Efficacy and safety of second-line treatments in ALK mutation-positive advanced non-small cell lung cancer after second- or third-generation ALK inhibitors: Turkish Oncology Group real-life study (TOG study)

Abstract

Introduction The fusion mutation occurring in the anaplastic lymphoma kinase (ALK) gene is one of the most important driver mutations detected in the adenocarcinoma subtype of non-small cell lung cancer (NSCLC). In first-line treatment, second- and third-generation ALK inhibitors are recommended at the category 1 evidence. Data on the choice of sequential ALK inhibitor use are limited. This study aimed to evaluate real-life data of second-line treatments after potent ALK inhibitors.Methods Patients who received a second- or third-generation ALK inhibitor in the first-line treatment of metastatic ALK-positive NSCLC and received any subsequent treatment in the second line were included in the study. Demographic, clinical, and laboratory data were collected retrospectively. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Survival outcomes were estimated using the Kaplan-Meier method. Response rates and safety data were analyzed using descriptive statistics.Results 98 patients were included in the study. In the first-line treatment, 88.8% (n = 87) of the patients received alectinib, 5.1% (n = 5) brigatinib, 4.1% (n = 4) ceritinib, and 2% (n = 2) lorlatinib. 38.8% (n = 38) of the patients received chemotherapy before ALK inhibitor. The most common second-line treatment was lorlatinib with 74.5% (n = 73). 17.3% (n = 17) patients received chemotherapy, 5.1% (n = 5) patients received brigatinib, one patient each (1%) received alectinib, ceritinib and pembrolizumab. At a median follow-up of 12.2 months, the estimated median OS was 7.3 months (95% CI, 1.9-12.7) and the median PFS was 4.6 months (95% CI, 2.6-6.6). Median OS was 11.6 months (95% CI, 6.5-16.8) in patients receiving ALK inhibitors in second-line treatment and 4 months (95% CI, 2.7-5.3) in patients receiving chemotherapy (p = 0.001). The median PFS in these groups was 5.9 months (95% CI, 4.4-7.5) and 2.5 months (95% CI, 1.2-3.8), respectively (p = 0.001).Conclusions The efficacy of second-line ALK inhibitors is limited in patients receiving potent treatments such as second- and third-generation ALK inhibitors. These findings highlight the limited efficacy of currently available second-line treatment options after failure of potent ALK inhibitors and underscore the need for improved treatment strategies in this setting. Lorlatinib is the most important treatment option in second line, and our results are consistent with real-life data.