Targeted lung cancer niche sees a German pharma battle

Boehringer Ingelheim's zongertinib and Bayer's BAY2927088 have had differing development histories, but they are now neck and neck in a race to become the first targeted small molecule approved for HER2-mutated non-small cell lung cancer.

Both have now started virtually identical phase 3 trials – Boehringer's began in February, six months before Bayer's – in virtually identical first-line NSCLC populations. One question is whether these studies are registrational or merely confirmatory, since neither company has stated publicly whether it indents to shoot for accelerated approval.

On the basis of efficacy alone, there's a good case for filing on mid-stage data and asking the FDA for an accelerated nod. At the recent World Lung conference both molecules showed remarkably similar response rates in HER2-mutant relapsed NSCLC: 74% and 72% in the relevant cohorts of zongertinib's Beamion Lung-1 and BAY2927088's Soho-01 studies respectively.

Safety

However, the two molecules' safety profiles could be concerning, and it might be that emerging toxicities seen in these mid-stage studies are holding back disclosure of specific filing plans.

Liver toxicity is especially noteworthy. At the relevant doses grade 3 or higher liver enzyme elevations were seen among 19-25% of patients on zongertinib, and among 14% of those given BAY2927088. Moreover, Bayer saw one patient death, due to dyspnoea, that was attributed to BAY2927088.

A clue to the worry that these profiles might be causing within Boehringer is Monday's quiet posting on the clinicaltrials.gov registry of a phase 1 study testing zongertinib's pharmacokinetic profile specifically in people with or without liver impairment. For its part Bayer has run BAY2927088 interaction trials with other drugs, but none testing liver effects specifically.

While Beamion Lung-1 and Soho-01 both concerned relapsed settings, the German companies are now gunning for the front line in phase 3. Beamion Lung-2 and Soho-02 both concern first-line HER2-positive NSCLC, test zongertinib or BAY2927088 respectively against Keytruda plus chemo, and have PFS as sole primary endpoint; enrolment targets are both around 275 patients.

HER2-mutated NSCLC is a novel niche, but it does at least have an FDA blessing of sorts: the US agency has given BAY2927088 breakthrough therapy designation in this setting.

But investors will want to know how big a market such a niche could represent. During its World Lung presentation Boehringer claimed that 2-4% of NSCLC cases featured HER2 mutation, without splitting this out by line of treatment, something that would amount to roughly 6,500 new US cases a year.

What's the target?

This wasn't always the target for these two molecules. Bayer used to call BAY2927088 a non-covalent EGFR inhibitor with activity in exon 20 insertion mutations, while Boehringer previously described zongertinib as a HER2 exon 20 inhibitor; now both are targeting HER2-mutated NSCLC, with Boehringer additionally claiming activity in wild-type as well as mutated HER2.

Two things might have prompted such rethinks. Firstly, the availability of Johnson & Johnson's bispecific MAb Rybrevant for EGFR exon 20 NSCLC likely closed off that niche, and has already seen the discontinuation of a small-molecule blocker, Takeda's Exkivity.

Secondly, exon 20 insertion in HER2 was a space Spectrum Pharmaceuticals had targeted with poziotinib, a small molecule acquired from the South Korean group Hanmi. But poziotinib's US filing ended in a negative adcom vote, where reviewers cited toxicities and other treatment options, and after a complete response letter Spectrum was effectively wound up.

A final fact that might caution against accelerated approval filings for zongertinib and BAY2927088 is that AstraZeneca/Daiichi Sankyo's Enhertu is already approved for HER2-expressing relapsed NSCLC, on the basis of a 57% ORR in the Destiny-Lung01 study. However, this too in on an accelerated basis, so in theory it doesn't preclude other similar approvals.

Moreover, Enhertu is an ADC that simply binds to any HER2. If targeting the mutated protein specifically with a small molecule represents a new niche then there could be much to play for, so any word on filing plans will be keenly awaited.

Selected small molecules in HER2-mutated NSCLC

Source: OncologyPipeline.