Journal of Oncology Navigation & Survivorship. 2018;9:200.
Updated guidelines from the National Comprehensive Cancer Network (NCCN) on the management of metastatic non–small cell lung cancer (NSCLC) reflect the addition of osimertinib as a first-line option in patients with an epidermal growth factor receptor (EGFR)-sensitizing mutation and as subsequent therapy in patients whose disease progresses following another tyrosine kinase inhibitor (TKI) if they develop a T790M resistance mutation.
The latest developments in targeted therapy for metastatic NSCLC were discussed by Karen Reckamp, MD, Co-Director of the Lung Cancer and Thoracic Oncology Program, City of Hope Comprehensive Cancer Center, Duarte, CA.
“We have a growing list of oncogenic mutations and therapeutic options for patients with lung cancer,” she said. Oncogenic targets for which therapies are currently approved are EGFR, ALK, ROS1, and BRAF. Version 3.2018 of the NCCN Guidelines has multiple pages to guide first-line treatment options of metastatic NSCLC based on histologic subtype and the results of molecular testing, which is recommended for all patients as part of the initial workup at presentation of metastatic NSCLC.
Added to the mix of TKIs in the NCCN Guidelines is osimertinib. In the double-blind FLAURA study, osimertinib was compared with erlotinib or gefitinib (considered standard therapy) in patients with previously untreated EGFR mutation-positive advanced NSCLC. The median progression-free survival (PFS) improved from 10.2 months with standard therapy to 18.9 months with osimertinib (hazard ratio, 0.46; P <.0001). Patients with and without central nervous system (CNS) metastases benefited similarly from osimertinib. An overall survival interim analysis demonstrated a trend toward improved survival with osimertinib. Rates of grade 3/4 rash and liver function abnormalities were less with osimertinib than with standard therapy.
Based on these data, “we now have 4 drugs in the guideline for the first-line therapy of NSCLC—erlotinib, afatinib, gefitinib, or osimertinib,” said Dr Reckamp.
Patients with EGFR-sensitizing mutations who respond to EGFR-targeted therapy will develop progression and secondary resistance. The T790M in exon 20 accounts for approximately 50% of acquired erlotinib resistance. Osimertinib is approved for T790M-positive NSCLC when acquired resistance occurs. “We believe that resistance will be quite different if people start using osimertinib as first-line therapy,” she said.
Other questions that remain are the specific sequence of TKIs and whether earlier generations of EGFR TKIs and chemotherapy will work following first-line osimertinib. Dr Reckamp indicated that a movement toward osimertinib in the first-line setting is taking place because of the FLAURA data.
With progression on a first- or second-generation TKI, T790M testing is recommended. “At this point, we consider plasma testing equivalent to tissue testing if it’s positive…and can often save the patient a biopsy,” said Dr Reckamp. As subsequent therapy, the guidelines list local therapy to the metastatic site (including brain), osimertinib (category 1) or continuation of erlotinib, afatinib, or gefitinib. For an isolated metastasis, local therapy or continuation of erlotinib, afatinib, or gefitinib are options. “When there are multiple sites and multiple lesions, then it’s clearly time to change therapies,” she said, such as osimertinib if not previously given for T790M-positive disease or cytotoxic therapy for T790M-negative disease.
In ALK-rearranged NSCLC, alectinib has been moved up to first-line as the preferred therapy on the basis of the ALEX study. In ALEX, alectinib was superior to crizotinib on the end point of median PFS, with an even greater improvement in median PFS with alectinib in patients with baseline CNS metastases. The same activity in the CNS was seen with alectinib in the J-ALEX trial.
Resistance mutations may guide the sequence of therapy in previously treated ALK-positive NSCLC, although at this time testing for resistance mutations is not standard of care, said Dr Reckamp. Multiple drugs (ceritinib, alectinib, brigatinib) with excellent systemic and CNS activity are approved in the post-crizotinib setting, and these appear in the guidelines as options.
For patients with ROS1 rearrangement, crizotinib is now listed as the preferred first-line therapy, with ceritinib as an option. With progression, cytotoxic therapy is recommended.
Also making a recent appearance in the guidelines is specific treatment for BRAF-mutated NSCLC, with first-line therapy options being dabrafenib plus trametinib or cytotoxic therapy.