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Abstract

Background:

EGFR L858R mutation is associated with poorer efficacy of EGFR-tyrosine kinase inhibitors (TKIs) than EGFR Ex19del in patients with non-small cell lung cancer (NSCLC). However, ramucirumab (RAM) + erlotinib (ERL) therapy exhibited comparable efficacy between patients with L858R mutation and Ex19del mutation (median progression-free survival (PFS): 19.6 vs 19.4 months) in the RELAY study, with favorable PFS for both gene mutations at 19.4 months in the Japanese subset. Meanwhile, the FLAURA study revealed shorter PFS with osimertinib (OSI) for L858R mutation than Ex19del mutation, with poorer PFS in the Japanese subset than in the overall population. The treatment discontinuation rates of RAM + ERL and OSI in Japanese patients were 18% and 29%, respectively. Consequently, RAM + ERL may exhibit superior efficacy and safety in Japanese patients with the L858R mutation.

Objectives:

To evaluate the therapeutic efficacy and safety of RAM + ERL as a first-line treatment for advanced or recurrent NSCLC harboring the L858R mutation in Japanese patients.

Design:

A multicenter, noninterventional, retrospective cohort study.

Methods and analysis:

This study will involve patients with advanced or recurrent NSCLC (ECOG PS score 0–2) with L858R mutation who received RAM + ERL between November 1, 2020 and August 31, 2023, with the planned sample size of 200 patients. The primary endpoint is time to treatment failure, and the secondary endpoints are overall survival, PFS, PFS2, time to discontinuation of any EGFR-TKI, time to failure of strategy, objective response rate, disease control rate, and safety. Exploratory endpoints are effects of ERL and RAM on PD-L1 expression and neutrophil-to-lymphocyte ratio.

Discussion:

To the best of our knowledge, this is the first retrospective study focusing on L858R mutations associated with the RELAY regimen, providing the corresponding real-world data.

Trial registration:

UMIN Clinical Trials Registry identifier: UMIN000052047.

Keywords

erlotinib L858R non-small cell lung cancer ramucirumab

Introduction

Since the launch of gefitinib, the development of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has drastically improved the prognosis of patients with non-small cell lung cancer (NSCLC) harboring EGFR major mutations (Ex19del and L858R). The FLAURA study demonstrated the greater efficacy of osimertinib (OSI) compared with the first-generation EGFR-TKIs, such as gefitinib or erlotinib (ERL), in patients with EGFR mutation-positive NSCLC.¹ Consequently, following its approval, OSI is widely used as the preferred treatment for these patients. Several clinical studies have assessed the effectiveness and tolerability of novel treatments, including combination therapy of EGFR-TKIs and angiogenesis inhibitors or cytotoxic agents, for therapeutic EGFR mutation-positive NSCLC. Combination therapy with ramucirumab (RAM) and ERL has been approved as the standard pharmacotherapy.²

The superior molecular-targeting drugs in terms of EGFR mutation subtypes (Ex19del and L858R), race, and adverse events (AEs) remain unclear. As shown in table 1, the FLAURA study—a randomized, double-blind, phase III trial—reported significantly prolonged progression-free survivals (PFS) in the OSI group at 18.9 months (hazard ratio (HR) = 0.46, 95% confidence interval (CI): 0.37–0.57; p < 0.001), whereas subgroup analysis revealed differences in PFS by EGFR mutation (Ex19del vs L858R, 21.4 vs 14.4 months, respectively).¹ Meanwhile, the RELAY study—a randomized, double-blind, phase III study—established the PFS benefit of RAM + ERL (19.4 months) compared with placebo + ERL (12.4 months) in untreated EGFR-mutated metastatic NSCLC (HR = 0.59, 95% CI: 0.46–0.76, p < 0.0001). Furthermore, its benefit was consistent with EGFR mutation (Ex19del vs L858R, 19.6 vs 19.4 months, respectively), contrasting with the FLAURA study.²

Table 1.

Efficacy and safety data of the FLAURA and RELAY studies.

