Future Perspectives for Targeted Therapy in NSCLC

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New approaches are needed in the future to further improve outcomes with targeted therapy in NSCLC.
New approaches are needed in the future to further improve outcomes with targeted therapy in NSCLC.
The following article features coverage from the International Association for the Study of Lung Cancer (IASLC) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

Although targeted therapy has substantially improved outcomes for patients with non-small cell lung cancer (NSCLC) who have driver mutations, new approaches are needed in the future to address inevitable treatment resistance, according to a presentation at the IASLC's 19th World Conference on Lung Cancer in Toronto, Canada.1

Tetsuya Mitsudomi, MD, of the Kindai  University of Medicine in Japan, stated that the purpose of his presentation was to “envision what has to be done in the next 10 years to further improve the outcomes of the patients with driver gene [mutations] and, ultimately, to cure their disease.”

The current standard of care for patients with NSCLC who harbor genetic driver mutations is treatment with the corresponding tyrosine kinase inhibitor (TKI). The emergence of TKIs substantially improved outcomes for patients with NSCLC. EGFR inhibitors, for example, improved the median survival from approximately 1 year to 3 to 4 years.

Treatment resistance, however, occurs in nearly every patient, and highlights the need for new approaches in the future to improve patient outcomes.

Current clinically actionable aberrations include EGFR, ALK, ROS1, and BRAF. But new targets need to be identified to encompass tumors driven by other mechanisms. Inhibitors targeting the proteins of genetic aberrations in RET, MET, HER2, NTRK1, and KEAP1/Nrf1 are in development and may become additional options in the future. KRAS is also frequently mutated in NSCLC, yet attempts to target this pathway have not yet been successful.

More mutation-specific and wild-type–sparring TKIs are needed, as more specific TKIs have proven more efficacious than their less-specific counterparts. Osimertinib, an EGFR inhibitor that targets T790M-resistant mutants is more effective than earlier-generation EGFR inhibitors and is generally better tolerated. The ALK inhibitor alectinib is also more effective and better tolerated than others in this class.

The heterogeneity of NSCLC indicates that combination regimens that include targeted therapy are a promising strategy to overcome resistance. This approach can target multiple pathways that may be involved in the disease.

Although immunotherapy was thought to not be as effective in patients with driver mutations, the results of the IMpower150 study of the combination of chemotherapy with bevacizumab and atezolizumab demonstrated an effect regardless of the presence of EGFR or ALK alterations after first-line TKI treatment. Additional work is needed to understand these results and to determine the optimal sequencing in patients with EGFR or ALK mutations.

Read more of Cancer Therapy Advisor's coverage of the IASLC 2018 meeting by visiting the conference page.

Reference

  1. Mitsudomi T. The future of targeted therapy. Presented at: International Association for the Study of Lung Cancer 19th World Conference on Lung Cancer; Toronto, Canada; September 23-26, 2018. Abstract PL03.06.

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