Astra starts a pivotal lung cancer combo

AstraZeneca’s second phase 3 trial of rilvegostomig, the anti-PD-1 x TIGIT bispecific underpinning much of the group’s next-generation immuno-oncology push, will test a combination with datopotamab deruxtecan.

The latter, a high-profile TROP2-targeting ADC licensed from Daiichi Sankyo, is awaiting monotherapy approvals in two settings, and is being tested in a further eight pivotal trials of its own. The newly revealed combo study, Tropion-Lung10, is notable for the fact its co-primary survival endpoints focus on TROP2-expressing patients, and for including a rilvegostomig monotherapy cohort.

The trial, specifically in front-line non-squamous NSCLC, will enrol only patients with high PD-L1 expression (on ≥50% of tumour cells), and uses Keytruda as the comparator. In PD-L1 ≥50% expressing first-line NSCLC the Merck & Co drug's registrational Keynote-024 study showed median OS of 26.3 months and median PFS of 7.7 months.

OS and PFS are the co-primary endpoint in Tropion-Lung10, but a straight cross-trial comparison isn't especially helpful as the Astra study's primary endpoints will look only at TROP2 biomarker-positive participants; The trial will enrol patients irrespective of their TROP2 expression status, and secondary efficacy metrics include OS and PFS in all-comers.

There has so far been mixed evidence about the relevance of TROP2 expression in various cancers. Last year’s ASCO saw some datasets of TROP2-targeting projects that retrospectively suggested at least some correlation between expression and efficacy, though few studies preselect for TROP2-positive disease, likely because expression levels tend to be relatively high anyway.

Alpha allocation?

With no publicly available statistical analysis plan to go on it’s hard to gauge the relative importance of Tropion-Lung10’s primary endpoints.

However, it seems likely that most of the alpha is allocated to the OS metric for the rilvegostomig plus dato-dxd combo versus Keytruda, with relatively little alpha spend being assigned to rilvegostomig monotherapy versus Keytruda. Rilvegostomig monotherapy represents a long shot, given previous studies adding TIGIT on top of PD-(L)1 blockade.

Astra had earlier highlighted rilvegostomig and the anti-PD-1 x CTLA-4 MAb volrustomig as two key bispecifics in its next wave of oncology projects, and the former started its first phase 3 trial last year. That study, Artemide-Biliary01, concerns the niche setting of cholangiocarcinoma, suggesting that Astra is seeking a relatively easy pathway to initial approval. 

Meanwhile, including Tropion-Lung10 dato-dxd is now in 11 phase 3 trials, two of which, Tropion-Lung01 and Tropion-Breast01, have been submitted for FDA approval. The first of those showed efficacy only in patients with non-squamous disease, a fact that might explain the histology being pursued in Tropion-Lung10.

Neither use has priority review at the FDA, however. The PDUFA dates are 20 December for the Lung01 indication and February 2025 for Breast01.

Phase 3 trials of datopotamab deruxtecan and rilvegostomig

Notes: *filed for US approval in non-squamous patients, 20 Dec 2024 PDUFA date; **filed for US approval, Feb 2024 PDUFA date. Source: OncologyPipeline.