Outcomes of ALK + non-small cell lung cancer (NSCLC) patients treated with ALK inhibitors in the clinical trial setting and in a referral Institution.
Authors: Matres Rojo Ana , Felip Enriqueta , Dienstmann Rodrigo , Navarro Garces Victor , Viaplana Cristina 
Published: June 2022

e20604

Background: ALK rearrangements are present in 5% of NSCLC patients and its identification is of relevance as it confers sensitivity to ALK tyrosine kinase inhibitors (ALK-TKI). This study pretends to show treatment response and survival outcome in ALK+ patients treated in clinical trials at Vall Hebron Institute of Oncology (VHIO). Methods: This retrospective study includes 109 patients with ALK+ stage IV NSCLC, treated between 2010 and 2020 in the clinical trial setting. Objective response rate (ORR), progression free survival (PFS), overall survival from metastatic diagnosis (OS-d) and overall survival from targeted therapy start (OS-t) were assessed. A Multivariate Cox regression was applied to determine correlations between clinical features and OS-d. Results: Out of 109 patients with ECOG 0-1, 67% were women and 33% men. Median age at diagnosis was 53 yr, 64% were never-smokers, 30% former smokers, 5% current smokers. Histology was mainly adenocarcinoma (96%) and brain metastases were present in 58% cases at clinical trial treatment initiation. 13% of patients were treatment-naive, 42% were ALK-TKI naïve, 39% had previously received crizotinib, 21% had previously received second-generation ALK-TKIs. Most patients were treated in phase I clinical trials (54%), followed by phase II (22%), III (19%) and IV (5%). 7% were treated with crizotinib, 66% were treated with second-generation ALK-TKIs, 27% were treated with third-generation ALK-TKIs. Global ORR was 69% (83% in ALK-TKI naïve patients, 69% in patients previously treated with crizotinib and 56% in patients previously treated with a second-generation ALK-TKI) with no differences between patients with and without brain disease at study entry (68% vs. 70%). Median PFS was 16 months (m) (95% CI 11-24), 30m in ALK-TKI naïve patients (p = 0.06), 10m in patients previously treated with crizotinib (p = 0.04) and 10m in patients previously treated with second-generation ALK-TKIs (p < 0.001). No significant differences were seen between patients with and without brain metastasis at study entry (11 m vs. 16 m, p = 0.64). Global OS-d was 71m. Global OS-t was 60m. Multivariate Cox analysis showed smoking history [HR = 0.66 p = 0.358], presence of brain metastatic disease at clinical trial inclusion [HR = 0.87 p = 0.73] or gender [HR = 1.74 p = 0.231] did not affect OS-d. Having received, at least, a second generation ALK-TKI prolonged OS-d (p = 0.007) as well as having received third generation ALK-TKIs [HR 0.09, p < 0.001]. Conclusions: Clinical trials represent an opportunity of access to novel therapies and may provide an alternative for patients with no treatment options. This study, with 54% of patients treated in phase I clinical trials, has shown high ORR and prolonged PFS and OS for ALK + patients, regardless of brain disease extension. Sequential therapy with ALK inhibitors has also been proven important for OS.