Nuvalent (NUVL) Study Update summary

Background and Treatment Landscape

• ALK-positive NSCLC patients have limited options after progression on current ALK TKIs, especially Lorlatinib, which is associated with CNS adverse events and limited durability in pretreated settings.

• Neladalkib was designed to address ALK resistance mutations, achieve strong brain penetrance, and avoid TRK-related neurotoxicities, aiming to improve both efficacy and tolerability.

ALKOVE-1 Study Design and Enrollment

• ALKOVE-1 is a global, multi-cohort Phase I/II trial evaluating Neladalkib in TKI pretreated and TKI-naive ALK-positive NSCLC patients, with 781 patients enrolled by August 2025.

• The pivotal safety population included 656 patients at the recommended Phase II dose (150 mg daily), and the primary efficacy analysis included 253 patients with measurable disease.

• The study included a high proportion of Lorlatinib-experienced patients, those with ALK resistance mutations, and CNS disease.

Efficacy Results in TKI Pretreated Patients

• In the primary efficacy population, Neladalkib achieved a 31% ORR, with a median DOR not reached and 53% of responses ongoing at 18 months.

• Among Lorlatinib-experienced patients, ORR was 26% with a median DOR of 17.6 months, showing double the durability compared to Lorlatinib.

• Patients with the G1202R mutation had a 68% ORR, and those with compound mutations had a 58% ORR, both with durable responses.

• Activity was observed across subgroups, including those with resistance mutations and CNS disease.

• Median duration of response was not reached in several subgroups, indicating ongoing benefit.