એલેક્ટીનિબ

A 4th generation TKI under trial. The recommended dose is 150mg taken daily.

Introduction

Neladalkib is a 4th generation investigational brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. It is manufactured by Nuvalent Inc.

It is designed to remain active in tumours that have developed resistance to first, second, and third generation ALK inhibitors, including tumours with single or compound treatment-emergent ALK mutations such as G1202R.

In addition, Neladalkib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family.

Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy.

Phase 1/2 Trial – ALKOVE-1

Neladalkib is being evaluated in ALKOVE-1, a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors. The recommended Phase 2 dose (RP2D) for neladalkib of 150 mg once daily (QD) was determined during the Phase 1 dose-escalation portion of the trial. The global, single-arm, multi-cohort, open-label Phase 2 portion is designed to evaluate neladalkib at the RP2D with registrational intent for TKI pre-treated patients with advanced ALK-positive NSCLC. Global enrollment in ALKOVE-1 remains ongoing for adolescent patients.

Summary of Topline Pivotal Data (Published November 2025)

In this topline pivotal dataset for the TKI pre-treated ALK-positive NSCLC population, data are pooled across Phase 1 and 2 and reported for the primary objective of objective response rate (ORR, RECIST 1.1) by blinded independent central review (BICR). Key secondary objectives include duration of response (DOR), intracranial ORR (IC-ORR), and safety.

As of the data cut-off date of August 29, 2025, 781 patients with ALK-positive solid tumors had received neladalkib at any starting dose across the Phase 1 and Phase 2 portions of the ALKOVE-1 clinical trial. Of these, 656 patients with advanced ALK-positive NSCLC were treated with neladalkib at the RP2D (150mg daily)

Efficacy Analysis in TKI Pre-treated Advanced ALK-positive NSCLC

The pivotal primary analysis population consisted of 253 TKI pre-treated patients with advanced ALK-positive NSCLC with measurable disease by BICR who received neladalkib at the RP2D by September 30, 2024, with DOR follow-up of at least 6 months available for nearly all responders.

The pivotal primary analysis population was distinct from the ALK TKI pre-treated populations that have been reported for the currently available ALK TKIs:

Patients received a median of 3 prior lines of therapy (range, 1 – 11) and 51% had received prior chemotherapy.
78% of patients had received 2 or more prior ALK TKIs ± prior chemotherapy, of which 91% had received prior lorlatinib. No approved therapies have demonstrated activity after lorlatinib.
19% of patients had a secondary ALK G1202R resistance mutation, and 17% had a compound ALK resistance mutation, which are key drivers of disease progression.
40% of patients had active CNS disease by BICR at baseline.

Of the overall TKI pre-treated population, 25% (63/253) of patients were lorlatinib-naïve. Within this subpopulation:

25% received prior chemotherapy.
100% had received ≥ 1 prior 2G ALK TKI ± prior chemotherapy, of which 70% received prior alectinib only. No patients received crizotinib as their only ALK TKI.
19% of patients had a secondary ALK G1202R mutation.
35% had active CNS disease by BICR at baseline.

Activity was observed across subsets of TKI pre-treated patients, and durability of response was assessed as the probability of patients remaining in response for at least 6, 12, and 18 months by Kaplan-Meier estimate (Table 1).

Safety Analysis

Neladalkib demonstrated a generally well-tolerated safety profile consistent with its ALK-selective, TRK-sparing design.

In the 656 patients with advanced ALK-positive NSCLC treated at RP2D as of the data cut-off date, the median duration of exposure was 6.0 months (range, 0.1, 28.4). The most frequent treatment-emergent adverse events (TEAEs) occurring in ≥ 15% of patients were alanine aminotransferase increased (47%), aspartate aminotransferase increased (44%), constipation (28%), dysgeusia (23%), peripheral edema (18%), cough and nausea (16% each).

