P45.07 Real-World Clinically-Relevant Toxicities of ALK TKIs in a Cohort of Patients With Advanced/Metastatic ALK+ NSCLC

Abstract

Treatment with ALK-TKIs significantly prolongs overall survival (OS) in patients with ALK+ non-small cell lung cancer (NSCLC). Approximately 20-40% of patients experience adverse events (AEs) leading to dose reductions/temporary discontinuation in the published phase III trials and permanent treatment discontinuation due to toxicity in approximately 5-15%. Toxicity profiles of the different inhibitors overlap but some are also distinct. We describe rates of clinically-significant AEs and specific toxicity profiles in a real-world cohort of patients with ALK+ NSCLC. Patients with ALK+ advanced NSCLC at Princess Margaret Cancer Centre were included in this analysis; date of data cut-off was March 18, 2021. All AEs leading to treatment modifications were abstracted retrospectively along with clinico-demographic, treatment and survival data. Treatment modifications included dose reduction and temporary/ permanent discontinuation due to toxicity. Of 147 patients with advanced ALK+ NSCLC, 138/94% received at least one ALK-TKI: alectinib (103/75%), crizotinib (75/54%), ceritinib (31/22%), lorlatinib (27/20%) and brigatinib (22/16%). In total, 258 individual ALK TKI lines (138 first-line, 72 second-line, 30 third-line, 20 fourth-to-seventh lines) of TKI-treatment were given. Median follow-up time was 26.4 months; 79 patients in active follow-up had ongoing ALK-TKI treatment at data cut-off. Summing all treatment durations, median (IQR) duration of receiving any ALK-TKI therapy/patient was 19.1 (29.0) months. While on ALK-TKI, 170 adverse events (AE) leading to treatment modifications occurred. In 112/66% cases these were related to a single AE: 59/53% were attributed to symptomatic toxicities; 53/47% were attributed to asymptomatic laboratory abnormalities. In contrast, 58/34% treatment modifications were attributed to a combination of AEs. Combined AEs were mostly symptom-related (23/40%) and symptom and lab-related (30/52%) and only rarely driven by multiple asymptomatic laboratory abnormalities alone (5/8%). Overall, 74/54% patients had at least one ALK-TKI treatment modification due to toxicity. Older aged patients (median age 62 vs 53 years, p=0.007) and never-smokers (84% vs 68%, p=0.04) were significantly associated with increased risk of AEs leading to treatment modification. Counting only one treatment modification per patient per ALK-TKI, treatment modifications occurred in 102/40% treatment lines: 28/37% patients on crizotinib, 19/61% with ceritinib, 33/32% with alectinib, 9/41% with brigatinib, and 8/30% with lorlatinib. Permanent discontinuation was observed in 63/24% treatment lines overall and in a much higher rate with crizotinib and ceritinib (45/43%) compared to the new generation-TKIs (alectinib, brigatinib and lorlatinib; 18/12%). As expected, AEs leading to treatment modifications were mainly gastrointestinal (26%) and liver toxicity (16%) with crizotinib and ceritinib, whereas the spectrum of AEs with the new-generation TKIs (alectinib, brigatinib, lorlatinib) leading to treatment modifications was broader, with less gastrointestinal (7%) and liver toxicity (10%) but more myalgia/CK elevation (6%) and slightly more neurotoxicity (5%). Median overall survival (OS) in patients with at least one treatment modification trended, but was not significantly different from patients without any treatment modification (47.0 vs 57.8 months, p=0.09). In a real-world cohort, treatment modifications on ALK-TKI were needed frequently, even with the newer generation of ALK-TKIs, highlighting the importance of availability of different ALK-TKIs for patients experiencing AEs to ensure tolerable targeted treatment.