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NSCLC Molecular Profiling
Have We Reached the Tipping Point for Broad Molecular Profiling in Advanced NSCLC?

Released: August 09, 2017

Expiration: August 08, 2018

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When a patient presents today with a new diagnosis of advanced non-small-cell lung cancer (NSCLC), we know that molecular biomarker testing is needed to guide our treatment planning. But what type of testing is best for our patients at this particular time? The answer to this question continues to evolve.

Targeted vs Broader Molecular Testing
Extensive evidence indicates that there is profound clinical value in testing for genetic driver events in EGFR, ALK, and ROS1 among patients with advanced NSCLC. With the recent approval of dabrafenib plus trametinib for patients with advanced NSCLC who are positive for the BRAF V600E mutation, we might also add this biomarker to the list. But should we do broader molecular testing?

On one hand, broader molecular testing using, for example, next-generation sequencing enables extensive examination of tumors to find well-established actionable biomarkers, along with potential biomarkers backed by much more limited clinical data, and numerous other biomarkers of unclear significance. This approach can be very informative, particularly in the context of a clinical trial.

Although we might reflexively say that more information is inherently better than less information, identifying these less-established biomarkers may lead to misuse of the information—particularly for biomarkers associated with an available agent that was approved in a completely different setting. Some clinicians and/or patients might place too much value in such speculative treatments that are not supported by high-quality data from lung cancer patients. We should be careful to avoid replacing established treatments with these very speculative approaches. We should also not ignore the possibility that extensive molecular testing is financially more costly and does offer a significant opportunity for clinical benefit.

Although we still face many questions as we consider broader molecular testing, the array of biomarkers for NSCLC that are worth identifying is expanding every year.

New and Emerging Actionable Biomarkers
Over the past few years, the list of biomarkers that constitute a clear standard of care to test for in patients with nonsquamous NSCLC has been limited to EGFR, ALK, and ROS1. Others were arguably helpful if identified, but they lacked sufficient data and/or treatment availability to be considered as a standard of care. So, which biomarkers should be added to that list?

Of note, BRAF V600E—a mutation occurring in approximately 2% of patients—is now an established biomarker with an effective targeted therapy. As I previously mentioned, dabrafenib plus trametinib was recently approved for patients with metastatic NSCLC and a BRAF V600E mutation, based on phase II data indicating a response rate of 63% and a duration of response exceeding 1 year. Whether the therapeutic index of this combination is clearly superior to other first-line therapy options remains debatable, so it is not self-evident whether this testing should be done in the initial workup before a first-line treatment option is pursued. However, dabrafenib plus trametinib has sufficient efficacy to make it highly worth detecting the BRAF V600E mutation, if present—particularly now that this combination is commercially available for such patients.

At ASCO 2017, Awad and colleagues reported in a multicenter retrospective analysis that the survival time among patients with metastatic NSCLC and MET exon 14 deletions was improved when they received a MET inhibitor during their treatment. The median OS among these patients was 24.6 months when they were treated with a MET inhibitor compared with 8.1 months when they were not treated with a MET inhibitor. Based on these results, I favor treating MET mutation–positive patients with a MET inhibitor (eg, crizotinib) at some point during their treatment. Of note, crizotinib is available for MET-positive patients who enroll in ASCO’s widely available TAPUR trial. There are other clinical trials for such patients that will not only provide an opportunity for these patients to experience the benefit of the potential efficacy of a MET inhibitor, but will also move the field forward in terms of our understanding of the optimal treatment for patients with advanced NSCLC and MET mutations.

We have also seen some provocative, if not completely convincing, phase II data supporting targeted agents among patients with advanced NSCLC who have a HER2 mutation as well as RET translocations and NTRK mutations.

Given this increasing number of actionable biomarkers with supporting evidence for effective therapies and the new FDA approval for dabrafenib plus trametinib in advanced BRAF V600E–mutated NSCLC, I believe that the balance has tipped in favor of broader molecular testing. I do not believe it is necessarily feasible to perform individual biomarker testing beyond 3-4 biomarkers, especially because many of these biomarkers are found in approximately 1% to 2% of our patients with advanced NSCLC. By contrast, being able to pursue a single test to identify the majority of these rare, actionable mutations is very valuable; we have passed a tipping point where it makes good clinical sense in the setting of advanced NSCLC. We can find not only the 4-5 biomarkers with the strongest evidence and 1 or more associated effective targeted therapies, but we can identify several additional biomarkers for which the evidence is not as strong, but for which there are potential later-line treatment options, particularly clinical trials that may lead to some of these biomarkers becoming linked to effective new targeted therapies in the future.

Practical Implementation Recommendations
Whereas testing for individual markers can typically be done in less than 2 weeks, broader genomic testing often takes 3 weeks or longer. Although most patients can wait a couple weeks before starting first-line therapy, a longer delay becomes problematic. Consequently, I favor initially testing for the most immediately actionable biomarkers (EGFR, ALK, and ROS1) because their presence guides first-line therapy selection. It is currently debatable whether BRAF V600E should be added to that list; I believe it is critical to attempt to detect it, but not clearly necessary to identify before first-line therapy selection. For other markers, such as a MET exon 14 mutation or less-established biomarkers with potentially effective therapies, it would be appropriate to start first-line treatment with chemotherapy and/or immunotherapy-based treatment while waiting for next-generation sequencing results, and initiate the targeted therapy later.

Future Directions
I anticipate that broad molecular testing will displace other testing within the next few years as more actionable biomarkers are identified, the cost of this testing decreases, and the time needed for broader genomic testing shortens with improving technology. Moreover, as this technology improves and the sensitivity increases, our ability to perform broad genomic testing using smaller biopsy specimens will also increase. We will also gain experience with liquid biopsies to detect mutations from circulating tumor DNA as a supplement to tissue testing, at least after the initial diagnosis. We are increasingly using plasma-based testing for patients who lack sufficient tissue for additional biomarker testing, those with inaccessible tumors, and those who have greater safety risks associated with doing another tissue biopsy. Plasma-based testing is particularly informative for serially assessing tumor genomics to examine acquired resistance mechanisms that will increasingly guide our treatment decisions.

The one thing we can be most confident about is that the list of relevant biomarkers among patients with NSCLC continues to increase and the technology for broad molecular testing improves. As we reach a point where broad molecular testing is universally available with a turnaround time under 2-3 weeks, we should expect that within the next several years, it will emerge as a standard of care in the workup of patients with advanced NSCLC.

Let me know your thoughts about molecular testing for patients with advanced NSCLC. Please leave a comment below.

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