Ramucirumab Combination Expands Lung Cancer Options

In non–small cell lung cancer (NSCLC), the choices for frontline treatment are swiftly growing. The landscape now includes ramucirumab (Cyramza) in combination with erlotinib (Tarceva).

On May 29, 2020, the FDA approved ramucirumab plus erlotinib for the firstline treatment of patients with metastatic NSCLC with EGFR exon 19 deletions (Ex19del) or exon 21 (L858R) mutations. Ramucirumab previously was approved in combination with docetaxel for patients with metastatic NSCLC with disease progression after prior therapy.

The approval is based on efficacy data from the phase 3 RELAY study (NCT02411448) which demonstrated progression-free survival (PFS) benefit with the dual-drug approach. The study enrolled 449 patients with untreated metastatic NSCLC whose tumors harbored EGFR Ex19del or exon 21 (L858R) substitution mutations.

In an interview with OncLive, Edgardo Santos, MD, a clinical affiliate associate professor at Charles E. Schmidt College of Medicine at Florida Atlantic University in Boca Raton, Florida, and a medical oncologist at Florida Precision Oncology, a Division of 21st Century Oncology, in Aventura, Florida, discussed the unprecedented PFS in patients with EGFR mutations.

OncLive: What is noteworthy about the efficacy data that led to this approval?

Santos: The RELAY study is no different from most of the other studies of EGFR [tyrosine kinase inhibitors] TKIs in patients with EGFR-mutant NSCLC that have been conducted since 2008: all had a primary end point of PFS. The RELAY study met its primary end point and the FDA approved ramucirumab and erlotinib as a frontline therapy for patients with NSCLC who have EGFR exon 19 or exon 21 mutations based on the combination’s superior PFS compared with the comparator group using erlotinib alone.

In the history of EGFR TKI development, regardless of the TKIs that we have used in the past, including gefitinib [Iressa], erlotinib, afatinib [Gilotrif], dacomitinib [Vizimpro], and even osimertinib [Tagrisso], patients with the exon 21 abnormality have been less sensitive to TKIs and therefore, their PFS has been lower than those with exon 19 deletions. For example, in the FLAURA study [NCT03521154] of upfront osimertinib, the PFS in this group was 14.4 months compared with 21.4 months for patients with an exon 19 deletion.

However, in RELAY the PFS in patients with exon 21 deletions was comparable to [that] for patients with exon 19 deletions. The PFS for these patients with exon 21 deletions was 19.4 months. We have never seen that kind of PFS in this particular group.

How does this regimen affect the use of TKIs available for treating this disease?

By National Comprehensive Cancer Network [NCCN] data, therapy for patients with EGFR-mutant lung cancer is saturated with TKIs. We have first-generation TKIs such as gefitinib and erlotinib, second-generation TKIs including afatinib and dacomitinib, and third-generation inhibitors like osimertinib. These are all classified as category 1 treatments by the NCCN. Of them, osimertinib has been chosen as the preferred agent because it had the longest PFS reported of all the single-agent TKIs, which was 18.4 months. Recently, reported data from the FLAURA study [NCT02296125] showed an overall survival [OS] benefit favoring osimertinib over gefitinib or erlotinib, with a median OS of 38.4 months versus 31.8 months.

Erlotinib in combination with ramucirumab is classified as a category 2A recommendation by the NCCN because of the unprecedented PFS of 19.4 months that was seen with this doublet therapy. Overall survival data from RELAY are immature.

Please describe the doublet therapy’s safety profile.

There have not been any red flags in terms of toxicities that we have not seen with either agent alone, meaning that the safety data are consistent with what we have seen to date with both agents, not only in lung cancer but also in other tumor types. Ramucirumab is an antiangiogenic agent that has FDA approval in several other tumor types. The toxicity profiles of both agents are very well known.

In the RELAY study, some toxicities that we are accustomed to seeing occurred a little more frequently; however, most of the toxicities in the trial were grade 1 and grade 2, so the adverse events were very mild and easy to handle. We saw hypertension, which is very classic of antiangiogenic agents like ramucirumab, as well as proteinuria; rash was also seen at [a] higher incidence with the combination than when we use erlotinib alone. In RELAY, the incidence of hypertension was higher than in other trials where ramucirumab has been studied.

What causes these agents to have synergy?

In the past, several preclinical studies have shown that dual blockade of the EGFR and VEGF pathways is synergistic. The antitumor activity is higher when compared with inhibition of the EGFR pathway alone. We also know that when tumor cells harbor EGFR mutations, VEGF is upregulated in the tumor microenvironment, so we know that dual blockade makes sense in this instance.

What are the next steps for this combination?

We are waiting for the OS data from the RELAY study, which [are] immature at the time of publication. We will wait for this data to see how much the addition of ramucirumab to erlotinib improved the OS that we have seen so far with osimertinib monotherapy.

Ramucirumab is also being studied in combination with osimertinib, so we are eagerly awaiting these efficacy results.

Also, the addition of ramucirumab to erlotinib did not affect the incidence of EGFR T790M mutation, a genomic abnormality which confers resistance to first- and second-generation TKIs, leaving the door open to use osimertinib as a salvage therapy in this scenario.