Practical Implications of the RELAY Trial in EGFR+ NSCLC

John Heymach, MD: The RELAY study compared erlotinib and ramucirumab versus erlotinib with placebo.

What’s the preclinical rationale for the RELAY study? Well, it’s been known for some time that tumors with EGFR mutations upregulate VEGF and the VEGF pathway. This appears to be, at least in part, through something called the HIF pathway. HIF stands for hypoxia-inducible factor.

Normally when cells have low oxygen, they turn on this HIF pathway, and that turns on all these factors that help the cells survive. In fact, the Nobel Prize in Physiology or Medicine this past year was awarded for understanding the mechanisms underlying this HIF pathway. It was awarded to Bill Kaelin, MD at Dana-Farber Cancer Institute, as well as Peter John Ratcliffe, FRS, FMedSci and Gregg Semenza, MD, PhD, who’s at Johns Hopkins Medicine for showing how this mechanism works.

Tumors with an EGFR mutation, when you turn on this HIF pathway, that leads to VEGF getting upregulated. They’re highly dependent on the VEGF pathway for these tumors to survive. And that’s why we believe that EGFR-mutated tumors are particularly vulnerable to VEGF inhibitors like bevacizumab or ramucirumab. And this has been observed now in a number of different studies.

Early on, the BeTa study was conducted, that was erlotinib with bevacizumab, and that was in unselected patients. But it was noted that the patients with EGFR mutations were really the group that got the most benefit from adding a VEGF inhibitor. Building on those results, the RELAY study was designed testing erlotinib and ramucirumab, a VEGF receptor-2 blocker, as compared to erlotinib and placebo.

Now, it is worth noting in that study, the patients had to have a typical EGFR mutation, either exon 19 deletion or the L858R mutation. And this patient in this case had an exon 19 deletion, and would certainly be suitable for it. They had to have a good performance status and then did not have untreated brain metastases, as this patient did not have. Now, in this regimen, there were 449 patients who were randomized, 224 in one arm, 225 patients to the other, the 2 arms were pretty well balanced. And overall, the study showed that progression-free survival [PFS] was significantly improved with the ramucirumab plus erlotinib combination. The progression-free survival on the treatment arm was 19.4 months versus 12.4 months in the control arm, so that’s a 7-month improvement in PFS. Seven months is really a remarkable difference. If you think back of all the studies with EGFR-targeted agents, typically we were seeing just a couple of months difference, even if you compared, for example, gefitinib or erlotinib versus chemotherapy. Here you’re comparing an active regimen, an EGFR inhibitor, erlotinib, versus the combination, and you’re still improving on erlotinib by 7 months in terms of PFS. So really a striking difference.

What about this patient’s response to erlotinib plus ramucirumab? Well, the response I think in many ways is a typical one, with initial regression and tumor shrinkage. More shrinkage, it seems, with patients with typical EGFR mutations does happen in the first 8 to 12 weeks. Patients often get rapid benefit, and then it’s often followed there by sustaining stable disease for a long time. This patient we saw at 18 months. The patient still had stable disease after the initial partial response, and that’s typical. Again, the median progression-free survival for patients with this regimen is 19.4 months, and I’ve seen patients with regimens like this going on for years in many cases. I think prolonged benefit and good tolerability are the hallmarks of first-line regimens for EGFR-mutated non–small cell lung cancer now. So in that sense, this patient’s response is really a typical one.

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