A Phase 3 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 Compared to Alectinib in First-Line Treatment of Patients With ALK-Positive Advanced Non-Small Cell Lung Cancer (ALKAZAR)

More details:

Neladalkib (NVL-655, NUV-655) is a novel, brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to address limitations of previous generations of ALK inhibitors. It was developed to target anaplastic lymphoma kinase (ALK) alterations in non-small cell lung cancer (NSCLC) and other cancers, with activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations such as G1202R/L1196M and G1202R/G1269A [1]. A key design feature of neladalkib is its selectivity for ALK over tropomyosin receptor kinase B (TRKB), which may help avoid neurologic toxicities associated with TRKB inhibition seen with other ALK inhibitors [2].

Efficacy

In the Phase 1 portion of the ALKOVE-1 trial (NCT05384626), neladalkib demonstrated encouraging clinical activity in heavily pretreated ALK-positive NSCLC patients. Among 133 patients who received doses ranging from 15-200 mg once daily, the objective response rate (ORR) was 39% in the overall population of heavily pretreated patients [3]. Higher response rates were observed in specific subgroups: 52% in patients with CNS metastases, 54% in patients with ALK resistance mutations, and 71% in patients with ALK G1202R mutations [4]. The drug also showed activity in patients who had exhausted available therapies, including those previously treated with lorlatinib (a third-generation ALK inhibitor). The recommended Phase 2 dose was determined to be 150 mg once daily [3].

Safety

Neladalkib has demonstrated a favorable safety profile consistent with its ALK-selective, TRK-sparing design. In the ALKOVE-1 trial, side effects were reported to be minimal, with only 15% of patients requiring dose reductions and just 2% discontinuing treatment due to adverse effects [5]. The maximum tolerated dose was not reached during the Phase 1 portion of the trial [3]. This safety profile appears to support the drug's design goal of avoiding the neurological toxicities associated with TRK inhibition seen with other ALK inhibitors. Based on these promising results, neladalkib has received breakthrough therapy designation from the FDA, and the Phase 2 portion of the ALKOVE-1 trial is ongoing with registrational intent for previously treated patients [3].

Sources:

[1] Cancer Discovery Article on NVL-655 [2] AACR Journal Abstract on NUV-655/NVL-655 [3] Annals of Oncology ALKOVE-1 Trial Results [4] Nuvalent Press Release on Phase 1 Data [5] ALK Positive Organization Summary of ALKOVE-1 Results

Last updated: Apr 2025

• NVL-655 Preclinical Data and Early Clinical Results
  pubmed.ncbi.nlm.nih.gov
  This publication provides preclinical data and early clinical evidence supporting NVL-655, the investigational drug in the ALKAZAR trial. NVL-655 shows ">50-fold selectivity for ALK over 96% of the kinome tested" and "≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs." The article includes three case studies from an early phase I/II trial demonstrating "preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations."

Last updated: Apr 2025

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

Exclusion Criteria:

1. Patient's cancer has a known oncogenic driver alteration other than ALK.

2. Known allergy/hypersensitivity to excipients of neladalkib 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