Positioning of erlotinib plus ramucirumab therapy in current clinical practice for EGFR-mutated non-small cell lung cancer

Introduction

Lung cancer remains one of the leading causes of cancer-related mortality worldwide (1). Despite this persistently high mortality, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have substantially improved clinical outcomes for patients with advanced non-small cell lung cancer (NSCLC) harboring common activating EGFR mutations (exon 19 deletion or exon21 L858R mutation) (2).

The RELAY study was a global, randomized, double-blind, placebo-controlled phase III trial that evaluated the efficacy and safety of dual EGFR and vascular endothelial growth factor (VEGF) pathway inhibition in previously untreated patients with advanced EGFR-mutated NSCLC. Patients were randomly assigned to receive erlotinib in combination with either ramucirumab or placebo. The primary endpoint was progression-free survival (PFS) assessed by independent review, with overall survival (OS), objective response rate (ORR), and safety as key secondary endpoints. The study demonstrated a statistically significant and clinically meaningful improvement in PFS with erlotinib plus ramucirumab compared with erlotinib alone, establishing EGFR-VEGF dual inhibition as an effective first-line treatment strategy in this molecularly defined population (3,4). At the final OS analysis (median follow-up 45.1 months), the ramucirumab plus erlotinib group showed a sustained improvement in PFS compared with the placebo plus erlotinib group [median: 19.6 vs. 12.4 months, hazard ratio (HR) =0.66, 95% confidence interval (CI): 0.53–0.83]. The median OS was 51.1 and 46.0 months, respectively (HR =0.98, 95% CI: 0.78–1.24). In subgroup analyses by EGFR mutation type, the median OS for the L858R mutation was 51.6 months in the ramucirumab group and 45.8 months in the placebo group (HR =0.87, 95% CI: 0.62–1.22), and for the ex19del mutation, it was 49.0 months and 51.4 months, respectively (HR =1.13, 95% CI: 0.83–1.55) (4).

Overview of the final analysis from the RELAY study

In the final OS analysis of the RELAY study, the addition of ramucirumab to erlotinib did not result in a statistically significant OS advantage compared with erlotinib alone (HR 0.98), despite a clear and sustained PFS benefit (3,4). This finding should be interpreted within the context of the study design. First, OS was not the primary endpoint, and the trial was not specifically powered to detect modest survival differences, particularly in an era where effective subsequent therapies substantially influence long-term outcomes. Secondly, post-progression survival (PPS) was markedly prolonged in both treatment arms, reflecting extensive and well-balanced use of active post-study treatments. More than 80% of patients received subsequent systemic therapy, and over half were treated with osimertinib, a highly effective third-generation EGFR-TKI known to attenuate OS separation even when earlier disease control differs between treatment strategies.

Although a statistically significant OS advantage was not demonstrated, clinically meaningful findings were observed in predefined subgroup analyses, particularly according to EGFR mutation subtype. While L858R-mutated NSCLC have generally derived less benefit from EGFR-TKI therapy than those harboring exon 19 deletions, the RELAY study showed a consistent PFS benefit with erlotinib plus ramucirumab across both major EGFR mutation subtypes; exon 19 deletion: 19.6 months (HR 0.65; 95% CI: 0.47–0.90) and L858R: 19.4 months (HR 0.62; 95% CI: 0.44–0.87) (3). Moreover, in the final analysis, median OS in the ramucirumab arm was 49.0 months (95% CI: 43.9–58.7) in patients with exon 19 deletion, corresponding to an absolute differences of –2.4 months (4). In contrast, in the L858R subgroup, median OS was extended to 51.6 months (95% CI: 43.6–59.3), representing a larger absolute gain of 5.8 months and showing a consistent upward separation of the Kaplan-Meier curves (4). These findings suggest a biologically relevant and clinically meaningful benefit of VEGF inhibition in this population.

Clinical and biological context of L858R-mutated NSCLC

Across multiple generations of EGFR-TKIs, NSCLC with the L858R mutation has consistently been associated with inferior clinical outcomes compared with those with exon 19 deletions (5-7). Even with newer combination strategies, this gap has not been fully overcome. In the phase III MARIPOSA trial, amivantamab plus lazertinib established an overall PFS benefit compared with osimertinib (HR 0.70; 95% CI: 0.58–0.85) (8). However, the efficacy in patients with L858R-mutated disease remained numerically less favorable (HR 0.78; 95% CI: 0.59–1.02) than those with exon 19 deletion (HR 0.65; 95% CI: 0.51–0.85) (8). In contrast, the FLAURA2 study exhibited improved outcomes in patients with L858R-mutated NSCLC; however, this benefit may have been driven by the addition of platinum-based chemotherapy (9).

In EGFR-mutant NSCLC, the presence of concurrent TP53 mutations should be carefully considered, which was evaluated in the RELAY study. Somatic mutations in TP53 represent by far the most prevalent co-alteration in EGFR-mutant NSCLC (54.6–65%) (10,11). These alterations have been associated with attenuated responses to EGFR-TKI therapy and more rapid development of acquired resistance, particularly in NSCLC harboring the L858R mutation (12,13). Importantly, exploratory biomarker analyses from the RELAY study suggested that the PFS benefit of erlotinib plus ramucirumab was maintained regardless of TP53 mutation status, indicating that VEGF pathway inhibition may partially mitigate the adverse prognostic impact of TP53 alterations (3). These observations provide a biologically plausible rationale for considering intensified or combination strategies in selected patients with unfavorable genomic features.

