Avistone’s Met challenge

Met overexpression is having a moment with the recent FDA approval of AbbVie’s Met-targeting ADC Emrelis, but China’s Avistone is looking at a new Met-amplified niche. While AbbVie has focused on EGFR wild-type NSCLC, Avistone is starting a Chinese phase 3 of its EGFR exon 20 inhibitor andamertinib in second-line EGFR-mutant NSCLC with Met amplification and/or overexpression.

As such, Avistone looks to be targeting a population encompassed by Johnson & Johnson’s anti-EGFR x Met MAb Rybrevant, which has US approval across EGFRm disease more broadly. Avistone is taking a mechanistically similar approach, combining andamertinib with the Met inhibitor vebreltinib – but the new study will compare this against chemo rather than Rybrevant. Presumably Rybrevant isn’t widely established in China.

EGFRm, Met overexpressed

Avistone’s phase 3, slated to begin in May, will enrol patients with EGFR-mutant, Met-amplified or overexpressed NSCLC, who have progressed following an EGFR tyrosine kinase inhibitor like AstraZeneca’s Tagrisso.

The study will test andamertinib plus vebreltinib versus pemetrexed plus cisplatin or carboplatin, with progression-free survival as the primary endpoint.

In a phase 1/2 Chinese study in a similar population, the combo produced an overall response rate of 59% among 32 evaluable patients, according to data presented at last year's World Lung meeting. That trial will also feature in a poster presentation at this year’s ASCO conference.

The figure isn’t dissimilar to what Rybrevant, plus the oral EGFR-TKI Lazcluze, has shown in post-TKI patients with EGFR mutation and Met overexpression. In the Chrysalis-2 trial, J&J has reported an ORR of 61% in this population. The usual caveats about cross-trial comparisons apply, and are complicated here by the addition of Lazcluze.

Indeed, Rybrevant is only approved in the broad EGFRm setting in combinations – with Lazcluze in first-line disease, and with chemo in the second line. 

As monotherapy, the J&J drug is approved for second-line NSCLC with EGFR exon 20 insertion mutations – a smaller niche that has presumably negligible revenues, given that the company has only given sales figures for the Lazcluze combo.

While Rybrevant is establishing itself, various other projects targeting exon 20 insertions have exited, including Takeda’s Exkivity, Spectrum’s poziotinib and Rain Oncology’s tarloxotinib. However, others are still targeting this niche, including Dizal and Otsuka’s Taiho subsidiary, with sunvozertinib and zipalertinib respectively. 

Both of those groups are also targeting first-line disease, with global phase 3s ongoing: WU-Kong28 for Dizal and Rezilient-3 for Taiho. But, again, these are focused on exon 20 insertion mutations. 

Avistone could have a chance to set itself apart from the pack.

EGFR inhibitors with exon20 activity in clinical development

Source: OncologyPipeline.