Molecular Testing Beyond EGFR and ALK in Stage IV NSCLC


Alexander Drilon, MD:To summarize, this gentleman is a 72-year-old factory worker with a former history of smoking, having quit about 30 years ago, who presented with a lung mass. At the same time, he was also found to have lymph node involvement and a pleural effusion, which qualified him for a diagnosis of stage IV disease. And on biopsies of the lung mass and the lymph nodes, this returned positive for a large cell carcinoma, which is a subtype of non—small cell lung cancer that’s nonsquamous. Molecular testing only forEGFRandALKwas performed, which also returned negative, or unremarkable, for an actionable driver.

The definition of driver-negative, or PAT-negative, it’s really a moving target, and that’s evolved a lot over the years. In the late 90s, the slice of the pie that was unknown was about 75%. And we only knew aboutKRAS. Until about 2 years ago, the slice of the pie that was unknown, the incidence, the frequency, went down to about 33%—so, 1 out of 3 patients. But, with the advances in next-generation sequencing—and, now, plasma-based genotyping—at least in our hands, the unknown slice of the pie is about 15% with our internal assay, which is a next-generation sequencing assay similar to the commercial assays that are out there like Foundation One from Foundation Medicine.

And so, beyondEGFRandALK, which make up, in aggregate, in a Caucasian population of maybe about 20% of cases, the other events that fill up the rest of the pie includeROS1andRETrearrangements,BRAFV600E mutations,METexon 14 skipping alterations,HER2mutations, andPIK3CA. So, there’s really a host of other potentially targetable events that either have therapies that are in the NCCN guidelines, in the Table of Emergent Agents, or approved for other indications that we’re able to get for lung cancer patients in the clinic and beyond that, obviously clinical trial therapy.

One important concept to lead with is the fact thatEGFRandALKare not the be-all, end-all of actionable drivers in non—small cell lung cancer. Even in patients who are former smokers, which was the case with Robert, there are other potentially actionable events that are missed on molecular diagnostic testing, if it’s restricted toEGFRandALK. So, my first recommendation, for this case, is to send his tumor for a more comprehensive test like next-generation sequencing, which may pick up other events likeMETexon 14 alterations,BRAFV600E, other recurrent gene rearrangements, for which targeted therapies have been prospectively tested.

But, considering that we’ve done that for this gentleman already, and the comprehensive report comes back negative for any actionable alterations, then things to consider for him would either be chemotherapy or immune therapy. And, for chemotherapy, obviously we know that the standard of care is a platinum doublet, with or without an antiangiogenic agent. Robert had a nonsquamous tumor. So, the use of bevacizumab is something to consider for him. But, also we have recent data showing that patients whose tumors are positive for PD-L1, meaning 50% or greater, they do better if they receive an immune checkpoint inhibitor in the first-line setting, and this is specifically pembrolizumab.

The decision as to what therapy to give a patient with advanced non—small cell lung cancer in the first-line setting is very complicated. I don’t personally go by somebody’s age as a number. I think that performance status is a better predictor of how they’re going to do with systemic therapy. Beyond that, of course, you consider things like organ function, kidney, liver function, and just their general fitness. So, the basic questions I ask patients are whether or not they’re able to take care of themselves at home, make a sandwich, shower, walk around the house. And those are rudimentary elements that we would require before seeing that someone’s fit for therapy. And then, that includes the factors that I mentioned earlier in terms of diagnostics, of course: the absence of an actionable mutation and also whether or not the tumor stains positive for PD-L1.

Casee Scenario 1:

Robert P is a 72 year old retired factory worker from Detroit, Michigan.His medical history is notable for hypertension (well-controlled), hyperuricemia, and gout.

In September of 2015, he presents to his PCP with fatigue, progressive dyspnea, and a persistent, nonproductive cough of approximately 1 month’s duration. He is a former smoker and quit approximately 30 years ago.

  • Chest X-ray in October 2015 showed a large mass in the upper left lobe and CT scan showed a left malignant pleural effusion and enlargement of the right mediastinal and hilar lymph nodes.
  • MRI of the brain was negative for intracranial metastases.
  • The patient underwent resection of the primary mass and biopsy of the affected lymph nodes which showed large cell carcinoma.
  • His lung cancer was staged as 4; Biopsy of the primary lesion and lymph node metastases were sent for molecular testing and showed no actionable mutations in EGFR or ALK.
  • His current performance status is 0.
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