Neladalkib for Non-Small Cell Lung Cancer

(ALKAZAR Trial)

Recruiting at 1 trial location

Overseen By Nuvalent Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Nuvalent Inc.

Must not be taking: ALK inhibitors

Disqualifiers: Other oncogenic drivers, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 5 years

450 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that you cannot have had prior treatment with ALK inhibitors like alectinib.

What data supports the effectiveness of the drug Alectinib, which is part of the treatment Neladalkib for Non-Small Cell Lung Cancer?

Research shows that Alectinib, a drug used in Neladalkib, significantly improves progression-free survival (the time during which the cancer does not get worse) and has a good response rate in the brain for patients with ALK-positive non-small-cell lung cancer, especially those who have been treated with other drugs like crizotinib. ^{1 2 3 4 5}

Is Neladalkib (Alectinib) safe for humans?

Alectinib, also known as Neladalkib, is generally well tolerated but can cause serious side effects, such as hyperbilirubinemia (high levels of bilirubin in the blood). It has been studied for safety in patients with non-small cell lung cancer. ^{1 6 7 8 9}

What is the purpose of this trial?

Multicenter, randomized, controlled, open-label, Phase 3 study designed to demonstrate that neladalkib (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).

Research Team

Viola Zhu, MD, PhD

Principal Investigator

Nuvalent Inc.

Eligibility Criteria

This trial is for patients with advanced ALK-positive NSCLC who haven't had any systemic anticancer treatments (except certain chemotherapies over a year ago). They must have measurable disease, documented ALK rearrangement, and be in good enough health to perform daily activities.

Inclusion Criteria

I can provide samples of my tumor before treatment.

My cancer has at least one tumor that can be measured.

My lung cancer is advanced and cannot be treated with combined therapies.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either neladalkib (NVL-655) or alectinib to assess progression-free survival

Up to 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Alectinib
• Neladalkib (NVL-655)

Trial Overview The study compares Neladalkib (NVL-655) with Alectinib to see which is better at delaying cancer progression in treatment-naive patients. It's a Phase 3 trial where participants are randomly assigned to one of the two drugs.

Participant Groups

Group I: Neladalkib (NVL-655) Experimental Treatment 1 Intervention

150mg taken orally once daily (QD)

Group II: Alectinib Active Control 1 Intervention

600mg taken orally twice daily (BID)

Who Is Running the Clinical Trial?

Nuvalent Inc.

Lead Sponsor

Trials

6

Recruited

1,400+

Findings from Research

In a phase 3 trial involving 207 Japanese patients with ALK-positive non-small-cell lung cancer, alectinib demonstrated significantly better progression-free survival compared to crizotinib, with a hazard ratio of 0.34, indicating a strong efficacy advantage for alectinib.

Alectinib also showed a better safety profile, with fewer grade 3 or 4 adverse events (26% vs. 52% for crizotinib) and lower rates of treatment discontinuation due to adverse effects, suggesting it may be a safer first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Hida, T., Nokihara, H., Kondo, M., et al.[2022]

In a phase 2 study involving 87 patients with ALK-positive non-small-cell lung cancer who had progressed after crizotinib, alectinib demonstrated a 48% objective response rate, indicating significant clinical activity.

Alectinib was generally well tolerated, with most adverse events being mild (grade 1 or 2), although there were some serious events related to laboratory values; this suggests it could be a suitable treatment option for patients who have not responded to crizotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Shaw, AT., Gandhi, L., Gadgeel, S., et al.[2022]

Alectinib significantly improved progression-free survival (PFS) compared to chemotherapy, with a median PFS of 10.9 months versus 1.4 months in patients with advanced ALK-positive non-small-cell lung cancer.

The objective response rate (ORR) was also much higher with alectinib at 50.6% compared to only 2.5% with chemotherapy, and it showed a remarkable CNS ORR of 66.7% in patients with measurable CNS metastases, indicating its efficacy in treating brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. Wolf, J., Helland, Å., Oh, IJ., et al.[2022]

Alectinib is an effective first-line treatment for metastatic ALK-positive non-small cell lung cancer (NSCLC), but it can lead to rare complications such as pneumoperitoneum, as seen in a case involving a 74-year-old female patient.

The pneumoperitoneum in this case was likely due to rapid tumor regression in the gastrointestinal tract, highlighting the need for oncologists to monitor for gastrointestinal perforation when starting treatment with alectinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib-associated pneumoperitoneum in stage IV non-small cell lung cancer - A case report. Maina, RM., Rader, CA., Muenyi, CS., et al.[2022]

Two cases of early-stage ALK-positive non-small cell lung cancer (NSCLC) showed complete pathological responses after receiving over 30 weeks of neoadjuvant alectinib, indicating its potential effectiveness in this setting.

A systematic review of the literature, which included seven additional cases, supports the feasibility of using neoadjuvant alectinib for resectable NSCLC, but emphasizes the need for larger clinical trials to confirm its efficacy and optimal treatment duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathological complete response to long-course neoadjuvant alectinib in lung adenocarcinoma with EML4-ALK rearrangement: report of two cases and systematic review of case reports. Shi, L., Gao, S., Tong, L., et al.[2023]

Alectinib shows a high overall response rate of 70% and a disease control rate of 88% in treating non-small cell lung cancer, based on a meta-analysis of 8 studies involving 626 patients.

While alectinib is generally well-tolerated, it has a higher incidence of certain side effects like myalgia (18%) and anemia (25%) compared to the first-generation ALK inhibitor crizotinib, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of alectinib in the treatment of ALK+ NSCLC: a systematic review and meta-analysis. Fan, J., Xia, Z., Zhang, X., et al.[2022]

Alectinib is an effective next-generation ALK inhibitor for patients with metastatic ALK-positive non-small-cell lung cancer (NSCLC), showing improved progression-free survival and a reduction in brain metastases compared to crizotinib, especially in patients who are intolerant or have progressed on crizotinib.

Common side effects of alectinib include fatigue, constipation, and peripheral edema, with more serious effects being increases in liver enzymes and creatine phosphokinase, indicating it is generally well-tolerated in clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib for advanced ALK-positive non-small-cell lung cancer. Ly, AC., Olin, JL., Smith, MB.[2019]

Alectinib, while effective for treating advanced non-small-cell lung cancer (NSCLC) with ALK rearrangements, can lead to serious side effects such as grade 4 hyperbilirubinemia, as seen in a patient after five months of treatment.

After discontinuing alectinib and using an artificial liver support system to manage the hyperbilirubinemia, the patient was successfully treated with ensartinib, achieving stable disease without recurrence of hyperbilirubinemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC. Peng, L., Xiao, K., Cui, J., et al.[2022]

Alectinib significantly improves overall survival compared to crizotinib in patients with metastatic or locally advanced ALK-positive non-small cell lung cancer (NSCLC), based on a systematic review of 13 randomized controlled trials.

In terms of progression-free survival, alectinib also outperformed crizotinib and ceritinib, demonstrating a favorable safety profile compared to other ALK inhibitors, particularly in patients with brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis. Samacá-Samacá, D., Prieto-Pinto, L., Peréz, AY., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Alectinib-associated pneumoperitoneum in stage IV non-small cell lung cancer - A case report. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Pathological complete response to long-course neoadjuvant alectinib in lung adenocarcinoma with EML4-ALK rearrangement: report of two cases and systematic review of case reports. [2023]

6. New Zealand pubmed.ncbi.nlm.nih.gov

The efficacy and safety of alectinib in the treatment of ALK+ NSCLC: a systematic review and meta-analysis. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Alectinib for advanced ALK-positive non-small-cell lung cancer. [2019]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis. [2023]