ENCORE: Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs. crizotinib (CZ) in untreated advanced ALK+ NSCLC

Background The primary ALEX (NCT02075840) analysis showed superior investigator (INV)-assessed progression-free survival (PFS) with ALC vs. CZ (HR 0.47, 95% CI 0.34 – 0.65, p < 0.001; median 11.1 months [m] CZ, not estimable [NE] ALC) in untreated ALK+ NSCLC. Here, we report updated data (cutoff Dec 1 2017).

Methods ALEX enrolled patients (pts) with stage IIIB/IV ALK+ NSCLC (by central IHC) and no prior systemic therapy for advanced NSCLC; asymptomatic CNS metastases (mets) were allowed. Pts were randomized 1 : 1 to receive ALC 600 mg BID (n = 152) or CZ 250 mg BID (n = 151). Primary endpoint: PFS (INV, RECIST v1.1), with q8w CNS imaging in all pts. Secondary endpoints: ORR, time to CNS progression, DOR, OS, and safety.

Results With 10 months longer follow-up (median 22.8 m CZ vs. 27.8 m ALC), ALC significantly reduced the risk of disease progression/death by 57% vs. CZ (ITT; stratified HR 0.43, 95% CI 0.32 – 0.58): median PFS (INV) was 34.8 m ALC vs. 10.9 m CZ. Median PFS by baseline (BL) CNS mets status was 27.7 m ALC vs. 7.4 m CZ (HR 0.35, 95% CI 0.22 – 0.56) in pts with, and 34.8 m vs. 14.7 m (HR 0.47, 95% CI 0.32 – 0.71) in pts w/out BL CNS mets. In the BL CNS mets group, the number of pts who received WBRT (n = 16 ALC, n = 17 CZ) or SRS (n = 4 ALC, n = 6 CZ) was balanced, as was the number of BL lesions (median 2 per arm). Updated secondary endpoint data (INV): ORR 82.9% ALC (95% CI 75.95 – 88.51; n = 152) vs. 75.5% CZ (95% CI 67.84 – 82.12; n = 151); median DOR 33.3 m ALC (95% CI 31.1–NE; n = 126) vs. 11.1 m CZ (95% CI 7.5 – 13.0; n = 114), stratified HR 0.33, 95% CI 0.23 – 0.48. OS data are still immature (events ALC 28.3%, CZ 31.8%; stratified HR 0.76, 95% CI 0.50 – 1.15). Despite significantly longer treatment (Tx) duration with ALC (27.0 m vs. 10.8 m), proportion of pts with grade 3 – 5 AEs (44.7% vs. 51.0%), AEs leading to dose reduction (16.4% vs. 20.5%) or interruption (22.4% vs. 25.2%) were lower with ALC vs. CZ. Proportion of pts with AEs leading to discontinuation: 13.2% each arm. Fatal AEs: 5% CZ (2 Tx-related AEs) and 4% ALC pts (0 Tx related).

Conclusions ALC 600 mg BID showed superior efficacy vs. CZ (PFS HR 0.43, median 34.8 m ALC vs. 10.9 m CZ) in untreated ALK+ NSCLC, regardless of BL CNS mets, and favorable and durable tolerability despite longer Tx duration, consolidating ALC as the new standard of care.

Funding F. Hoffmann-La Roche Ltd

• Reference

• 1 Camidge et al. ASCO-GU 2018.