Erlotinib Plus Ramucirumab Considered a New Option for Treating EGFR+ Metastatic NSCLC

The combination of erlotinib and ramucirumab showed better progression-free survival in patients with newly diagnosed&nbsp;<em>EGFR</em>-mutant metastatic non&ndash;small cell lung cancer compared with erlotinib plus placebo, based on findings from the RELAY trial presented during the 2019 ASCO Annual Meeting.&nbsp;

Marina Chiara Garassino, MD

The combination of erlotinib (Tarceva) and ramucirumab (Cyramza) showed better progression-free survival (PFS) in patients with newly diagnosedEGFR-mutant metastatic non—small cell lung cancer (NSCLC) compared with erlotinib plus placebo, based on findings from the RELAY trial presented during the 2019 ASCO Annual Meeting.

RELAY, a multinational, double-blind, randomized phase III study, evaluated the efficacy and safety of the combination in patients with untreated metastatic NSCLC who either presented with anEGFRexon 19 deletion or L858R mutation without central nervous system metastasis. Trial participants received erlotinib (150 mg/day) plus ramucirumab (10 mg/kg every 2 weeks) or the same dosages of erlotinib plus placebo. Treatment continued until progression of disease or unacceptable toxicity.

Ramucirumab plus erlotinib showed a significant improvement in PFS compared with erlotinib plus placebo (HR, 0.591; 95% CI, 0.461-0.760;P<.0001). Meeting the primary endpoint of the study, the median PFS for ramucirumab plus erlotinib was 19.4 months versus 12.4 months for the erlotinib plus placebo arm. In patients with exon 19 deletions, the PFS with ramucirumab and erlotinib was 19.6 months, and was 19.4 months in patients with exon 21 L858R mutations.

Overall survival (OS) data were not yet mature at the time of the analysis, after 20.7 months of follow-up, but favored the ramucirumab and erlotinib combination with a hazard ratio of 0.832 (95% CI, 0.532-1.303). A trend toward improved progression-free survival 2 (PFS2), or progression after subsequent therapy, was also noticed with the combination regimen (HR, 0.690; 95% CI, 0.490-0.972).

Based on these data, the study researchers consider the combination, ramucirumab plus erlotinib, to be a new treatment option for patients with previously untreatedEGFR-mutated metastatic NSCLC.

Treatment-emergent adverse events (TEAEs) such as diarrhea, acneiform dermatitis, paronychia, hypertension, increased ALT, increased AST, and stomatitis, occurred more frequently in subjects receiving ramucirumab (72%) than those receiving placebo (54%). In 156 cases, drug dosages were adjusted due to TEAEs, and in 24 patients, all treatment was discontinued. Nine patients experienced severe adverse events and also discontinued treatment.

In an interview withTargeted Oncology, Marina Chiara Garassino, MD, chief of Thoracic Oncology, Istituto Nazionale dei Tumori, Milan, Italy, discusses the background of the RELAY study and how the study findings may change the treatment landscape for patients withEGFR-mutated metastatic NSCLC.

TARGETED ONCOLOGY:Can you provide some background on the phase III RELAY study?

Garassino:[At ASCO] the combination of erlotinib and ramucirumab [was presented]. It was a positive randomized trial suggesting that the progression-free survival of ramucirumab plus erlotinib was 19.4 months with a manageable toxicity. Now, we have to interpret these data and how to [implement] them in clinical practice [and] if these data are enough to remove osimertinib from the first line. There was a great debate about that because in one case you give an oral drug [and it is] very well tolerated. In [another] situation, you have to ask the patients to come every 2 weeks to receive intravenous antiangiogenics. It would be great to have a head-to-head trial. There was also a presentation about the chemotherapy plus EGFR tyrosine kinase inhibitors. So, the situation in theEGFR[NSCLC patient population] is becoming challenging.

TARGETED ONCOLOGY:If this combination becomes available in clinical practice, will there be a lot of challenges with sequencing?

Garassino:When people listen to the results [from the RELAY trial], they [will think] okay, we have 19.4 months with the combination and about 19 with osimertinib only. The potential is in half of the patients, you can go with osimertinib again. I think that we don't have a head-to-head trial, so we don't have a final solution about this. I think we have to ask the patients what their personal feelings are.

Second, we don't know [anything] about the brain metastases. The brain metastases are a huge unmet need for these patients. We know about the results of prevention with osimertinib for the brain metastases, [but] we don't know erlotinib and ramucirumab. I think that we have to digest the data presented [during ASCO]. Maybe we have to wait for more mature OS and PFS2 data. Then, I think we have to talk to the people—if the drugs will be available.

TARGETED ONCOLOGY:Do you think we could alter these EGFR TKI combinations?

Garassino:We don't know. We have the data on erlotinib and ramucirumab. It is possible that ramucirumab is the most important antiangiogenic because it is directed against the VEGF2R, which is the most relevant receptor for non—small cell lung cancer. Now that we have those data for erlotinib plus ramucirumab, I don't think we can switch and combine gefitinib and ramucirumab, [for example]. The best data with antiangiogenics that [used to be] controversial are now with this kind of combination. I think that nowadays we have to start with a combination of drugs or with a single-agent upfront.

TARGETED ONCOLOGY:What are some of the key messages oncologists show take away from this trial?

Garassino:I think that these data are really interesting. A couple of minor curves at the end, closed, so, we don't have a plateau. What seems clear is that you don't have an increase of the disease shrinkage, but you do have a longer duration of the response. I think, and this is very relevant for these patients, that we have to put everything into context and balance the toxicity and [address] the availability of the patient to come to the hospital every 2 weeks.


Nakagawa K, Garon EB, Seto T, et al. RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC).J Clin Oncol.2019;37(suppl; abstr 9000).