Changing Landscape of EGFR+ mNSCLC

John Heymach, MD: To give a summary about the changing landscape of EGFR-mutated non–small cell lung cancer, I think this is a really exciting time, and we’re seeing clear advances. And the survival in these patients has gone from less than a year not very long ago to now more than 3 years, heading toward 4 years. A lot of patients have a much more durable benefit than that. A way to think about the landscape now, these are for typical EGFR mutations, the exon 19 deletion, or the L858R, in the first-line setting we now have third-generation inhibitors, like osimertinib, that are clearly better than the first- and second-generation inhibitors.

But we also have the option of adding a drug like ramucirumab, assuming this regimen is FDA approved from the RELAY study, to a first-generation inhibitor and then using the third-generation inhibitor later in the treatment paradigm. I think these are 2 ways the landscape is shifting, either starting with a third-generation inhibitor or starting with a first- or second-generation inhibitor with the addition of a VEGF pathway inhibitor like ramucirumab.

What about at the time of resistance? Well, we’re developing more and more tools to tackle resistance. Right now, if there’s a T790M mutation as the mechanism of resistance, we can switch to osimertinib. There are a lot of clinical studies underway to look at targeting, for example, MET amplification as a resistance mechanism. There are some other atypical mutations that can emerge as resistance mechanisms to EGFR, like C797S, or mutations at L718 in EGFR or L792 where we may have EGFR inhibitors in the near future that are effective.

I think what’s going to be developing over the next few years is more and more treatment options for smaller subgroups of resistant EGFR-mutated disease. Then after that we still have chemotherapy and we still have immunotherapy. Immunotherapy is not particularly effective for patients with EGFR-mutated disease, but occasionally it can provide benefit. I think our group and many others are working on ways to activate the immune system to get immunotherapy to work better for these patients. I think over the next few years, you’re going to see better regimens for targeting resistance in EGFR-mutated disease and more ways to activate the immune system for this group of patients.

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
  
  

Treatment

• 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