Sunvozertinib Shows Superior Efficacy vs Chemo in Frontline Advanced EGFR Exon 20+ NSCLC

Sunvozertinib (Zegfrovy) significantly improved progression-free survival (PFS) and induced a higher objective response rate (ORR) than platinum-based chemotherapy when given as first-line treatment in patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to findings from the primary analysis of the phase 3 WU-KONG28 study (NCT05668988).¹

The results, which were shared during the 2026 ASCO Annual Meeting, indicated that sunvozertinib (n = 163) led to a median PFS of 10.3 months (95% CI, 8.3-14.0) by blinded independent central review (BICR) vs 7.5 months (95% CI, 6.7-8.5) with chemotherapy (n = 161), translating to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.50-0.85; P = .0008) and meeting the primary end point of the study. The 12-month PFS rates in the respective arms were 46.1% and 26.7%, and the 18-month PFS rates were 33.2% and 17.1%.

Moreover, sunvozertinib monotherapy elicited a higher confirmed ORR than that achieved with chemotherapy, at 58.9% (95% CI, 50.9%-66.5%) vs 31.1% (95% CI, 24.0%-38.8%), respectively (odds ratio, 3.2; 95% CI, 2.0-5.0; P < .0001). The disease control rates in the respective arms were 94.5% (95% CI, 89.8%-97.4%) and 85.7% (95% CI, 79.3%-90.7%). The median duration of response (DOR) was also longer with sunvozertinib than chemotherapy, at 11.2 months (95% CI, 8.2-13.9) and 7.1 months (95% CI, 6.9-11.1), respectively.

“These results support sunvozertinib as first-line treatment for [patients with] NSCLC [and] EGFR exon 20 insertions, with the advantage of a single oral agent administration,” John V. Heymach, MD, PhD, said in a presentation of the data. Heymach is the endowed chair and Ruth Legett Jones Distinguished Chair and 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.

How might sunvozertinib address existing unmet needs in NSCLC harboring EGFR mutations?

It is known that EGFR exon 20 insertions comprise approximately 12% of all cases of EGFR-mutant NSCLC, Heymach said. He added that over 100 variants have been reported, which makes it a heterogeneous disease with a poor prognosis. Previously known as DZD9008, sunvozertinib is an oral EGFR TKI that was designed to target EGFR exon 20 insertions and other mutations, with selectivity against wild-type EGFR.

In July 2025, the FDA granted accelerated approval to sunvozertinib for use in adult patients with locally advanced or metastatic NSCLC and EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or following platinum-based chemotherapy.² The decision was supported by results from the phase 1/2 WU-KONG1b trial (NCT03974022), in which the agent induced an ORR of 46% (95% CI, 35%-57%) with a median DOR of 11.1 months (95% CI, 8.2-not evaluable).

At the time of the decision, Lyudmila A. Bazhenova, MD, of the University of California San Diego (UCSD) and UCSD Moores Cancer Center, spoke to OncLive® about the significance of the decision for this patient population:³

“Currently, at least in the United States, the [phase 3] PAPILLON trial [NCT04538664] established carboplatin, pemetrexed, and amivantamab-vmjw [Rybrevant] as a standard first-line treatment option,” she said in the Q&A.⁴ “Sunvozertinib can be used after [this regimen as] a second-line treatment option.” You can listen to the full OncLive On Air podcast episode to learn more.⁵

The regulatory agency also cleared the Oncomine Dx Express Test for tumor profiling and for use as a companion diagnostic for sunvozertinib in NSCLC.⁶ In another podcast episode, Apar Kishor Ganti, MD, and Allison Cushman-Vokoun, MD, PhD, FACP, discussed the significance of the launch of the test, explained the benefits and limitations of rapid next-generation sequencing, and more.⁷

Ganti is a professor in the University of Nebraska Medical Center (UNMC) Division of Oncology & Hematology, the Dr. and Mrs. D. Leon UNMC Research Fund Chair in Internal Medicine, and the associate director for Clinical Research at the Fred & Pamela Buffett Cancer Center in Omaha. Cushman-Vokoun is the Henry F. Krous Professor of Pathology, a professor in the UNMC Department of Pathology, Microbiology and Immunology, director of the Division of Diagnostic Molecular Pathology and Human Genetics, medical director of the Molecular Diagnostics and Personalized Medicine Laboratory at Nebraska Medicine, director of the Molecular Genetic Pathology Fellowship Program, and associate director of the UMNC MD-PhD Scholars Program.

In his presentation, Heymach noted that currently approved frontline treatment options for advanced NSCLC with EGFR exon 20 insertions are variations of the PAPILLON regimen of platinum-containing doublet chemotherapy with or without amivantamab.¹ He added that no EGFR TKI has been cleared for use in the frontline setting for this population.

What is the design of the WU-KONG28 study?

The study enrolled patients with cytologically or histologically confirmed locally advanced or metastatic nonsquamous NSCLC and documented EGFR exon 20 insertion mutations. Patients were required to have newly diagnosed or treatment-naive disease and an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive sunvozertinib at 300 mg once daily or platinum-based chemotherapy in the form of carboplatin at area under the curve of 5 plus pemetrexed at 500 mg/m² every 3 weeks for up to 6 cycles followed by pemetrexed maintenance therapy.

“Note that at progressive disease, patients could cross over to [receive] sunvozertinib,” Heymach said. All patients were stratified by the presence of baseline brain metastases (yes vs no).

In addition to the primary end point of BICR-assessed PFS, a key secondary end point is overall survival (OS). Other secondary end points include investigator-assessed PFS, ORR, DCR, DOR, and change in tumor size. A key exploratory end point is PFS2, which is defined as the time from randomization to second progression or death.

