Efficacy and Safety of Continuing Next-Generation ALK TKIs With Chemotherapy for Advanced ALK-Positive NSCLC: A Multicenter Retrospective Study

Background: Next-generation ALK tyrosine kinase inhibitors (TKIs; eg, alectinib, brigatinib, ceritinib, ensartinib, lorlatinib) are established first-line therapies for patients with ALK fusion–positive (ALK+) advanced/metastatic non–small cell lung cancer (NSCLC). Chemotherapy—with platinum/pemetrexed (PT/Pem) as the preferred regimen—is considered standard next-line therapy. However, limited data exist on outcomes of continuing next-generation ALK TKIs with subsequent PT/Pem after progression on TKI monotherapy. Patients and Methods: This multicentered, retrospective study included patients with ALK+ metastatic NSCLC who received PT/Pem alone or with alectinib or lorlatinib (PT/Pem/TKI) after progression on next-generation ALK TKIs. Endpoints included progression-free survival (PFS), overall survival (OS), 12-month cumulative incidence of intracranial progression, and treatment-related adverse events (trAEs). Results: We identified 156 patients, of whom 86 received PT/Pem and 70 received PT/Pem/TKI (alectinib: n=23; lorlatinib: n=47). Median PFS was numerically longer with PT/Pem/TKI versus PT/Pem (6.0 vs 3.5 months; hazard ratio [HR], 0.75; P =.11). In 78 patients treated with the current paradigm of first-line next-generation ALK TKIs, PT/Pem/TKI was associated with longer median PFS (6.6 vs 3.5 months; HR, 0.58; P =.042) and longer median OS (16.4 vs 11.4 months; HR, 0.55; P =.041) than PT/Pem alone. Among patients evaluable for intracranial outcomes (n=98), treatment with PT/Pem/TKI was associated with a significantly lower cumulative incidence of intracranial progression compared with PT/Pem alone (18.7% vs 34.0% at 12 months; HR, 0.33; P =.009). In the safety cohort (n=116), grade ≥3 trAEs occurred in 19 of 62 (30.6%) patients treated with PT/Pem, 5 of 18 (27.8%) patients treated with PT/Pem/alectinib, and 18 of 36 (50.0%) patients treated with PT/Pem/lorlatinib. There were no unanticipated safety signals in patients treated with PT/Pem plus alectinib or lorlatinib. Conclusions: Among patients who received next-generation ALK TKIs as first-line therapy, continuation of next-generation ALK TKI with PT/Pem led to longer PFS and OS than PT/Pem alone, with no unanticipated toxicities. The modest efficacy of PT/Pem-based regimens overall underscores the need for more effective therapies for TKI-refractory ALK+ NSCLC.