Formal discussant of the AP26113 trial at the European Cancer Congress, Frances A. Shepherd, MD, FRCPC, Professor at the University of Toronto Faculty of Medicine and Scott Taylor Chair in Lung Cancer Research at the Princess Margaret Cancer Centre, Toronto, Canada, explained that ALK rearrangements do not represent a single mutation but many mutations. Even though about 60% of patients with ALK-positive non–small cell lung cancer (NSCLC) respond to crizotinib (Xalkori), by 2 years, 90% have had disease progression or died, suggesting that newer approaches are needed. It is not clear whether an ALK/EGFR inhibitor such as AP26113 will improve outcomes compared with crizotinib.

Second-generation ALK inhibitors, including AP26113, LDK378, and ASP3026, all show responses in patients previously treated with crizotinib, and even in brain metastasis. “This is an attractive feature,” she noted.

An important issue in this setting is how best to incorporate these newer drugs and how best to use them: sequentially or in combination.

“Future studies may require rebiopsy to determine exact mechanisms of resistance, and we may treat differently depending on what new mutations or other resistance mechanisms are identified,” she commented. ■

Disclosure: Dr. Shepherd has served as a consultant or in an advisory role for Roche, Lilly, Biodesix, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Boehringer Ingelheim, and Recombio. She has stock ownership in Pfizer and Lilly. Dr. Shepherd has received honoraria from Roche, Lilly, and GlaxoSmithKline.