Sunvozertinib Improves PFS Over Chemotherapy in First-Line EGFR Exon 20–Mutant NSCLC

July 28, 2026 | Kyle Doherty

EGFR exon 20 insertions account for approximately 12% of EGFR mutations in non–small cell lung cancer (NSCLC), with more than 100 distinct variants described across the C-helix and the loop region following the C-helix, and historically limited efficacy with first-, second-, and third-generation EGFR TKIs, according to a presentation by Pasi A. Jänne, MD, PhD, during the 27th Annual International Lung Cancer Congress.¹

“In general, 2 strategies are being used here: We have antibodies that bind the extracellular domain of EGFR, and then exon 20–directed TKIs,” Jänne, the senior vice president for translational medicine, the director of the Belfer Center for Applied Cancer Science, the director of the Chen-Huang Center for EGFR Mutant Lung Cancers, senior physician, and the David M. Livingston, MD, Chair at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School in Boston, Massachusetts, said during the presentation.

During the presentation, Jänne reviewed the current standard of care for this population and new data across several classes of agents in development, including the phase 3 WU-KONG28 study (NCT05668988) of sunvozertinib (Zegfrovy), the REZILIENT program evaluating zipalertinib (CLN-081), ongoing trials of firmonertinib, enozertinib (ORIC-114), and STX-721, and early data with antibody-drug conjugates (ADCs) in this population.

What is the current standard of care for EGFR exon 20 insertion–mutant NSCLC?

The current first-line standard of care for EGFR exon 20 insertion–mutant NSCLC is platinum-based chemotherapy plus pemetrexed and amivantamab-vmjw (Rybrevant), which has demonstrated an overall response rate (ORR) of 73% and a median progression-free survival (PFS) of 11.4 months. In the second-line setting, amivantamab monotherapy has shown an ORR of 40% and a PFS of 8.3 months, while sunvozertinib has shown an ORR of 46% and a PFS ranging from 11.1 to 13.8 months across studies.

Jänne noted that each option carries distinct challenges. Amivantamab requires intravenous infusion and is associated with skin toxicity and infusion reactions, while sunvozertinib is associated with gastrointestinal toxicity and a lack of availability in the United States despite FDA approval, with a different approved dose in the United States than in China.

What Did the WU-KONG28 Trial Show for First-Line Sunvozertinib?

WU-KONG28 evaluated first-line sunvozertinib monotherapy at 300 mg once daily vs platinum-based chemotherapy every 3 weeks for up to 6 cycles, followed by pemetrexed maintenance in patients with cytologically or histologically confirmed locally advanced or metastatic nonsquamous NSCLC with documented EGFR exon 20 insertions.² Patients were randomly assigned 1:1 to sunvozertinib or chemotherapy and were stratified by baseline brain metastasis status. Patients on the chemotherapy arm were permitted to cross over to sunvozertinib upon blinded independent central review (BICR)–confirmed disease progression.

The primary end point was PFS by BICR, with overall survival (OS), investigator-assessed PFS, ORR, disease control rate (DCR), duration of response (DOR), tumor size change, safety, and pharmacokinetics as secondary end points.

The median PFS was 10.3 months (95% CI, 8.3-14.0) with sunvozertinib (n = 163) vs 7.5 months (95% CI, 6.7-8.5) with chemotherapy (n = 161; HR, 0.65; 95% CI, 0.50-0.85; P = .0008). The best ORR was 68.1% (95% CI, 60.4%-75.2%) with sunvozertinib vs 35.4% (95% CI, 28.0%-43.3%) with chemotherapy. The confirmed ORR was 58.9% (95% CI, 50.9%-66.5%) and 31.1% (95% CI, 24.0%-38.8), respectively (OR, 3.2; 95% CI, 2.0-5.0; P < .0001).

The DCR was 94.5% (95% CI, 89.8%-97.4%) with sunvozertinib vs 85.7% (95% CI, 79.3%-90.7%) with chemotherapy. At an interim analysis with 38.9% OS maturity and 90% crossover to sunvozertinib among patients in the chemotherapy arm, median OS was 29.8 months (95% CI, 21.8-not estimable [NE]) with sunvozertinib vs 28.8 months (95% CI, 20.7-NE) with chemotherapy.

