Neladalkib Demonstrates Promising Responses in ALK+ NSCLC

Neladalkib (NVL-655), an investigational anaplastic lymphoma kinase (ALK)-selective inhibitor, showed encouraging preliminary efficacy in pretreated advanced ALK fusion-positive (ALK+) non–small cell lung cancer (NSCLC).¹

Topline data from the phase 1/2 ALKOVE-1 trial (NCT05384626) captured durable responses in a patient population who received prior tyrosine kinase inhibitor (TKI) therapy. Here, the objective response rate (ORR) per blinded independent central review (BICR) among 253 TKI-pretreated patients with NSCLC was 31% (95% CI, 26%–37%), with estimated durability of response of 64% and 53% at 12 and 18 months, respectively.

Further, in a subset of TKI-pretreated patients who were lorlatinib (Lorbrena)-naive (n = 63), the ORR by BICR was 46% (95% CI, 33%–59%). The estimated durability of response at 12 and 18 months was markedly higher than what was observed in the NSCLC population (80% and 60%, respectively).

Another key highlight was evidence of intracranial responses, indicative of neladalkib’s potent brain-penetrating properties. Among 9 TKI-naive patients with measurable intracranial lesions, most (78%) experienced an intracranial OR.

Neladalkib was well-tolerated by patients (n = 656), with the most common treatment-emergent adverse events (TEAEs) being alanine aminotransferase elevation (47%), aspartate aminotransferase elevation (44%), constipation (28%), dysgeusia (23%), peripheral edema (18%), cough (16%), and nausea (16%). These events were expected with the known mechanisms of the agent. The most frequent TEAEs, transaminase elevations, were noted to be generally low-grade and reversible with dose interruptions or reductions. There were low rates of dose discontinuation (5%) and dose reduction (17%) due to TEAEs, suggesting an overall manageable safety profile.

"In treating ALK[+] lung cancer, our goal is not only to help patients live longer, but also to help them live well with their disease," said Alice T. Shaw, MD, PhD, thoracic oncologist at Dana-Farber Cancer Institute and ALKOVE-1 investigator, in a news release.¹ "These encouraging topline data suggest that neladalkib may represent a new and differentiated treatment option for ALK[+] lung cancer, offering durable clinical benefit while potentially reducing the risk of [adverse] effects that can affect quality of life."

There are 6 TKIs currently approved for ALK+ NSCLC treatment; however, they fail to address the combined challenges of acquired resistance, brain activity, and dose-limiting TRK inhibition.² In May 2024, the FDA granted neladalkib breakthrough therapy designation in ALK+ NSCLC in recognition of its potential to fill these gaps and spur a new generation of TKIs.

Regarding next steps, Nuvalent, the sponsor, plans to discuss these data with the FDA at a pre-new drug application meeting and will present detailed results at a future medical meeting. Additionally, global enrollment of TKI-naive patients is ongoing for the phase 3 ALKAZAR trial (NCT06765109), a randomized study of neladalkib against alectinib (Alecensa) that will run parallel to ALKOVE-1.

About the ALKOVE-1 Trial

The ongoing ALKOVE-1 trial is a first-in-human study of neladalkib seeking to enroll a total of approximately 840 patients across phases 1 and 2 with locally advanced or metastatic NSCLC or other solid tumors harboring an ALK rearrangement.³ The phase 1 dose-escalation and dose-expansion portion explored neladalkib’s safety and tolerability and established the recommended phase 2 dose (RP2D) at 150 mg once daily.

As of the August 29, 2025 data cut-off, 781 patients with ALK+ solid tumors were treated with neladalkib at any starting dose; of these, 656 patients with advanced ALK+ NSCLC were treated with neladalkib at the RP2D.

The ongoing global, single-arm, multi-cohort phase 2 portion aims to evaluate the ORR and other efficacy and safety end points at the RP2D. The study is enrolling patients into 1 of 6 cohorts, depending on prior lines of treatment received:

1. Cohort 2a: 1 prior second-generation ALK TKI and up to 2 prior lines of chemotherapy and/or immunotherapy.
2. Cohort 2b: 2–3 prior ALK TKIs and up to 2 prior lines of chemotherapy and/or immunotherapy.
3. Cohort 2c: Prior lorlatinib only and up to 1 prior line of chemotherapy and/or immunotherapy prior to lorlatinib.
4. Cohort 2d: ALK TKI treatment-naive and up to 1 prior line of chemotherapy and/or immunotherapy.
5. Cohort 2e: Those not eligible for other cohorts.
6. Cohort 2f: Those with other ALK+ solid tumors and have received at least 1 prior systemic therapy, or for whom no satisfactory standard therapy exists.

An expanded access program (NVL-655-EAP; NCT06834074) is also available across 30 global sites for patients with ALK+ solid tumors who do not have any other therapeutic alternatives and cannot participate in a neladalkib trial.⁴

REFERENCES

1. Nuvalent announces positive topline pivotal data from ALKOVE-1 clinical trial of neladalkib for TKI pre-treated patients with advanced ALK-positive NSCLC. News release. Nuvalent. November 17, 2025. Accessed November 19, 2025. https://tinyurl.com/yeyu5hkv

2. Lin JJ, Horan JC, Tangpeerachaikul A, et al. NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations. Cancer Discov. 2024;14(12):2367-2386. doi:10.1158/2159-8290.CD-24-0231

3. A study of neladalkib (NVL-655) in patients with advanced NSCLC and other solid tumors harboring ALK rearrangement or activating ALK mutation (ALKOVE-1). ClinicalTrials.gov. Updated October 30, 2025. Accessed November 19, 2025. https://clinicaltrials.gov/study/NCT05384626

4. Expanded access program of neladalkib (NVL-655) for patients with advanced ALK+ NSCLC or other ALK+ solid tumors (NVL-655-EAP). ClinicalTrials.gov. Updated November 4, 2025. Accessed November 19, 2025. https://clinicaltrials.gov/study/NCT06834074