Sunvozertinib Outperforms Chemotherapy as First-Line Therapy for EGFR Exon 20–Mutant NSCLC

The phase 3 WU-KONG28 trial (NCT05668988) has demonstrated that sunvozertinib (Zegfrovy), when used as an initial treatment for patients with advanced non–small cell lung cancer (NSCLC) carrying EGFR exon 20 insertion mutations, produced meaningfully longer progression-free survival (PFS) and a higher objective response rate (ORR) compared with platinum-based chemotherapy. These primary analysis findings were presented at the 2026 ASCO Annual Meeting.¹

By blinded independent central review (BICR), patients receiving sunvozertinib (n = 163) achieved a median PFS of 10.3 months (95% CI, 8.3-14.0), while those receiving chemotherapy (n = 161) reached a median PFS of 7.5 months (95% CI, 6.7-8.5). This translated to a 35% lower risk of disease progression or death with sunvozertinib (HR, 0.65; 95% CI, 0.50-0.85; P =.0008), satisfying the study's primary end point. At 12 months, PFS rates were 46.1% and 26.7% in the sunvozertinib and chemotherapy arms, respectively, and at 18 months, they were 33.2% and 17.1%.

Sunvozertinib also produced a substantially higher confirmed ORR than chemotherapy—58.9% (95% CI, 50.9%-66.5%) vs 31.1% (95% CI, 24.0%-38.8%)—corresponding to an odds ratio of 3.2 (95% CI, 2.0-5.0; P <.0001). Disease control rates were 94.5% (95% CI, 89.8%-97.4%) with sunvozertinib and 85.7% (95% CI, 79.3%-90.7%) with chemotherapy. Median duration of response (DOR) also favored sunvozertinib at 11.2 months (95% CI, 8.2-13.9) vs 7.1 months (95% CI, 6.9-11.1) for chemotherapy.

Sunvozertinib Advances to the Frontline in EGFR Exon 20–Mutant NSCLC

Sunvozertinib reduced the risk of disease progression or death by 35% relative to platinum-based chemotherapy in previously untreated patients with EGFR exon 20 insertion–mutant NSCLC, with a confirmed ORR of 58.9% versus 31.1% for chemotherapy. The WU-KONG28 data position sunvozertinib as a promising first-line option, offering the practicality of a once-daily oral agent in this challenging patient population.

"These findings support using sunvozertinib as a frontline therapy for patients with NSCLC harboring EGFR exon 20 insertions, with the added benefit of a single oral agent," said John V. Heymach, MD, PhD, who presented the data. Heymach holds an endowed chair as the Ruth Legett Jones Distinguished Chair and serves as a professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Addressing an Unmet Need in EGFR-Mutant NSCLC

EGFR exon 20 insertions account for roughly 12% of all EGFR-mutant NSCLC cases, Heymach noted. The condition is biologically heterogeneous, with over 100 identified variants and an unfavorable prognosis. Formerly known as DZD9008, sunvozertinib is an oral EGFR tyrosine kinase inhibitor (TKI) engineered to selectively target EGFR exon 20 insertions and other EGFR mutations while sparing wild-type EGFR.

The FDA granted accelerated approval to sunvozertinib in July 2025 for adult patients with locally advanced or metastatic NSCLC and EGFR exon 20 insertion mutations, as confirmed by an FDA-approved test, whose cancer had progressed during or after platinum-based chemotherapy.² This approval was based on data from the phase 1/2 WU-KONG1b study (NCT03974022), in which sunvozertinib achieved an ORR of 46% (95% CI, 35%-57%) with a median DOR of 11.1 months (95% CI, 8.2-not evaluable).

The FDA simultaneously approved the Oncomine Dx Express Test as a companion diagnostic for sunvozertinib and for broader tumor profiling in NSCLC.

Currently available first-line treatments for advanced NSCLC with EGFR exon 20 insertions consist of variations of the PAPILLON regimen of platinum-containing doublet chemotherapy with or without amivantamab. Heymach emphasized that no EGFR TKI has yet been approved in the frontline setting for this patient group.¹

WU-KONG28 Study Design

The trial enrolled patients with cytologically or histologically confirmed locally advanced or metastatic nonsquamous NSCLC with documented EGFR exon 20 insertion mutations. Eligible patients had newly diagnosed or treatment-naive disease and an ECOG performance status of 0 or 1.

Participants were randomized 1:1 to receive sunvozertinib at 300 mg once daily or platinum-based chemotherapy comprising carboplatin at an area under the curve of 5 plus pemetrexed at 500 mg/m² every 3 weeks for up to 6 cycles, followed by pemetrexed maintenance. Patients who progressed on chemotherapy were permitted to cross over to sunvozertinib. Stratification was based on the presence or absence of baseline brain metastases.

