ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• ALK-positive lung cancers are molecularly diverse and prone to relapse due to drug resistance.
• Dynamic monitoring of circulating tumor DNA (ctDNA) offers insights into treatment selection pressure and resistance pathways.

Purpose of the Study:

• To investigate the feasibility, safety, and efficacy of fixed alternating cycles of lorlatinib and crizotinib in patients with ALK-positive non-small cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors.
• To explore the correlation between dynamic ctDNA profiles, treatment response, and disease recurrence.

Main Methods:

• The ALKTERNATE study was a single-arm, pilot investigation.
• Participants received alternating cycles of lorlatinib and crizotinib.
• ctDNA was used to monitor disease response, resistance, and correlate with survival outcomes.

Main Results:

• The alternating therapy demonstrated safety, feasibility, and effectiveness in 12 participants.
• Median time-to-treatment failure was 10 months, and overall survival was 23 months.
• ctDNA profiles identified inferior survival in patients with preexistent TP53 mutations or uncleared ctDNA at baseline.

Conclusions:

• The alternating ALK inhibitor strategy is feasible for ALK-positive NSCLC.
• Real-time plasma profiling can inform flexible treatment designs.
• This approach may also benefit treatment-naive patients.