SUMMARY: The FDA on May 29, 2020 approved CYRAMZA® (Ramucirumab) in combination with TARCEVA® (Erlotinib) for first line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.
Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.
TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Previously published data from the Phase III FLAURA study showed that first-line treatment with TAGRISSO® was superior to first-line treatment with other first and second generation TKI’s, in patients with EGFR-mutated NSCLC, with improved median Overall Survival. Patients with the exon 21 L858R substitution mutation however are less sensitive to TKIs and their PFS therefore has been lower, than those with exon 19 deletions. In the FLAURA study the PFS in the exon 21 mutation group was 14.4 months compared with 21.4 months for patients with an exon 19 deletion, when treated with first line TAGRISSO®. Furthermore, widespread use of TAGRISSO® has led to acquired resistance. Evolving data has shown limited responses to immune checkpoint inhibitors after disease progression on TKIs. There is therefore a critical need to develop new TKI-based therapies, and novel treatment approaches, combining TKI’s with other targeted therapies. RELAY trial was designed to address this unmet need.
CYRAMZA® is a recombinant human monoclonal IgG1 antibody that binds to the human Vascular Endothelial Growth Factor Receptor- 2 (VEGFR-2), preventing the interaction of VEGFR-2 with its ligands. CYRAMZA® was previously approved for use in combination with TAXOTERE® (Docetaxel) for the treatment of patients with metastatic NSCLC who progressed while on or following treatment with platinum-based chemotherapy. Several preclinical studies have shown that dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic NSCLC is synergistic, with higher antitumor activity, when compared with inhibition of the EGFR pathway alone. This has been attributed to upregulation of VEGF in the tumor microenvironment, when tumor cells harbor EGFR mutations.
RELAY trial is global, multicenter, randomized, double-blind, placebo-controlled, Phase III study in which 449 patients with previously untreated metastatic NSCLC, who harbored either an EGFR exon 19 deletion or exon 21 L858R substitution mutation, were enrolled. Patients were randomized 1:1 to receive TARCEVA® 150 mg orally daily in combination with either CYRAMZA® 10 mg/kg IV (N=224) or placebo (N=225), every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity. Both treatment groups were well balanced. Patients had an ECOG performance status of 0-1, median age was 64 years, and about 60% of patients were never smokers. Those with a known EGFR T790M mutation, received prior treatment with an EGFR TKI or chemotherapy, or had brain metastases, were ineligible for study enrollment. Patients were stratified by sex, EGFR mutation type, and EGFR testing methodology. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), Overall Response Rate (ORR) and Duration of Response (DOR).
At a median follow up of 20.7 months, the median PFS was 19.4 months in the CYRAMZA® plus TARCEVA® group compared with 12.4 months in the placebo plus TARCEVA® group (HR= 0.59; P<0.0001). This PFS benefit was observed across several patient subgroups, and was consistent across Exon 19 and Exon 21 subgroups. Unlike in the FLAURA trial, in the RELAY trial, the PFS in patients with exon 21 mutation was comparable to patients with exon 19 deletions. The PFS for these patients with exon 21 mutation was 19.4 months. Further, the addition of CYRAMZA® to TARCEVA® did not increase the incidence of EGFR T790M mutation. The ORR was 76% in the CYRAMZA® plus TARCEVA® group and 75% in the placebo plus TARCEVA® group, with median DoR of 18.0 months and 11.1 months, respectively. At the time of the final analysis of PFS, the OS data were not mature. The most common adverse reactions in the CYRAMZA® plus TARCEVA® group were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. The most common laboratory abnormalities were increased ALT and AST as well as cytopenias.
It was concluded that CYRAMZA® plus TARCEVA® demonstrated superior PFS, compared with placebo plus TARCEVA®, in treatment naïve patients with EGFR-mutated metastatic NSCLC. Inhibiting the VEGFR and EGFR pathways together, is an important milestone in the treatment of EGFR-mutated NSCLC, with outcomes comparable to that with third generation TKIs, and furthermore, providing these patients an additional treatment option with TAGRISSO® upon progression.
Ramucirumab plus Erlotinib in Patients with Untreated, EGFR-mutated, Advanced Non-Small-Cell Lung Cancer (RELAY): A Randomised, Double-blind, Placebo-Controlled, Phase 3 trial. Nakagawa K, Garon EB, Seto T, et al. Lancet Oncol. 2019;20:1655-1669.
