BioNTech's pivotal bispecifics plan take shape

Barely a month after BioNTech bought out China's Biotheus for $800m, the first two of three promised new phase 3 trials of the acquired company's lead bispecific, BNT327, have materialised. The studies, due to start this month and just revealed in clinicaltrials.gov listings, are BioNTech-sponsored and will be carried out globally.

The new trials are in first-line small-cell and non-small cell lung cancers, with triple-negative breast cancer still to come, according to the plan BioNTech disclosed when it was buying Biotheus. They show the BNT327 development strategy diverging from that of ivonescimab, a key rival that Summit licensed from Akeso before BioNTech's Biotheus move.

Both bispecific antibodies are at the forefront of investor interest; they both target PD-(L)1 and VEGF, and have spurred several licensing deals for similarly acting China-originated projects, most recently seeing Merck & Co pay $500m for LaNova's LM-299.

PD-L1 biomarker

In taking BNT327 into first-line NSCLC BioNTech is mirroring Summit's efforts with ivonescimab – up to a point. Both rival trials concern chemo combos, and use Keytruda plus chemo as active comparator but, while Summit's global Harmoni-3 trial mandates PD-L1 expression, BioNTech's makes no mention of such an inclusion criterion.

Moreover, Summit wants to double down on the PD-L1 biomarker, promising early next year to start Harmoni-7, a global trial testing ivonescimab in first-line NSCLC patients who express PD-L1 at a high level, presumably 50% or more.

A focus on NSCLC is understandable given ivonescimab's successes here, both in the front-line monotherapy study Harmoni-2, and in the post-EGFR inhibitor setting of Harmoni-A. These two Akeso-sponsored studies fuelled much of the enthusiasm behind this bispecific mechanism, though the data came with important caveats.

Before BioNTech bought Biotheus the Chinese group started a phase 2/3 trial of BNT327 in post-EGFR NSCLC, with a design mirroring that of Harmoni. However, like Harmoni this is a China-only study.

Similar but different: selected pivotal trials

Note: *Harmoni-7 (PD-L1-high) trial to start in early 2025. Source: OncologyPipeline.

In SCLC the new BioNTech study tackles the front line, pitting a BNT327 chemo combo head to head against standard-of-care Tecentriq plus chemo. This mirrors the earlier Chinese study already under way and originally sponsored by Biotheus, which additionally took BNT327 into a Chinese pivotal trial in second-line SCLC.

However, for its part Summit is showing little interest in SCLC. Some time ago Akeso said it was planning to take ivonescimab into phase 3 development in first-line SCLC, but by late 2022 that idea had been dropped. Akeso is also running Chinese trials of ivonescimab in first-line bile duct and head and neck cancers, where no late-stage work is under way with BNT327.

Conversely, the promised phase 3 study of BNT327 in triple-negative breast cancer is largely untrodden ground for ivonescimab, barring a phase 2 trial that showed promise at ESMO.