NVL-655 for TKI-naive Patients With Advanced ALK-Positive NSCLC

Phase 3

Not yet recruiting

• Conditions: Non-small Cell Lung Cancer; Anaplastic Lymphoma Kinase-positive
• Interventions: Drug: NVL-655; Drug: Alectinib

• Registration Number: NCT06765109
• Lead Sponsor: Nuvalent Inc.

Brief Summary

Multicenter, randomized, controlled, open-label, Phase 3 study designed to demonstrate that NVL-655 is superior to alectinib in prolonging progression-free survival (PFS) in patients with treatment-naïve, Anaplastic Lymphoma Kinase (ALK) positive, advanced Non-Small Cell Lung Cancer (NSCLC).

Detailed Description

Patients will be randomized in a 1:1 ratio (approximately 225 in each arm) to receive either NVL-655 or alectinib.

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Status Verified: 2024-11
• Study First Submitted: 2024-11-08
• Study Start: 2025-01
• Study First Submitted QC: 2025-01-02
• Last Update Submitted: 2025-01-02
• Study First Posted: 2025-01-09
• Last Update Posted: 2025-01-09
• Primary Completion: 2029-10
• Study Completion: 2029-10

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 450

Inclusion Criteria

1. Histologically or cytologically confirmed locally advanced (not amenable for multimodality treatment) or metastatic Non-small Cell Lung Cancer (NSCLC)
2. Documented Anaplastic Lymphoma Kinase (ALK) rearrangement via testing of tissue or blood
3. No prior systemic anticancer treatment for NSCLC (adjuvant/neoadjuvant chemotherapy allowed if 12 months prior to randomization; prior ALK tyrosine kinase inhibitor [TKI] such as alectinib is not allowed in any setting)
4. Measurable disease (1 or more target lesions per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
5. Pretreatment tumor tissue (archived or a fresh biopsy)
6. Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2

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Exclusion Criteria

1. Patient's cancer has a known oncogenic driver alteration other than ALK.
2. Known allergy/hypersensitivity to excipients of NVL-655 or alectinib.
3. Ongoing or recent radiotherapy as per protocol-specified timeframes prior to randomization
4. Major surgery within 4 weeks prior to randomization
5. Uncontrolled clinically relevant infection requiring systemic therapy
6. Known active tuberculosis, or active Hepatitis B or C
7. QT corrected for heart rate by Fridericia's formula (QTcF) > 470 msec on repeated assessments
8. Clinically significant cardiovascular disease
9. Brain metastases associated with progressive neurological symptoms or requiring increasing doses of corticosteroids to control CNS disease
10. Active malignancy requiring therapy within 2 years prior to randomization

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NVL-655	NVL-655	150mg taken orally once daily (QD)
Alectinib	Alectinib	600mg taken orally twice daily (BID)

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS) per blinded independent central review (BICR)	Up to 5 years after first patient dosed	Time from randomization to BICR-assessed radiographic disease progression or death

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	Up to 5 years after first patient dosed	Time from randomization to death
Progression-free survival (PFS) per investigator assessment	Up to 5 years after first patient dosed	Time from randomization to investigator-assessed radiographic disease progression or death
Time to intracranial progression per BICR	Up to 5 years after first patient dosed	Time from randomization to the first BICR-assessed occurrence of disease progression in the central nervous system (CNS)
Intracranial objective response rate (IC-ORR)	Up to 5 years after first patient dosed	Proportion of patients with a confirmed intracranial response (intracranial complete response \[IC-CR\] or intracranial partial response \[IC-PR\]) among patients with measurable CNS disease at baseline
Intracranial duration of response (IC-DOR)	Up to 5 years after first patient dosed	Time from first intracranial response (IC-CR or IC-PR) to radiographic intracranial disease progression or death
Objective response rate (ORR)	Up to 5 years after first patient dosed	Proportion of patients with a complete response or partial response
Duration of response (DOR)	Up to 5 years after first patient dosed	Time from first response (complete or partial) to radiographic disease progression or death
Intracranial progression per investigator assessment	Up to 5 years after first patient dosed	Time to investigator-assessed intracranial progression
Treatment-emergent adverse events (TEAEs) and changes in clinically relevant laboratory parameters	Up to 5 years after first patient dosed	Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters
Patient-reported measures in health-related quality of life (QoL)	Up to 5 years after first patient dosed	Changes in patient-reported outcomes (PROs) assessed by the European Organization for Research and Treatment of Cancer QoL core questionnaire - Cancer (EORTC QLQ-C30)
Patient-reported measures in lung cancer symptoms and side effects of treatment	Up to 5 years after first patient dosed	Changes in PROs assessed by the European Organization for Research and Treatment of Cancer QoL - Lung Cancer module (EORTC QLQ-LC29)
Patient-reported measures in patient functioning	Up to 5 years after first patient dosed	Changes in PROs assessed by the European Quality of Life (EuroQol) 5-dimension questionnaire (EQ-5D-5L)