Repeat Testing at Progression of EGFR+ NSCLC


John Heymach, MD: What happens at the time of progressive disease for patients like this with a typical EGFR mutation who were treated with a first-line regimen? Well, if the patient has progressive disease that can be readily biopsied, I typically will try to get a tissue biopsy. If not, I’ll order a liquid biopsy. Liquid biopsies have the benefit that of course it’s less invasive getting a blood test than a tissue biopsy. They have the drawback that they don’t always detect the alterations. Typically, for EGFR mutations, most studies show that they detect somewhere between 85% and 90% of an EGFR mutation. I think our experience is consistent, so they’re very good, just not perfect for picking up alterations. I think it’s reasonable to start with either option.

I do think it’s important to test at the time of progressive disease for patients with EGFR mutations because there are alterations that can occur that are targetable. What are some of those alterations? Well, if somebody is getting a drug in the first-line setting, a first- or second-generation drug like erlotinib, then they have close to a 50% chance of developing T790M, a secondary alteration. And in the RELAY study, whether patients got erlotinib alone or erlotinib with ramucirumab didn’t seem to really impact the resistance mechanism. In both cases, T790M was detected in roughly half the cases, and that was just by liquid biopsy. And if they did have T790M, then osimertinib would be indicated.

Now, what if you start with osimertinib? If you start with osimertinib, we don’t have any FDA-approved regimens, but we do have a number of good clinical studies for patients who have progressive disease. For example, if you developed a MET amplification, we have a number of studies now testing MET inhibitors combined with EGFR inhibitors that show promising activity. Some of the MET inhibitors that are in clinical testing right now include savolitinib, capmatinib, and tepotinib, and they all showed promising results in this setting. It’s possible to get additional EGFR alterations, and some of those additional EGFR alterations may actually be responsive to other EGFR inhibitors.

I do think it’s important to do testing. There have even been reports, there’s one from Zosia Piotrowska, MD, and colleagues at MGH [Massachusetts General Hospital] where they showed RET fusions coming out in patients with EGFR inhibitor resistance. And there was a response subsequently to RET inhibitors. And we’ve also seen RET fusions arise in the setting of EGFR inhibitor resistance as well. I do think that it’s really important for patients to undergo molecular testing at the time of progressive disease. I think the good news is that more treatment options are coming out for patients who do have progression after EGFR inhibitors. Right now, the most common one for someone who starts with erlotinib will be osimertinib if you had T790M. But I’m expecting in the near future there will be a lot more options emerging.

What other treatment options are there for patients who progress after an EGFR inhibitor? Well, if they don’t have a targetable alteration, then chemotherapy certainly remains an option. Personally, I always try to incorporate a VEGF inhibitor with chemotherapy. For example, the ECOG 4599 regimen with carboplatin/paclitaxel, and bevacizumab, or the IMpower150 regimen, or find some way to use bevacizumab with platinum doublet chemotherapy, just because we know that patients with EGFR mutations depend on the VEGF pathway so much.

The KEYNOTE-189 study, which had tested platinum doublet with pembrolizumab, did not include patients with EGFR mutations. So, for patients with EGFR-mutated non–small cell lung cancer, the KEYNOTE-189 regimen is not FDA approved. I typically would use a platinum doublet regimen. I try to include bevacizumab wherever possible as long as the patient didn’t have a contraindication to bevacizumab. And I reserve immunotherapy for after platinum doublet chemotherapy, unless the patient had very high PD-L1 levels. If the patient had a PD-L1 level of greater than 50%, I might consider doing immunotherapy first, but it’s very rare for patients with EGFR mutations to have a PD-L1 level that high. Typically, they have low PD-L1 levels. A platinum doublet would usually be the next regimen and then considering immunotherapy, or docetaxel, or docetaxel with ramucirumab after a platinum doublet.

We really want to stretch out the time for which patients are on an EGFR inhibitor, and I think this is an important concept. I think patients being treated for EGFR-mutated non–small cell lung cancer really think of their time on EGFR inhibitors as where their quality of life is usually very good, really dealing with some mild and manageable adverse effects from the EGFR inhibitor. And then when they stop on the EGFR inhibitor and move to chemotherapy, that’s often where the quality of life can be compromised by the treatment to a significant extent. The treatment is still worth carrying out, but I and I think most oncologists, really try to stretch out that period on EGFR inhibitors for as long as possible.

Let me mention 1 other option for people treated with a first-line EGFR inhibitor who only have progression at a couple of sites, we call that oligoprogression, I’ll often recommend local therapy to those sites. For example, let’s say this patient subsequently had progression, and there was only 1 bone metastasis, or bone metastasis and 1 spot in the lung, I would commonly radiate those 2 spots. And then if the patient had a T790M, switch over to osimertinib. If they didn’t have a T790M, I’d often continue the treatment that I was using.

We recently reported, for patients on osimertinib, that if you consolidated them at the time of progression with radiation, they could go on for another year on osimertinib. This shows you that even after progression with consolidative radiotherapy, you often can get durable benefit afterward. I think you want to be as creative as possible at figuring out how to keep using EGFR inhibitors for as long as it’s clinically indicated, either by finding alterations that can be targeted with the combination, like T790M, or consolidating the sites of progression, if it’s only a couple, and continuing the regimen.

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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