Rare ALK: Clinical characteristics and efficacy of targeted therapy in NSCLC with ALK fusions other than EML4::ALK.

Abstract

8625 Background: More than 90% of ALK rearrangements in NSCLC lead to recurrent fusions with EML4. The remainder is a heterogeneous group involving more than twenty different fusion partners. Data on prognosis and management of these patients is limited to case reports. Methods: This is an international, multicenter, retrospective analysis of advanced NSCLC patients with a non-EML4::ALK-fusion ( rare ALK ) compared to a control cohort of patients harboring typical EML4::ALK-translocations. Results: Out of 26,152 NSCLC patients tested by NGS 0.2% showed rare ALK with 21 distinct fusion partners identified. The prevalence of typical EML4::ALK fusions in the cohort was within the expected range (1.9%). Sufficient clinical data was available for a total of 51 rare ALK and 277 EML4::ALK patients. Median age within the rare ALK cohort was 66 years. 59% were male. The majority (88%) presented with adenocarcinoma, 10% had squamous-cell carcinoma. The choice of first-line TKI in rare ALK patients was similar to the EML4::ALK control cohort and with alectinib used predominantly (around 50%). Compared to EML4::ALK, patients with rare ALK were significantly older, more likely to have ever smoked (59% vs 35%) and, among smokers, had more pack years (15 vs 7 pack years). Objective response rate (ORR) to firstline ALK inhibitor treatment across all treatment lines in patients with rare ALK was 68% (95% confidence interval [CI] 53%-80%), while EML4::ALK patients had an ORR of 85% (CI 80%-89%; p=0.01). ALK inhibitors in first-line palliative treatment led to similar PFS in the rare ALK (23 months [mo]; CI 7.1-38.9) and the EML4::ALK cohort (25 mo; CI 19.9-30.1; HR 0.92; CI 0.6-1.5; p=0.7). Median overall survival (OS) was 40 mo (CI censored) for rare ALK compared to 57 mo (CI 50.7-63.3) for EML4::ALK (HR 0.9; CI 0.5-1.6; p=0.6). Within the rare ALK cohort, first-line treatment with platinum-doublet chemotherapy was associated with shorter PFS as compared to ALK inhibitors (5 mo vs 23 mo; HR 3.1; CI 1.2-8.0; p = 0.021) and trended towards shorter OS (24 mo vs 40 mo; HR 2; CI 0.7-5.9; p=0.2). Conclusions: Acknowledging the limitations of a retrospective analysis, our data suggest that, compared to EML4::ALK, patients with rare ALK fusions derive similar benefit from treatment with ALK inhibitors, which should be preferred over platinum-based therapies as first-line palliative treatment.