Frank Vinluan , 2025-07-03 23:57:00
One of the more competitive targets in lung cancer is a certain mutation that has eluded many available targeted therapies. A drug developed by Dizal Pharmaceutical has received FDA approval for treating patients whose disease exhibits this genetic signature, giving the Shanghai-based company its first U.S. product along with the opportunity to show differentiation from therapies generated by the labs of some big pharmaceutical companies.
Dizal’s drug was developed for treating non-small cell lung cancer (NSCLC) that carries an exon 20 insertion mutation in the EGFR gene. That genetic signature must be identified by a Thermo Fisher Scientific companion diagnostic. The FDA approved both late Wednesday. Treatment with Dizal’s once-daily pill is approved for patients whose disease has progressed during or after treatment with chemotherapy. The drug, known in development as sunvozertinib, will be commercialized under the brand name Zegfrovy.
EGFR plays a key role in cellular processes in the body, but mutations to this protein can lead to the uncontrolled proliferation of cells that drive cancer. The top-selling EGFR inhibitor is AstraZeneca’s Tagrisso, an oral small molecule. But this blockbuster cancer drug has not been effective against EGFR exon 20 insertion mutations. Dizal CEO Xiaolin Zhang knows firsthand. Before founding Dizal in 2017, his 20-year career at AstraZeneca included working on Tagrisso.
Exon 20 insertion mutations stem from the insertion of genetic material into the EGFR gene. Zhang said one way AstraZeneca tried to drug this target was to use higher doses of Tagrisso. While tests of this approach showed some activity, it also led to unacceptable toxicity. The challenge for drugging the exon 20 insertion mutation is that it’s not a single mutation. Zhang said the insertions can happen in many ways and research has revealed more than 120 types of this mutation, each one depending on the position of the gene and the size of the insertion.
“One of the biggest challenges designing a molecule is that is it flexible enough to fit, to be able to inhibit all these different type of insertional mutations?” he said in an interview at the 2025 annual meeting of the American Society of Clinical Oncology. “But also, you don’t want your compound too floppy that it is not stable enough. That is the key challenge.”
Zegfrovy was internally discovered and developed by Dizal scientists, who designed the small molecule to target a wide range of EGFR mutations — not just exon 20 insertion mutations. Another key property of the drug: It’s selective to mutant versions of EGFR protein. An antibody can only addresses the outside of its target. The problem is that the extracellular region of EGFR is the same for both normal EGFR and mutant forms. That means an antibody intended to drug mutant EGFR can also affect normal EGFR, sparking adverse effects elsewhere in the body, Zhang said.
The FDA decision for Zegfrovy is an accelerated approval based on results from an open-label Phase 2 study. In the efficacy population of 85 patients, results showed the overall response rate was 46% and the duration of response was 11.1 months. A confirmatory Phase 3 study has completed enrollment. Zhang said this global study could support use of Zegfrovy as a first-line treatment for eligible NSCLC patients. Dizal aims to file an FDA application seeking to expand the drug’s label early next year.
The first drug for NSCLC driven by EGFR exon 20 insertion mutations was Johnson & Johnson’s Rybrevant, which received accelerated approval in 2021 as a second-line treatment. This bispecific antibody blocks EGFR and a second receptor called MET, both of which are overexpressed on the surface of surface of NSCLC cells. Last year, the FDA approved Rybrevant for first-line use in this type of cancer, converting the drug’s status to full approval.
Rybrevant is administered as an intravenous infusion that can take up to five hours. Dizal is one of several drug companies working to develop more convenient oral small molecules for the target. Takeda Pharmaceutical was first to secure accelerated FDA approval for an oral drug for EGFR exon 20 insertion mutations, a regulatory decision that came months after Rybrevant’s accelerated approval. But this drug, Exkivity, went on to fail its confirmatory Phase 3 study. Takeda voluntarily withdrew Exkivity from the market in 2023. Spectrum Pharmaceuticals did not even get that far. The FDA turned down Spectrum’s oral small molecule, poziotinib, in 2022.
There are other companies developing oral small molecules for exon 20 insertion mutations. During the ASCO meeting, Cullinan Therapeutics said it plans an FDA submission in the second half of this year for zipalertinib. Similar to Dizal, Cullinan executives say their drug is more selective to mutant EGFR. ArriVent BioPharma has reached late-stage clinical development with its oral small molecule, firmonertinib. ArriVent has said its drug can stand apart with brain-penetrating properties that enable it to treat NSCLC that has metastasized to the brain.
“There are a few others behind us, but for second-line [treatment of EGFR exon 20-mutated NSCLC], we are the leader,” Zhang said.
Compared to Rybrevant, Zhang said the oral small molecule formulation of Zegfrovy gives it safety and tolerability advantages. Even so, the FDA noted that warnings for the Dizal drug include interstitial lung disease and lung inflammation; gastrointestinal problems; skin reactions; and eye toxicity. The drug is already commercially available in China, where it was approved in 2023.
As for U.S .commercialization of Zegfrovy, Zhang said his company has had discussions with potential partners. He noted that Dizal already has commercial infrastructure in China, and commercialization strategies differ between the East and West. In the U.S., many biotech companies are single-asset companies whose goal is to out-license the drug or be acquired outright by a big pharmaceutical company. In China, the expectation is that a biotech company goes from discovery to commercialization. Dizal has a second commercialized cancer drug in China and a pipeline spanning oncology and immunology.
“We do have a commercial organization in China doing very well but, [in the] U.S. and Europe, gradually we are going to build our commercial presence because we have multiple assets and in the next few years we are going to have three to five assets approved,” Zhang said.
Illustration: Mohammed Haneefa Nizamudeen, Getty Images