Any-grade treatment-related adverse effects (TRAEs) with sunvozertinib included diarrhea (84.0%; grade ≥3, 13.5%), increased blood creatine phosphokinase (55.2%; grade ≥3, 20.2%), rash (51.5%; grade ≥3, 0.6%), and paronychia (48.5%; grade ≥3, 3.7%). Any-grade TRAEs in the chemotherapy arm included diarrhea (10.0%), increased blood creatine phosphokinase (3.3%), rash (5.3%), and paronychia (0%).

What Other Agents Are in Development for This Population?

In REZILIENT1, zipalertinib (CLN-081) displayed an ORR of 35% to 40% in patients who received prior platinum-based chemotherapy, 30% in those treated with prior amivantamab without another exon 20–targeted therapy, and 14% in those with prior exposure to amivantamab and another exon 20–targeted agent.¹ Based on REZILIENT1, zipalertinib’s new drug application (NDA) was accepted by the FDA, with a Prescription Drug User Fee Act date of February 27, 2027. The phase 3 REZILIENT3 study (NCT05973773) is evaluating zipalertinib plus pemetrexed and carboplatin or cisplatin vs pemetrexed and carboplatin or cisplatin alone in the first-line setting.

Firmonertinib, a third-generation, brain-penetrant, mutant-selective TKI, has shown early ORRs of 70% to 79% in small first-line cohorts. Firmonertinib received FDA breakthrough therapy designation for the first-line setting in October 2023 and is approved in a later line in China.

Enozertinib (ORIC-114) has shown an ORR of 67% across multiple phase 2 cohorts in the second-line-plus setting, including patients with central nervous system metastases, with additional data expected in mid-2026. STX-721, a covalent, mutant-selective EGFR/HER2 TKI, has shown an ORR of 54% in an ongoing first-in-human phase 1 dose-escalation study (NCT06043817) in the second-line-plus setting.

What role might ADCs play in this population?

Early data with ADCs have also emerged in EGFR exon 20–mutant and other nonclassical EGFR-mutant NSCLC. Izalontamab brengitecan (iza-bren) has shown an ORR of 69.2% in patients with EGFR exon 20 insertions or other nonclassical EGFR mutations, while sacituzumab tirumotecan (sac-TMT) has shown an ORR of 36.8% in patients with EGFR exon 20 insertions.^4,5

“[We should] not dismiss that ADCs would have activity in this patient population, and as more of these become available, I think they are appropriate treatment options further down the line,” Jänne concluded.

References

Jänne PA. Evolving treatment landscape for EGFR exon 20 insertions. Presented at: 27th Annual International Lung Cancer Congress; July 24-25, 2026; Huntington Beach, CA.

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

Zhou C, Xiong A, Yao W, et al. Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (P) versus pembrolizumab (P) as first-line treatment for PD-L1–positive advanced non-small cell lung cancer (NSCLC): results from the randomized phase 3 OptiTROP-Lung05 study. J Clin Oncol. 2026;44(suppl 16):8506. doi:10.1200/JCO.2026.44.16_suppl.8506

Wu J, Zhang J, Ouyang O, et al. Izalontamab brengitecan (iza-bren) versus physician’s choice of chemotherapy in patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC): a randomized phase III study. J Clin Oncol. 2026;44(suppl 17):LBA1003. doi:10.1200/JCO.2026.44.17_suppl.LBA1003

Sidebar: Sunvozertinib Moves the Needle in First-Line EGFR Exon 20–Mutant NSCLC

• In the phase 3 WU-KONG28 trial, sunvozertinib nearly doubled confirmed ORR vs chemotherapy (58.9% vs 31.1%) and significantly improved PFS (10.3 vs 7.5 months; HR, 0.65; P = .0008), positioning it as a potential new first-line option.
• Backed by REZILIENT1 data, the NDA for zipalertinib has been accepted with a PDUFA date of February 27, 2027, while firmonertinib (78.6% ORR in early first-line cohorts) advances through the phase 3 FURVENT/FURMO-004 trial.
• First-line platinum/pemetrexed/amivantamab remains effective but requires IV infusion and carries skin-toxicity and infusion-reaction risk, while second-line sunvozertinib causes GI toxicity and a US access gap despite FDA approval.