The Evolving Landscape of Molecular Alterations in NSCLC: Optimizing Testing and Treatment to Improve Outcomes - Episode 14

Overcoming Barriers to Molecular Profiling in NSCLC Management

Expert perspectives on the prevalence of molecular profiling in NSCLC, and the unmet needs and barriers preventing the uptake of routine molecular testing.

John V. Heymach, MD, PhD:
Molecular testing for non–small cell lung cancer used to be limited to advanced-stage metastatic patients because that’s where our therapies were approved. Recently, with the ADAURA study, that’s really changed. I’ll remind people that ADAURA is the study in early stage resectable EGFR-mutant non–small cell lung cancer that showed a gigantic benefit for osimertinib. We recommend testing all patients—early stage resectable and advanced patients—to see if they have an actionable alteration. A benefit of this is it also provides the opportunity to refer patients for appropriate clinical studies, even if they’re in the early stage setting. I can summarize it by saying that all patients with non–small cell lung cancer should get molecular profiling.

I test at the time of progression as well if somebody has an actionable alteration because it may reveal additional targetable alterations. For example, if somebody has an EGFR mutation and you’re treating with first-line therapy like osimertinib or afatinib, and they have progression, then I retest at the time of progression because they may have a METamplification or a RETfusion added. Or they may have an EGFR alteration that we could target with another approach, with the different therapy, if they’ve got T790M,C797S, or a different EGFR mutation. I recommend retesting upon progression if somebody has a targetable alteration, and I recommend testing all stages of non–small cell lung cancer patients.

For health care providers treating non–small cell lung cancer, there are a number of barriers to complete comprehensive molecular profiling. One is that we often don’t have enough tissue. This reflects the fact that there’s an increasing burden in terms of the amount of tissue needed for next-generation sequencing [NGS] as well as PD-L1. None of this takes into account the tissue that’s often needed for non–small cell lung cancer diagnosis, where pathologists may be doing staining for TTF1, CK7, CK20 and a number of other immunotherapies to chemical markers. That’s 1 barrier: there often isn’t enough tissue. One way to overcome that is by incorporating liquid biopsies. That’s an approach where we can certainly increase the yield.

A second barrier is having the appropriate testing method on hand. For a long time, we used to test for only EGFR and ALK, and a lot of laboratories locally started testing for them. For example, within community hospitals, they would run the assays for EGFR and ALK. That could be done competently in many hospitals. But now that we’re using next-generation sequencing, this becomes extremely complicated to profile all the genes that need to be profiled. From my perspective, it’s best handled by companies that do next-generation sequencing. A handful of cancer centers convert large teams to doing this profiling, but it becomes challenging to do this in this small hospital laboratory given the complexity of next-generation sequencing on a large scale and how to report that as well.

A third issue is that there are often questions about what assays are going to be reimbursed and whether you get reimbursement for both liquid biopsies and tumor and tissue assays if they’re done concurrently. Often people just want to do 1 assay and get the result back before they send another, but these assays take so long to complete because they’re very complicated; patients often need to get treated before then.

One other barrier that’s worth mentioning—I experience this all the time—is that patients want to get started with therapy very quickly. In some cases, they need to get started with therapy very quickly. Sometimes patients come in and they’re very symptomatic from bone metastases, or they’ve got a lobe of their lung that’s about to collapse because a bronchus is getting compressed by the tumor. These patients need to get started on treatment and can’t wait 3 or 4 weeks for all this testing to come back.

The final barrier is how long the testing takes. This is something that often needs to be sent out. This isn’t like doing immunohistochemistry for 1 or 2 markers, which can be done in a day or 2 routinely. Next-generation sequencing is pretty complicated. One strategy I’d recommend is having a routine assay that everybody goes to and agrees to, and with a partner who knows how to do this competently and report on the results. Have somebody who’s routinely running all the assays, which are needed as part of an NGS panel. At a minimum, the 8 oncogenes—and a ninth, HER2 [human epidermal growth factor receptor 2]—will likely need to be tested in the near future.

We need to have a liquid biopsy assay that covers all the required genes that can be sent routinely, and clear guidelines for when to send the liquid biopsy relative to the tissue biopsy. This is a place where we need to have good standard operating practices within a practice because it’s changing so quickly. If a busy oncologist is treating all these tumor types, it’s hard to keep in mind all the oncogenes you have to be testing. This is a case where having clearly expressed guidelines, following NCCN [National Comprehensive Cancer Network] Guidelines or other relevant guidelines, is important.

In this respect, it’s worth highlighting an abstract from a real-world experience reported by investigators at US Oncology and collaborators. This was an abstract at 2021 ASCO [American Society of Clinical Oncology Annual Meeting], reported by Dr [Nicholas] Robert and colleagues. This was from theMYLUNG Consortium of community centers, and it looked at molecular profiling. They profiled over 3000 patients with non–small cell lung cancer, and there were a few interesting take-home messages.

First, the vast majority of patients got at least 1 biomarker done. That was most commonly EGFR,and at least 90% of the patients had 1 marker done. But if you look at all 5 oncogenes considered the standard when that study started, they were ALK, BRAF, EGFR, ROS1, and PD-L1. Less than half of patients had complete profiling; it was about 46% overall. As you can see, even from groups that have well-established standard operating procedures participating in this research, the majority of patients didn’t have complete profiling. Keep in mind that was only 5 markers, not the 9 we’re looking for now, so it’s even more complicated.

This highlights the importance of having a standard procedure for broad NGS profiling that’s routinely done, making sure you’re getting adequate biopsies from the people who are doing the biopsies, and making sure pathology and medical oncology and the surgical colleagues are all aligned on what markers will be done and what priority. My recommendation is to prioritize NGS above PD-L1 or any other assay once the patient is diagnosed.

Transcript edited for clarity.