World Lung – Ignyta’s chance to make up lost ground on Loxo

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While Loxo Oncology has pulled away from its rival Ignyta in the novel cancer mutation called NTRK, the latter is trying to get back into the game in the related setting of Ros1.

Yesterday’s update at the World Conference on Lung Cancer made a strong case for using Ignyta’s lead asset, entrectinib, in Ros1-positive NSCLC, sending the group’s stock up 20% this morning. As in the case of Alk-mutated lung cancer, the inability of Pfizer’s Xalkori to cross into the central nervous system has left competing agents an open goal.

A couple of days previously the World Lung meeting heard how the next-generation Alk-inhibitor space was hotting up, with Xalkori being challenged on numerous fronts, most importantly by Roche’s Alecensa (World Lung – Alks impress, but the real fight is elsewhere, October 17, 2017).

The Ros1 parallel

There is an important analogy here with Ros1-positive tumours, because after being approved in Alk-positive disease Xalkori gained a first-line label in Ros1-mutated NSCLC too, and is currently the only drug indicated for this genetic niche.

From Ignyta’s point of view it is just as well that its pivotal phase II Startrk-2 study of entrectinib enrols patients with Ros1, as well as Alk and NTRK mutations. These three genetic aberrations are related, but in contrast Loxo’s lead asset, larotrectinib, was designed specifically as an NTRK inhibitor.

On a call today Ignyta boasted that entrectinib was 30 times more potent than Xalkori against Ros1. Even more importantly, entrectinib, unlike Xalkori, crosses the blood/brain barrier, meaning that it can tackle brain metastases, which are a major problem in NSCLC.

And this presents the opportunity for CNS-penetrating agents like Alecensa in Alk mutations, and for entrectinib in Ros1. Ignyta said it was increasingly important to target the CNS with a CNS-active drug before the emergence of brain metastases – thus setting its sights squarely on first-line use.

At World Lung entrectinib’s Startrk-2 update showed a 69% best remission rate in 32 Ros1 inhibitor-naive subjects, with five of six patients with brain metastases responding. Median duration of response was 28.6 months, and median progression-free survival 29.6 months, Ignyta said.

In comparison, available phase I data for Xalkori in Ros1-positive NSCLC suggest 18.3-month duration and 19.2-month PFS, presumably driven by non-CNS lesions. Ignyta said it would aim to file for Ros1-mutated NSCLC in the second half of next year, with a dataset of over 50 patients; currently over 70 Ros1-positive subjects have been enrolled into Startrk-2, and a pre-filing update is expected.

As if not wanting to be outdone, Loxo today provided an update of its three larotrectinib studies in NSCLC patients with NTRK fusions, showing remission rates by independent review broadly supporting investigator-assessed numbers. Larotrectinib is to be filed in the US late this year or in early 2018.

Loxo’s own World Lung presentation concerned two RET fusion patients, one of whom had progressed on Ignyta’s RXDX-105 but went into partial remission on receiving LOXO-292.

Genetic subtypes

This all suggests the carving up of NSCLC into ever smaller genetic subtypes, so it is highly relevant to question the economic opportunities – notwithstanding the possibility of orphan pricing. Ignyta reckons that there are over 5,000 Ros1-mutated patients globally.

At present, the Ros1 space is looking a lot less crowded than the broadly comparable Alk-positive segment. Clinicaltrials.gov reveals relatively little Ros1-mutated NSCLC activity besides Xalkori, lorlatinib and entrectinib; importantly, Alecensa does not seem to be studied specifically for this mutation.

Perhaps this all gives Ignyta a brand new opportunity to shoot for. If only its valuation would reflect this – even after this morning’s rise Loxo’s $2.6bn market cap is almost three times higher than Ignyta’s – investors would really be on to something.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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