mutated lung cancer is being reshaped into a competitive three-way competition among these strategies.

On the 14th, new results from the Phase 3 REZILIENT-3 and PAPILLON trials, which evaluated the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 20 insertion mutations, were unveiled at the World Conference on Lung Cancer (WCLC 2026).

EGFR exon 20 insertion mutations are rare, accounting for approximately 1% to 2.5% of all NSCLC cases and about 10% of all EGFR mutations. This disease is highly heterogeneous, with over 100 variant subtypes reported to date.

Unlike typical EGFR exon 19 deletions or L858R mutations, these mutations are structurally difficult for conventional EGFR TKIs to bind, characteristically resulting in low response rates to first- to third-generation TKIs. Consequently, the development of monoclonal antibodies and TKIs specifically targeting EGFR exon 20 insertion mutations has continued.

Daniel Tan, Professor at the National Cancer Centre Singapore (NCCS) and Duke-NUS Medical School, presents clinical trial results for zipalertinib at the World Conference on Lung Cancer (WCLC 2026), held on the 14th. 

Zipalertinib, PFS of 14.5 Months… 50% reduction in the risk of disease or risk of death

REZILIENT-3 is a Phase 3 study comparing zipalertinib plus chemotherapy against chemotherapy alone in previously untreated patients with metastatic NSCLC harboring EGFR exon 20 insertion mutations.

Zipalertinib is a TKI designed with enhanced selectivity for EGFR exon 20 insertion mutations. This study evaluated the strategy of adding zipalertinib to 'Alimta (pemetrexed)' and platinum-based chemotherapy. In the interim analysis, the zipalertinib combination therapy significantly improved the primary endpoint of PFS. The median PFS, as assessed by a Blinded Independent Central Review (BICR), was 14.5 months, outperforming the 8.5 months in the chemotherapy group, and reduced the risk of disease progression or death by 50% (HR 0.50).

The combination therapy group also had a higher tumor response rate. The objective response rate (ORR) was 65% in the zipalertinib group, surpassing the 40.3% in the chemotherapy group, and the duration of response was also longer in the combination therapy group.

Daniel Tan, Professor at the National Cancer Centre Singapore (NCCS) and Duke-NUS Medical School, explained, "The zipalertinib combination therapy demonstrated a clinically meaningful improvement in PFS compared with chemotherapy, meeting the study's primary endpoint."

In this study, approximately 31% of the patients had baseline brain metastases. The trial was designed to enroll not only patients with previously treated brain metastases but also those with asymptomatic lesions of 2 cm or less, featuring a relatively broad inclusion of patients with central nervous system (CNS) metastases.

The study also observed a trend toward PFS improvement with the zipalertinib combination therapy in patients with brain metastases. However, because this is a subgroup analysis, additional evidence is needed to directly compare its CNS efficacy with other therapeutic agents.

The OS data are not yet fully mature. Given the short median follow-up of 10.9 months and the inclusion of a substantial number of patients who crossed over to zipalertinib following disease progression in the chemotherapy group, additional follow-up is necessary to determine the long-term survival impact.

Regarding safety, a reduction in the number of mature blood cells emerged as a major burden. Anemia, neutropenia, and thrombocytopenia were observed more frequently than with chemotherapy alone, appearing particularly pronounced during the initial combination phase with platinum-based chemotherapy.

Professor Tan stated, "Considering these toxicities, management through patient selection, dose modification, and supportive care is crucial." 

Rybrevant, Long-term survival outcomes presented after four years of follow-up

For the PAPILLON trial, the final OS analysis of Rybrevant plus chemotherapy was presented.

This Phase 3 study compared Rybrevant plus chemotherapy with chemotherapy alone in previously untreated patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations.

Previous analyses showed that the Rybrevant combination significantly improved PFS, supporting its use as first-line treatment in this patient population. This time, the authors presented long-term survival results with an extended median follow-up of 48.6 months.

According to the clinical results, the median OS was 34.3 months in the Rybrevant combination group and 27.9 months in the chemotherapy group. Although the survival duration was numerically longer in the combination group, it was not statistically significant in the intention-to-treat (ITT) analysis.

Chul Kim, Professor at Georgetown University and MedStar Georgetown University Hospital, presented results for Phase 3 clinical trials evaluating the efficacy of Rybrevant plus platinum-based chemotherapy.

Chul Kim, Professor at Georgetown University and MedStar Georgetown University Hospital, highlighted the high crossover rate as a factor to consider in interpreting the results.

The PAPILLON trial was designed to allow crossover to Rybrevant treatment following disease progression in the chemotherapy group. About three-quarters of patients in the chemotherapy group who discontinued treatment because of progression subsequently received Rybrevant.

In the analysis adjusting for this crossover, the researchers confirmed the survival benefit of the Rybrevant combination therapy. Progression-free survival 2 (PFS2)—assessed from the time of initial treatment to the second disease progression or death—was also longer in the combination therapy group.

Professor Kim explained, "The therapeutic efficacy of the Rybrevant combination was maintained in long-term follow-up, and it is likely that the high crossover rate diminished the final OS difference between the two groups."

The safety profile was largely consistent with prior reports. Neutropenia, rash, paronychia, hypoalbuminemia, peripheral edema, and infusion-related reactions were major adverse events, and no new safety signals emerged during this long-term follow-up.

Sunvozertinib... First-line treatment landscape becomes a "three-way race"

With the presentation of new clinical results for zipalertinib and Rybrevant at this conference, the first-line treatment competition for EGFR exon 20 insertion mutation NSCLC has become even clearer.

Rybrevant plus chemotherapy showed positive Phase 3 results in the PAPILLON trial, sunvozertinib monotherapy in the WU-KONG 28 trial, and zipalertinib plus chemotherapy in the REZILIENT-3 trial.

However, it is difficult to determine superiority based solely on the figures from different studies. Each study has different patient enrollments, CNS metastasis inclusion criteria, follow-up periods, and crossover structures, and no direct head-to-head study compares the three treatment strategies.

Health professionals suggested that evidence is currently insufficient to judge one treatment as superior to the others, and that in clinical practice, factors such as CNS activity, toxicity, treatment burden, accessibility, and patient preference must be considered collectively.

The administration methods also differ. Rybrevant utilizes a monoclonal antibody in combination with chemotherapy, while sunvozertinib is an oral TKI monotherapy. Zipalertinib employs a strategy of adding chemotherapy to an oral TKI.

Beyond efficacy, their adverse event profiles differ. Zipalertinib has a notable burden of cytopenias, whereas Rybrevant requires managing adverse events associated with EGFR/MET inhibition and intravenous infusion. While sunvozertinib offers the convenience of oral monotherapy, diarrhea and elevated blood creatine kinase (CK) have been cited as key adverse events.

Because treatment convenience and adverse event patterns differ not only in terms of efficacy, treatment selection may vary depending on the patient's clinical status and preferences.

The structural characteristics of EGFR exon 20 insertion mutations, which encompass diverse variant subtypes, are also considered a variable in treatment selection. The WCLC 2026 conference emphasized that current evidence is insufficient to dictate first-line treatment based solely on the specific mutation location or predicted resistance mechanisms. Comprehensive next-generation sequencing (NGS) is crucial to avoid missing diverse variants.