The preclinical study provides a biological rationale for differential sensitivity to VEGF pathway inhibition according to EGFR mutation subtype (14). Using an isogenic cell line system generated by CRISPR knock-in technology (15), in which EGFR exon 19 deletion–positive PC9 cells were engineered to express homozygous L858R mutation, Zhao et al. found that L858R-mutant cells exhibit lower EGFR expression together with increased activation of alternative receptor tyrosine kinases, including ERBB3 and VEGFR2. Integrated transcriptomic and multiplex proteomic analyses revealed that L858R-mutant cells rely on more heterogeneous and redundant growth and survival signaling networks at baseline and following EGFR inhibition. Functionally, PC9EX21 cells showed reduced sensitivity to erlotinib. Importantly, the addition of VEGF pathway inhibition with ramucirumab enhanced the antiproliferative effects of EGFR-TKI, accompanied by augmented suppression of downstream PI3K/AKT signaling, including inhibition of GSK3 phosphorylation. Collectively, these preclinical observations support the concept that EGFR L858R-mutated NSCLC represents a biologically distinct subtype characterized by partial dependence on non-EGFR signaling pathways, thereby providing a mechanistic rationale for EGFR-VEGF combination strategies in this patient population.

Limitation and future directions

A key limitation of the RELAY trial is the exclusion of patients with baseline central nervous system (CNS) metastases. Patients with CNS metastases represent a clinically important subgroup of EGFR-mutated NSCLC, in whom intracranial disease often influences treatment selection and overall prognosis. Anti-VEGF therapy has been shown to normalize abnormal tumor vasculature, reduce vascular permeability, and potentially enhance the delivery of small-molecule agents to metastatic lesions, including those within the CNS (16-18). These biological effects provide a plausible rationale for exploring EGFR-VEGF combination strategies in patients with intracranial disease, even though such patients were not represented in the RELAY population (19,20). The phase I RELAY-brain trial evaluated the clinical activity and survival outcomes of ramucirumab in combination with erlotinib or osimertinib in patients with EGFR-mutated NSCLC and CNS metastases. This study reported a high ORR of 83.3%, with a PFS ranging from 10.46 to 42.07 months and an OS from 30.14 to 52.25 months, indicating encouraging antitumor activity in this clinically challenging population (21). In addition, the combination of erlotinib and ramucirumab demonstrated a favorable and manageable safety profile in patients with EGFR-mutant NSCLC and CNS metastases. Treatment-related adverse events were predominantly mild to moderate (grade 1–2), with hypertension, rash, and diarrhea being the most frequently observed toxicities. Grade ≥3 adverse events were uncommon, occurring in only one of six patients, and dose modifications were required in a limited number of cases. No novel safety profiles or treatment-related deaths were reported (22). In this context, the SPIRAL-BRAIN study, a prospective multicenter phase II trial, was designed to evaluate the efficacy and safety of erlotinib plus ramucirumab in patients with EGFR-mutated NSCLC and CNS metastases. The study is expected to provide critical prospective data on intracranial activity, durability of disease control, and bleeding risk, addressing key evidence gaps left by prior pivotal trials. These data may help clarify the role of EGFR-VEGF combination therapy in patients with CNS involvement and inform more individualized treatment strategies (23).

Clinical positioning of the RELAY regimen in the era of third-generation EGFR-TKI-based combination strategies

Although escalation strategies from FLAURA 2 and MARIPOSA trials have demonstrated significant clinical benefit and are now positioned as favorable first-line options, the optimal sequential treatment strategy remains controversial (8,9). Moreover, these strategies have been associated with higher rates of grade ≥3 toxicities and higher treatment costs than EGFR-TKI monotherapy.

In the era of combination-based treatment such as osimertinib plus chemotherapy, erlotinib plus ramucirumab remains a suitable option that may be considered for selected patients with EGFR L858R-mutated NSCLC. While this regimen is associated with a higher incidence of dermatologic adverse events, the overall safety profile is characterized by a relatively low frequency of severe toxicities, and treatment-related adverse events are generally manageable. Importantly, these toxicities do not appear to compromise subsequent lines of therapy, thereby allowing smooth transition to later-line treatments and supporting their role within a sequential treatment strategy. In this context, erlotinib plus ramucirumab may represent a clinically meaningful option for patients in whom the cumulative burden of more intensive combination regimens is a concern. Further insights from real-world and mutation-focused studies, including the retrospective REAL-SPEED study (24) and the prospective REVOL858R trial (25), both focusing on L858R-mutated disease, are awaited to better define its clinical positioning in routine practice.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Shanghai Chest. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2026-1-0007/coif). M.I. received honoraria from AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, and Taiho Pharmaceutical. N.S. received grants from Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, and Nippon Kayaku; and received honoraria from Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Nippon Kayaku, Daiichi Sankyo, Shionogi, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, Pfizer and Eisai. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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