Optimizing Molecular Testing and Treatment Strategies in NSCLC


Expert Joel Neal, MD, PhD, shares his perspectives on the frontline management of NSCLC and optimal strategies for molecular profiling in this setting.


Joel Neal, MD, PhD: When this patient was referred to us, we reviewed the history. I agreed with most of what was done. Oftentimes, we will use carboplatin in the first-line setting instead of cisplatin. For non–small cell adenocarcinoma, I think that the choice of pemetrexed was perfectly appropriate. And when I have a patient with a light, or distant, or never-smoking history, I do favor starting with chemotherapy without immunotherapy, despite that PD-L1 of 75%.

This oncologist should be commended for not starting the immunotherapy up front because with the light smoking history, despite the high PD-L1, there was a significant chance, maybe 30%, 40%, 50%, that this patient would have a tumor with an EGFR mutation. I think cisplatin is a reasonable choice, oftentimes more of a standard in other countries than the United States. Carboplatin is a little bit easier to give, less nephrotoxicity, less ototoxicity, but both are reasonable choices. So, platinum-based plus pemetrexed chemotherapy in the first-line setting while waiting for molecular testing.

Second, as far as the molecular testing, increasingly I’m seeing that patients are having blood-based molecular testing up front. We’re seeing that these testing companies can do next-generation sequencing from liquid biopsies with turnaround times that are impressive, in a week, or a week and a half or so. Oftentimes, [they are] faster than the tissue testing, which requires some time to get tissue from pathology to a central testing facility, and then perhaps a week or two turnaround after that.

I think a liquid biopsy could have been appropriate in the first-line setting here, while waiting for the tissue too. But my preference is, if I’m sending [a] liquid biopsy, to also send the tissue at the same time, just as a backup because a negative liquid biopsy test, even by next-generation sequencing, can be falsely negative up to 25% or 30% of the time. Conversely, sometimes the tissue is inadequate or can fail in next-generation sequencing. For example, a bone biopsy may have been decalcified and not be adequate. Sometimes liquid biopsies can provide more information. I think increasingly, we’re seeing that these are complementary. I think sending for DNA next-generation sequencing, absolutely, and starting on chemotherapy since the patient was somewhat symptomatic, I think that’s perfectly appropriate.

We covered the basic initial molecular testing on this patient. Another question that we get when we’re seeing this patient for consideration of second-line therapy is, should we repeat the molecular testing? For me, usually, I repeat the molecular testing when the patients have a targeted therapy and demonstrated acquired resistance in the tumor to that targeted therapy. For example, a patient with EGFR-mutated lung cancer that’s sensitive to the first-line EGFR TKI [tyrosine kinase inhibitor], such as osimertinib. When we give the osimertinib and we see a tremendous response of the tumor, and then we see growth afterward, then the tumor cells that are growing afterward are by definition resistant to the targeted therapy that we’re giving. And it can be of interest, both scientifically as well as for the patient, to understand what are those cells? What’s the nature of those cells that are growing out and acquired resistance?

For patients who are getting chemotherapy, or even for the most part with chemotherapy and immunotherapy, or immunotherapy alone, we don’t understand those molecular changes nearly as much. And so, a repeat biopsy of tissue or repeat molecular tests by liquid biopsy don’t generally yield more information when we have a reliable molecular test in the first-line setting. For this patient, I probably wouldn’t do a repeat biopsy, either by liquid or tissue, if I thought that the initial result of that EGFR exon 20 insertion mutation was reliable.

Transcript edited for clarity.

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