Treatment resistance has been the focus of research in non-small cell lung cancer (NSCLC) for many years, specifically in regard to acquired resistance with frontline EGFR inhibitors. In a phase I/II study, the combination of cetuximab and afatinib demonstrated an overall response rate (ORR) of 29% for patients with resistant NSCLC. However, the side effect profile with the combination of afatinib and cetuximab was a concern, with approximately 20% of patients discontinuing therapy as a result, notes D. Ross Camidge, MD, PhD. To further explore these agents, a phase II/III study is currently underway that will compare afatinib plus cetuximab with afatinib alone in treatment-naive patients with advanced NSCLC.

The TIGER-1 study is comparing the next-generation EGFR inhibitor rociletinib (CO-1686) with erlotinib in patients with NSCLC who have not received a prior EGFR inhibitor. When comparing these two agents head-to-head, Camidge believes a large advantage should be demonstrated in order to determine superiority for frontline use. It has been established that rociletinib can be utilized after erlotinib; however, the reverse sequence remains unclear.

The wealth of novel agents in the pipeline warrants rebiopsy for patients with resistant NSCLC, Mark A. Socinski, MD, states. In many situations, resistance is not only the result of an acquired mutation. In approximately 5-10% of patients, EGFR resistance is caused by transformation to small cell histology, notes Alice T. Shaw, MD, PhD.

In ALK-positive patients, frontline treatment with crizotinib is the standard of care. The drug was granted an accelerated approval in 2011, which was transitioned to a full approval in 2013 based on findings from the PROFILE 1007 study. This study was conducted in the second-line setting, following progression on chemotherapy, adds Shaw.

In the phase III PROFILE 1007 study, 347 patients with ALK-positive advanced NSCLC were randomized to crizotinib or chemotherapy (pemetrexed or docetaxel). The median progression-free survival (PFS) was 7.7 months with crizotinib compared with 3.0 months with chemotherapy. The ORR was 65.3% versus 19.3%, for crizotinib and chemotherapy, respectively.

The phase III PROFILE 1014 study explored crizotinib in the first-line setting in comparison with pemetrexed plus cisplatin or pemetrexed and carboplatin in patients with ALK-positive NSCLC. In this setting, the median PFS was 10.9 months with crizotinib versus 7.0 months with chemotherapy. The ORR was 74% versus 45%, for crizotinib and chemotherapy, respectively.