Heymach noted that baseline characteristics were relatively well balanced, although there were fewer females (53.4% vs 65.2%) and never-smokers (62.0% vs 66.5%) in the sunvozertinib arm vs the chemotherapy arm; there were also fewer patients with 1 to 3 organs or sites of disease involvement in the sunvozertinib arm (56.4% vs 65.8%).

“Note that there were 54 different EGFR exon 20 insertions representative of the broad exon 20 population,” Heymach said. “The 2 most common were the 769_ASV insertion [31.3%; 32.3%] and the 770_SVD insertion [12.9%; 19.9%]. These are typically the most common in exon 20 studies.”

What did the WU-KONG28 subgroup analysis of BICR-assessed PFS reveal about sunvozertinib?

A PFS benefit was broadly observed across major subgroups, according to Heymach. A “relatively greater benefit was seen in Asians [HR, 0.56; 95% CI, 0.41-0.77] vs non-Asians [HR, 0.93; 95% CI, 0.58-1.48], in patients without brain metastases [HR, 0.62; 95% CI, 0.47-0.83] vs with brain metastases [HR, 0.96; 95% CI, 0.44-2.08], and those with near loop [HR, 0.59; 95% CI, 0.43-0.82] vs far loop [HR, 0.83; 95% CI, 0.49-1.38] insertions,” he said.

What were the PFS2 and OS data from the primary analysis of WU-KONG28?

The median PFS2 with sunvozertinib was 21.7 months (95% CI, 16.1-24.3) vs 15.5 months (95% CI, 13.4-18.6) with chemotherapy (HR, 0.70; 95% CI, 0.52-0.95; P = .0111). In terms of first subsequent therapy, 46.6% of patients in the sunvozertinib arm started subsequent treatment, and 72.4% of these patients received chemotherapy. Of the 72.0% of patients who started subsequent therapy in the chemotherapy arm, 91.4% received sunvozertinib.

“That [rate] was 90.2% through in-study crossover, and [with] an additional 5 patients who received sunvozertinib outside the study, the total [was] 91.4%,” Heymach explained.

The OS analysis was only at 38.9% data maturity, with 62 events reported in the sunvozertinib arm and 64 events in the chemotherapy arm. “The survival analysis is confounded by the [90.2]% of patients who’ve crossed over to [receive] sunvozertinib after progression on the chemotherapy arm,” Heymach said.

What was the safety profile of sunvozertinib in WU-KONG28?

All safety-evaluable patients in the sunvozertinib arm (n = 163) experienced treatment-related adverse effects (TRAEs) vs 97.3% of those in the chemotherapy arm (n = 150); these effects were grade 3 or higher for 61.3% and 49.3% of patients, respectively. Treatment-related serious toxicities were experienced by 18.4% of patients in the sunvozertinib arm vs 12.7% of those in the chemotherapy arm. TRAEs led to dose interruption and reduction or discontinuation in 45.4%, 40.5%, and 7.4% of patients, respectively, in the sunvozertinib arm; in the chemotherapy arm, these rates were 27.3%, 24.0%, and 11.3%, respectively.

“There were no TRAEs with fatal outcomes in the sunvozertinib arm,” Heymach said.

The most common TRAEs in the sunvozertinib arm were diarrhea (all grade, 84.0%; grade ≥ 3, 13.5%), increased blood creatine phosphokinase levels (55.2%; 20.2%), rash (51.5%; 0.6%), and paronychia (48.5%; 3.7%).

“[There were] many EGFR-related AEs,” Heymach concluded.

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. FDA. July 2, 2025. Accessed May 29, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sunvozertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20
3. Bazhenova LA. Dr Bazhenova on the FDA approval of sunvozertinib for EGFR-mutated NSCLC. OncLive.com. July 2, 2025. Accessed May 29, 2026. https://www.onclive.com/view/dr-bazhenova-on-the-fda-approval-of-sunvozertinib-for-egfr-mutated-mnsclc
4. Flaherty C. Sunvozertinib approval fills treatment gap in pretreated EGFR exon 20–mutant NSCLC. OncLive.com. September 26, 2025. Accessed May 29, 2026. https://www.onclive.com/view/sunvozertinib-approval-fills-treatment-gap-in-pretreated-egfr-exon-20-mutant-nsclc
5. Bazhenova LA. FDA approval insights: sunvozertinib in EGFR-mutated metastatic NSCLC: with Lyudmila Bazhenova, MD. OncLive.com. October 8, 2025. Accessed May 29, 2026. https://www.onclive.com/view/fda-approval-insights-sunvozertinib-in-egfr-mutated-metastatic-nsclc-with-lyudmila-bazhenova-md
6. Thermo Fisher’s NGS assay receives FDA approval as a companion diagnostic for Zegfrovy and for tumor profiling. Thermo Fisher. July 3, 2025. Accessed May 29, 2026. https://newsroom.thermofisher.com/newsroom/press-releases/press-release-details/2025/Thermo-Fishers-NGS-Assay-Receives-FDA-Approval-as-a-Companion-Diagnostic-for-ZEGFROVY-and-for-Tumor-Profiling/default.aspx
7. Ganti AK and Cushman-Vokoun A. FDA approval insights: Oncomine Dx Express test companion diagnostic for sunvozertinib in non–small cell lung cancer: with Apar Kishor Ganti, MD; and Allison Cushman-Vokoun, MD, PhD, FACP. OncLive.com. July 14, 2025. Accessed May 29, 2026. https://www.onclive.com/view/fda-approval-insights-oncomine-dx-express-test-companion-diagnostic-for-sunvozertinib-in-non-small-cell-lung-cancer-with-apar-kishor-ganti-md-and-allison-cushman-vokoun-md-phd-fcap