Zipalertinib + Chemotherapy Extends PFS by 6 Months in Frontline EGFR Exon 20 Insertion–Positive NSCLC

Adding zipalertinib to platinum-pemetrexed chemotherapy reduced the risk of disease progression or death by 50% versus lone chemotherapy in patients with previously untreated advanced non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, according to interim analysis results from the phase 3 REZILIENT3 trial (NCT05973773) presented at the IASLC 2026 World Conference on Lung Cancer (WCLC).¹

At a data cutoff of May 29, 2026, the median progression-free survival (PFS) by blinded independent central review (BICR) was 14.5 months (95% CI, 12.9 - 21.4) among patients receiving zipalertinib plus chemotherapy (n = 140) versus 8.5 months (95% CI, 7.0 - 10.9) among patients receiving lone chemotherapy (n = 139; HR, 0.50; 95% CI, 0.34 - 0.73; P = .00015), crossing the prespecified boundary for superiority.

The BICR-assessed objective response rate (ORR) was 65.0% (95% CI, 56.5 - 72.9) versus 40.3% (95% CI, 32.1 - 48.9), respectively (P < .0001), and the median duration of response (DOR) was 14.2 months (95% CI, 10.5 - not estimable [NE]) versus 9.9 months (95% CI, 6.8 - NE).

At the interim overall survival (OS) analysis, with 30% maturity and a median follow-up of 10.9 months, the median OS was NE in both arms, and the HR for death was 0.72 (95% CI, 0.42 - 1.23; P = .111). One fourth (24.5%) of patients in the chemotherapy arm had crossed over to zipalertinib.^1,2

"REZILIENT 3 demonstrated that adding zipalertinib to platinum-based chemotherapy produced a statistically significant and clinically meaningful six-month improvement in progression-free survival for patients with advanced NSCLC and EGFR exon 20 insertion mutations," presenting author Daniel S.W. Tan, PhD, MBBS, MRCP, professor at Duke-NUS Medical School, said in a news release issued by the IASLC.² "The combination also produced a substantially higher response rate, supporting its potential as a first-line treatment approach for this patient population."

What Was the Rationale for the REZILIENT3 Trial?

EGFR exon 20 insertions account for 5 - 10% of EGFR mutations in NSCLC and represent a heterogeneous molecular subgroup with variable sensitivity to EGFR-directed therapy.

Amivantamab-vmjw (Rybrevant) plus platinum-pemetrexed chemotherapy and the oral TKI sunvozertinib (Zegfrovy) have each improved PFS versus chemotherapy in randomized frontline trials. Zipalertinib (TAS6417; CLN-081) is an oral TKI with a pyrrolopyrimidine scaffold that forms an irreversible covalent bond with C797 and is highly selective for EGFR exon 20 insertions over wild-type EGFR; phase 1/2 data demonstrated activity in the central nervous system and after prior amivantamab.¹

The interim result follows the sponsor's August 2026 announcement that the trial met its primary end point,³ and arrives alongside the final OS analysis of the phase 3 PAPILLON trial (NCT04538664), which reported a median OS of 34.3 months with frontline amivantamab plus chemotherapy in the same population.⁴

In an interview with OncLive at WCLC 2026, Luis E. Raez, MD, chief scientific officer and medical director of Memorial Cancer Institute at Memorial Healthcare System, said that amivantamab plus chemotherapy remains his frontline standard for EGFR exon 20 insertion–positive disease, but noted that the chemotherapy backbones in PAPILLON and REZILIENT3 are identical. The TKI-based regimen could become the preferred option if its toxicity profile compares favorably with amivantamab, Raez explained.⁵

"The orals are very attractive,” he said. “Instead of coming for infusions every 2 weeks or every 3 weeks for other agents, taking a pill at home is more appealing for patients. All of these agents are very good drugs, but I think the fact that they are oral makes it easier for patients and physicians to move the oral agents to the front line."⁵

How Was the REZILIENT3 Trial Designed?

The international, open-label study enrolled patients with metastatic NSCLC and a locally tested EGFR exon 20 insertion, an ECOG performance status of 0 or 1, and available archival tissue who had received no prior treatment for advanced disease; stable brain metastases, including untreated asymptomatic lesions up to 2 cm, were permitted. Following a 6- to 12-patient safety lead-in cleared by the independent data monitoring committee, 279 patients were randomly assigned 1:1 to zipalertinib at 100 mg twice daily plus pemetrexed and carboplatin or cisplatin, or to pemetrexed-platinum alone, with optional crossover to zipalertinib at progression. Randomization was stratified by ECOG performance status, brain metastases, and region.¹

