1 Introduction
In 2020, lung cancer was the second most common cancer worldwide, with approximately 2.21 million new cases, and was associated with the highest number of cancer deaths at 1.80 million [
1]. In Taiwan, lung cancer has the highest mortality rate of all cancers and accounts for nearly 19% of all cancer deaths [
2]. Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer globally, accounting for 85% of all lung cancer cases [
3].
Epidermal growth factor receptor (EGFR) gene mutations are commonly associated with NSCLC in certain populations [
4] and occur more commonly in East Asian populations (30–60%) than in Caucasian populations (7–20%) [
4‐
6]. EGFR mutations have been reported in 34.0–55.7% of Taiwanese patients with lung cancer [
5,
7]. Of note, EGFR mutations are also more commonly found in women and non-smokers [
5,
8].
The presence of specific activating EGFR mutations—exon 19 deletion or exon 21 (L858R) substitution—is indicative of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the current first-line standard of care in EGFR-mutated NSCLC [
9], and should be considered when deciding on the treatment strategy [
6,
10]. Unfortunately, most patients with EGFR mutant lung cancers receiving EGFR TKIs will eventually experience disease progression due to acquired resistance, which limits the long-term efficacy of these agents [
11‐
13]. This highlights the need for additional first-line treatment options that extend EGFR TKI efficacy and delay disease progression and the emergence of TKI resistance.
A potential treatment strategy is dual inhibition of the EGFR and vascular endothelial growth factor (VEGF) signaling pathways [
14]. EGFR and VEGF have interconnected signaling pathways [
15]; VEGF is a key regulator of angiogenesis, and dysregulation of the EGFR pathway results in upregulation of the VEGF pathway [
15]. Dual inhibition of these pathways has been shown to reduce angiogenesis and attenuate tumor resistance to EGFR TKIs [
14,
16]. Targeting these pathways to improve outcomes in patients with EGFR-mutated NSCLC is supported by preclinical and clinical data [
15,
17‐
19].
Ramucirumab (RAM) is a human immunoglobulin G1 monoclonal antibody against VEGF receptor 2 (VEGFR-2) that demonstrated efficacy in patients with untreated, EGFR-mutated, stage IV NSCLC in the RELAY study [
20]. This global, randomized, phase III study compared the efficacy and safety of RAM combined with the EGFR TKI erlotinib (ERL) versus ERL plus placebo (PBO). East Asian patients comprised 75% (336/449) of the overall population and included 56 patients from Taiwan (12% of the overall population). In the intention-to-treat (ITT) population, the primary endpoint, progression-free survival (PFS), was significantly longer in the RAM+ERL group compared with the ERL+PBO group (median PFS: 19.4 vs 12.4 months; stratified hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.46–0.76;
p < 0.0001). In addition, there were no new safety signals and safety outcomes were consistent with similar studies investigating RAM and ERL [
20].
Currently, RAM+ERL is an approved first-line regimen for patients with EGFR-mutated NSCLC in Taiwan. However, there is a lack of published evidence on the efficacy and safety of RAM in Taiwanese patients with NSCLC. This manuscript presents the efficacy and safety findings from an exploratory analysis of the subgroup of patients from Taiwan included in the RELAY study and examines them in the context of the overall study results.
4 Discussion
In this exploratory subgroup analysis of the Taiwanese patient population within the RELAY study, RAM+ERL demonstrated numerically longer PFS versus PBO+ERL in patients with untreated metastatic NSCLC and sensitizing EGFR mutations. This finding is consistent with that of the overall RELAY study (Fig.
1B, in which PFS was significantly longer with RAM+ERL vs PBO+ERL (
p < 0.0001) [
20]. The median duration of follow-up for the Taiwanese subgroup was consistent with that for the overall RELAY population (~ 21 months) and, hence, was considered sufficient for the detection of PFS events. Tolerability likewise was consistent between the RAM+ERL treatment arms in the Taiwanese subgroup and the overall RELAY safety population, with no unexpected safety concerns in the Taiwanese subgroup. Considering secondary outcomes, DoR was higher with RAM+ERL than with PBO+ERL in both the Taiwanese subgroup and the overall RELAY population, and DCR was consistent across treatment arms in both populations.
