ASCO-GI – Astellas makes a case for its Vyloy triplet

Astellas has used ASCO's Gastrointestinal Cancers symposium to make a clear case for why it is betting on a Vyloy-based triplet with immunotherapy in first-line gastric cancer. In a late-breaking presentation on Thursday the company unveiled fresh phase 2 data helping explain the launch of its Lucerna phase 3 trial.

The data came from the Ilustro study, where patients with first-line Claudin18.2-positive gastric cancer were given Vyloy alongside Opdivo and chemotherapy, and where those with the highest Claudin18.2 expression (≥75%) yielded median progression-free survival of 18 months. This looks better than the eight to 10-month median PFS on the back of which a Vyloy/chemo doublet is approved in this patient population.

Of course, that's a cross-trial comparison, but the Ilustro data do back taking the triplet into phase 3. The ASCO-GI data concerned cohort 4 of Ilustro, where 77 patients enrolled across 4a, a safety lead-in, and 4b were treated. In the overall population the triplet achieved a median PFS of 12.9 months, rising to 14.8 months among those with high Claudin18.2.

Cohort 4b data appeared stronger. In 59 patients with ≥75% Claudin18.2 expression treated with the selected dose of Vyloy, median PFS hit 18.0 months. This looks favourable versus prior phase studies of Vyloy plus chemotherapy: in the Glow and Spotlight trials, which support the approval of Vyloy plus chemo in the same indication, median PFS was reported at 8.2 months and 10.6 months respectively.

PD-L1 expression

Astellas also highlighted a striking signal in PD-L1 expressers. In the 31 patients with high Claudin18.2 and a PD-L1 expression level of at least 1%, the median PFS reached 23.6 months. This helps to explain the design of Lucerna, which started last year, and which mandates that patients' tumours be Claudin18.2 ≥75% and PD-L1 ≥1% espressing.

Meanwhile, the Keynote-859 trial of Keytruda plus chemo, the regimen that is being used in the Lucerna trial as the control arm, yielded a median PFS of 6.9 months in patients with PD-L1 ≥1% expression, although of course that study did not stratify patients by Claudin18.2 expression. 

The take-home message from the Lucerna study's design, and the new Ilustro data, is that Astellas wants the use the triplet approach to improve on Vyloy's efficacy in a narrower patient population than the drug's currently approved use, rather than to expand its reach into those with lower levels of Claudin18.2 expression.

That's relevant because Vyloy is only one piece of the company's broader strategy in gastric cancer. Astellas is already lining up a phase 3 trial of an anti-Claudin18.2 T-cell engager, ASP2138, developed in a partnership with Xencor in first-line gastric cancer. The study aims to combine a triple combination of ASP2138 with a PD-(L)1 inhibitor and chemo, and could kick off in the second half of 2026. 

It's the T-cell engager that Astellas believes might work in patients with lower Claudin18.2 expression than those currently eligible for Vyloy.

In parallel, Astellas is advancing ASP546C, an antibody-drug conjugate originally resulting from a collaboration between Evopoint and MediLink. Evopoint licensed the asset to Astellas outside China last May, shortly before ASCO poster data from a Chinese phase 1/2 study showed a 51% overall response rate across three dose levels in relapsed gastric cancer. 

Evopoint has since initiated a phase 3 trial in China, while Astellas aims to begin a bridging study in Western populations in early 2026.

Selected Vyloy data in first-line, HER2-negative, Claudin18.2-high (≥75%) gastric cancer

Notes: *high Claudin18.2 expressers were a subgroup, as the trial enrolled patients with Claudin18.2 levels down to 50%; **Claudin ≥75% and PD-L1 ≥1% expressers. Source: OncologyPipeline.