World Lung 2024 – Boehringer and Bayer battle over a lung cancer niche

Two small molecules are battling for dominance in HER2 mutation-driven lung cancer: Boehringer Ingelheim’s zongertinib and Bayer’s BAY2927088. Both recently entered phase 3 trials, and both featured at World Lung’s presidential session on Monday, at which mid-stage data showed their potential in this somewhat niche indication.

Both molecules appear to be very efficacious though, as is the case with all small-molecule tyrosine kinase inhibitors, a close eye will have to be kept on some worrying toxicities. It’s also notable how each molecule is being positioned; Bayer and Boehringer’s target NSCLC populations might not be identical, and the companies’ views of each molecule’s activity have shifted.

Until recently Bayer was describing BAY2927088 as a non-covalent EGFR inhibitor with activity at exon 20 insertions and EGFR resistance mutations. But by this year’s ASCO meeting the focus was firmly on NSCLC driven by mutated HER2, including insertions in exon 20, and it’s in HER2-mutant NSCLC that the phase 3 Soho-02 trial has been initiated.

Meanwhile, Boehringer has previously described zongertinib as a HER2 exon 20 inhibitor, but its phase 3 Beamion Lung-2 trial, which began last year, enrols first-line NSCLC patients with any mutation in HER2. And now the focus appears to have broadened further, with the World Lung presentation claiming the molecule’s ability to bind to and block mutated as well as wild-type HER2.

Beamion Lung-1

At ASCO Boehringer presented a broad dataset from the phase 1/2 Beamion Lung-1 trial, which actually included several cancer types with aberrant HER2 activity, but gave special mention to a phase 1b part specifically in pretreated NSCLC, where ORR in 23 efficacy-evaluable patients was 74%.

This cleared a first futility analysis, and a much larger phase 1b dataset, from zongertinib 120mg and 240mg, comprised Monday's World Conference on Lung Cancer presentation. The two doses have now been given to 58 and 55 efficacy-evaluable patients respectively, and the ORRs have been revealed as 72% and 78%, with activity including patients with brain metastases.

However, adverse events leading to dose reductions occurred in 11% of patients, and ALT and AST elevations were seen at grade 3 or above in 8% and 5% of 120mg patients, and in 11% and 7% of 240mg patients. 120mg is the dose being tested in the phase 3 Beamion Lung-2. Zongertinib is Boehringer’s most advanced oncology project, and the company says HER2 mutations occur in 2-4% of NSCLCs.

Soho-01

This is the space Bayer has decided to shoot for with BAY2927088, and Soho-02 is also a first-line trial.

At World Lung Bayer updated results from the phase 1/2 Soho-01 trial’s cohort D, which at ASCO was said to have shown a 70% ORR among 33 patients. With 43 efficacy-evaluable patients the ORR now stands at 72%, Bayer told World Lung on Monday – similarly also highlighting activity in those with brain metastases at baseline.

Again, there were some troubling adverse events, however, and overall these led to dose reductions in 32% of patients. Two of five treatment-related EAs involved abnormal liver function, and there was one death, due to dyspnoea, attributed to BAY2927088.

The Bayer cohort focuses specifically on HER2 exon 20 insertion, and 71% of the patients here had a particular insertion, called HER2 Y772_A775dup (YVMA), which the group says makes up 75% of all HER2-mutant lung cancers. YVMA also featured the majority of the Boehringer patients (63%), with the remainder being accounted for by P780_Y781insGSP and “other” HER2 mutations.

For molecules with activity at exon 20 insertions HER2 thus looks relevant, especially after the related exon 20 insertion EGFR space saw the withdrawal of Takeda’s Exkivity as Johnson & Johnson’s Rybrevant seized this niche. Spectrum tried and failed in HER2 exon 20 with poziotinib, so – assuming that this niche is big enough to play for – the race is on to develop something better.

Boehringer vs Bayer in HER2-mutant relapsed NSCLC

Source: IASLC.