Zegfrovy May Offer New First-Line Option for Patients With EGFR-Mutated Lung Cancer

Patients with advanced non-small cell lung cancer (NSCLC) that carries an EGFR exon 20 insertion mutation lived longer without their cancer worsening when treated with Zegfrovy (sunvozertinib) compared with standard chemotherapy, according to findings from the phase 3 WU-KONG28 trial presented at the 2026 ASCO Annual Meeting.

The study showed that patients who received Zegfrovy went a median of 10.3 months before their disease worsened, compared with 7.5 months for patients treated with chemotherapy. Patients receiving Zegfrovy were also more likely to see their tumors shrink, and those responses lasted longer than those seen with chemotherapy.

Presenting the findings, Dr. John V. Heymach, chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, said the trial achieved its main goal.

“WU-KONG28 met its primary endpoint with a statistically significant and clinically meaningful PFS improvement with [Zegfrovy] sunvozertinib,” Heymach said. “There was also an improved objective response rate and prolonged duration of response with [Zegfrovy].”

What Are EGFR Exon 20 Insertion Mutations?

EGFR exon 20 insertion mutations are uncommon genetic changes found in a small percentage of patients with NSCLC. These mutations account for about 12% of all EGFR-mutated lung cancers. They can be more difficult to treat because many EGFR-targeted therapies that work well for other EGFR mutations are less effective against exon 20 insertion mutations.

According to Heymach, more than 100 different exon 20 insertion mutations have been identified, making this a complex group of cancers.

Currently, patients with newly diagnosed advanced EGFR exon 20-mutated NSCLC are often treated with platinum-based chemotherapy, with or without Rybrevant (amivantamab-vmjw). Although Zegfrovy is already approved by the FDA after platinum-based chemotherapy, no EGFR-targeted pill is currently approved as an initial treatment for these patients.

More Patients Saw Their Tumors Shrink With Zegfrovy

The WU-KONG28 trial enrolled 324 patients with advanced or metastatic EGFR exon 20-mutated NSCLC who had not received prior treatment for metastatic disease. Patients were randomly assigned to receive either oral Zegfrovy once daily or platinum-based chemotherapy.

In addition to helping patients live longer without their cancer worsening, Zegfrovy improved tumor response rates.

Nearly 59% of patients treated with Zegfrovy experienced tumor shrinkage compared with about 31% of patients who received chemotherapy. Researchers also found that tumors shrank more with Zegfrovy than with chemotherapy.

Patients whose tumors responded to treatment also tended to remain in response longer. The median duration of response was 11.2 months with Zegfrovy compared with 7.1 months with chemotherapy.

“These results support Zegfrovy as first-line treatment for NSCLC patients with EGFR exon 20 insertions with the advantage of a single oral agent administration,” Heymach said.

Could the Benefits Last Beyond Initial Treatment?

Researchers also looked at how long patients lived before their cancer worsened a second time or they died. This measurement, known as PFS2, can provide insight into whether a treatment continues to benefit patients even after they move on to another therapy.

Patients who started treatment with Zegfrovy went longer before reaching that point than patients who started with chemotherapy. Median PFS2 was 21.7 months with Zegfrovy compared with 15.5 months with chemotherapy.

“The OS data were immature, but the PFS2 suggested a possible long-term survival benefit with [Zegfrovy],” Heymach said.

Researchers are still following patients to determine whether Zegfrovy helps patients live longer overall.

At the time of the analysis, overall survival data were not yet mature. It may also be difficult to see a survival difference because many patients who initially received chemotherapy later switched to Zegfrovy after their cancer progressed. More than 90% of eligible patients in the chemotherapy group eventually received the targeted therapy.

What Side Effects Were Reported?

According to investigators, the safety findings were consistent with previous studies of Zegfrovy.

“The safety profile was similar to what had been seen in previous reports and was manageable with no new safety signals,” Heymach said.

Serious treatment-related side effects were more common with zegfrovy than with chemotherapy. However, fewer patients stopped treatment because of side effects in the Zegfrovy group.

The most common side effects reported with Zegfrovy included diarrhea, elevated creatine phosphokinase levels, rash and paronychia, an infection or inflammation around the fingernails or toenails.

Severe diarrhea occurred in 13.5% of patients, while severe elevations in creatine phosphokinase levels occurred in 20.2%. Only one patient experienced severe rash. No treatment-related deaths were reported among patients who received Zegfrovy.

What the Findings Mean for Patients

For patients with EGFR exon 20-mutated NSCLC, treatment options have historically been more limited than those available for patients with more common EGFR mutations.

The WU-KONG28 results suggest that starting treatment with Zegfrovy may help patients delay disease progression and improve the likelihood of tumor shrinkage compared with chemotherapy alone. Because the drug is taken by mouth, it may also offer a more convenient treatment option for some patients.

Researchers will continue following patients to better understand whether these benefits lead to longer overall survival. However, the findings establish Zegfrovy as a potential new first-line treatment option for patients with advanced EGFR exon 20-mutated NSCLC.

References

1. 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). John V. Heymach . Presented at the 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL.
2. First-Line Sunvozertinib in NSCLC With EGFR Exon 20 Insertions. John V. Heymach et al. New England Journal of Medicine. Published May 2026.

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