Brigatinib vs alectinib in crizotinib-refractory advanced ALK+ NSCLC by James Chih-Hsin Yang et al.
In November 2022, a paper by James Chih-Hsin Yang et al. was published in Annals of Oncology:
Authors: James Chih-Hsin Yang, Geoffrey Liu, Shun Lu, Jianxing He, Mauricio Burotto, Sylvie Vincent, Jiani Yin, Xin Ma, Sanjay Popat.
The ALTA-3 trial (NCT03596866) was a phase 3 study designed to compare the efficacy of brigatinib (BRG) and alectinib (ALC) in patients with ALK-positive non-small cell lung cancer (NSCLC) who had progressed on the first-generation ALK inhibitor crizotinib (CRZ).
While prior single-arm trials reported median progression-free survival (mPFS) of less than 12 months for ALC and over 16 months for BRG, ALTA-3 aimed to determine whether BRG was superior in this setting. Patients were randomized 1:1 to either BRG 180 mg once daily (with a 7-day lead-in at 90 mg) or ALC 600 mg twice daily.
The primary endpoint was BIRC-assessed PFS, with secondary endpoints including overall survival (OS), objective response rate (ORR), and safety. Patients were stratified based on baseline brain metastases (BL BM) and best response to prior CRZ.
At the interim analysis (IA) after 107 PFS events (43% of patients), BRG and ALC demonstrated nearly identical median PFS (19.3 vs. 19.2 months; HR 0.97, P=0.867), failing to show BRG superiority. The trial met futility criteria (P>0.6948) and was discontinued. OS data remained immature.
ORR was 52% for BRG and 61% for ALC, while intracranial ORR in patients with measurable BL BM was 73% vs. 68%. BRG had higher rates of dose interruption (54% vs. 26%) and treatment discontinuation (9% vs. 6%) due to adverse events, with the most common toxicities being increased CPK (71%), AST (56%), and ALT (43%) for BRG, and elevated AST (40%), ALT (38%), and anemia (37%) for ALC.
These findings indicate that while both next-generation ALK inhibitors were effective post-CRZ, BRG did not offer a significant advantage over ALC in this setting.
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