Sequencing Immunotherapy in Biomarker-Driven Advanced NSCLC

Julie Renee Brahmer, MD, MSc, director of the thoracic oncology program and professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, discusses the issues with using tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) in patients with locally advanced non–small cell lung cancer (NSCLC).

According to Brahmer, sequencing therapies for locally advanced NSCLC is limited by data that show using TKIs following IO can lead to serious toxicities in patients. In addition, studies of stage IV disease also indicate that patients with the subtypes EGFR, ALK, ROS1, HER2, and RET generally do not respond to single-agent IO, leaving fewer options for patients resistant to targeted therapy.

Based on retrospective studies, patients with stage IV adenocarcinoma with a KRAS mutation had better survival outcomes with immunotherapy. Patients with metastatic disease with the V600E mutation in the BRAF gene demonstrated responses to immunotherapy in addition to targeted BRAF/MEK therapy.

Based on the survival benefit seen in the PACIFIC trial (NCT02125461) of durvalumab following chemoradiotherapy, Brahmer says that more research is needed on the efficacy of IO following concurrent chemotherapy and radiation therapy.

TRANSCRIPTION:

0:08 | If you start TKIs after IO or shortly after IO, then you may run into issues with toxicities much more than if you would start with TKIs by [themselves] in the stage IV setting. So you do have to take that into consideration. And then trying to extrapolate from advanced disease where we know that IO as a single agent does not work at all for patients with EGFR, ALK, ROS1, HER2, or RET disease. Now I think the jury's out for patients with KRAS mutations, where single agent IO in advanced disease does work quite well. Same for BRAF…there [are] data to support single agent IO use in BRAF (V600E) disease in the metastatic setting. However, the jury's out for patients after concurrent chemotherapy and radiation, we just don't have that information. And we really need that information if we're truly going to deliver precision oncology.