Nuvalent Announces Positive Topline Pivotal Data from ALKOVE-1 Clinical Trial of Neladalkib for TKI Pre-treated Patients with Advanced ALK-positive NSCLC
Nuvalent (Nasdaq: NUVL) reported positive topline pivotal data from the ALKOVE-1 Phase 1/2 trial for neladalkib in TKI pre-treated patients with advanced ALK-positive NSCLC (data cut-off Aug 29, 2025; primary cohort n=253).
Key efficacy: ORR 31% by BICR in the TKI pre-treated cohort and 46% in the lorlatinib‑naïve subset (n=63). Durability: estimated DOR ≥12 months of 64% overall and 80% in lorlatinib‑naïve patients; DOR ≥18 months of 53% and 60%, respectively. Intracranial activity and responses in ALK G1202R patients were reported. Safety: low discontinuation rate 5% and dose reductions 17%, with transaminase elevations noted.
Company plans a pre‑NDA meeting with FDA and will present detailed results at a future medical meeting.
Nuvalent (Nasdaq: NUVL) ha riportato dati pivotal positivi di topline dallo studio ALKOVE-1 di fase 1/2 per neladalkib in pazienti pre-trattati con TKI con NSCLC avanzato positivo per ALK (data cut-off 29 agosto 2025; coorte primaria n=253).
Efficacia chiave: ORR 31% secondo BICR nella coorte pre-trattata con TKI e 46% nella sotto-popolazione lorlatinib-naïve (n=63). Durata: DOR stimato ≥12 mesi del 64% in generale e 80% nei pazienti lorlatinib-naïve; DOR ≥18 mesi del 53% e 60%, rispettivamente. Attività intracranica e risposte nei pazienti ALK G1202R sono state riportate. Sicurezza: basso tasso di interruzione 5% e riduzioni della dose 17%, con elevazioni delle transaminasi segnalate.
La società prevede un incontro pre-NDA con la FDA e presenterà i risultati dettagliati in un futuro congresso medico.
Nuvalent (Nasdaq: NUVL) informó datos positivos de eficacia topline del ensayo ALKOVE-1 de fase 1/2 para neladalkib en pacientes pretratados con TKI con NSCLC avanzado ALK-positivo (corte de datos 29 de agosto de 2025; cohorte primaria n=253).
Eficacia clave: ORR 31% por BICR en la cohorte pretratada con TKI y 46% en la subpoblación lorlatinib-naïve (n=63). Durabilidad: DOR estimado ≥12 meses de 64% en general y 80% en pacientes lorlatinib-naïve; DOR ≥18 meses de 53% y 60%, respectivamente. Actividad intracraneal y respuestas en pacientes ALK G1202R reportadas. Seguridad: baja tasa de discontinuación 5% y reducciones de dosis 17%, con elevaciones de transaminasas observadas.
La compañía planea una reunión pre-NDA con la FDA y presentará resultados detallados en una próxima reunión médica.
Nuvalent (Nasdaq: NUVL)은 ALKOVE-1 1/2상에서 neladalkib의 긍정적인 topline 데이터를 TKI 선치료를 받은 진행성 ALK 양성 NSCLC 환자에서 보고했습니다(데이터 컷오프: 2025년 8월 29일; 주요 코호트 n=253).
핵심 효능지표: ORR 31% (BICR 기준) TKI 선치료 코호트에서, 46%는 lorlatinib-나이브 서브셋(n=63)에서 확인되었습니다. 지속성: 추정 DOR ≥12개월이 64%로 전반에 걸쳐 나타났고 lorlatinib-나이브 환자에서 80%였습니다; DOR ≥18개월은 각각 53%와 60%였습니다. 두개내 활동 및 ALK G1202R 환자에서의 반응도 보고되었습니다. 안전성: 중단률 5%, 용량 감소 17%, 트랜스아미네이스 상승이 보고되었습니다.
회사는 FDA와의 pre-NDA 회의를 계획하고 있으며 향후 의학 학회에서 자세한 결과를 발표할 예정입니다.
Nuvalent (Nasdaq: NUVL) a annoncé des données topline positives clés de l'essai ALKOVE-1 de phase 1/2 pour neladalkib chez des patients prétraités par TKI atteints d'un NSCLC avancé ALK-positif (données à la coupe au 29 août 2025; cohorte principale n=253).
