By Nathan Pennell, MD, PhD
Posted: April 16, 2020
It’s an exciting time to be a thoracic oncologist. We live in an era of unprecedented discovery in medicine—and in oncology in particular—with basic scientific breakthroughs such as targetable driver oncogenes translating into highly effective treatments for patients in record time. In my relatively short career, I have seen treatments change the lives of patients whose tumors harbor EGFR mutations,1 followed later by ALK gene fusions2 and then in short order ROS1 gene fusions3 and BRAF V600E mutations.4 Although a decade or so ago, median survival for patients with advanced NSCLC was less than 1 year,5 for the first time in my career, I can now tell some patients that their expected median survival with targeted drugs may be numbered in multiples of years.6 And these were just the first wave of driver oncogenes, with effective therapies emerging in trials for patients whose tumors harbor NTRK fusions, RET fusions, MET exon 14 mutations, HER2 mutations, and perhaps even KRAS G12C mutations.7,8
What do all of these examples have in common? They all rely on biomarker testing of tumor biopsies to identify the salient genetic alteration before the patient can receive treatment. This type of universal testing has been automatic and widely accepted in other diseases like breast cancer and hematologic malignancies for a long time, but for some reason, there is still debate about the value of testing for lung cancer. It is time to put this debate to rest.
Finding Elegant Solutions
The era of biomarker testing for NSCLC began with EGFR mutation testing, recommended by the American Society of Clinical Oncology in 2011.9 Guidelines now recommend routine testing at diagnosis of all patients with nonsquamous NSCLC for EGFR, ALK, ROS1, and BRAF, at a minimum.10 There have been some successes, as the limited data on testing rates suggest that by 2018, the majority (87%) of eligible patients in the United States were being tested for EGFR. However, when we get beyond EGFR, testing rates are much less impressive, with even ALK testing coming in at only 69%.11 Approved treatments for ROS1– and BRAF-positive NSCLC have been available since 2016 and 2017, respectively, but the data suggest that only patients getting broad genomic testing have these assays routinely done, which is infrequent.12 Outside of the United States, testing rates are highly variable but likely either similar to the United States, in the best cases, or considerably lower in others.13
In part, this has to do with how testing is done and how it is reimbursed. Initial testing for genetic markers in NSCLC was done with single-gene tests (SGT) such as PCR or FISH, and those tests have been reimbursed by insurance for some time. However, each test uses up valuable tissue and takes time, especially if done sequentially (waiting for results before the next test is ordered), and each test has a cost. One study found that while one SGT was successful in 88% of biopsies, any subsequent test had a significantly lower rate of success due to tissue exhaustion. By the fourth recommended test (the minimum recommended today), only 53% could be successfully tested.14 How well can this strategy work when we have six, nine, or more tests to perform?
A much more elegant solution is a multiplexed assay that can examine all the targets of interest at once—both current as well as emerging targets—most commonly using next-generation sequencing (NGS). This is, in fact, the recommended strategy already in the College of American Pathologists/IASLC/Association for Molecular Pathology Guidelines.10 Clearly, NGS testing is the most efficient use of tissue, but how does it compare to SGTs on cost? In other words, would it cost more to do multiple tests, each individually less expensive than NGS, than to do a single test for all required markers but that costs more than the SGT? And how does this affect turnaround time and success rates?
We looked at this by constructing a model from a payers’ perspective comparing the cost and turnaround time (TAT) of NGS to multiple simultaneous and sequential SGT strategies. The model indicated that for the four current recommended markers, NGS testing was both less costly and faster than any strategy that used single-gene tests, and perhaps most importantly, it identified the highest percentage of patients with targetable findings.15 A separate recent analysis comparing multiplexed testing to SGTs in NSCLC was able to show improved cost-effectiveness with this strategy as well.16 This imbalance will only become more marked as we move to use an increasing number of markers, and these results are starting to be reflected into better payer coverage for NGS testing, although this is still far from settled.13
It is past time to stop debating the utility and value of broad genomic testing for patients with NSCLC and to move to improving routine implementation. Although there are meaningful debates to be had about the utility of extending broad NGS testing for all patients with cancer,17 this simply doesn’t apply to lung cancer. Although each of the current and emerging targets in NSCLC is rare individually (1% to 15% of cases), when combined, an “actionable” target should be present in up to 45% to 50% of patients. There is still much work to do in making testing widely available, accurate, and timely as well as convincing payers that it is necessary. Let’s roll up our sleeves and get to work. ✦
About the Author: Dr. Pennell is director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute and an assistant professor of Medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.
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