Matching Treatment to Molecular Alteration Yields Best Outcomes
Tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for patients with EGFR mutation–positive non–small cell lung cancer (NSCLC), according to the most recent guideline on management of NSCLC issued by the National Comprehensive Cancer Network (NCCN).
Version 4.2016 of the guideline recommends EGFR testing as part of broader molecular testing in patients with NSCLC. The guideline describes the evolving strategies to personalize medicine in lung cancer.
“EGFR testing should not be limited to patients who have a high probability of having an EGFR mutation. EGFR testing should be done for every patient with a nonsquamous histology,” said Rogerio Lilenbaum, MD, at the NCCN 21st Annual Conference. “It’s important that clinical enrichment is no longer a criterion to guide molecular testing. It should be routine in clinical practice.”
Survival is enhanced when patients with lung adenocarcinoma receive appropriate therapy for their molecular alteration compared with patients who have wild-type lung cancer or who have molecular alterations but do not receive appropriate treatment, noted Dr Lilenbaum, Professor of Medicine, Yale Cancer Center, New Haven, CT.
Without information about EGFR testing, treatment should not be initiated with a TKI, Dr Lilenbaum advised. “If you need to treat someone quickly...even if you anticipate a high probability of EGFR mutation, use chemotherapy first, and switch to a TKI when the information comes back.”
How tumors are molecularly profiled is a work in progress, he said. A multidisciplinary collaboration at Yale resulted in a tiered approach to tumor profiling. Tier 1 is reflex testing in which any patient with a diagnosis of nonsquamous NSCLC has a tumor sample automatically sent to the molecular profiling lab for testing of 8 genes, most of which are actionable, and the results are sent to the clinicians in 5 to 7 days. If Tier 1 testing is negative, a sample is sent for analysis using the Oncomine Cancer Panel, a panel of >140 genes and >40 translocations or fusions. Tier 3 is whole exome sequencing with future custom panels.
Dr Lilenbaum pointed to data showing a consistent advantage on the end point of progression-free survival (PFS) to selecting a TKI (erlotinib, afatinib, or gefitinib) as first-line therapy in EGFR mutation–positive NSCLC. Of these, afatinib also demonstrated an improvement in overall survival over chemotherapy. In the lone comparison between TKIs in this setting, afatinib was associated with superior overall response rate, PFS, and time to failure compared with gefitinib.
Most patients with EGFR-positive NSCLC will experience disease progression following initiation of a TKI, at which time they have developed acquired resistance, most often a T790M mutation being the mechanism behind acquired resistance, said Leora Horn, MD, MSc, Clinical Director, Thoracic Oncology Research Program, Vanderbilt-Ingram Cancer Center, Nashville, TN.
“The type of progression drives second-line treatment,” she said. Switching therapy is recommended for patients with systemic disease progression characterized by multiple new lesions and multiple sites of disease. For patients with oligo-progression, maintaining the patient’s current TKI is a reasonable action, said Dr Horn.
For progression only in the central nervous system (CNS), radiation of the lesions in the CNS while maintaining the patient’s TKI is an appropriate course, “although switching to third- or fourth-generation TKIs may eventually prove more effective,” she said.
Before switching systemic therapy, all patients should have a biopsy to evaluate for T790M, said Dr Horn. A serum-based test is an option in patients in whom a tissue biopsy is not possible.
Version 4.2016 of the guideline recommends osimertinib, a third-generation TKI, or continuation of erlotinib, afatinib, or gefitinib as subsequent therapy upon progression in asymptomatic patients with a sensitizing EGFR mutation. For symptomatic patients, the subsequent therapy is based on the site of progression.