Clinical Perspectives and Emerging Updates in Advanced NSCLC
Panelists discuss how the unprecedented 5-year progression-free survival benefit (60% vs 8%) demonstrated in the CROWN trial supports starting with the most effective treatment (lorlatinib) up front rather than sequential therapy approaches.
Current treatment approaches for ALK-positive non–small cell lung cancer emphasize starting with the most effective available therapy rather than following sequential treatment paradigms that were historically used in EGFR-positive disease. This philosophy represents a fundamental shift from the earlier approach of starting with first-generation agents and advancing through subsequent generations upon progression. The overwhelming efficacy benefit demonstrated with lorlatinib in the CROWN trial, particularly the unprecedented 5-year progression-free survival probability exceeding 60%, supports this front-loading strategy for maximal initial disease control.
Treatment selection continues to require individualized approaches based on patient-specific factors, with particular attention to contraindications for lorlatinib, including significant psychiatric or neurological comorbidities that may be exacerbated by the agent’s central nervous system effects. For patients who cannot tolerate or have contraindications to lorlatinib, alectinib remains an excellent alternative with proven efficacy and generally favorable tolerability profile. The decision-making process involves careful assessment of patient motivation, support systems, and ability to manage potential adverse effects.
Recent updates from American Society of Clinical Oncology presentations have provided additional supportive data for flexible dosing approaches, demonstrating that patients who require dose modifications or treatment interruptions for lorlatinib still derive significant benefit from therapy. Furthermore, depth of response correlates with improved progression-free survival, supporting the strategy of maintaining patients on effective therapy even with dose adjustments when necessary. These findings are consistent with preclinical data suggesting that intermittent dosing may delay resistance development, providing theoretical support for individualized dosing strategies that optimize both efficacy and tolerability for long-term disease control.
