The first test of Spectrum’s shift

By the end of December poziotinib will deliver results that could justify the strategic refocusing Spectrum undertook this year.

Earlier this year Spectrum ditched a portfolio of ageing marketed products to focus on developing two key pipeline assets. Next month it will see the results of a trial that will show whether the first of these, poziotinib, can be filed for US approval.

Poziotinib is being targeted at a highly intractable lung cancer niche, exon 20 mutations, that might be equal in prevalence to Alk, amounting to some 7,000 US patients. It appears to be the most advanced industry project in development here, and if the first cohort of the Zenith20 trial is sufficiently positive Spectrum reckons it can be used for a US filing.

Zenith20 is an uncontrolled study split into several cohorts, almost any of which might be registrational, Spectrum hopes. The first comprises 87 relapsed NSCLC subjects who have documented EGFR exon 20 insertions.

Project Poziotinib
Company Spectrum
Product NPV* $257m
% of mkt cap 26%
Event Data from cohort 1 of Zenith20 trial
Due December 2019
*18% risk-adjusted. Source: EvaluatePharma.

Fortunately investors can handicap the result, thanks to a single-centre poziotinib study run earlier by MD Anderson and presented at the World Lung conference last year. Here, in 44 evaluable EGFR exon 20 mutant subjects the Spectrum asset yielded a 43% overall remission rate, with over 40% of patients still on therapy at a median seven months or so.

It would clearly be unrealistic for a more robust, potentially registrational trial to show a similar level of efficacy, but the earlier study does set some baseline expectations. Spectrum says it will remain blinded to the open-label Zenith20 study, and the data it hopes to present next month include remissions, safety and durability.

Serendipity

Why MD Anderson even ran such a study shines a light on the serendipitous nature by which Spectrum came to be developing poziotinib in this setting.

Poziotinib is a Her2 inhibitor that Spectrum had licensed for an undisclosed amount from the South Korean group Hanmi. Spectrum had initially been developing it for breast cancer, but in the meantime MD Anderson’s Cancer Moon Shots programme had started looking at exon 20 mutations, and preclinically identified poziotinib as a seemingly potent agent.

On the basis of this the hospital ran its own, academic trial, and after being persuaded by MD Anderson of the opportunity Spectrum moved to focus on mutated lung rather than breast cancer. Sellside forecasts, as compiled by EvaluatePharma, see the Spectrum drug generating an impressive $449m of sales in 2024.

Exon 20 mutations are thought to be particularly intractable owing to steric hindrance. There are a few other competitors, all behind poziotinib in development, including Takeda’s TAK-788, Rain Therapeutics’ tarloxotinib and Otsuka’s TAS6417 (Asco 2019 – tepotinib and capmatinib fight over a new lung cancer niche, June 4, 2019).

The mutation can occur as a resistance pathway resulting from various types of targeted therapy, hence the multiple settings in Zenith20. For now, however, all the attention is on cohort 1.

Poziotinib's Zenith20 study in lung cancer
Cohort Setting Subjects Data
1 Relapsed, EGFR exon 20 insertions 87 Dec 2019
2 Relapsed, Her2 exon 20 insertions 87 Mid-2020
3 1st-line EGFR exon 20 insertions 70
4 1st-line Her2 exon 20 insertions 70
5* Cohort 1 & 2 expanded access programme 180
6 EGFR Tagrisso failures 30
7 Atypical EGFR or Her mutations 30
*Non-registrational. Source: Spectrum.

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