Alectinib Receives FDA Approval for Early-Stage ALK-Positive Lung Cancer

On April 18, 2024, the US Food and Drug Administration (FDA) approved adjuvant alectinib (Alecensa, Genentech, Inc.) after surgery for ALK-positive non-small cell lung cancer (NSCLC).

Lung cancer remains the world's most common cancer and leading cause of cancer death, with 2.5 million new diagnoses each year. It is now clear that it is not one disease but several biological subtypes requiring different treatments. One is ALK-positive non-small cell lung cancer (NSCLC), characterized by rearrangement of the anaplastic lymphoma kinase (ALK) gene. ALK positivity occurs in approximately 5% of NSCLC and is generally seen in younger people who do not smoke.

Early-stage ALK-positive NSCLC is particularly important because complete surgical removal is possible. Recurrence risk persists after surgery, however, increasing the importance of adjuvant treatments—additional therapies intended to prevent the disease from returning.

Traditionally, platinum-based chemotherapy has been standard adjuvant treatment at this stage. ALK-targeted therapies have generally been used in advanced disease, particularly stage 4, with FDA approvals restricted to advanced ALK-positive NSCLC based on clinical trials. Demonstrating efficacy in advanced cancer is easier because survival outcomes become available sooner. Research in early-stage lung cancer, such as the April 10, 2024, NEJM publication of ALINA, requires longer-term results to assess targeted drugs. Such research shows that ALK inhibitors, including alectinib, may be effective in early-stage NSCLC and produce better outcomes than chemotherapy, suggesting the potential to transform treatment.

The ALINA Clinical Trial

Below is the design of ALINA, a global phase 3, open-label randomized trial in early-stage ALK-positive NSCLC:

• Participants: Patients had completely resected ALK-positive NSCLC at stage IB (tumors ≥4 cm), II or IIIA.

• Treatment Arms: Patients were randomized 1:1 to:

  • Oral alectinib: Alectinib 600 mg orally twice daily for 24 months.

  • Intravenous Platinum-Based Chemotherapy: Four cycles of intravenous platinum-based chemotherapy, each lasting 21 days (3 months in total).

• Primary Endpoint: Disease-free survival was tested hierarchically first in stage II or IIIA patients, then across the entire population.

• Other Endpoints:

  • Central Nervous System (CNS) Disease-Free Survival: Measured how long patients survived without CNS recurrence.

  • Overall Survival: Patients' total survival was followed.

  • Safety: Safety profiles and potential adverse events were examined in detail.

Results

• Participants and Groups:

  • The study enrolled 257 patients.
  • Of these, 130 were randomized to alectinib and 127 to chemotherapy.

• Results at 2 Years:

  • Among stage II or IIIA NSCLC patients, at 2 years:
    • Disease-free survival with alectinib was 93.8%,
    • compared with 63% with chemotherapy.
  • Across All Participants:
    • Alectinib: 93.6%,
    • Chemotherapy: 63.7%.

• Statistical Assessment:

  • Hazard ratio for recurrence or death:
    • Stage II or IIIA: 0.24 (95% confidence interval [CI], 0.13 - 0.45; P<0.001)
    • Entire population: 0.24 (95% CI, 0.13 - 0.43; P<0.001).
  • In other words, postoperative alectinib in early-stage ALK-positive lung cancer reduced disease recurrence and death risk by 76% compared with chemotherapy.

• Central Nervous System (CNS) Survival:

  • Alectinib provided a clinically meaningful benefit in CNS disease-free survival versus chemotherapy.
  • It reduced CNS recurrence or death risk by 78% (hazard ratio 0.22; 95% CI, 0.08 - 0.58).

• Overall Survival and Safety:

  • Overall survival data were still immature.
  • No unexpected safety findings were observed.

In conclusion, ALK inhibitors offer high disease-free survival rates and the potential to extend overall survival, including in the central nervous system, for ALK-positive patients. Strong scientific grounds are therefore emerging for adopting ALK-targeted treatment as a new standard in early-stage lung cancer. The findings offer hope for preventing recurrence and improving quality of life.