One of many extra aggressive targets in lung most cancers is a sure mutation that has eluded many obtainable focused therapies. A drug developed by Dizal Pharmaceutical has obtained FDA approval for treating sufferers whose illness displays this genetic signature, giving the Shanghai-based firm its first U.S. product together with the chance to indicate differentiation from therapies generated by the labs of some large pharmaceutical firms.
Dizal’s drug was developed for treating non-small cell lung most cancers (NSCLC) that carries an exon 20 insertion mutation within the EGFR gene. That genetic signature have to be recognized by a Thermo Fisher Scientific companion diagnostic. The FDA accredited each late Wednesday. Therapy with Dizal’s once-daily capsule is accredited for sufferers whose illness has progressed throughout or after remedy with chemotherapy. The drug, identified in growth as sunvozertinib, will probably be commercialized below the model title Zegfrovy.
EGFR performs a key position in mobile processes within the physique, however mutations to this protein can result in the uncontrolled proliferation of cells that drive most cancers. The highest-selling EGFR inhibitor is AstraZeneca’s Tagrisso, an oral small molecule. However this blockbuster most cancers drug has not been efficient in opposition to EGFR exon 20 insertion mutations. Dizal CEO Xiaolin Zhang is aware of firsthand. Earlier than founding Dizal in 2017, his 20-year profession at AstraZeneca included engaged on Tagrisso.
Exon 20 insertion mutations stem from the insertion of genetic materials into the EGFR gene. Zhang mentioned a method AstraZeneca tried to drug this goal was to make use of increased doses of Tagrisso. Whereas exams of this method confirmed some exercise, it additionally led to unacceptable toxicity. The problem for drugging the exon 20 insertion mutation is that it’s not a single mutation. Zhang mentioned the insertions can occur in some ways and analysis has revealed greater than 120 sorts of this mutation, each relying on the place of the gene and the scale of the insertion.
“One of many greatest challenges designing a molecule is that’s it versatile sufficient to suit, to have the ability to inhibit all these totally different kind of insertional mutations?” he mentioned in an interview on the 2025 annual assembly of the American Society of Medical Oncology. “But additionally, you don’t need your compound too floppy that it’s not secure sufficient. That’s the key problem.”
Zegfrovy was internally found and developed by Dizal scientists, who designed the small molecule to focus on a variety of EGFR mutations — not simply exon 20 insertion mutations. One other key property of the drug: It’s selective to mutant variations of EGFR protein. An antibody can solely addresses the skin of its goal. The issue is that the extracellular area of EGFR is identical for each regular EGFR and mutant kinds. Which means an antibody meant to drug mutant EGFR can even have an effect on regular EGFR, sparking antagonistic results elsewhere within the physique, Zhang mentioned.
The FDA resolution for Zegfrovy is an accelerated approval based mostly on outcomes from an open-label Section 2 research. Within the efficacy inhabitants of 85 sufferers, outcomes confirmed the general response price was 46% and the length of response was 11.1 months. A confirmatory Section 3 research has accomplished enrollment. Zhang mentioned this international research might help use of Zegfrovy as a first-line remedy for eligible NSCLC sufferers. Dizal goals to file an FDA software looking for to develop the drug’s label early subsequent yr.
The primary drug for NSCLC pushed by EGFR exon 20 insertion mutations was Johnson & Johnson’s Rybrevant, which obtained accelerated approval in 2021 as a second-line remedy. This bispecific antibody blocks EGFR and a second receptor referred to as MET, each of that are overexpressed on the floor of floor of NSCLC cells. Final yr, the FDA accredited Rybrevant for first-line use in this kind of most cancers, changing the drug’s standing to full approval.
Rybrevant is run as an intravenous infusion that may take as much as 5 hours. Dizal is one in all a number of drug firms working to develop extra handy oral small molecules for the goal. Takeda Pharmaceutical was first to safe accelerated FDA approval for an oral drug for EGFR exon 20 insertion mutations, a regulatory resolution that got here months after Rybrevant’s accelerated approval. However this drug, Exkivity, went on to fail its confirmatory Section 3 research. Takeda voluntarily withdrew Exkivity from the market in 2023. Spectrum Prescription drugs didn’t even get that far. The FDA turned down Spectrum’s oral small molecule, poziotinib, in 2022.
There are different firms creating oral small molecules for exon 20 insertion mutations. In the course of the ASCO assembly, Cullinan Therapeutics mentioned it plans an FDA submission within the second half of this yr for zipalertinib. Just like Dizal, Cullinan executives say their drug is extra selective to mutant EGFR. ArriVent BioPharma has reached late-stage scientific growth with its oral small molecule, firmonertinib. ArriVent has mentioned its drug can stand aside with brain-penetrating properties that allow it to deal with NSCLC that has metastasized to the mind.
“There are just a few others behind us, however for second-line [treatment of EGFR exon 20-mutated NSCLC], we’re the chief,” Zhang mentioned.
In comparison with Rybrevant, Zhang mentioned the oral small molecule formulation of Zegfrovy offers it security and tolerability benefits. Even so, the FDA famous that warnings for the Dizal drug embrace interstitial lung illness and lung irritation; gastrointestinal issues; pores and skin reactions; and eye toxicity. The drug is already commercially obtainable in China, the place it was accredited in 2023.
As for U.S .commercialization of Zegfrovy, Zhang mentioned his firm has had discussions with potential companions. He famous that Dizal already has business infrastructure in China, and commercialization methods differ between the East and West. Within the U.S., many biotech firms are single-asset firms whose purpose is to out-license the drug or be acquired outright by an enormous pharmaceutical firm. In China, the expectation is {that a} biotech firm goes from discovery to commercialization. Dizal has a second commercialized most cancers drug in China and a pipeline spanning oncology and immunology.
“We do have a business group in China doing very effectively however, [in the] U.S. and Europe, progressively we’re going to construct our business presence as a result of now we have a number of belongings and within the subsequent few years we’re going to have three to 5 belongings accredited,” Zhang mentioned.
Illustration: Mohammed Haneefa Nizamudeen, Getty Photographs
