The FDA has granted accelerated approval to Dizal Pharmaceuticals’ Zegfrovy (sunvozertinib) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations (Ex20Ins).
The approval specifically applies to patients whose disease has progressed on or after platinum-based chemotherapy.
This marks the approval of the first oral, targeted tyrosine kinase inhibitor (TKI) designed specifically for this rare and difficult-to-treat molecular subtype of NSCLC.
Zegfrovy is an oral, irreversible EGFR inhibitor engineered with a distinctive molecular structure that targets a broad range of EGFR mutations while maintaining selectivity for wild-type EGFR.
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The FDA based its decision on efficacy data from the Phase I/II WU-KONG1B trial, which enrolled 85 previously treated patients who received 200 mg of sunvozertinib once daily with food.
Results demonstrated a confirmed overall response rate (ORR) of 46%, as assessed by a blinded independent review committee using RECIST criteria.
In addition, the median duration of response (DOR) was 11.1 months, indicating that the drug not only shrank tumors in nearly half of the patients, but also delivered a meaningful duration of clinical benefit in this heavily pretreated population.
Results from the study were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and will be published in the Journal of Clinical Oncology, according to Dizal.
To support appropriate patient selection, the FDA also approved the Oncomine Dx Express Test as a companion diagnostic. Developed by Life Technologies, the next-generation sequencing test is designed to detect EGFR Ex20Ins and guide clinical decision-making regarding the use of sunvozertinib.
The FDA’s decision to grant accelerated approval was supported by previous designations of breakthrough therapy and priority review by both the FDA and China’s National Medical Products Administration (NMPA).
Zegfrovy received accelerated approval in China in August 2023.
“We are proud to have developed Zegfrovy, a first-in-class oral therapy that offers a more effective treatment option with enhanced safety and ease of administration for NSCLC patients with EGFR Ex20Ins,” said Dizal CEO Dr. Xiaolin Zhang in the press release announcing the approval. “The accelerated approval of Zegfrovy marks a significant milestone that underscores our commitment to developing groundbreaking new medicines for patients with high unmet medical needs around the world.”
Notably, sunvozertinib arrives at a time when other targeted agents for EGFR Ex20Ins mutations, such as Takeda’s Exkivity (mobocertinib), have been withdrawn from the US market.
Takeda withdrew Exkivity after its Phase III confirmatory trial, EXCLAIM-2, failed to meet the primary endpoint of progression-free survival, falling short of the data needed to validate its accelerated approval. As a result, Takeda voluntarily collaborated with the FDA to remove the drug, citing the need for reliable evidence of clinical benefit to support continued approval.
Janssen’s EGFR and MET-targeting bispecific antibody Rybrevant (amivantamab-vmjw) is the only other therapy approved for NSCLC with Ex20Ins mutations for adults with locally advanced or metastatic disease after progression on platinum-based chemotherapy. It was granted accelerated FDA approval in May 2021 and received full approval in 2023 following confirmatory trial data.
“As the world’s only approved targeted oral therapy for EGFR Ex20Ins NSCLC, Zegfrovy has expanded the treatment paradigm in this therapeutic area that has long lacked convenient and effective treatment options,” said Pasi A. Jänne, MD, PhD, Dana-Farber Cancer Institute of Harvard Medical School and lead principal investigator of WU-KONG1B.
“Research findings from WU-KONG1B have demonstrated Zegfrovy’s significant therapeutic effects with consistent efficacy across both Asian and non-Asian patient populations.”
She explained that the drug’s “convenient once-daily oral dosing substantially improves administration convenience and patient adherence, which is an increasingly critical factor as lung cancer care shifts toward chronic disease management.”
Dizal said it has completed enrollment in its global Phase III pivotal WU-KONG28 study, which is evaluating Zegrovy in the front-line setting, comparing it to platinum-based doublet chemotherapy in treatment-naïve NSCLC patients with EGFR Ex20Ins across 16 countries and regions.
At the 2023 ESMO Annual Meeting, Dizal reported that Zegfrovy achieved a 78.6% confirmed ORR and a median PFS of 12.4 months as a first-line oral treatment for EGFR Ex20Ins NSCLC.
There are currently no EGFR Ex20Ins-specific therapies approved in the first-line setting.
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