The primary end point was BICR-assessed PFS, with overall survival (OS) as a key secondary end point. Additional secondary end points included investigator-assessed PFS, ORR, disease control rate (DCR), DOR, and change in tumor size. PFS2, defined as time from randomization to second progression or death, served as a key exploratory end point.

Baseline characteristics were broadly balanced between arms, though the sunvozertinib arm had slightly fewer female patients (53.4% vs 65.2%), fewer never-smokers (62.0% vs 66.5%), and fewer patients with 1 to 3 organs or disease sites involved (56.4% vs 65.8%). Fifty-four distinct EGFR exon 20 insertion variants were identified. The two most frequent were the 769_ASV insertion (31.3%; 32.3%) and the 770_SVD insertion (12.9%; 19.9%).

Subgroup and Exploratory Findings

A PFS benefit with sunvozertinib was observed broadly across major subgroups. More pronounced benefit was seen in Asian patients (HR, 0.56; 95% CI, 0.41-0.77) than non-Asian patients (HR, 0.93; 95% CI, 0.58-1.48), in patients without brain metastases (HR, 0.62; 95% CI, 0.47-0.83) compared with those with brain metastases (HR, 0.96; 95% CI, 0.44-2.08), and in patients with near-loop (HR, 0.59; 95% CI, 0.43-0.82) vs far-loop insertions (HR, 0.83; 95% CI, 0.49-1.38).

Median PFS2 was 21.7 months (95% CI, 16.1-24.3) with sunvozertinib and 15.5 months (95% CI, 13.4-18.6) with chemotherapy (HR, 0.70; 95% CI, 0.52-0.95; P =.0111). Among patients in the sunvozertinib arm, 46.6% went on to receive subsequent therapy, with 72.4% of those receiving chemotherapy. In the chemotherapy arm, 72.0% of patients proceeded to subsequent treatment, of whom 91.4% received sunvozertinib: 90.2% via in-study crossover, with an additional 5 patients receiving sunvozertinib outside the study.

OS data remained immature at the primary analysis, with only 38.9% event maturity (62 events in the sunvozertinib arm; 64 in the chemotherapy arm). Heymach noted that survival interpretation is complicated by the high rate of crossover to sunvozertinib from the chemotherapy arm.

Safety Profile

All safety-evaluable patients in the sunvozertinib arm (n = 163) experienced treatment-related adverse events (TRAEs), compared with 97.3% in the chemotherapy arm (n = 150). Grade 3 or higher TRAEs occurred in 61.3% and 49.3% of patients, respectively. Treatment-related serious AEs were reported in 18.4% of sunvozertinib patients and 12.7% of chemotherapy patients. In the sunvozertinib arm, TRAEs led to dose interruption in 45.4% of patients, dose reduction in 40.5%, and discontinuation in 7.4%; comparable rates in the chemotherapy arm were 27.3%, 24.0%, and 11.3%.

No treatment-related deaths occurred in the sunvozertinib arm. The most frequently reported TRAEs with sunvozertinib were diarrhea (all grade, 84.0%; grade ≥3, 13.5%), elevated blood creatine phosphokinase (55.2%; 20.2%), rash (51.5%; 0.6%), and paronychia (48.5%; 3.7%)—a pattern consistent with on-target EGFR inhibition.

DISCLOSURES: Heymach disclosed serving in a consulting or advisory role for AbbVie, ALK Positive, ArriVent Biopharma, AstraZeneca, BioNtech, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Lilly, Mirati Therapeutics, ModeX Therapeutics, Novartis, Ottimo Pharma, Regeneron, Sanofi/Aventis, Spectrum Pharmaceuticals, Taiho Pharmaceutical, and Takeda. Research funding was provided by AstraZeneca, Boehringer Ingelheim, Mirati Therapeutics, Spectrum Pharmaceuticals, and Takeda. He noted a licensing agreement between Spectrum and MD Anderson regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations; patents pending regarding classification of EGFR mutations; and patents pending regarding subtyping of SCLC.

REFERENCES

1. Heymach JV, Liu G, Xing L, et al. Sunvozertinib monotherapy versus platinum-based chemotherapy as first-line treatment for advanced NSCLC with EGFR exon20ins: primary analysis of a multinational phase 3 randomized study (WU-KONG28). J Clin Oncol. 2026;44(suppl 17):LBA8500. doi:10.1200/JCO.2026.44.17_suppl.LBA8500

2. FDA grants accelerated approval to sunvozertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. US FDA. July 2, 2025. Accessed June 10, 2026. https://tinyurl.com/52k2z4z6