Targeting NSCLC Through Molecular Markers

The era of molecular medicine is poised to bring about even greater advancements in the management of non-small cell lung cancer (NSCLC) than what has already occurred, according to Gerard A. Silvestri MD, MS, a professor at the Medical University of South Carolina.

In the 1980s, no effective therapy was available for NSCLC, and the median survival was 4 to 6 months. With the 2002 publication of a study by Schiller and colleagues, it seemed that science had reached the maximum benefit possible with traditional chemotherapy, noted Dr Silvestri. In this study, 1207 patients with advanced NSCLC and performance status scores of 0 to 2 (ECOG scale) were randomized equally to receive cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, or carboplatin/paclitaxel. At the conclusion of the trial, median survival was 7.8 months, and the survival rates at 1 year and 2 years were 33% and 11%, respectively. No treatment was better than any other in terms of treatment of patients with advanced NSCLC.¹

Dr Silvestri explained that a study published in 2009 by Mok and colleagues shed some light on the benefit of biologic therapy in NSCLC and the role of genetic markers in outcomes. The study compared the tyrosine kinase inhibitor (TKI) gefitinib with carboplatin/paclitaxel-based treatment in patients with adenocarcinoma of the lung. After 12 months, progression-free survival rates were higher among patients receiving gefitinib (24.9%) than among patients receiving traditional doublet chemotherapy (6.7%). The study authors confirmed, in a final analysis, that gefitinib significantly reduced the risk of either disease progression or death versus traditional chemotherapy (P <.001).²

Results from a subgroup analysis showed that patients with mutated epidermal growth factor receptor (EGFR) genes responded exceptionally well to gefitinib therapy. By contrast, patients who did not have mutated EGFR genes experienced better outcomes with traditional chemotherapy, noted Dr Silvestri. Similar results with mutated EGFR genes in patients with NSCLC were found in several other trials, including EURTAC, OPTIMAL, WJTOG 3405, NEJSG, IPASS, First-signal, and LUX-lung 3.

According to Dr Silvestri, “Everyone is just a little bit different. Every individual’s tumor profile is different, and we have to look at targets for [these individuals’] tumors.”

More recently, a study by Kris and colleagues sought to determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. The multicenter study, published earlier this year, included 1007 patients with metastatic lung cancer. From 2009 to 2012, patients across 14 sites in the United States were tested for up to 10 driver mutations. Patients in this study had good performance status, with an ECOG of 0 to 2. In 64% of patients, oncogenic driver mutations were identified. These include mutations of such genes as EGFR, PI3K, BRAF, KRAS, and EML4-ALK.³

A total of 275 patients, or 28% of patients involved in the trial, received targeted therapies for the mutations identified. In these patients who received genotype-directed therapy, the median survival was 3.5 years, versus 2.4 years for patients who did not receive any genotype-directed therapy (propensity-adjusted P = .006).

Using targeted therapies has led to a dramatic improvement in survival for a certain subset of patients whose cancers have specific driver mutations, noted Dr Silvestri. “If they get the directed therapy they live amazingly long.”

REFERENCES

1. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-98.
2. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
3. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006.