Efficacité clé : ORR 31% selon BICR dans la cohorte prétraitée par TKI et 46% dans la sous-population lorlatinib-naïve (n=63). Durabilité : DOR estimé ≥12 mois de 64% dans l’ensemble et 80% chez les patients lorlatinib-naïve; DOR ≥18 mois de 53% et 60%, respectivement. Activité intracrânienne et réponses chez les patients ALK G1202R rapportées. Sécurité : faible taux d’interruption 5% et réductions de dose 17%, avec des élévations des transaminases notées.
L’entreprise prévoit une réunion pré-NDA avec la FDA et présentera les résultats détaillés lors d’une prochaine réunion médicale.
Nuvalent (Nasdaq: NUVL) meldete positive topline pivotal Daten aus der ALKOVE-1 Phase-1/2 Studie für neladalkib bei TKI-vorbehandelten Patientinnen und Patienten mit fortgeschrittenem ALK-positivem NSCLC (Daten-Cutoff am 29. August 2025; primäre Kohorte n=253).
Wichtige Wirksamkeit: ORR 31% nach BICR in der TKI-Vorbehandlungs-Kohorte und 46% in der lorlatinib-naiven Untergruppe (n=63). Dauerhaftigkeit: geschätzte DOR ≥12 Monate von 64% insgesamt und 80% bei lorlatinib-nahiven Patienten; DOR ≥18 Monate von 53% bzw. 60%. Intrakranielle Aktivität und Reaktionen bei ALK-G1202R-Patienten wurden berichtet. Sicherheit: niedrige Abbruchrate von 5% und Dosisreduktionen von 17%, mit Transaminasen-Hebungen.
Das Unternehmen plant ein Pre-NDA-Gespräch mit der FDA und wird die detaillierten Ergebnisse bei einer zukünftigen medizinischen Sitzung präsentieren.
Nuvalent (Nasdaq: NUVL) أبلغت عن بيانات topline حاسمة إيجابية من تجربة ALKOVE-1 من المرحلة 1/2 لـ neladalkib في مرضى مُعالجين بواسطة TKI سابقاً المصابين بـ NSCLC إيجابي لـ ALK في المراحل المتقدمة (قطع البيانات حتى 29 أغسطس 2025؛ العينة الأساسية n=253).
الفعالية الأساسية: ORR 31% وفقاً لـ BICR في مجموعة TKI قبل المعالجة و 46% في مجموعة lorlatinib-naïve (n=63). الاستمرارية: DOR المقدر ≥12 شهراً بنسبة 64% بشكل عام و 80% في المرضى lorlatinib-naïve؛ DOR ≥18 شهراً بنسبة 53% و 60% على التوالي. نشاط داخل الجمجمة والاستجابات لدى مرضى ALK G1202R أُبلغ عنها. السلامة: انخفاض معدل الإيقاف 5% وتقليل الجرعة 17%، مع ارتفاعات إنزيمات ناقلة.
تخطط الشركة لعقد اجتماع قبل NDA مع FDA وسيتم عرض النتائج التفصيلية في مؤتمر طبي مستقبلي.
- ORR 31% (79/253) by BICR in TKI pre-treated ALK-positive NSCLC
- ORR 46% (29/63) in lorlatinib‑naïve TKI pre-treated patients
- DOR ≥12 months 64% overall; 80% in lorlatinib‑naïve subset
- IC-ORR 32% overall; 63% in lorlatinib‑naïve patients with measurable CNS lesions
- ALK G1202R ORR 68% (32/47) in patients with G1202R mutation
- Low discontinuation 5% and dose reduction 17% due to TEAEs
- High transaminase rates: ALT increased 47%, AST increased 44%
- Median exposure 6.0 months (data maturity limited for long-term outcomes)
- Overall ORR modest 31% in heavily pre-treated population (median 3 prior lines)
Insights
Positive pivotal signals for neladalkib in heavily pre-treated ALK+ NSCLC, with notable intracranial activity and an FDA pre-NDA meeting planned.
