A 68-Year-Old Man With Metastatic EGFR+ NSCLC - Episode 6

Manageable Adverse Effects Associated With Treatments for EGFR+ NSCLC

May 21, 2020
John Heymach, MD, PhD

John Heymach, MD: What about the toxicities of this regimen? There were more adverse events noted in the ramucirumab arm, but overall these toxicities were, as expected, based on what we already knew about ramucirumab, and readily managed. In particular, patients treated with ramucirumab had higher rates of hypertension, and hypertension is a well-known class effect with drugs blocking the VEGF receptor. And that’s typically managed with antihypertensives as well. There was increased risk of proteinuria, and proteinuria is something that is picked up on laboratory tests and also happens with the VEGF receptor inhibitors. It’s not something that patients can typically notice. It really just has to do with their laboratory testing.

There were some adverse events of special interest. There was a bit more bleeding. Most of this was epistaxis, or nosebleeds that would happen. This is an adverse effect that also happens with VEGF inhibitors, thought to be related to the mucus membranes getting dried out a bit in the nasal canal. Again, this is not something that’s limiting, and it’s typically readily managed. But those were the primary adverse events that occurred at an increased rate in the ramucirumab arm. There were slightly higher rates of diarrhea, acne, and myelosuppression, but none of those were clinically significant differences between the 2 arms. Overall, the adverse events were as expected, readily managed, and something that we had experience dealing with because ramucirumab is a drug that’s been FDA approved for a long time, and we have a lot of experience with these adverse effects.

In fact, my experience with ramucirumab has been consistent with what’s been seen in the RELAY study. I have a lot of experience using it for years in combination with docetaxel, based on its earlier FDA approval. And I find that patients can be readily managed. Hypertension does occur occasionally, and sometimes we have to start additional antihypertensive regimens. I commonly use calcium channel blockers or β-blockers in this situation, but in general, patients do very well. And it’s exceedingly rare, at least in my hands and in the RELAY study, that I would have to stop the ramucirumab because of adverse events. That’s the safety and adverse events, and I think in general the RELAY regimen was well tolerated overall and readily managed with predictable and known adverse events. There was an increased rate of adverse events in the treatment arm, but again, in the context that it dramatically improved overall outcomes, I think a favorable benefit versus risk ratio in that setting.

What about the safety and efficacy of other treatments out there? Well, the other treatment that I would use most commonly would be osimertinib based on the first-line FLAURA study. Osimertinib is a very good drug in the first-line setting for patients with typical EGFR mutations. The median progression-free survival [PFS] with osimertinib by itself is 18.9 months, compared with the 19.4 months in the RELAY study. Compared to erlotinib or the first- or second-generation drugs against which it was tested in the FLAURA study—erlotinib or gefitinib—osimertinib has a favorable safety profile. It’s got slightly lower rates of acne. It still does have diarrhea, but the rates are a little better overall. And in general, patientsdo very well with osimertinib. I think in particular the lower rates of skin toxicity make this a particularly appealing option.

Osimertinib absolutely remains an option, and I would typically go with one of those 2 regimens, osimertinib, or if FDA approved, erlotinib and ramucirumab, compared to the other regimens. I would particularly go with osimertinib with patients who present with brain metastases in the beginning because of the well documented efficacy in the CNS [central nervous system] for osimertinib, based on a number of studies. That would be an option that would push me toward osimertinib as opposed to erlotinib and ramucirumab, but I would certainly discuss both options with a vast majority of patients who present with the typical EGFR mutation.

I mentioned already that ramucirumab adds significant efficacy on top of erlotinib as seen in the RELAY study. Would it add similar efficacy if we combined ramucirumab with osimertinib and really put those 2 things together? And I certainly think that’s an extremely promising regimen. As part of RELAY, they have opened an arm C where they’re looking at that combination. In my group, we’ve opened a multi-center study. This is led by Xiuning Le, MD, at The University of Texas MD Anderson Cancer Center, testing ramucirumab and osimertinib versus osimertinib. There we’re using every-3-week ramucirumab. And there are similar studies testing VEGF inhibitors with osimertinib, for example, bevacizumab with osimertinib is also being studied in randomized trials. I think both the preclinical rationale and all the clinical data so far strongly support that VEGF inhibitors can offer benefit in patients with EGFR-mutated non–small cell lung cancer. And the RELAY trial is the first randomized phase 3 that achieved its primary end point in terms of PFS and showed a really striking benefit.

Is there going to be an overall survival benefit? Well, the overall survival data thus far are not mature, so certainly we’re waiting to see the results of that. But the results we have seen so far really do show a striking magnitude of benefit, 7-month improvement in progression-free survival with ramucirumab plus erlotinib compared to erlotinib alone. From my perspective and given that patients who start with that regimen often then go on to osimertinib later, so you can have 2 lines of EGFR-targeted therapy. Certainly, from my perspective, this becomes an appealing first-line option that I would offer to the vast majority of patients who present with an EGFR exon 19 deletion or an L858R exon 21 point mutation, so-called typical mutations.

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