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Matching treatment to molecular profiles improves outcomes
VBCC - June 2016, Vol 7, No 5 - Lung Cancer
Wayne Kuznar

Tyrosine kinase inhibitors (TKIs) are the mainstay of therapy for patients with epidermal growth factor receptor (EGFR) mutation–positive non–small-cell lung cancer (NSCLC), according to the updated National Comprehensive Cancer Network (NCCN) NSCLC guideline. The NCCN guideline recommends EGFR testing as part of a broad molecular profiling in patients with NSCLC.

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 C. Lilenbaum, MD, MS, Chief Medical Officer, Smilow Cancer Hospital, Yale Cancer Center, New Haven, CT, at the 2016 NCCN annual conference.

“It is important that clinical enrichment is no longer a criterion to guide molecular testing. It should be routine in clinical practice,” he added.

Survival is enhanced when patients with lung adenocarcinoma receive appropriate therapy for their molecular mutations compared with patients who have wild-type lung cancer, or those who have genetic mutations but who do not receive appropriate treatment, said Dr Lilenbaum.

Without information about EGFR testing, treatment should not be initiated with a TKI, he 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.”

The way in which tumors are molecularly profiled is a work in progress, Dr Lilenbaum said. A multidisciplinary collaboration at the Yale Cancer Center 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 laboratory for testing of 8 genes, the majority of which are actionable; the results are sent to the clinicians in 5 to 7 days. If results from Tier 1 are negative, a sample is sent for analysis using the Oncomine Cancer Panel, a panel of more than 140 genes and more than 40 translocations or fusions; this represents Tier 2 tumor profiling. Tier 3 is whole-exome sequencing with future custom panels.

Dr Lilenbaum pointed to data showing a consistent advantage in progression-free survival (PFS) when selecting a TKI, such as erlotinib (Tarceva), afatinib (Gilotrif), or gefitinib (Iressa), versus chemotherapy as first-line therapy for EGFR mutation–positive NSCLC. Of these TKIs, afatinib also demonstrated an improvement in overall survival over chemotherapy. In the lone comparison between TKIs in this setting, afatinib was associated with a superior overall response rate, PFS, and time to failure compared with gefitinib.

Therapies for NSCLC Progression

The majority of patients with EGFR mutation–positive NSCLC will experience disease progression after starting therapy with a TKI, at which time they will have developed acquired resistance to EGFR TKIs, with the T790M mutation most often being the mechanism behind the resistance, said Leora Horn, MD, MSc, Clinical Director, Thoracic Oncology Program, Vanderbilt-Ingram Cancer Center, Nashville, TN.

“The type of progression drives second-line treatment,” Dr Horn 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, she said.

For disease progression confined to the central nervous system (CNS), radiation of the lesions in the CNS while maintaining the patient’s TKI is an appropriate course of action, “although switching to third- or fourth-generation TKIs may eventually prove more effective,” Dr Horn said.

Before switching systemic therapy, all patients should be evaluated for the T790M mutation, she said.

The updated NCCN guideline recommends the use of the newly approved osimertinib (Tagrisso), a third-generation TKI and the only therapy available specifically for patients with NSCLC that harbors the T790M mutation, or the continuation of erlotinib, afatinib, or gefitinib, as subsequent therapy for disease progression in asymptomatic patients with a sensitizing EGFR mutation. For symptomatic patients, subsequent therapy is based on the site of disease progression.

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Last modified: June 24, 2016
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