The most common TEAE of transaminase elevations were generally observed to be asymptomatic lab abnormalities that were low-grade, transient, and reversible with dose interruptions or reductions. Preliminary data suggest increased incidence in less heavily pre-treated patients. Enhanced monitoring for transaminase elevations and prompt dose interventions have been implemented in the protocol for the ALKAZAR Phase 3 randomized, controlled trial.

Across the 656 patients treated in ALKOVE-1 at RP2D, dose reductions due to TEAEs occurred in 17% of patients and 5% of patients discontinued treatment due to TEAEs.

The company plans to discuss the topline pivotal data for TKI pre-treated ALK-positive NSCLC with the U.S. Food and Drug Administration (FDA) at a pre-New Drug Application (NDA) meeting. Additionally, Nuvalent plans to present detailed study results at a future medical meeting.

In the UK, the trial was available at The Marsden Hospital, London, The Christie at Manchester and Western General in Edinburgh

Global enrolment in ALKOVE-1 is now closed for new recruits, except for adolescent patients, although Nuvalent has opened an Expanded Access Programme (EAP). This is a potential pathway for patients to gain access to Neladalkib outside of a clinical trial when no comparable or satisfactory alternative therapy option is available. The EAP is available at the three original participating hospitals and they will accept out-of-area referrals.

Neladalkib has received U.S. Food and Drug Administration (FDA) breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.

For the drug to become available in the UK for patients who have received at least one previous TKI, the manufacturer will need to obtain opproval of the National Institute for Health and Care Excellence (NICE).

Phase 3 Trial - ALKAZAR

This is a multicentre, randomised, controlled, open-label study designed to demonstrate that Neladalkib is superior to Alectinib in prolonging progression-free survival (PFS) in patients with treatment-naïve ALK-positive NSCLC, i.e as a first line treatment.

Preliminary Data from Exploratory Cohort for TKI-Naïve Patients with Advanced ALK-positive NSCLC

Encouraging preliminary data were available for 44 TKI-naïve patients with advanced ALK-positive NSCLC and measurable disease by BICR. These patients were treated with neladalkib at RP2D in an exploratory cohort of ALKOVE-1, with data cut-off of August 29, 2025. Patients may have received up to one prior line of chemotherapy.

The preliminary ORR was 86% (38/44; 2 uPRs) and a CR rate of 9% (4/44; 1 uCR with prior confirmed PR) was observed. DOR ranged from 1.7+ to 14.8+ months with DOR ≥ 6 and 12 months of 91% (95% CI: 70, 98) and only two progression events among responders. In 9 patients with measurable intracranial lesions, the IC-ORR was 78% (7/9) and the intracranial CR rate was 44% (4/9; 1 IC-uCR with prior confirmed IC-PR). The IC-DOR ranged from 3.1+ to 7.0+ months with no CNS progression among responders.

Global enrollment of TKI-naïve patients is ongoing in ALKAZAR, Nuvalent's Phase 3 randomized controlled trial of neladalkib versus alectinib.

The trial will enrol 450 patients who will be randomised 1:1 to receive Neladalkib or Alectinib.

The primary endpoint is progression free survival (PFS) based on Blinded Independent Central Review (BICR). Secondary endpoints include overall survival, PFS based on investigator's assessment, time to intracranial response, and BICR assessment of intracranial objective response rate (IC-ORR), intracranial duration of response (IC-DOR), objective response rate (ORR), duration of response (DOR), time to intracranial progression, and safety.

Additional details can be found on www.clinicaltrials.gov (NCT06765109).

In the UK, the trial is available at (November 2025) –

Addenbrooke’s Hospital, Cambridge
Guy’s Hospital, London
The Royal Marsden Hospital, London
Maidstone Hospital, Kent

These hospitals will invite newly diagnosed ALK-positive patients to participate in the trial and they will receive either Alectinib or Neladalkib.

The trial will end in December 2029 and results will be reported sometime in 2030.