“The definition of molecular subsets of lung cancer [in terms of] driver mutations has revolutionized the care of patients with non–small cell lung cancer [NSCLC],” said formal discussant Christine M. Lovly, MD, PhD, Instructor in Medicine at Vanderbilt-Ingram Cancer Center, Nashville.

ALK rearrangements occur in about 5% of all NSCLC patients, primarily in younger patients, nonsmokers, and patients with adenocarcinoma. ALK gene fusion is also found in NSCLC and other cancers, and there are various fusion partners, but these cannot be identified by current ALK fluorescence in situ hybridization (FISH) testing, the current clinical gold standard. It is not clear whether specific fusion variants affect response rates to crizotinib (Xalkori) and other ALK inhibitors, but clinical diagnostics are under development to identify particular fusions.

Continuing Challenges

LDK378 is highly potent with preclinical activity against all the mutations associated with resistance to crizotinib. The response to LDK378 in this study is comparable to that of crizotinib, Dr. Lovly noted. However, she cited the following remaining challenges:

• Ascertaining presently unidentified mechanisms of resistance to ALK inhibitors and developing strategies to overcome them.
• Identifying the best sequence of ALK tyrosine kinase inhibitor administration for ALK-positive lung cancer.
• Anticipating mechanisms of resistance to LDK378, and developing strategies to overcome it.
• Improving clinical responses with rational combination therapy, such as an HSP90 inhibitor, MEK inhibitor, mTOR inhibitor, or EGFR inhibitor.
• Identifying whether differences in response rates are due to distinct fusions. ■

Disclosure: Dr. Lovly has received honoraria from Abbott Molecular and the National Comprehensive Cancer Network.