Neladalkib produced an objective response rate of
The safety profile shows frequent transaminase elevations but mostly low‑grade, transient lab abnormalities; dose reductions occurred in
-
In 253 ALK TKI pre-treated patients, ORR by BICR was
31% (95% CI: 26, 37), with initial estimated durability of response of64% and53% at the 12-month and 18-month landmarks, respectively
-
In the subset of 63 TKI pre-treated patients who were lorlatinib-naïve, ORR by BICR was
46% (95% CI: 33, 59), with initial estimated durability of response of80% and60% at the 12- and 18-month landmarks, respectively
-
Neladalkib demonstrated intracranial responses, ability to address key drivers of disease progression, and a generally well-tolerated safety profile with low rates of dose discontinuation (
5% ) and dose reduction (17% ) due to TEAEs, consistent with its ALK-selective, TRK-sparing design
-
Company plans to discuss pivotal data for the TKI pre-treated ALK-positive NSCLC population with the FDA at a pre-NDA meeting; detailed study results are planned for presentation at a future medical meeting
- Company to host a conference call today, November 17th at 8:00am ET
"Today's announcement adds to the growing body of research that is transforming potential outcomes for ALK-positive lung cancer and offering new hope to patients," said Kirk Smith, patient and President of the Board of ALK Positive Inc. "We encourage the continued innovation and development of new therapeutic options for patients, with the hope that one day, advanced ALK-positive NSCLC could be managed as a chronic condition more often than as a life-threatening disease."
"In treating ALK-positive 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, M.D., Ph.D., a thoracic oncologist at Dana-Farber Cancer Institute and ALKOVE-1 trial investigator. "These encouraging topline data suggest that neladalkib may represent a new and differentiated treatment option for ALK positive lung cancer, offering durable clinical benefit while potentially reducing the risk of side effects that can affect quality of life."
"We are deeply grateful to the patients, caregivers and investigators who have made this milestone possible for our neladalkib program. I continue to be inspired by the unwavering dedication of the Nuvalent team to making a difference for patients, and humbled by the courage and conviction of the over 1,000 patients that have already chosen to receive neladalkib through either our ALKOVE-1 trial or our global Expanded Access Program," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "Our focus remains on delivering our precisely targeted therapies to patients as quickly as possible, and we look forward to discussing these pivotal data with the FDA and aligning on a potential registration path for neladalkib in TKI pre-treated patients with advanced ALK-positive NSCLC."
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 which91% had received prior lorlatinib. No approved therapies have demonstrated activity after lorlatinib.19% of patients had a secondary ALK G1202R resistance mutation, and17% 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% received prior chemotherapy.100% had received ≥ 1 prior 2G ALK TKI ± prior chemotherapy, of which70% 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 |
TKI Pre-treated, Lorlatinib-naïve b |
|
n |
253 |
63 |
|
ORR, % (n/N)
( |
(26, 37) |
(33, 59) |
|
% DOR ≥ 6 months f
( |
(64, 84) |
(69, 96) |
|
% DOR ≥ 12 months f
( |
(51, 75) |
(58, 91) |
|
% DOR ≥ 18 months f
( |
(34, 68) |
(19, 85) |
|
G1202R mutation g |
||
|
n |
47 |
12 |
|
ORR, % (n/N)
( |
(53, 81) |
(52, 98) |
|
% DOR ≥ 6 months f
( |
(65, 93) |
(47, 99) |
|
% DOR ≥ 12 months f
( |
(61, 91) |
(34, 94) |
|
% DOR ≥ 18 months f
( |
(42, 86) |
(34, 94) |
|
Measurable CNS lesions |
||
|
n |
92 j |
24 k |
|
IC-ORR, % (n/N)
( |
(22, 42) |
(41, 81) |
|
IC-CR, % (n/N) |
|
|
|
% IC-DOR ≥ 6 months f
( |
(59, 91) |
(57, 99) |
|
% IC-DOR ≥ 12 months f
( |
(48, 85) |
(57, 99) |
|
% IC-DOR ≥ 18 months f
( |
(48, 85) |
(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 =
e For patients receiving only 1 prior 2nd generation ALK TKI (alectinib [n = 44] or brigatinib [n = 2]) ± chemotherapy, ORR was 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 = i Includes 1 uPR.
