AACR 2025 – Boehringer still has broad zongertinib hopes

Boehringer Ingelheim, awaiting approval of its HER2-selective small molecule zongertinib in second-line HER2-mutated NSCLC, still has hopes in HER2 wild-type disease. That’s what the company told ApexOnco ahead of the AACR meeting, pointing to two ongoing trials that include patients with HER2 overexpression and amplification.

The main focus at the meeting, however, was HER2-mutant disease courtesy of Beamion Lung-1, the basis of an FDA filing that was accepted in February with priority review, putting zongertinib ahead of a similarly acting project from Bayer. While the overall response rate in Beamion Lung-1 has previously been reported, progression-free survival data were released for the first time.

HER2 mutant vs amplified

Zongertininb is due an FDA decision by the third quarter in relapsed HER2-mutated NSCLC; these mutations are said to occur in 2-4% of NSCLC patients.

Bayer’s filing plans for its hopeful, BAY2927088, are still unclear, although that group’s phase 1/2 Soho-01 study included second-line NCLC patients with HER2 mutations (as well as those with EGFR mutations).

Still, Boehringer has claimed for some time that zongertinib could be active in HER2 wild-type disease. When asked about this during the pre-AACR interview the group’s head of oncology, Itziar Canamasas, told ApexOnco that this was still an area of active research, and noted the Beamion Pantumor-1 and Beamion BCGC-1 studies in patients with wild-type, but overexpressed or amplified HER2.

Notable zongertinib trials

Source: OncologyPipeline & clinicaltrials.gov.

Bayer also has a phase 2 pan-tumour trial, PanSoho, but this is only enrolling patients with HER2 mutations.

And both companies are carrying out phase 3 studies in first-line HER2m NSCLC: Beamion Lung-2 for zongertinib, and Soho-02 for BAY2927088. Canamasas declined to say when Beamion Lung-2 was expected to read out.

Progression-free survival

Meanwhile, the Beamion Lung-1 trial, presented at AACR and published simultaneously in the NEJM, reported a 71% ORR among 75 patients receiving zongertinib at 120mg once daily in cohort 1; this arm included patients whose tumours harboured a HER2 mutation in the tyrosine kinase domain (TKD). The figure is the same as that presented at last year’s ESMO Asia conference.

What was new at AACR was a median PFS of 12.4 months in these patients. On a cross-trial basis this looks better than BAY2927088, which produced a PFS of 7.5 months in second-line HER2m NSCLC. 

Also at AACR, for the first time Boehringer presented data from Beamion Lung-1’s cohort 3 (patients with non-TKD mutations) and cohort 5 (those with TKD mutations, previously treated with a HER2-directed ADC).

ORR was 30% in cohort 3, and 48% in cohort 5. The company hopes for a broad approval in HER2m patients, including TKD and non-TKD mutations, Canamasas said.

The study also included a 240mg daily arm, but the filing focused on the lower dose, with Canamasas noting that 120mg produced the optimal benefit/risk ratio.

The higher dose was linked with a higher rate of liver enzyme elevations. Still, these were also seen fairly frequently with 120mg, with one patient experiencing a grade 4 suspected drug-induced liver injury. Canamasas claimed that zongertinib in fact fared positively on liver toxicity versus other TKIs, adding that tolerability was acceptable, with only two patients discontinuing treatment.

It should soon become apparent whether the FDA has any issues on this score.