Molecular Testing for Newly Diagnosed NSCLC


John Heymach, MD, PhD: What molecular tests should be ordered for a patient with a newly diagnosed non–small cell lung cancer. Well, it’s worth noting that this patient was an ex-smoker, 30-pack-years, so a relatively heavy smoker, and quit 10 years ago. And sometimes I hear that we should only order detailed molecular testing for people that are nonsmokers or very light former smokers. And that really isn’t the case. Anybody with nonsquamous, non–small cell lung cancer should get detailed molecular testing, and I order it in all my non–small cell lung cancer patients, both squamous and nonsquamous. And that’s because sometimes there’s disagreement about the histology, or the histology is obtained with just a fine needle aspirate [FNA], that it can be very hard to see the exact histology. And, as I mentioned before, pathologists will often disagree.

Now what does the detailed molecular testing look like? Well, at a minimum, patients with nonsquamous, non–small cell lung cancer should be tested for EGFR, ALK, ROS1, and BRAF mutations, because we have FDA-approved drugs for all of those, and now NTRK fusions, because we now have FDA-approved therapies.... And I think in the very near future we can expect a good likelihood there will be agents available for MET exon 14 alterations, as well as RET fusions. These are changing quickly, and in the near future we may have drugs for HER2 as well. So, when you take all that, there’s a minimum [of] 5 or 6 assays that need to be done. And really we advocate for broader profiling here at MD Anderson Cancer Center with next-generation sequencing where you get an entire panel that covers not only the alterations for which we have FDA-approved drugs right now, but other alterations [for] which we have active drugs that are currently in clinical testing.

That’s why I really think the next-generation sequencing with broader profiling is more appropriate. In addition, PD-L1 testing is commonly done. Now, that may have less of a role in patients with EGFR mutations, but it is something that should be broadly done as well.

A question arises when you have a patient there in the office, do you start treatment right away and then change later if the results come in and suggest the new agents. Or, do you wait for the results to come? Unless the patient is really in extremis, unless they have something, for example, like an airway obstruction or are really highly symptomatic, I try to wait until the molecular testing comes back and of course try to get it done as quickly as possible.

The reason we recommend against starting immunotherapy up front before you know the results of this is because if somebody gets immunotherapy, there’s some evidence that with a TKI like erlotinib or osimertinib, you may have a higher rate of pneumonitis down the road.

Secondly, it’s better not to start therapy and then immediately stop it afterwards. I advocate for testing and waiting for the results, unless, as I said, there’s some impending issues that really force you to treat early.

Now practically speaking in the clinic, what most often prompts doctors to get the treatment started before the test results are back are patient concerns or anxiety, the desire to get going quickly. And that’s entirely understandable that the patient would want to get treatment started quickly.

I try to let them know this cancer has likely been around for a couple of years, and all that’s really changed in the recent weeks from a patient’s perspective is their awareness of the cancer. Waiting an extra two weeks in the vast majority if it is not likely to make a big difference in outcome, and it could lead to a more appropriate therapy. In general, we want to get patients on the right therapy in the first line setting and not be sending off test results and then starting chemotherapy or chemotherapy with immunotherapy and then changing it when the results come back.

So, when at all possible, I certainly advocate for waiting for test results to come back before starting therapy and explaining to patients that this is unlikely to make a difference given that the cancer has been around in most cases for years.

Transcript edited for clarity.

Case:A 68-Year-Old Man With Metastatic EGFR+ NSCLC

Initial presentation

  • A 68-year-old man presented with recent onset shortness of breath and unintentional weight loss; he denies nausea, vomiting or headaches
  • PMH: Hyperlipidemia controlled on a statin; former smoker, quit 10 years ago with a 30 pack-year history
  • PE: Decreased breath sounds in left lower lung field on auscultation

Clinical workup

  • Labs: WNL
  • PFT: FEV1/FVC 55%; DLCO 65%
  • Chest X-ray showed a left lower lobe soft tissue mass
  • Chest/abdominal/pelvic CT showed a 3.3-cm solid pulmonary mass involving the left main bronchus and ipsilateral subcarinal lymph nodes, and adrenal metastases
  • CT-guided core needle biopsy lung lesion and lymph nodes revealed grade 2 lung adenocarcinoma
  • Contrast‐enhanced MRI of the brain was negative
  • Molecular testing: EGFR exon 19 deletion, ALK-, ROS1-, BRAF-, PD-L1 TPS 20%
  • Stage IVA – T2N2M1a; ECOG PS 1


  • Patient was started on erlotinib 150 mg PO qDay + ramucirumab 10 mg/kg IV q2weeks
    • Imaging at 3-month showed partial response with decrease size of lung and adrenal lesions
    • Imaging at 6-, 12- and 18-month follow-up showed stable disease
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