patient care perspectives

Importance of the Early Recognition of Actionable Mutations in Non–Small Cell Lung Cancer

by Bruce E. Johnson, MD

Overview

There are now 8 actionable biomarkers/mutations for which there are agents approved by the US Food and Drug Administration (FDA) to treat patients with non–small cell lung cancer (NSCLC). At a minimum, all patients should undergo testing for these biomarkers.

Expert Commentary

Bruce E. Johnson, MD

Chief Clinical Research Officer
Dana-Farber Cancer Institute
Professor of Medicine
Harvard Medical School
Boston, MA

“Patients with NSCLC should undergo testing for PD-L1, and those with nonsquamous NSCLC should, at a minimum, be tested for the 7 different genomic changes for which there are FDA-approved agents and for the 3 mutations for which we will likely soon have FDA-approved agents.” 

Bruce E. Johnson, MD

Testing for biomarkers is critically important because more than half of patients with NSCLC will be positive for a biomarker that will inform their treatment. There are biomarkers that should be tested for in all patients with NSCLC. For example, patients with NSCLC should undergo testing for PD-L1, and those with nonsquamous NSCLC should, at a minimum, be tested for the 7 different genomic changes for which there are FDA-approved agents, including agents targeted against EGFR, ALK, ROS1, RET, BRAF, and NTRK abnormalities. Importantly, these abnormalities can be identified by a single next-generation sequencing panel, so you do not have to perform separate gene mutation, immunohistochemical, or fluorescence in situ hybridization tests to pick up these genetic changes.

In addition, using a full panel approach to assess all of the genetic abnormalities at the same time is preferable to performing sequential individual tests. Since it often takes 7 to 14 days to get the results of each test, sequential testing will result in delays in treatment while you are waiting for the results as each is performed. Getting a comprehensive panel up front prevents these unnecessary delays, so that is the strategy that we recommend. Indeed, broader molecular testing with next-generation sequencing up front has been associated with substantial cost savings and a shorter time to test results compared with sequential testing in newly diagnosed metastatic NSCLC.

There are also new targets for which we expect there to be FDA-approved agents within a year. For example, there will likely be 1 or 2 FDA approvals within the next 6 months for agents that target KRAS G12C mutations. KRAS mutations are important because they are reported in approximately 12% of NSCLCs. We also expect new approvals of agents that target HER2 mutations. It is important to recognize the differences in the genomic changes that activate HER2 breast cancer where HER2 is amplified, and lung cancer, where we see activation by insertion mutations of the same gene. Thus, the anti-HER2 agents that are effective in patients with breast cancer (trastuzumab and trastuzumab emtansine) do not work well in those with lung cancer. However, a recent study reported that trastuzumab deruxtecan (a trastuzumab-based drug conjugate) was associated with a nearly 62% overall response rate in patients with HER2-mutated metastatic NSCLC. Exon 20 insertion mutations in EGFR are another target of investigational therapy. These make up approximately 5% of EGFR mutations, and there are bispecific antibodies under investigation for the treatment of patients with these mutations that appear to be effective.

In conclusion, I recommend that all patients with NSCLC get PD-L1 testing and, at a minimum, that patients with nonsquamous NSCLC be tested for the 7 mutations for which there are currently available agents and for these 3 mutations for which we will likely soon have FDA-approved agents.

References

Hanna NH, Robinson AG, Temin S, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol. 2021;39(9):1040-1091. doi:10.1200/JCO.20.03570

Hofman P. The challenges of evaluating predictive biomarkers using small biopsy tissue samples and liquid biopsies from non-small cell lung cancer patients. J Thorac Dis. 2019;11(suppl 1):S57-S64. doi:10.21037/jtd.2018.11.85

Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207-1217. doi:10.1056/NEJMoa1917239

Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-358. doi:10.1016/j.jtho.2017.12.001

Mason C, Ellis PG, Lokay K, et al. Patterns of biomarker testing rates and appropriate use of targeted therapy in the first-line, metastatic non-small cell lung cancer treatment setting. J Clin Pathw. 2018;4(1):49-54. doi:10.25270/jcp.2018.02.00001

Pennell NA, Mutebi A, Zhou Z-Y, et al. Economic impact of next-generation sequencing versus single-gene testing to detect genomic alterations in metastatic non–small-cell lung cancer using a decision analytic model. JCO Precis Oncol2019;3. doi:10.1200/PO.18.00356

Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504

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