Nuvalent loses ground in the front line

Having been beaten to the punch by Nuvation's Ibtrozi, Nuvalent is making a concerted push with its rival ROS1 inhibitor zidesamtinib. A key update from the latter's Arros-1 study has resulted in what Nuvalent calls "alignment" with the FDA on a US filing, which is to be initiated on a rolling basis next month and be completed in the third quarter.

However, this will for now only concern lung cancer patients relapsed after treatment with earlier-generation tyrosine kinase inhibitors like Pfizer's Xalkori or Roche's Rozlytrek. This means that Nuvalent has lost ground to Nuvation, which two weeks ago scored approval for the Daiichi Sankyo-originated Ibtrozi in ROS1-mutant NSCLC irrespective of therapy line.

First first-line data

That's not to say that Nuvalent is abandoning first-line use; the company has for the first time revealed data in 35 tyrosine kinase inhibitor-naive ROS1-mutant NSCLC patients, where it claims a confirmed ORR of 89%. This looks exactly in line with the ORR numbers Nuvation cites in the TKI-naive setting for Ibtrozi.

The zidesamtinib data relate to a 21 March cutoff, and concern patients enrolled as at the end of last August. Nuvalent says that as of 16 June it's recruited 104 TKI-naive patients into Arros-1, but for now it's too early to report how these have fared.

More importantly, Nuvalent has also been able to say little about how or when it might seek front-line approval for zidesamtinib. Tuesday's release, giving the updated numbers from Arros-1, states only that the group "continues to engage with the FDA on potential opportunities for line-agnostic expansion".

This might not matter much were it not for the clear disparity in the market's perception of Nuvation and Nuvalent. The former, now with a marketed drug under its belt, carries a $670m market cap, while the latter is valued at a meaty $5.4bn even though it might now be a year behind its competitor, and in a later-line setting.

Cross-trial ORR comparison

Note: *includes 2 patients who had received only Augtyro, and 2 who had received only Ibtrozi; 1 of these 4 had a response. Source: OncologyPipeline.

As for that later-line setting, it is at least good news for Nuvalent investors that earlier Arros-1 data in 68 TKI-pretreated ROS1-mutant NSCLC patients have more or less held up in a bigger population, which now totals 117 subjects given the 100mg zidesamtinib recommended phase 2 dose.

The ORR cited here is 44%, including 49% among patients who had received just one prior TKI. The latter includes four patients who had received only Augtyro or Ibtrozi, so Nuvalent cites a more realistic number of 51% (28/55 responders), in post-Xalkori or Rozlytrek patients only, and it's this that should be compared against Ibtrozi, which across its two trials scored a 56% ORR in patients after one prior TKI.

There is much nuance to comparing across two different datasets, especially given that anti-ROS1 TKIs differ greatly, and a relapse on one isn't equal to a relapse on another. It's intriguing, for instance, that Nuvalent is able to cite ORRs of 47% and 43% in 17 and seven patients whose prior TKI treatment included Augtyro or Ibtrozi respectively.

Safety too is being closely watched. Though Ibtrozi avoided some warnings its label cites notable toxicities; in Arros-1 10% of patients had to have their zidesamtinib dose reduced, and 2% discontinued because of TEAEs.

Nuvalent has shown itself to be highly skilled at designing a molecule that can claim to be truly ROS1 selective, something that in itself is no mean feat. But it now risks being outmanoeuvred by a first-to-market competitor with an asset discarded by a previous developer.