Renato G Martins, MD, MPH
Medical Director, Thoracic/Head and Neck Medical Oncology, Seattle Cancer Care Alliance/Fred Hutch Professor, University of Washington School of Medicine Panel Member (Writing Committee), NCCN Guidelines for NSCLC
Ten or 15 years ago, a diagnosis of advanced non– small cell lung cancer (NSCLC) led directly to a discussion of chemotherapy. Median survival was around 8 months. Treatment toxicities were significant. Few other options were available.
Today, patients with advanced NSCLC have many more treatment choices and substantially improved outcomes. In some cases, patients can be maintained on new oral therapies for years before seeing progression that requires chemotherapy. Even more exciting, the newest wave of targeted agents and immunotherapies now in clinical testing are extending this responsive period. With each passing month, strategies evolve, survival improves—and medical decision-making becomes more complex. This update highlights recent advances in NSCLC treatment and makes practical recommendations to help oncologists and their patients take full advantage of the latest emerging therapies.More Targets, Moving Targets
Several therapies target specific molecular pathways that drive tumor growth in advanced NSCLC. Erlotinib, gefitinib, and afatinib are small-molecule EGFR inhibitors, while crizotinib and ceritinib target ALK. These tyrosine kinase inhibitors (TKIs) are approved by the FDA for firstline treatment of patients who are known to have the sensitizing EGFR mutation (about 15% of patients overall) or the ALK gene rearrangement (about 5% of patients). The TKIs are extremely effective in delaying progression. However, only patients with the specific mutation will see a major benefit and resistance is common. That’s why several kinase inhibitors are now being developed to attack additional NSCLC molecular subtypes (eg, HER2, BRAF, RET, and ROS1) or to treat secondary mutations that confer tumor resistance (eg, MET, T790M).1
Ceritinib is an example of a second-generation ALK inhibitor that has shown efficacy in both crizotinib- naïve and crizotinib-resistant patients.2 The most recent ceritinib data showed an overall response rate of 58.5% in 246 patients.3
Until recently, no second-line therapy has succeeded in treating treatment-resistant EGFR+ tumors. Response rates with afatinib are low4 and combining afatinib with cetuximab causes significant rash.5
Two new oral agents that target the T790M mutation, see n in at least half of EGFR-resistant tumors, show promising signs of extended activity in clinical trials.
AZD 9291, a selective third-generation EGFR-TKI, was well tolerated and produced a 64% response rate in 89 EGFR T790M+ patients.6
CO-1686, another potent inhibitor of EGFR and T790M, showed good efficacy (58% response rate in 40 patients) without the dose-related rash and diarrhea associated with wild-type EGFR inhibition.7 Seattle Cancer Care Alliance (SCCA) is currently enrolling patients with NSCLC and EGFR mutations in two clinical trials of CO-1686 (UW 14031 and UW 14055, www.seattlecca.org/clinicaltrials). Meanwhile, long-awaited results from the RADIANT clinical trial showed no overall survival benefit of adjuvant erlotinib in early NSCLC.8 However, in a subset analysis of EGFR+ patients, disease-free survival was 46.4% in 102 patients on erlotinib versus 28.5% in 59 patients on placebo; these statistically nonsignificant yet intriguing results are leading to further testing in this context of early disease.
Given the growing number of clinical trials with targeted agents, oncologists are encouraged to work with specialists at research-based cancer treatment centers such as SCCA to consider enrolling patients in appropriate studies. Although new targeted agents and new indications are being approved faster than ever, helping patients access new drugs a year or two earlier—while they are still in clinical trials—can make a meaningful difference in patients’ lives.Broad Molecular Profiling—The Key to Tumor Targeting