The identification of molecular targets and the development of agents to treat those targets has changed the paradigm for the management of non–small cell lung cancer (NSCLC).
“The progress in NSCLC has been absolutely amazing. EGFR and KRAS mutations are the most common genetic alterations, and ALK, ROS1, and RET rearrangements and BRAF mutations are also targetable. Less than half of NSCLCs of adenocarcinoma histology have no known alterable genotype,” explained Rogerio A. Lilenbaum, MD, Chief Medical Officer of Smilow Cancer Hospital.
The updated version of the NCCN Guidelines for NSCLC recommends that testing for EGFR and ALK mutations should be conducted as part of broad molecular profiling, which is now recommended for all patients with NSCLC (nonsquamous histology) to recognize rare actionable mutations. The results of the molecular profiling can be used to counsel patients and enroll them in clinical trials. “Broad molecular profiling is a key component of the improvement in care for patients with NSCLC,” the NCCN Guidelines state.
“Genotyping should be performed for every patient with nonsquamous NSCLC,” Dr. Lilenbaum told the audience. “Testing should not be limited to patients with a high probability of EGFR mutations. It is critical that [physicians] perform genotyping, the same as you would check hormone receptor expression and HER2/neu in breast cancer.”
The best way to profile/sequence a tumor is still a work in progress. Dr. Lilenbaum said that at Yale Cancer Center/Smilow Cancer Hospital they use a tiered approach: tier 1 uses the TaqMan platform (Thermo Fisher Scientific, Waltham, MA; 8 genes, most actionable) with results available in less than 1 week; tier 2 uses the Oncomine Comprehensive Assay (Thermo Fisher Scientific, Waltham, MA; 143 genes and >2,500 translocations/fusions), which takes up to 2 weeks to receive results; and tier 3 is whole-genome sequencing with future custom panels per organ system specification, with results available in 3 to 4 weeks.
Dr. Lilenbaum noted that patients with an EGFR mutation have better outcomes with gefitinib compared with chemotherapy, based on the results of the IPASS trial1, and that patients without the mutation experience a poor response on gefitinib. “If the EGFR mutation is not present, do not treat the patient with a tyrosine kinase inhibitor [TKI]. If you need to treat the patient before receiving the genomic profiling report, use chemotherapy first. You can always switch to gefitinib (or any 1 of the 3 TKIs) if the patient [has] the mutation,” Dr. Lilenbaum told listeners.
The updated NCCN Guidelines recommend gefitinib, erlotinib, and afatinib as appropriate first-line therapy options for EGFR-positive NSCLC. Afatinib is the only one of these agents to demonstrate an overall survival (OS) benefit in patients with del 19 mutations.2 In the LUX-Lung 3 trial, OS with first-line afatinib was 31.7 months versus 20.7 with chemotherapy (P=.0001). Patients with L858R mutations do not do as well as those with del 19, although these patients should still be treated with an EGFR inhibitor, he said.
The LUX-Lung 7 trial directly compared afatinib versus gefitinib in patients with EGFR-positive NSCLC and stratified them according to del 19 and L858R mutations.3 Objective response rates and disease control rates favored afatinib (70% vs 56%, respectively). Survival data are immature, but progression-free survival curves split at 12 months, favoring afatinib. The analysis of the del 19 and L858R mutations is not yet available.
Thus, the efficacy of the 3 NCCN Guideline–recommended first-line TKIs is not exactly the same. At the recommended doses, afatinib has a higher rate of toxicity than gefitinib and erlotinib at the recommended doses. Toxicities should be considered when choosing among the available TKIs for first-line therapy, Dr. Lilenbaum said.
Combination erlotinib plus bevacizumab and afatinib plus cetuximab are currently being evaluated as first-line therapy. Studies thus far are promising, he said, but phase III results are awaited.
Currently, no TKI has been shown to be more effective than first-line chemotherapy for EGFR-positive NSCLC tumors that harbor the T790M and exon 20 insertions.
The third-generation TKI, osimertinib, is being evaluated in the FLAURA study as first-line therapy for patients with del 19 and other mutations. That trial has just completed accrual (ClinicalTrials.gov identifier: NCT02296125). Other third-generation TKIs are in development, including rociletinib and ASP8273. The efficacy of the third-generation TKIS is currently being compared with first-line EGFR TKIs in the SOLAR trial (ClinicalTrials.gov identifier: NCT02588261).
Dr. Lilenbaum has disclosed that he is a scientific advisor for Boehringer Ingelheim GmbH, Celgene Corporation, and Genentech, Inc.; he also receives grant/research support from Celgene Corporation. Dr. Horn has disclosed that she is a scientific advisor for Bayer HealthCare, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, and Xcovery; receives grant/research support from AstraZeneca Pharmaceuticals LP; is on the product/speakers bureau for Biodesix, Inc.; and receives consulting fees and/or honoraria from Genentech, Inc. and Merck & Co., Inc.
Mok TS, Wu YL, Thongprasert S et al.. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–957.
Yang JC, Wu YL, Schuler M et al.. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 23 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015;16:141–151.
Park K, Tan EH, Zhang L et al.. Afatinib (A) vs gefitinib (G) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations: results of the global, randomized, open-label, Phase IIb trial LUX-Lung 7 (LL7) [abstract]. Ann Oncol 2015;26(Suppl 9):ix61–62. Abstract LBA2_PR.
- Search Google Scholar
- Export Citation
. Park K Tan EH Zhang L Afatinib (A) vs gefitinib (G) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations: results of the global, randomized, open-label, Phase IIb trial LUX-Lung 7 (LL7) [abstract]. Ann Oncol 2015; 26( Suppl 9): ix61– 62. Abstract LBA2_PR.
Soria JC, Wu YL, Nakagawa K et al.. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 2015;16:990–998.