The future of lung cancer is looking ever smaller. Spectrum Pharmaceuticals followed Ignyta this week by demonstrating compelling efficacy in a small subset of the disease, this time with poziotinib, a pan-Her inhibitor being tested in patients who harbour an exon 20 insertion.
This mutation renders existing drugs that target EGFR-positive tumours largely useless, and poziotinib’s objective response rate of 73% was much better than expected. Data were generated in only 11 patients – a huge caveat that investors chose to ignore yesterday – but, with few others working in this space, Spectrum’s progress deserves to be closely watched (see table below).
To put the opportunity in perspective, the EGFR exon 20 population is considerably smaller than the NTRK or Ros1 populations, the focus of Loxo with larotrectinib and Ignyta with entrectinib respectively. Of non-small cell lung cancer cases, around 3% are thought to harbour NTRK mutations and 2% Ros1, while less than 1% carry an EGFR exon 20 insertion.
Exon 20 insertions can also occur in Her2 mutations, and this presents a bigger opportunity for poziotinib, if efficacy can be shown. Her2 is thought to drive around 3% of NSCLC cases, almost all of which carry exon 20 insertions.
Poziotinib blocks signalling through both EGFR and Her kinases, and the trial presented this week at the World Conference on Lung Cancer is being run by MD Anderson Cancer Center and is recruiting patients with both forms of activating mutation. Only data on EGFR-positive patients are available so far, however, and these remain very early readouts – duration of response is not yet calculable, for example.
It is understandable why a 73% ORR generated some excitement – response rates have historically been measured in single digits in this population. Spectrum believes that because poziotinib is a much smaller and more flexible molecule than existing EGFR inhibitors it can more successfully access the exon 20 insertion binding pocket. This in itself is hard to access – in technical terms it is known as sterically hindered – hence the inability of larger molecules like Tagrisso and Gilotrif to bind successfully.
Still, the $440m in market cap that Spectrum gained yesterday was arguably an overreaction, given that the company has a long way to go to prove poziotinib’s worth. The MD Anderson study is aiming to recruit 60 patients in total, while a 90-patient confirmatory trial that Spectrum is planning has yet to get under way.
The company did nothing to quell optimism yesterday, with talk of rushing to the FDA to win breakthrough therapy designation and seeking permission to begin testing in first-line patients.
|Targeting the exon 20 insertion… the pipeline|
|Project||Pharma class||Company||Comment||Trial IDs|
|Poziotinib||Pan-Her inhibitor||Spectrum (Hanmi)||Phase II lung cancer trial ongoing by MD Anderson, data 2021?||NCT03066206|
|AP32788/TAK-788||EGFR/Her2 inhibitor||Takeda (Ariad)||Phase I/II ongoing, data 2018?||NCT02716116|
|Onalespib||Hsp90 inhibitor||Otsuka (Astex)||Phase I/II ongoing + Tarceva, with exon 20 cohort, data 2018?||NCT02535338|
|Tagrisso||EGFR inhibitor||Astrazeneca||NCI funded phase II in exon 20 registered but not yet started||NCT03191149|
|ASP8273 (naquotinib)||EGFR inhibitor||Astellas||Abandoned in May 2017, but in phase III for EGFR activating mutations||NCT02113813|
|AUY922 (luminespib)||Hsp90 inhibitor||Vernalis||Novartis handed back rights in 2014, no active development||NCT01124864|
Investors might also be getting excited by the lack of competition here – among industry players only Takeda and Otsuka appear to be actively exploring the exon 20 niche.
Takeda is testing a similar kinase inhibitor that it gained with Ariad, while Otsuka is investigating an Hsp90 inhibitor it inherited with Astex – Clinicaltrials.gov indicates that data could emerge on both in the coming year.
Early data for poziotinib is looking good, and success stories like Xalkori show that targeted agents should not be overlooked in the madness of the immuno-oncology gold rush. But, while mechanisms to get these promising approaches quickly to patients are in place, even the newly receptive FDA will want to see data in more than 11 patients.