j For intracranial (IC) responders, the emerging IC-mDOR was 21.6 months (
k For IC-responders, the emerging IC-mDOR was 21.6 months ( l Includes 2 IC-uPRs.
m IC responses were also observed in lorlatinib-experienced patients with measurable CNS lesions at baseline (IC-ORR = 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
Global enrollment of TKI-naïve patients is ongoing in ALKAZAR, Nuvalent'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 ≥
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
The company plans to discuss the topline pivotal data for TKI pre-treated ALK-positive NSCLC with the
Webcast and Conference Call Information
A conference call with management will be held today at 8:00 am ET. To access the call, please dial +1 (800) 836-8184 (domestic) or +1 (646) 357-8785 (international) at least 10 minutes prior to the start time and ask to be joined to the Nuvalent call.
Accompanying slides and a live video webcast will be available in the Investors section of the Nuvalent website at https://investors.nuvalent.com/events. A replay and accompanying slides will be archived on the Nuvalent website for 30 days.
About Neladalkib
Neladalkib is an investigational brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. Neladalkib is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors 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. Neladalkib has received breakthrough therapy designation from the
About the ALKOVE-1 Phase 1/2 and ALKAZAR Phase 3 Clinical Trials
The ALKOVE-1 trial (NCT05384626) is a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors. The completed Phase 1 portion enrolled ALK-positive NSCLC patients who previously received at least one ALK TKI, or patients with other ALK-positive solid tumors who had been previously treated or for whom no satisfactory standard of care exists. The Phase 1 portion of the trial was designed to evaluate the overall safety and tolerability of neladalkib, with additional objectives including determination of the recommended Phase 2 dose (RP2D), characterization of the pharmacokinetic profile, and evaluation of preliminary anti-tumor activity. The global, single arm, open label Phase 2 portion is designed 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 outside of NSCLC, and adolescent patients with ALK-positive NSCLC.
The ALKAZAR trial (NCT06765109) is a global, randomized, controlled trial designed to enroll approximately 450 patients with TKI-naïve ALK-positive NSCLC. Patients are randomized 1:1 to receive neladalkib or ALECENSA® (alectinib). The primary endpoint is progression free survival (PFS) based on Blinded Independent Central Review (BICR). Secondary endpoints include PFS based on investigator's assessment, and BICR assessment of objective response rate (ORR), intracranial objective response rate (IC-ORR), overall survival (OS), and safety.
About Nuvalent
Nuvalent, Inc. (Nasdaq: NUVL) is a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer, designed to overcome the limitations of existing therapies for clinically proven kinase targets. Leveraging deep expertise in chemistry and structure-based drug design, we develop innovative small molecules that have the potential to overcome resistance, minimize adverse events, address brain metastases, and drive more durable responses. Nuvalent is advancing a robust pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung cancer, and multiple discovery-stage research programs.
Forward-Looking Statements
This press release 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 Nuvalent's strategy, business plans, and focus; the expected timing of data announcements; the clinical development programs for our investigational product candidates, including neladalkib; the potential clinical effects of our investigational product candidates, including neladalkib; the design and enrollment of Nuvalent's clinical trials, including for the ALKOVE-1 and ALKAZAR trials their intended pivotal registration-directed design; the potential of Nuvalent's pipeline programs, including neladalkib, zidesamtinib and NVL-330; the implications of data readouts and presentations; timing and content of FDA submissions and interactions; Nuvalent'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," "expect," "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 press release 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 press release, including, without limitation: risks that Nuvalent 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 our clinical trials may not be sufficient to support registration and that Nuvalent 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 our potential products on the timelines we expect, or at all; risks of unexpected costs, delays, or other unexpected hurdles; risks that Nuvalent 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 Nuvalent's clinical trials, strategy, and future operations, including the ALKOVE-1 and ALKAZAR trials; the timing and outcome of Nuvalent's planned interactions with regulatory authorities and the ability of Nuvalent to interact with such officials as a result of government shutdowns or other political circumstances; and risks related to obtaining, maintaining, and protecting Nuvalent's intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Nuvalent'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 Nuvalent's views only as of today and should not be relied upon as representing its views as of any subsequent date. Nuvalent explicitly disclaims any obligation to update any forward-looking statements.
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FAQ
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