The primary end point was BICR-assessed PFS. Secondary end points included OS, investigator-assessed PFS, ORR, DOR, safety, and patient-reported outcomes. The primary analysis was planned at 162 PFS events to detect an HR of 0.60 with 90% power at a 2-sided α of .05, with the pre-specified interim analysis at 122 events.¹

Baseline characteristics were balanced. Median patient age was 66.5 years (range, 30 - 89) in the combination arm and 64.0 years (range, 27 - 82) in the chemotherapy arm; 65.7% and 63.3% of patients were female, 40.0% and 40.3% were enrolled in Asia, 41.4% and 40.3% had an ECOG performance status of 0. Another 31.4% and 31.7% had baseline brain metastases, and 59.3% and 61.2% were never smokers. Adenocarcinoma histology was present in 97.1% of patients in each arm.¹

What Additional Efficacy Data Were Reported?

The PFS benefit was consistent across prespecified subgroups, including patients with brain metastases (HR, 0.38). Best overall response by BICR with zipalertinib plus chemotherapy comprised complete responses in 9 patients (6.4%), partial responses in 82 (58.6%), stable disease in 29 (20.7%), and progressive disease in 4 (2.9%); with chemotherapy alone (n = 136), the rates were 2.2%, 38.1%, 39.6%, and 8.6%, respectively.

The disease control rate was 89.3% (95% CI, 82.9 - 93.9) versus 81.3% (95% CI, 73.8 - 87.4), and the median time to response was 1.4 versus 2.6 months.^1,2

What Was the Safety Profile of the Combination?

Treatment-related adverse events (TRAEs) of any grade occurred in 98.6% of patients receiving zipalertinib plus chemotherapy (n = 140) versus 88.2% receiving chemotherapy alone (n = 136), and grade ≥3 TRAEs occurred in 80.7% versus 40.4%.

Treatment-related serious AEs occurred in 37.9% versus 12.5%. In the combination arm, AEs led to zipalertinib interruption in 82.9% of patients, dose reduction in 43.6%, and discontinuation in 17.1%. The median relative dose intensity of zipalertinib was 87.1%. AEs resulting in death occurred in 13 patients (9.3%) in the combination arm versus 4 (2.9%) in the chemotherapy arm, and TRAEs with an outcome of death—sepsis or septic shock—occurred in 3 patients (2.1%) versus none.¹

The most common grade ≥3 AEs with the combination versus chemotherapy were anemia (48.6% vs 12.5%), neutropenia (33.6% vs 22.1%), thrombocytopenia (30.0% vs 8.1%), rash (10.7% vs 0%), and stomatitis (5.0% vs 0.7%). Grade ≥3 diarrhea and paronychia each occurred in 1.4% of patients in the combination arm, and any-grade pneumonitis occurred in 5.7% versus 2.2%, with grade ≥3 events in 2.1% versus 1.5%.¹

Investigators concluded that the excess grade ≥3 toxicity was largely related to cytopenias and their sequelae, concentrated in the first 4 cycles, and manageable with dose reductions, and that zipalertinib plus platinum-based chemotherapy represents a new frontline option for metastatic EGFR exon 20 insertion–positive NSCLC. Follow-up is ongoing to further characterize OS and the AE profile, and the phase 3 REZILIENT4 trial (NCT07128199) is evaluating adjuvant zipalertinib in uncommon EGFR mutations.¹

References

1. Tan DSW. Zipalertinib plus chemotherapy for 1st line NSCLC with EGFR exon 20 insertions: results from the phase 3 trial (REZILIENT 3). Presented at: International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.04.
2. Zipalertinib plus chemotherapy significantly extends progression-free survival in first-line EGFR exon 20 insertion-positive NSCLC. News release. International Association for the Study of Lung Cancer. September 14, 2026. Accessed September 15, 2026.
3. Zipalertinib Plus Chemotherapy Improves PFS in First-Line EGFR Exon 20 Insertion+ NSCLC. OncLive. Published August 13, 2026. Accessed September 15, 2026. https://www.onclive.com/view/zipalertinib-plus-chemotherapy-improves-pfs-in-first-line-egfr-exon-20-insertion-nsclc
4. Frontline Amivantamab Plus Chemotherapy Yields 34.3-Month Median OS in EGFR Exon 20 Insertion–Positive NSCLC. OncLive. Published September 14, 2026. Accessed September 15, 2026. https://www.onclive.com/view/frontline-amivantamab-chemotherapy-34-3-month-median-os-egfr-exon-20-insertion-nsclc-papillon
5. Dr Raez on Oral Options Reshaping ROS1+, HER2-Mutant, and EGFR Exon 20+ NSCLC. OncLive. Published September 14, 2026. Accessed September 15, 2026. https://www.onclive.com/view/dr-raez-on-oral-options-reshaping-ros1-her2-mutant-and-egfr-exon-20-nsclc