EGFR exon 20 insertions account for roughly 12% of EGFR‑mutant non-small cell lung cancer (NSCLC) cases. More than 100 distinct variants have been reported, making this a heterogeneous disease with a generally poor prognosis and historically limited treatment options.
The currently approved first-line treatment options for advanced NSCLC with EGFR exon 20 insertions include platinum‑containing doublet chemotherapy, with or without amivantamab. However, no EGFR tyrosine kinase inhibitor (TKI) has been approved for this patient population in the first‑line setting to date.
Sunvozertinib is an oral, potent, and selective EGFR TKI designed to target EGFR exon 20 insertions and other EGFR mutations, demonstrating selectivity over wild‑type EGFR. It is the only EGFR TKI approved by the US Food and Drug Administration (FDA) for the treatment of EGFR exon 20 insertion-positive NSCLC following platinum-based chemotherapy.
The WU‑KONG28 trial evaluated sunvozertinib versus standard platinum-based chemotherapy as initial systemic therapy in this patient population.
John V. Heymach, MD, PhD, Chair of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center, presented results from the primary analysis at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
Study Design
The phase III trial enrolled 324 patients who were randomly assigned in a 1:1 ratio to receive either sunvozertinib at 300 mg orally once daily or standard platinum-based chemotherapy administered intravenously every three weeks for up to six cycles, followed by standard pemetrexed maintenance therapy.
Crossover to sunvozertinib was permitted for patients in the chemotherapy cohort with confirmed progressive disease. Key eligibility criteria included confirmed EGFR exon 20 insertions, no prior systemic therapy for metastatic disease, and an ECOG performance status of 0 or 1.
The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review (BICR). Key secondary endpoints included overall survival (OS), objective response rate (ORR), and duration of response (DoR).
An additional key secondary endpoint was PFS2, defined as the time from randomization to objective tumor progression on next-line therapy, as assessed by investigators, or to death from any cause.
Baseline characteristics were generally well balanced among patients. However, the sunvozertinib group included fewer females, fewer patients with no smoking history, and fewer patients with oligometastatic disease compared to the chemotherapy cohort.
Results
WU-KONG28 met its primary endpoint, demonstrating a statistically significant improvement in PFS, with a median of 10.3 months versus 7.5 months with chemotherapy.
This PFS benefit was consistent across major subgroups, specifically in patients who were Asian, those with near-loop insertions, and patients without brain metastases. The BICR-assessed tumor response also favored sunvozertinib over chemotherapy, demonstrating higher ORR, greater tumor shrinkage, and longer DoR.
“The confirmed ORR for sunvozertinib was 58.9%, compared to 31.1% for chemotherapy. The median tumor shrinkage for sunvozertinib was 42.1%, versus 24.7% with chemotherapy,” Dr. Heymach said. “The odds ratio for response was 3.2, favoring sunvozertinib, and the DoR was 11.2 months with sunvozertinib, as compared to 7.1 months for chemotherapy.”
The key secondary endpoint—PFS2—also favored sunvozertinib over chemotherapy (median PFS2: 21.7 months vs. 15.5 months), indicating a potential long-term survival benefit, he said.
The number of patients experiencing treatment-related adverse events (TRAEs) of any grade was similar between the treatment arms (100% with sunvozertinib vs. 97.3% with chemotherapy). Grade 3 or higher TRAEs were observed in 61.3% of patients receiving sunvozertinib, compared with 49.3% of those treated with chemotherapy.
Sunvozertinib was associated with a higher incidence of TRAEs leading to dose reduction compared with chemotherapy (40.5% vs. 24%). However, Dr. Heymach said dose discontinuation was relatively rare in the sunvozertinib group, occurring in 7.4% of patients, compared with 11.3% in the chemotherapy group.
The most common TRAEs, occurring in more than 20% of patients, were diarrhea, elevated creatine phosphokinase levels, rash, and paronychia. Dr. Heymach noted that these were largely associated with EGFR-wild-type inhibition. Additionally, no fatal TRAEs were reported in the sunvozertinib group.
“These results support sunvozertinib as a first-line treatment for patients with NSCLC harboring EGFR exon 20 insertions, offering the advantage of a single oral agent administration,” Dr. Heymach said.
