NUVL announces pivotal ALKOVE-1 neladalkib results and plans pre-NDA

Rhea-AI Filing Summary

Nuvalent, Inc. reported positive topline pivotal data for neladalkib, its 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 trial. Among 253 evaluable TKI pre-treated patients treated at the recommended Phase 2 dose, the objective response rate was 31%, rising to 46% in the 63 lorlatinib‑naïve patients, with high estimated durability of responses through 18 months. Strong activity was also observed in patients with the G1202R resistance mutation and those with measurable brain metastases, including intracranial complete responses.

Nuvalent also shared encouraging preliminary data in 44 TKI‑naïve advanced ALK‑positive NSCLC patients, showing an 86% objective response rate and 9% complete response rate, with most responses ongoing beyond 6 and 12 months. Across 656 NSCLC patients treated at the recommended dose, neladalkib showed a generally well‑tolerated safety profile; the most common side effects were liver enzyme elevations and manageable gastrointestinal and constitutional events, with 17% requiring dose reductions and 5% discontinuing due to adverse events. The company plans a pre‑NDA meeting with the FDA and continues its Phase 3 ALKAZAR trial versus alectinib.

Positive

• Robust efficacy in difficult ALK NSCLC populations: Neladalkib achieved a 31% ORR in 253 TKI pre-treated patients, with higher response rates in lorlatinib-naïve, G1202R-mutant, and CNS-involved subgroups, alongside high estimated durability of response.
• Compelling early-line and intracranial activity: In 44 TKI-naïve advanced ALK-positive NSCLC patients, neladalkib showed an 86% ORR and strong intracranial responses without observed CNS progression among responders, supporting use in earlier lines of therapy.
• Manageable safety profile at scale: Among 656 NSCLC patients treated at the recommended dose, adverse events were generally manageable with 17% requiring dose reductions and 5% discontinuing, enabling continued development and planned FDA pre-NDA discussions.

Negative

• None.

Insights

Biotech equity analyst

Strong neladalkib efficacy and durability signal a potentially pivotal ALK NSCLC asset for Nuvalent.

The disclosed data position neladalkib as a competitive late‑stage ALK inhibitor candidate. In 253 TKI pre‑treated advanced ALK‑positive NSCLC patients at the recommended Phase 2 dose, the objective response rate of 31% and high response durability estimates out to 18% months address a heavily pre‑treated population. The lorlatinib‑naïve subgroup showed a higher 46% response rate, suggesting meaningful activity even after prior TKIs.

Importantly, activity in patients harboring the difficult G1202R resistance mutation (ORR 68%, rising to 83% in lorlatinib‑naïve G1202R patients) and in those with measurable CNS disease, including intracranial complete responses and durable intracranial benefit, supports a profile relevant to real‑world resistance patterns. Preliminary data in 44 TKI‑naïve patients, with an 86% ORR and 9% complete responses, extend the potential into earlier‑line treatment and underpin the ongoing ALKAZAR Phase 3 trial versus alectinib.

Safety appears manageable in 656 NSCLC patients at the recommended dose, with liver enzyme elevations and other adverse events largely handled by protocol‑directed monitoring, dose interruptions, and reductions; only 5% discontinued due to adverse events. The planned pre‑NDA meeting with the FDA for the TKI pre‑treated setting and the registrational intent of ALKOVE‑1 and ALKAZAR indicate that neladalkib has advanced into a registration‑directed phase of development, making these results strategically significant for Nuvalent’s pipeline and potential future revenue base.

Clinical oncology trial specialist

ALKOVE‑1 data show robust systemic and intracranial activity with a tolerable safety profile for neladalkib.

The ALKOVE‑1 design, pooling Phase 1 and 2 data at the recommended 150 mg once‑daily dose, offers a large safety and efficacy dataset: 781 ALK‑positive solid tumor patients overall and 656 NSCLC patients at the pivotal dose. The pivotal analysis focuses on blinded independent central review of response, with key secondary endpoints including duration of response and intracranial activity, aligning with regulatory expectations for a registration‑directed ALK NSCLC program.

The durability metrics are noteworthy: in the TKI‑pretreated group, Kaplan‑Meier estimates show that a majority of responders remain in response at 6, 12, and 18 months, and similar trends are seen in G1202R and CNS‑involved subgroups. In TKI‑naïve patients, very high response rates and early durability, combined with strong intracranial activity and absence of CNS progression among responders at the current follow‑up, support exploration in the frontline setting in the ALKAZAR Phase 3 trial.

On safety, the most frequent treatment‑emergent adverse events—particularly transaminase elevations—are described as mostly low‑grade, transient, and reversible with dose modifications. The implementation of enhanced liver monitoring and prompt dose interventions in ALKAZAR reflects a proactive safety management strategy based on ALKOVE‑1 experience. The overall pattern of manageable toxicity, modest discontinuation rates, and substantial antitumor activity supports continued development and regulatory discussions for neladalkib in ALK‑positive NSCLC.

8-K Event Classification

Item 8.01 — Other Events

1 item

Item 8.01 Other Events Other

Voluntary disclosure of events the company deems important to shareholders but not covered by other items.

Understanding 8-K Material Events →

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): November 17, 2025

NUVALENT, INC.

(Exact name of registrant as specified in its charter)

Delaware		001-40671		81-5112298
(State or other jurisdiction of incorporation)		(Commission File Number)		(I.R.S. Employer Identification No.)

Nuvalent, Inc.

