Dizal's US first; now what?

Four years after the then virtually unknown Chinese company Dizal burst onto the scene at ASCO with a tyrosine kinase inhibitor coded DZD9008, that drug has secured its first US approval. The setting in question is a lung cancer niche, NSCLC with exon 20 insertion in EGFR, and is the same indication for which the drug, now trademarked Zegfrovy, was approved in China in 2023.

That the US green light came at Dizal's first attempt is highly positive, as is the fact that the FDA hasn't deemed failure on Johnson & Johnson's Rybrevant to be a precondition of patients being prescribed Zegfrovy. However, since Dizal has no commercial US presence, Zegfrovy won't appear on pharmacy shelves in the absence of a licensing deal or some other partnering tie-up.

Dizal, which is listed on the Shanghai stock exchange and had once considered floating on Nasdaq, recently told ApexOnco that it was investigating various collaborations, but confirmed that without such a deal a formal launch couldn't take place.

Chemo progressed

For now the stage is set, with Zegfrovy being given a broad second-line label in exon 20 insertion NSCLC patients who have progressed on platinum chemo. Because the supporting WU-Kong1 part B study had included patients who had progressed additionally on Rybrevant, one risk was that the FDA might restrict approval to a post-Rybrevant subgroup.

Rybrevant has full approval in the exon 20 niche, either as monotherapy after platinum or in combination with chemo in the front line, yet despite this the FDA deemed it fit to greenlight Zegfrovy on an accelerated basis. However, Rybrevant is a bispecific antibody, targeting wild-type EGFR and c-Met, whereas Zegfrovy is a small molecule designed specifically to hit mutated EGFR.

Dizal is running the phase 3 WU-Kong28 study, which will serve as the confirmatory trial. However, even if full approval comes, exon 20 will remain a small setting, as suggested by Rybrevant's sales; the J&J drug's more important use is in NSCLC patients with sensitising/classical EGFR mutations, where its Lazcluze combo competes against AstraZeneca's Tagrisso in the front line.

Moreover, the history of developing small molecules against EGFR exon 20 insertion mutation isn't overwhelmingly positive. The only other targeted drug to be approved here, Takeda's Exkivity, was marred by toxicity and ended up being pulled after failing its confirmatory trial; in addition there have been notable discontinuations in mid-stage development.

There is one other hopeful waiting in the wings, however, namely Otsuka's zipalertinib. That project was once licensed to Cullinan before being bought back, and is expected to be filed for accelerated US approval in the second half of this year, based on a 35% ORR among 176 patients in the Rezilient-1 study, last updated at ASCO.

It's notable that Dizal had designed sunvozertinib, Zegfrovy's active ingredient, to act broadly against EGFR mutations, and the company claims activity in sensitising as well as resistance (T790M) and uncommon mutations. It's possible that it sees exon 20 as a first rung on the ladder, but even here it has some way to go before it cracks the US.

Selected small-molecule EGFR exon 20 insertion inhibitors

Source: OncologyPipeline.