Molecular Testing in Patients With NSCLC

Benjamin Levy, MD: The testing algorithm, or diagnostic algorithm, for patients with advanced non—small cell lung cancer [NSCLC] has evolved over the past 12 to 24 months. Patients with advanced stage adenocarcinoma at a minimum should have EGFR, ALK, ROS, and BRAF. Those are the 4 genetic aberrations that have targeted therapies that we can deliver. But we’ve learned recently of emerging biomarkers, or genetic aberrations, that also may be predictive of targeted therapy. NTRK fusions, now we have a drug, larotrectinib, that is approved. MET exon 14 skipping mutations, HER2 mutations. And so I think because of this, because we have approved biomarkers, but we also have these emerging biomarkers, we should be doing comprehensive genomic profiling on all of our patients with advanced adenocarcinoma of the lung. And so we get fell swoop, we get it in 1 testing. We get all of the genes of interest that we’re looking for, and we can then make treatment decisions based on that.

I would say for patients with squamous cell, advanced stage squamous cell, we generally do not recommend molecular testing. But if a patient is a never smoker or light smoker with squamous cell, then we would do the same testing—a comprehensive genomic profiling on these patients, and attempts to find a molecular aberration that we could act on with a targeted therapy.

In addition to molecular testing for patients with both advanced adenocarcinoma and squamous cell, we, of course, need to be doing PD-L1 [programmed death-ligand 1] testing. PD-L1 should be done, again, on all patients, and it can help drive decision making for patients who don’t have a genetic aberration. We know that patients who have a PD-L1 greater than 50%, these patients should be offered single-agent pembrolizumab, or can be offered the triplet therapy with carboplatin/pemetrexed/ pembrolizumab, if they’re symptomatic. And patients with less than 50% should probably not be offered single-agent immunotherapy. These patients should be offered generally chemotherapy with immunotherapy, but not single-agent immunotherapy. And just a reminder that the PD-L1 testing should be done in conjunction with molecular testing. PD-L1 shouldn’t be driving the decision making until we know the molecular aberration.

It’s important that all patients with advanced stage non—small cell lung cancer, specifically adenocarcinoma patients, get tested up front for comprehensive genomic profiling. I think there’s a lot of questions still unanswered about whether testing should be done upon relapse. Patients who are on targeted therapies who do have progression or develop progression, I think this is an opportunity to perform comprehensive genomic profiling to understand what the genetic underpinnings are for mechanisms of resistance. This can be done of course with a tissue biopsy, or oftentimes with a liquid biopsy. So patients who are on a targeted therapy who have a genotype that we’re giving this targeted therapy to, I would say that molecular testing is important both at diagnoses and when they are progressing or have relapse.

Patients without genetic aberrations who aren’t on targeted therapy, I wouldn’t consider testing comprehensively upon relapse unless I didn’t get all the information up front. If there was some limited tissue the first go-around, they started on treatment with chemotherapy and immunotherapy, and when they progressed, this may be an opportunity to re-biopsy the patient. But on a routine patient in clinical practice, if I have enough comprehensive genomic profiling, the results, I generally will not retest them if they’re not on a targeted therapy.

It’s so important that comprehensive genomic profiling, our next-generation sequencing, is done on all of our patients. We’ve learned not just about EGFR and ALK and ROS and BRAF, but these emerging biomarkers that have really effective, minimally toxic genotype-directed therapies that we can give to these patients, and it makes a huge difference in terms of how likely are their tumors to shrink, but also their quality of life. So I highly encourage every effort being made for comprehensive genomic profiling, specifically for advanced adenocarcinoma patients, but also for our advanced squamous cell patients who are light or never smokers.