In triple-negative pumitamig concedes PD-L1-high disease

BioNTech is moving ahead with its long-planned phase 3 trial of the anti-PD-L1 x VEGF project pumitamig in triple-negative breast cancer, but will focus only on patients deemed PD-L1-low, with expression of this protein below 10%. 

As such, BioNTech and its partner Bristol Myers Squibb are targeting the niche in which Keytruda isn’t approved. The Merck & Co juggernaut, alongside chemo, has a US green light only in TNBC patients with PD-L1 expression of 10% or higher.

BioNTech’s decision could be read in two ways: as a lack of confidence in pumitamig’s broader potential, or as a pragmatic strategy to carve out a pathway to faster market approval.

Rosetta Breast-01 

According to clinicaltrials.gov, the Rosetta Breast-01 study is set to begin in October and will test pumitamig plus chemotherapy, versus chemotherapy alone.

Last November BioNTech disclosed that data from the ongoing global phase 2 dose-optimisation trial would inform the phase 3, though these results have not yet been published. 

But at last year’s ESMO meeting BioNTech and pumitamig’s originator Biotheus presented data from a small China-based trial of pumitamig given to triple-negative patients irrespective of their PD-L1 expression. In patients with low expression (<10%), pumitamig achieved a confirmed ORR of 56% and a median PFS of 14.0 months. 

Among PD-L1-positive patients (≥10%), confirmed ORR was 100% and median PFS was 10.8 months; although these numbers seem impressive, PFS was only modestly higher than the 9.7 months seen with Keytruda plus chemo in its key TNBC trial, Keynote-355. 

This could raise questions about pumitamig’s ability to beat Merck’s drug in a head-to-head trial, a fact that might explain why BioNTech has chosen instead to pit its project against chemotherapy in the PD-L1-low niche.

More crowded

Since Keytruda’s FDA approval in TNBC in 2020 the treatment landscape has become crowded.

TROP2-targeting ADCs have have made significant headway, most notably Gilead’s Trodelvy. In the Ascent-04 trial, Trodelvy plus Keytruda improved median PFS versus Keytruda monotherapy in PD-L1-positive patients, as well as showing a trend towards an overall survival improvement. 

Trodelvy also recently met the primary PFS endpoint in the Ascent-03 trial, which tested the drug as monotherapy versus chemotherapy in triple-negative patients ineligible for PD-(L)1 treatment, including those previously treated with PD-(L)1 inhibitors and those with PD-L1-negative disease. 

Notably, the latest is the same population that BioNTech is targeting in Rosetta Breast-01; still, Gilead seemed less positive on OS, only saying that a detriment was not seen. 

Either way, Gilead plans to file both datasets with regulators during the last months of 2025. If Trodelvy is approved here, it could put pay to BioNTech/Bristol's chances of an accelerated approval of pumitamig; Rosetta Breast-01 has dual primary endpoints of PFS and OS.

Meanwhile, Daiichi Sankyo/AstraZeneca’s rival anti-TROP2 ADC Datroway is due pivotal results soon in TNBC, from Tropion-Breast02 in PD-(L)1-ineligible patients (results expected this year), and Tropion-Breast05 in PD-(L)1-eligible patients (2026 or later). Both studies have been delayed.

Akeso is also running a phase 3 trial in PD-L1-negative TNBC testing its Summit-partnered PD-1 x VEGF project ivonescimab versus chemo, but this trial is only enrolling patients in China. 

BioNTech is also pursuing a parallel strategy testing its TROP2 ADC sacituzumab drozuntecan in triple-negative breast cancer, both as monotherapy and in combination with pumitamig. TNBC data from the early-stage trial will be presented at ESMO this year.

Cross-trial comparison in first-line TNBC

Source: OncologyPipeline.