“This is a very exciting time [in treating lung cancer]. We have always sought to use the right tool for the right job, with the focus placed on making better tools. We just kept varying the chemotherapy combinations leading to a plateau in efficacy. Now we have shifted emphasis toward identification of the ‘job’ and using the right ‘tool’ by way of biomarkers,” said Wallace Akerley, MD, Director, Thoracic Program, Huntsman Cancer Institute at the University of Utah, and member of the NCCN Non–Small Cell Lung Cancer (NSCLC) Panel. Dr. Akerley reviewed biomarker-based treatment selection at the NCCN 22nd Annual Conference.
NSCLC is a broad term for a collection of cancers of lung origin with different molecular drivers and different ways of circumventing the immune system. Molecular markers such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS1 are now required in the 2017 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for testing in stage IV NSCLC, in addition to other actionable mutations. Currently, immune testing for programmed death ligand-1 (PD-L1) is required at diagnosis of stage IV NSCLC to identify a more immune-responsive population for consideration of pembrolizumab treatment.
“We don't do immune panels yet, but I expect that in the near future we will be testing for several biomarkers as we better understand the role of the immune system in cancer,” Dr. Akerley predicted.
For the purposes of first-line therapy, biomarkers divide NSCLC into 3 groups: (1) those with molecular-defined actionable targets, (2) PD-L1–defined immunosensitive populations, and (3) those fitting neither group who are further categorized by histology as squamous (p63) versus nonsquamous (TTF1). For squamous cell cancers, a platinum doublet excluding pemetrexed is preferred; whereas for nonsquamous cancers, a platinum doublet or triplet with pemetrexed and/or bevacizumab are good choices.
Approximately two-thirds of NSCLC tumors (64%) will have a driver mutation, among which approximately 25% are actionable with available therapies. EGFR accounts for approximately 17%, ALK for 8%, and ROS1 for 1%. Approximately 17% of patients will have a KRAS mutation, but there is no effective drug yet targeted to that mutation.1 Molecular targets with emergent treatment pathways include HER2, MET amplification, BRAFV600E, and RET.
Dr. Akerley stated, “Multiplex panels to identify all actionable mutations are critical to the care of patients with NSCLC because these mutations afford very effective treatment, can only be found if evaluated, and will show increasing prevalence in clinic as effective treatments prolong their survival over those without targetable mutations. For example, a review of one clinic day last week at Huntsman Cancer Institute at the University of Utah showed that 8 of 12 patients under treatment for metastatic NSCLC had actionable mutations. These included 5 of 7 NCCN-defined actionable mutations: EGFR, ALK, MET, RET, and BRAF.”
EGFR is the most frequent of the actionable mutations in NSCLC. It occurs more frequently in Asians (>30% vs 15% in whites) and never-smokers (38% vs 5% in current smokers). Three generations of tyrosine kinase inhibitors (TKIs) are approved to treat EGFR-biomarker–defined NSCLC. Among those with mutations, 90% will have a deletion in exon 19 or L858R in exon 21 of EGFR, Dr. Akerley said.
In the early days when EGFR was not yet recognized as the biomarker for response to EGFR inhibitors, a study enriched for those likely to respond to EGFR therapy (Asians and never-smokers) showed that those with EGFR-positive NSCLC had significantly superior progression-free survival (PFS) on treatment with gefitinib (an EGFR inhibitor) versus carboplatin/paclitaxel (P<.001), whereas those who were EGFR-negative had significantly improved PFS on carboplatin/paclitaxel versus gefitinib (P<.001).2
“This early study showed that PFS was significantly improved if you give the right drug to the right patient and established biomarker-directed therapy of NSCLC,” Dr. Akerley stated. “EGFR mutation is predictive for response and prognostic for survival. In my opinion, EGFR-mutated and EGFR wild-type NSCLC are 2 discrete cancers, as different as breast cancer and colon cancer,” he said.
“All EGFR mutations are not created equal. First-generation TKIs block EGFR sensitivity mutations (exons 19 and 21) of the cancer, as well as the wild-type EGFR of the skin and gut, which accounts for the most common side effects. Osimertinib, a third-generation TKI, affects the same EGFR sensitivity mutations plus the T790 mutation, the acquired mutation that is the most common cause of eventual resistance to first- and second-generation TKIs,” he said. Additionally, it has less effect on wild-type EGFR of the gut and skin, so adverse effects are minimized.
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