Efficacy of platinum/pemetrexed combination chemotherapy in ALK-positive non-small cell lung cancer refractory to second-generation ALK inhibitors

ABSTRACT Background The current standard initial therapy for advanced ALK-positive non-small cell lung cancer (NSCLC) is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in patients refractory to second-generation TKIs. Methods This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to ≥1 second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy. Results Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11/37; 95% CI, 15.9% to 47.0%), with median duration of response of 6.4 months (95% CI, 1.6 months to not reached). The median progression-free survival (PFS) for the entire cohort was 4.3 months (95% CI, 2.9 to 5.8 months). PFS was longer in patients who received platinum/pemetrexed in combination with an ALK TKI, compared to those who received platinum/pemetrexed alone (6.8 months vs 3.2 months, respectively; HR 0.33, p=0.025). Conclusions Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.