One Broadway, 14th Floor, Cambridge, Massachusetts 02142

(Address of principal executive offices, including zip code)

(857) 357-7000

(Registrant’s telephone number, including area code)

Not Applicable

(Former Name or Former Address, if Changed Since Last Report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

Title of each class		Trade Symbol(s)		Name of each exchange on which registered
Class A Common Stock, $0.0001 par value per share		NUVL		The Nasdaq Global Select Market

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Item 8.01 Other Events.

On November 17, 2025, Nuvalent, Inc. (the “Company”) announced 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.

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 2^nd 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.

Cautionary Note Regarding Forward-Looking Statements

This Current Report on Form 8-K contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding the Company’s strategy, business plans, and focus; the expected timing of data announcements; the clinical development programs for the Company’s investigational product candidates, including neladalkib; the potential clinical effects of the Company’s investigational product candidates, including neladalkib; the design and enrollment of the Company’s clinical trials, including for the ALKOVE-1 and ALKAZAR trials their intended pivotal registration-directed design; the potential of the Company’s pipeline programs, including neladalkib, zidesamtinib and NVL-330; the implications of data readouts and presentations; timing and content of FDA submissions and interactions; the Company’s research and development programs for the treatment of cancer; and risks and uncertainties associated with drug development. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “aim,” “goal,” “intend,” “believe,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” or the negative of these terms and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. You should not place undue reliance on these statements or the scientific data presented.

Any forward-looking statements in this Current Report on Form 8-K are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties, and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this Current Report on Form 8-K, including, without limitation: risks that the Company may not fully enroll its clinical trials or that enrollment will take longer than expected; unexpected concerns that may arise from additional data, analysis, or results obtained during preclinical studies and clinical trials; the risk that preliminary results of clinical trials may not be predictive of future results from the same or other trials; the risk that results of earlier clinical trials may not be predictive of the results of later-stage clinical trials; the risk that data from the Company’s clinical trials may not be sufficient to support registration and that the Company may be required to conduct one or more additional studies or trials prior to seeking registration of zidesamtinib and neladalkib; the occurrence of adverse safety events; risks that the FDA may not approve the Company’s potential products on the timelines the Company expects, or at all; risks of unexpected costs, delays, or other unexpected hurdles; risks that the Company may not be able to nominate drug candidates from its discovery programs; the direct or indirect impact of public health emergencies or global geopolitical circumstances on the timing and anticipated timing and results of the Company’s clinical trials, strategy, and future operations, including the ALKOVE-1 and ALKAZAR trials; the timing and outcome of the Company’s planned interactions with regulatory authorities and the ability of the Company to interact with such officials as a result of

government shutdowns or other political circumstances; and risks related to obtaining, maintaining, and protecting the Company’s intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in the Company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2025, as well as any prior and subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent the Company’s views only as of today and should not be relied upon as representing its views as of any subsequent date. the Company explicitly disclaims any obligation to update any forward-looking statements.

SIGNATURE

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

				Nuvalent, Inc.
Date: November 17, 2025				By:		/s/ Deborah Miller
						Deborah Miller, Ph.D.
						Chief Legal Officer and Secretary

FAQ

What did Nuvalent (NUVL) announce about neladalkib in ALK-positive NSCLC?

Nuvalent announced positive topline pivotal data for neladalkib, its investigational ALK-selective inhibitor, from the global ALKOVE-1 Phase 1/2 trial in TKI pre-treated advanced ALK-positive NSCLC, along with encouraging preliminary data in TKI-naïve patients.

What were the key efficacy results for neladalkib in TKI pre-treated ALK-positive NSCLC?

In 253 TKI pre-treated patients with measurable advanced ALK-positive NSCLC at the recommended dose, neladalkib achieved an objective response rate of 31%, rising to 46% in the 63 lorlatinib-naïve patients, with high Kaplan-Meier estimates for maintaining responses up to 18 months.

How did neladalkib perform in patients with G1202R mutations and brain metastases?

Among patients with the G1202R mutation, neladalkib showed an ORR of 68%, and 83% in the lorlatinib-naïve G1202R subgroup. In patients with measurable CNS lesions, intracranial ORR reached 32% in the broader group and 63% in lorlatinib-naïve patients, including intracranial complete responses with durable intracranial benefit.

What were the preliminary results for neladalkib in TKI-naïve ALK-positive NSCLC patients?

In 44 TKI-naïve advanced ALK-positive NSCLC patients treated at the recommended dose, neladalkib showed an 86% objective response rate and a 9% complete response rate. Most responders maintained benefit at 6 and 12 months, and in 9 patients with measurable brain lesions the intracranial ORR was 78% with a 44% intracranial complete response rate.

What safety profile did neladalkib show in the ALKOVE-1 trial?

Across 656 advanced ALK-positive NSCLC patients treated at the recommended dose, the most frequent adverse events were liver enzyme elevations, constipation, dysgeusia, peripheral edema, cough, and nausea. These events were generally low-grade and manageable; 17% of patients required dose reductions and 5% discontinued due to treatment-emergent adverse events.

What are the next clinical and regulatory steps for neladalkib according to Nuvalent?

Nuvalent plans to discuss the topline pivotal data for TKI pre-treated ALK-positive NSCLC with the U.S. FDA at a pre-New Drug Application meeting. The company also continues global enrollment in ALKAZAR, a Phase 3 randomized controlled trial of neladalkib versus alectinib in TKI-naïve ALK-positive NSCLC, and intends to present detailed ALKOVE-1 results at a future medical meeting.