On November 17, 2025 Nuvalent, Inc. (the "Company") reported positive topline pivotal data for neladalkib, an investigational ALK-selective inhibitor, in tyrosine kinase inhibitor ("TKI") pre-treated patients with advanced ALK-positive non-small cell lung cancer ("NSCLC") from the global ALKOVE-1 Phase 1/2 clinical trial. Additionally, the Company shared the first report of preliminary data from the Phase 2 exploratory cohort for TKI-naïve patients with advanced ALK-positive NSCLC from the ALKOVE-1 study.

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Summary of Topline Pivotal Data

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 adult and adolescent patients with ALK-positive solid tumors other than NSCLC, and for adolescent patients with ALK-positive NSCLC.

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.

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).

Table 1. Any prior ALK TKI
± chemotherapy a
TKI Pre-treated,

Lorlatinib-naïve b

n

253 63
ORR, % (n/N)

(95% CI)

31% (79/253) c, d

(26, 37)

46% (29/63) e

(33, 59)

% DOR ≥ 6 months f

(95% CI)

76%

(64, 84)

89%

(69, 96)

% DOR ≥ 12 months f

(95% CI)

64%

(51, 75)

80%

(58, 91)

% DOR ≥ 18 months f

(95% CI)

53%

(34, 68)

60%

(19, 85)

G1202R mutation g

n

47 12
ORR, % (n/N)

(95% CI)

68% (32/47) h, i

(53, 81)

83% (10/12)

(52, 98)

% DOR ≥ 6 months f

(95% CI)

84%

(65, 93)

90%

(47, 99)

% DOR ≥ 12 months f

(95% CI)

80%

(61, 91)

77%

(34, 94)

% DOR ≥ 18 months f

(95% CI)

70%

(42, 86)

77%

(34, 94)

Measurable CNS lesions

n

92 j 24 k
IC-ORR, % (n/N)

(95% CI)

32% (29/92) l, m

(22, 42)

63% (15/24) l

(41, 81)

IC-CR, % (n/N)

13% (12/92) n 21% (5/24) n
% IC-DOR ≥ 6 months f

(95% CI)

81%

(59, 91)

92%

(57, 99)

% IC-DOR ≥ 12 months f

(95% CI)

71%

(48, 85)

92%

(57, 99)

% IC-DOR ≥ 18 months f

(95% CI)

71%

(48, 85)

92%

(57, 99)

a Median DOR ("mDOR") not reached with median follow-up of 11.3 months.

b mDOR not reached.

c Includes 2 unconfirmed partial responses ("uPRs").

d Includes responses in patients previously treated with lorlatinib (ORR = 26% [50/190 including 2 uPRs] with mDOR = 17.6 months [95% CI: 6.9, NE]).

e For patients receiving only 1 prior 2nd generation ALK TKI (alectinib [n = 44] or brigatinib [n = 2]) ± chemotherapy, ORR was 48% (22/46) with mDOR not reached, and DOR ≥ 12 and 18 months of 74% (95% CI: 48, 88).

f Estimated for responders by Kaplan-Meier analysis.

g ALK G1202R mutation identified in local or central testing of blood ("ctDNA") or tissue. Patients may have had other mutations in addition to ALK G1202R.

h Includes responses in patients with compound ALK mutations (≥2 ALK mutations, cis allelic configuration not determined in all cases) after ≥ 2 prior ALK TKIs (ORR = 58% [25/43, including 1 uPR] with DOR ≥ 12 months of 69% [95% CI: 45, 84]) and in patients with ALK resistance mutations other than G1202R, including C1156Y, I1171N, I1171T, F1174C, F1174L, V1180L, L1196M, L1198F, D1203N, E1210K, and G1269A.

i Includes 1 uPR.

j For intracranial ("IC") responders, the emerging IC-mDOR was 21.6 months (95% CI: 10.1, NE) and continues to mature.

k For IC-responders, the emerging IC-mDOR was 21.6 months (95% CI: 21.6, NE) and continues to mature.

l Includes 2 IC-uPRs.

m IC responses were also observed in lorlatinib-experienced patients with measurable CNS lesions at baseline (IC-ORR = 21%, 14/68) with IC-mDOR not reached, IC-DOR ≥ 6 months of 71% (95% CI: 41, 88), and IC-DOR ≥ 12 and 18 months of 55% (95% CI: 26, 77).

n Includes 1 IC-uCR with prior confirmed IC-PR.

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, the Company’s Phase 3 randomized controlled trial of neladalkib versus alectinib.

Safety Analyses in Advanced ALK-positive NSCLC

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 (the "FDA") at a pre-New Drug Application ("NDA") meeting. Additionally, the Company plans to present detailed study results at a future medical meeting.

(Press release, Nuvalent, NOV 17, 2025, View Source [SID1234660025])