The finding that ORR was higher with RAM+ERL than with PBO+ERL in the Taiwanese subgroup but similar across both groups in the overall RELAY population should be interpreted with caution due to the small sample size of the Taiwanese subgroup. Overall survival and PFS2 results for the Taiwanese subgroup and the overall RELAY population were premature at cut-off, precluding comparison of the two groups. Patients enrolled in RELAY were representative of a real-world NSCLC population with a higher percentage of women and non-smokers [
22]—a profile reflected in the Taiwanese subgroup.
In patients receiving RAM or PBO in the Taiwanese subgroup, the median duration of therapy was numerically shorter in the RAM+ERL treatment arm than in the PBO+ERL treatment arm, whereas the duration of therapy for ERL was longer in the RAM+ERL arm than in the PBO+ERL arm. In contrast, patients in the overall RELAY population had longer duration of therapy for both drugs in the RAM+ERL arm compared with the PBO+ERL arm. The numerically shorter duration of therapy for RAM or PBO in patients receiving RAM+ERL versus PBO+ERL in the Taiwanese subgroup is probably a consequence of small sample sizes on the point estimation of the median using Kaplan–Meier methodology. This was further explored using restricted mean survival time (RMST), an alternative measure that may overcome some of the limitations of proportional hazards modeling. RMST is the average time free from an event up until a milestone time point—a numeric expression of the area under the Kaplan–Meier survival curve [
23]. In restricted mean analyses, duration of therapy for RAM or PBO in patients receiving RAM+ERL versus PBO+ERL in the Taiwanese subgroup was in line with findings in the overall RELAY population.
Median duration of treatment was calculated in the RELAY study using the last known treatment stop date at data cut-off, and so did not take into account patients who were still on treatment or those without progression who had discontinued study treatment for other reasons. Hence, median duration of therapy is an underestimate of the true, expected therapy duration. In the overall RELAY population, at the time of data cut-off, 107/449 patients were still on study treatment, 64/224 patients randomized to RAM+ERL and 43/225 randomized to PBO+ERL [
20]. For the Taiwanese subgroup, 8/56 patients were on treatment at data cut-off, 6/26 receiving RAM+ERL and 2/30 PBO+ERL. The limited number of patients included in the Taiwanese subgroup could have increased the magnitude of variability in this finding.
Treatment resistance with first- and second-generation EGFR TKIs is primarily mediated through the emergence of gatekeeper T790M resistance mutations and remains a therapeutic challenge in patients with mutated NSCLC [
11‐
13]. The third-generation EGFR TKI, osimertinib, inhibits T790M resistance mutations [
24,
25] and thus may be an effective strategy after first- (or second-) generation EGFR TKI treatment failure. Consequently, osimertinib is the preferred first-line treatment option for patients with EGFR-mutant stage IV NSCLC recommended by the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) [
26‐
28]. However, the ESMO guidelines note that the osimertinib PFS and OS benefits were less pronounced in Asian patients. These results were evident from the subgroup analysis of the FLAURA study. Patients receiving osimertinib in the non-Asian subgroup achieved longer OS than those in the Asian subgroup (HR 0.54; 95% CI 0.38–0.77 vs HR 1.00; 95% CI 0.75–1.32) [
29]. Furthermore, like first- and second-generation EGFR TKIs, osimertinib-treated patients may also develop treatment resistance. The mechanisms of treatment resistance in osimertinib are heterogenous and yet to be fully elucidated, highlighting the need for further treatment options.
