ALEX phase III study (NCT02075840) of alectinib (ALC) vs crizotinib (CRZ) in treatment-naïve advanced ALK+ NSCLC, met its primary endpoint of improved progression-free survival (PFS). Pts with asymptomatic brain mets at baseline (BL), treated with radiotherapy (RT) or not, were eligible. We present comprehensive CNS efficacy data.
Pts aged ≥18 years were randomized 1:1 to ALC 600mg or CRZ 250mg (both twice daily) until disease progression (PD), toxicity, withdrawal or death. CNS MRIs were done at BL and every 8 wks in all pts. An Independent Review Committee (IRC) assessed CNS endpoints (RECIST v1.1 and RANO). Endpoints (analysed by subgroup: pts with/without BL CNS disease; pts with/without prior RT) included patterns of PD, CNS objective response rates (CORR), CNS PD and PFS.
Overall, 303 pts were randomised (ALC n = 152; CRZ n = 151); 122 had BL CNS mets by IRC (ALC n = 64 [42%]; CRZ n = 58 [38%]), of whom 43 had IRC-assessed measurable lesions (ALC n = 21; CRZ n = 22); 47/122 pts had received prior RT (ALC n = 26 [62% WBRT]; CRZ n = 21 [71% WBRT]). Subgroup analyses of PFS and CNS PD are in Table 1. In the CRZ arm first PD was more common in CNS than in non-CNS sites in pts with (CNS PD 57% vs non-CNS PD 24%) and without (CNS PD 38% vs non-CNS PD 20%) CNS mets at BL. In the ALC arm first PD was more common in non-CNS sites in pts without CNS mets at BL (CNS PD 6.8% vs non-CNS PD 28%); first PD in CNS and non-CNS was similar in pts with CNS mets at BL (CNS PD 19% vs non-CNS PD 17%). CORR (RECIST) in pts with measurable CNS mets at BL was ALC 85.7% vs CRZ 71.4% for pts with prior RT and ALC 78.6% vs CRZ 40.0% for pts without RT. In pts with measurable and non-measurable CNS mets at BL, CORR was ALC 36.0% vs CRZ 28.6% for pts with prior RT, and ALC 74.4% vs CRZ 24.3% for those without. Data by RANO criteria will be presented.Table:
1298O_PR Subgroup analysis of PFS and CNS PD§
|Pts without CNS disease at BL (IRC)||Pts with CNS disease at BL (IRC)|
|All patients||Pts who had received prior RT||Pts who had not received prior RT|
|ALC N = 88||CRZ N = 93||ALC N = 64||CRZ N = 58||ALC N = 25*||CRZ N = 21||ALC N = 39||CRZ N = 37|
|Median PFS by INV, months (95% CI)||NE (NE)||14.8 (10.8–20.3)||NE (9.2–NE)||7.4 (6.6–9.6)||NE (11.0–NE)||12.7 (7.2–14.6)||14.0 (5.6–NE)||7.2 (3.9–8.6)|
|HR (95% CI) P value||0.51 (0.33–0.80)||0.40 (0.25–0.64)||0.34 (0.15–0.78)||0.44 (0.25–0.78)|
|p = 0.0024||p |
ALC showed significantly superior CNS activity vs CRZ in previously untreated advanced ALK+ NSCLC, irrespective of prior RT, and had a protective effect in the CNS.
Clinical trial identification
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
S. Gadgeel: Consulting fees from Boehringer Ingelheim, ARIAD, Novartis, Genentech, Pfizer and AstraZeneca during the conduct of the study. S. Peters: Grants and personal fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, Roche, Guardant health, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Morphotek, Pfizer, Regeneron and Takeda. T.S.K. Mok: Personal fees: AZ, MSD, Novartis, BI, Pfizer, Roche/Genentech, BMS, Eli Lilly, Eisai, SFJ, Clovis, Taiho, Merck Serono, Celgene, OncoGenex Technologies, ACEA Biosciences, Vertex, Ignyta, Cirina, GeneDecode., Ariad/Tekeda. Stock ownership: Sanomics. A.T. Shaw: Personal fees from Genentech/Roche, Pfizer, Novartis, Genentech/Roche, Ariad, Ignyta, Daiichi-Sankyo, Taiho, Blueprint Medicines, Loxo, EMD Serono and Foundation Medicine. S-H.I. Ou: Personal fees from Pfizer, Roche, Astra Zeneca, ARIAD, Ignyta and Foundation Medicine. M. Perol: Personal fees from Roche, Lilly, BMS, Novartis, Astra-Zeneca, Boehringer-Ingelheim, Clovis Oncology, Merck, Pfizer, Pierre Fabre, Amgen. R. Dziadziuszko: Personal fees from Roche, Novartis, Tesaro, Clovis, Pfizer, Boehringer-Ingelheim, Ignyta and Astra-Zeneca. J.S. Ahn: Personal fees from BMS, Eisai, Janssen, Roche, Menarini and Boehringer Ingelheim. A. Zeaiter, E. Mitry, E. Nueesch: Full-time employee at F. Hoffmann-La Roche Ltd. B. Balas: Full-time employee at F. Hoffmann-La Roche Ltd with stock ownership. R. Camidge: Personal fees from Roche Genetech, Genoptix, G1 Therapeutics, Orion, Clovis, Ariad, Novartis, Celgene, Array, Abbvie and Eli Lilly. All other authors have declared no conflicts of interest.