Nuvalent sets out its two-pronged strategy

Nuvalent’s targeted oncology projects have looked to be heading towards the front line for a while, and at the JP Morgan healthcare conference the group gave more details on its plans – which have been thrown into focus by a recent pivotal listing on clinicaltrials.gov.

The phase 3 Alkazar trial will pit Nuvalent’s fourth-generation ALK inhibitor neladalkib (NVL-655) against Roche’s Alecensa in first-line ALK-positive NSCLC, with a primary endpoint of progression-free survival. Completion is slated for 2029.

However, things could move faster for Nuvalent’s ROS1 inhibitor zidesamtinib – the company eventually hopes for a line-agnostic nod in ROS1-positive NSCLC based on TKI-naive cohorts in the phase 1/2 Arros-1 trial. However, it hasn’t yet given a timeline for this.

The more immediate milestones are in relapsed disease, where pivotal data on both assets are due this year.

Nuvalent’s clinical-stage pipeline

Source: company presentation.

The ROS1-selective zidesamtinib is ahead, with phase 2 results from kinase inhibitor-pretreated Arros-1 cohorts slated for the first half, and an NDA filing expected in second-line-plus disease in mid-2025. 

Pfizer’s Xalkori – although imperfect – is the front-line standard for ROS1-positive NSCLC, but there are no good options for refractory patients, according to Nuvalent’s chief executive, James Porter, despite the availability of Roche’s Rozlytrek and Bristol Myers Squibb’s Augtyro. These two both have accelerated approvals for line-agnostic ROS1-positive NSCLC, based on uncontrolled trials.

Nuvalent eventually hopes to follow a similar path, and says Rozlytrek and Augtyro leave much to be desired as they also hit TRK, which is linked with CNS toxicity. Nuvalent hopes to solve this with the more selective zidesamtinib, first in relapsed disease, and then in the front line. 

ALK

The group is taking a similar approach in ALK-positive NSCLC with neladalkib, although a pivotal trial will be needed for a first-line filing.

Using Alecensa as the comparator in the phase 3 Alkazar trial was a “straightforward” choice, Porter noted, given that the Roche drug is the current first-line standard of care.

Pfizer’s Lorbrena is a more active compound, Porter conceded. However, he added that, as Lorbrena hits TRK as well as ALK, it’s linked with CNS side effects, which have largely restricted it to a second-line option.

In the refractory setting the phase 1/2 Alkove-1 trial is set to yield pivotal data by the end of 2025, in both the second and third lines.

Third-line patients have no current options, so if neladalkib can show activity here its approval chances look good. In the second line the benchmark to beat is the 31% ORR Lorbrena showed in a subset of patients who’d only received prior Alecensa, according to Porter.

Nuvalent’s $5bn valuation looks rich given that its clearest opportunity is in late-line niches, but it has big ambitions. In both ALK and ROS1-positive disease “we’re not looking to capture a portion of this market”, Porter said. “We’re looking to grow the market, by driving much more durable responses.”

He gave AstraZeneca’s Tagrisso, which has moved to the front line in EGFR-mutant NSCLC, as the kind of drug Nuvalent wants to emulate.

It could be a while before these aspirations are put to the test. In the meantime, the company needs to pick the low-hanging fruit.