Molecular Testing for NSCLC


Jonathan Riess, MD, MS:So, in terms of ordering molecular testing in patients with non—small cell lung cancer, I think there are a couple of components looking at both early versus late stage, as well as squamous versus non-squamous non–small cell lung cancer. In general, I order molecular testing on the majority of my patients with non–small cell lung cancer. I order it on all my patients with advanced non-squamous non–small cell lung cancer because we know that there are great therapies for both FDA-approved drugs, matching them to a particular mutation such as EGFR mutation, ALK rearrangement, ROS1 rearrangements. We also have a host of new potential targets that are actionable either using off-label drugs or on a clinical trial in terms of expanded panels.

For patients with squamous non—small cell lung cancer, if you look at the guidelines, they talk about ordering molecular testing if patients have a scant biopsy specimen, or if they have a never or light smoking history. I typically follow those guidelines and order the molecular testing on those patients as well because I found, in certain cases—it’s uncommon, but it does happen—in squamous lung cancer that’s obtained on a scant specimen or a patient who has a very light smoking history, actionable molecular alterations, EGFR mutations, ALK rearrangements. That’s really impacted and changed the patient’s course of care. And, for patients with squamous lung cancer, in general, I also order molecular testing. Although EGFR mutations and ALK rearrangements in patients with squamous lung cancer is very uncommon, we do have the Lung Master Protocol at UC Davis. This is a Southwest Oncology Group trial that allocates patients to different treatment arms based upon their molecular testing results to look at other targets beyond EGFR and ALK because they’re so uncommon in patients with squamous lung cancer. So, on a trial, even if a patient has a heavy smoking history with squamous lung cancer, I do order molecular testing because that could also impact their care as well.

In terms of early versus late stage non—small lung cancer, I generally do it on everybody with late stage non-squamous and non–small cell lung cancer. Patients with squamous have those characteristics of never or light smoking, or a scant biopsy specimen to look for EGFR, ALK, and ROS1 in particular, but also that expanded panel as well. I’m doing it more in earlier-stage patients, but that’s basically in association with the ALCHEMIST trial that we have open at UC Davis. So, generally, it’s not standard. You don’t have to do it on early-stage patients, but because we have the ALCHEMIST trial—which is an Intergroup trial—it randomizes patients with an EGFR mutation to receive erlotinib or placebo for 2 years or patients with an ALK rearrangement to receive crizotinib or placebo for 2 years. Those are two of the arms in the study and soon to be adding an immunotherapy arm as well. I generally obtain all those patients because I have something to offer them if it’s positive. But, I generally don’t treat with EGFR TKIs, for example, in EGFR-mutant lung cancer in early-stage patients off of a clinical trial.

So, in terms of my standard molecular testing panel for patients with advanced non—small cell lung cancer, I generally send a next-generation sequencing panel that has several different vendors. There’s several hundred genes on these panels, but the main ones you’re looking for are EGFR mutations, ALK rearrangements, and ROS1 rearrangements. Those are the big three. No matter what molecular testing you do, if you do targeting tested, just having EGFR mutation, ALK rearrangement by FISH, or ROS1 rearrangement by FISH is sufficient. But, the NCCN Guidelines note that there are potentially other actionable molecular alterations, such as MET exon 14 skipping events, HER2 insertions, and others. These could either open up patients to get clinical trials and have those available to them, or that you, potentially, at some point in treatment, can use an off-label drug that may have targeted activity, such as for BRAF-mutant lung cancer or MET exon 14 skipping events.

I generally start off with an NGS panel because I feel you get all the answers at once, but sending off an EGFR-mutation test, as well as ALK and ROS1 FISH for the rearrangements, is also sufficient. But then, keep in mind, if those are negative, particularly if a patient has a never or light smoking history, follow up with an NGS panel after they’ve progressed on a platinum-based chemotherapy, for example, because you may pick up some other actionable molecular alterations that you can match to a trial or some off-label therapies.

So, the status of plasma cell—free DNA, I think that’s an exciting, new option in terms of molecular diagnostics that are available to our patients. There are multiple different companies that offer these tests, as well as several academic institutions. And, basically, it’s looking at cell-free DNA in the blood that’s shed by the tumor to see if we could pick up these molecular alterations. There has been a lot of research and there’s still a tremendous amount of work that needs to be done, but it could be a useful adjunct to tissue testing. I have used it, particularly, in patients with EGFR-mutant lung cancer, to look at the emergence of T790M mutations. It is the most common resistant mechanism to erlotinib, gefitinib, afatinib, your standard frontline EGFR tyrosine kinase inhibitors. And so, I have started looking at that.

I’m generally using plasma cell—free DNA more and more, especially for detecting emergence of EGFR T790M, which is the most common resistance mechanism to your standard first-line EGFR TKIs such as afatinib, gefitinib, and erlotinib. Although, I don’t think it necessarily substitutes for tumor tissue. It’s a way of enhancing your detection for EGFR T790M and potentially accelerating that process since you don’t need to obtain a tissue biopsy, which can take some time as an invasive procedure in terms of getting that result back.

Riess case 1:

A 44-year-old female with relapsed stage IV adenocarcinoma.

  • This is a 44-year-old female diagnosed with stage IV adenocarcinoma
  • Tissue-based mutation testing showed an EGFR mutation with exon 19 deletion
  • She was subsequently treated with afatinib
  • After 11 months she became mildly symptomatic with small, nonspecific pulmonary nodules
  • Follow up CT scan showed growth of the primary lesion
  • The patient reported worsening of her cough
  • Cell-free DNA testing was ordered and was negative for both the EGFR driver mutation and for T790M
  • Subsequent tissue biopsy showed the presence of T790M
  • The patient was switched to osimertinib and continues to respond well to therapy with minimal toxicity
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