An additional approach to improve outcomes could be the addition of antiangiogenic treatment (e.g., the anti-VEGFR2 antibody ramucirumab) to an EGFR TKI. Preclinical trials have highlighted the role of VEGF/VEGFR expression in EGFR TKI resistance and further reported on the efficacy of combining VEGFR inhibitors and EGFR TKIs [
15,
17]. Combination treatment with ERL and an antiangiogenic treatment is an alternative first-line therapy recommended by the ESMO, ASCO and NCCN when osimertinib is unavailable [
26‐
28]. Ramucirumab and bevacizumab are both antiangiogenic treatments which have been investigated in separate clinical trials. The RELAY study has demonstrated the superiority of dual inhibition of VEGF and EGFR signaling pathways over EGFR TKI+PBO in global and, specifically, Asian populations [
20,
30,
31]. The ARTEMIS trial, a phase III, randomized, double-blinded study that compared a VEGF inhibitor (bevacizumab) with or without ERL in Chinese patients with untreated EGFR-mutant NSCLC, also reported a PFS benefit for bevacizumab+ERL over ERL alone [
32]. The combination of bevacizumab+ERL over ERL alone was also investigated in the phase II JO25567 study; Japanese patients with stage IIIB–IV EGFR-mutant NSCLC, receiving combination therapy of bevacizumab + ERL, achieved significant improvement in PFS than patients receiving ERL alone although this did not translate into a significant improvement in OS between the treatment groups [
33]. These results were validated by the NEJ026 phase III trial that confirmed significantly longer PFS in patients receiving combination therapy of bevacizumab+ERL than patients receiving ERL alone [
19].
The AE profile was consistent in type and severity between the RAM+ERL treatment arms in the Taiwanese subgroup and the overall RELAY safety population. The most commonly observed TEAEs in patients receiving RAM+ERL or PBO+ERL in either study group, diarrhea and dermatitis acneiform, are known AEs associated with ERL therapy [
34,
35]. Since EGFR is expressed in numerous cell tissues including the skin and gastrointestinal tract (GIT), the inhibition of EGFR TK activity has direct effects on these organ systems although exact mechanisms are poorly understood. In the skin, EGFR inhibition ultimately results in inflammation-induced dermatitis acneiform [
35]. In the GIT, multiple factors are considered to be the cause of diarrhea; one theory is excess chloride which leads to secretory diarrhea [
36]. Diarrhea and dermatitis acneiform of any grade was numerically higher in both treatments arms of the Japanese and overall RELAY safety population than in the Taiwanese subgroup; however, this could be explained by the small sample size [
20,
31].
Hypertension is a known AE of VEGF inhibitor therapy [
36], and was the most common grade ≥ 3 TE-AESI among both the Taiwanese subgroup and the overall RELAY safety population. ILD is one of the most serious AEs associated with TKIs. Despite the use of steroids to treat ILD, patients receiving TKIs for NSCLC often discontinue TKI therapy [
37]. Globally, the incidence of TKI-induced ILD in patients with NSCLC is approximately 1%; a higher incidence (3.5%) has been reported in Japanese populations [
37,
38]. Only one ILD/pneumonitis event was reported (in a patient receiving PBO+ERL) in the Taiwanese subgroup, and this is consistent with the few such events reported in the overall RELAY population [
20].
Declarations
Conflict of interest
Chao-Hua Chiu has received consulting fees or honorarium from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly and Company, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, Shionogi and Takeda. Gee-Chen Chang, Meng-Chih Lin, Jian Su, Wu-Chou Su and Yu-Feng Wei have no conflicts to declare. Te-Chun Hsia has received payment for lectures including service on speakers bureaus from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Roche, Takeda, Merck Sharp & Dohme, Merck KGaA, Bristol Myers Squibb and Amgen. Jin-Yuan Shih has received grants from Roche and Genconn Biotech; consulting fees or honorarium from ACT Genomics, Amgen, Genconn Biotech, AstraZeneca, Roche, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharmaceutical, Takeda, CStone Pharmaceuticals, Janssen, TTY Biopharm, Orient EuroPharma, Mundipharma, Ono Pharmaceutical and Bristol Myers Squibb; and travel support from AstraZeneca, Roche, Boehringer Ingelheim and Chugai Pharmaceutical. Anne Kuei-Fang Wang, Min-Hua Jen and Tarun Puri are employees of Eli Lilly and Company with stock options.