Frontline EGFR TKI Combination Reduces Risk of Progression or Death in EGFR+ NSCLC

Kazuhiko Nakagawa, MD, PhD

Kazuhiko Nakagawa, MD, PhD

The addition of ramucirumab (Cyramza) to erlotinib (Tarceva), a tyrosine kinase inhibitor (TKI) targeting EGFR, led to a reduction in the risk of disease progression or death by more than 40% in patients withEGFR-positive non—small cell lung cancer (NSCLC) compared with erlotinib alone in the frontline, according todata from the multicenter, double-blinded phase III RELAY trial.

Overall, 449 patients with stage IV NSCLC with either anEGFRexon 19 deletion or exon 21 L858R mutation and an ECOG performance status of 0 or 1 were enrolled across 13 institutions. Patients were randomized 1:1 to receive erlotinib in combination with either ramucirumab or placebo.

According to the findings presented at the 2019 ASCO Annual Meeting, at a median follow-up of 20.7 months, the median progression-free survival (PFS) by investigator-assessment was 19.4 months (95% CI, 15.4-21.6) in the ramucirumab arm versus 12.4 months (95% CI, 11.0-13.5) in the erlotinib alone arm, thus meeting the trial’s primary endpoint. These findings are comparable to the median PFS noted inthe phase III FLAURA trial for osimertinib(Tagrisso), noted Kazuhiko Nakagawa, MD, PhD, the primary investigator of the RELAY trial. The strong PFS time seen in the FLAURA trial had led to the FDA approval of osimertinib as a treatment for patients withEGFR-positive NSCLC.

Although overall survival (OS) data have not yet matured for the RELAY trial, there were 37 OS events in the ramucirumab arm versus 42 in the control arm at the data cutoff; the ramucirumab combination was favored with a hazard ratio of 0.832 (95% CI, 0.532-1.303). In the combination arm, the objective response rate was 76% versus 75% in the control arm. The median duration of response was also 18 months versus 11.1 months, favoring the ramucirumab combination.

The rate of grade 3 or higher treatment-emergent adverse events (TEAEs) in the ramucirumab arm compared with the control arm were 72% versus 54%, respectively. Rates of serious TEAEs were 29% versus 21%, respectively, while the rate of TEAE-related treatment discontinuation was 13% versus 1%.

In an interview withTargeted Oncology, Nakagawa of the Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan, discussed the findings from the RELAY trial for the combination of ramucirumab plus erlotinib compared to erlotinib plus placebo. He suggested that these data could be practice-changing for the treatment of newly diagnosed patients withEGFR-positive NSCLC.

TARGETED ONCOLOGY:Could you discuss the background to theEGFR-positive NSCLC treatment landscape prior to the RELAY study?

Nakagawa:Today, we have manageable EGFR TKIs to use as first-line treatment [of patients withEGFR-positive NSCLC], including first-, second-, and third-generation EGFR TKIs. However, osimertinib, a third-generation EGFR TKI, has shown a median PFS of 18.9 months. That is the longest PFS [that has been seen] in this setting, but there are no TKIs to overcome osimertinib resistance. Osimertinib can be used for almost half of the patients with anEGFRT790M resistance mutation after a first- or second-generation EGFR TKI.

TARGETED ONCOLOGY: What was your rationale for combining ramucirumab with erlotinib in the RELAY study?

Nakagawa:[The rationale was] to intensify the EGFR TKI [through] combinations with other targeted therapies. I believed a VEGFR inhibitor would be the most optimal to combine with an EGFR TKI. Ramucirumab is a human IgG1 monoclonal antibody that targets the VEGFR2 directly, so we combined the ramucirumab with the first-generation EGFR TKI erlotinib.

TARGETED ONCOLOGY:What was the goal and design of the trial?

Nakagawa:RELAY enrolled patients with stage IV NSCLC and common activating mutations and an ECOG performance status 0 through 1. We excluded the patients with anEGFRT790M mutation, prior [EGFR TKI or chemotherapy] treatment, or brain metastases. Patients were randomized in a 1:1 manner to receive either ramucirumab plus erlotinib or placebo plus erlotinib. RELAY demonstrated the superiority of the combination treatment of ramucirumab plus erlotinib as compared with the placebo/erlotinib combination.

The primary endpoint was PFS, and the patients were stratified byEGFRmutation status, gender, [geographic] region, andEGFRtesting method. In this study, the primary endpoint is investigator-assessed PFS, and some of the secondary endpoints included OS, tumor response, and duration of response. Also, the exploratory analysis included PFS2 and biomarker analyses.

There were 3 key points used to develop the study results for this trial. The first is this is a global phase III trial; we enrolled 449 patients across 13 countries. The second is that this trial is a double-blind, placebo-controlled trial. Third, we had a sensitivity analysis of PFS as assessed by the review committee.

TARGETED ONCOLOGY:What were the findings from the RELAY study presented at ASCO?

Nakagawa:We have very exciting results. The median PFS in the ramucirumab arm showed it was 19.4 months. This is almost comparable to the median PFS of osimertinib in the FLAURA trial. The hazard ratio was 0.591, which is highly statistically significant with aPvalue less than 0.0001. These are very amazing, solid data. The Kaplan-Meier curve has clear separation from the beginning, which continues. These data were confirmed by the independent review committee.

We have very exciting results from the subgroup analysis by mutation status. The median PFS of patients withEGFRexon 19 deletion was 19.6 months. The median PFS of exon 21 L858R was 19.4 months. If we look at the clinical outcome observed in both subpopulations, this is a very rare case; almost all EGFR TKIs showed a better clinical outcome in the patients withEGFRexon 19 deletion whereas the poorer result was shown in the patients with exon 21 point mutation. RELAY showed that we could improve the clinical outcome in both subpopulations.

TARGETED ONCOLOGY:Were there any toxicities noted in this trial that oncologists should be aware of when using this combination?

Nakagawa:The safety profile was consistent with the established safety profile of each drug, ramucirumab and erlotinib, respectively. The interstitial lung disease incidence rate in the ramucirumab arm was 2%, which was lower than was seen in the placebo arm.

TARGETED ONCOLOGY:What should community oncologists take away from this research?

Nakagawa:RELAY met its primary endpoint with a remarkable median PFS of 19.4 months. Based on these results, I believe we can now provide ramucirumab plus erlotinib combination therapy as a new and exciting initial treatment option for patients withEGFR-mutated metastatic NSCLC.

Reference:

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).