Outcome	FLAURA			RELAY
	All	Ex19del	L858R	All	Ex19del	L858R
Efficacy
Median PFS (95% CI) (months)	18.9 (15.2–21.4)	21.4 (16.5–23.4)	14.4 (11.1–18.9)	19.4 (15.4–21.6)	19.6 (15.1–22.2)	19.4 (14.1–21.9)
Median OS (95% CI) (months)	38.6 (26.6–36.0)	42^a	31^a	51.1 (44.9–57.3)	49.0 (43.9–58.7)	51.6 (43.6–59.3)
2-Year OS rate (%)	74	79^a	65^a	82.8	83.8	81.8
Safety
Interstitial pneumonitis (%)	4	–	–	2	–	–
Treatment discontinuation (%)	15	–	–	16	–	–

Estimated from the Kaplan–Meier curves.

CI, confidence interval; OS, overall survival; PFS, progression-free survival.

With respect to overall survival (OS), the FLAURA study reported prolonged OS with OSI than with the comparator TKI (median OS: 38.6 vs 31.8 months, respectively; HR = 0.799, 95% CI: 0.641–0.997; p = 0.0462). Nevertheless, the subset analysis indicated that OSI was more favorable for Ex19del (HR = 0.68, 95% CI: 0.51–0.90) than L858R (HR = 1.00, 95% CI: 0.71–1.41), with the OS for patients with Ex19del and L858R mutations being 42 and 31 months, respectively.³ In contrast, a recent final OS analysis of the RELAY trial reported a numerical increase in median OS in favor of RAM + ERL (OS: 51.1 months, HR = 0.98, 95% CI: 0.78–1.24; p = 0.864).⁴ Moreover, the RELAY study exhibited a similar trend in patients with each EGFR mutation (Ex19del vs L858R, 49.0 vs 51.6 months, respectively) in contrast to the FLAURA study.

Recently, an updated analysis of the Japanese subset in the RELAY study has been reported, demonstrating favorable outcomes in the L858R mutation group, with a median PFS of 20.8 months (95% CI: 14.1−25.1) and a median survival time of 54.3 months (95% CI: 45.8−72.1).⁵ Evaluating the reproducibility of these findings in retrospective studies offers substantial academic value.

Considering the strategic importance of sequence therapy for EGFR-mutant NSCLC, monitoring the AEs of first-line therapy is crucial for treatment continuation. In addition, particular attention should be paid to interstitial lung disease (ILD), which causes irreversible changes in the lung parenchyma and leads to fatal consequences. In the RELAY study, the frequency of ILD and discontinuation rate for RAM + ERL combination therapy were 2% and 16% (Table 1),⁴ respectively, with 2% and 18% in the Japanese subset, respectively.⁵ A recent systematic review reported that combining EGFR-TKIs with VEGF/VEGFR inhibitors significantly reduced the incidence of drug-induced ILD in patients with NSCLC. The odds ratio for ILD of any grade was 0.54 (95% CI: 0.32–0.90; p = 0.02) in the overall EGFR-TKI group, and 0.50 (p = 0.01) in Asian patients, suggesting improved safety with combination therapy.⁶ Conversely, in the FLAURA study, the frequency of ILD and discontinuation rate for OSI were 4% and 15% among all patients, with the highest frequency at 12% and 29% in the Japanese subset, respectively.^1,7 In the OSI-FACT study, a retrospective multicenter study for 538 EGFR mutation-positive patients, who received OSI as the initial treatment, the frequency of pneumonitis and discontinuation rates due to AEs were 13% and 17%.⁸

In light of the aforementioned considerations, the clinical benefit of first-line treatment with OSI in prolonging OS among Japanese patients with L858R mutations remains uncertain. While several retrospective studies of OSI have been reported, no such studies have been published for RAM + ERL therapy. Therefore, we planned a retrospective observational cohort study to evaluate the therapeutic efficacy and safety in Japanese patients who received RAM + ERL as first-line treatment for advanced or recurrent NSCLC harboring the L858R mutation.

Methods

Study cohort enrollment

This multicenter, retrospective, observational study is named REAL-SPEED (Figure 1). The eligibility criteria for patient enrollment are as follows: histologically or cytologically confirmed metastatic or locally advanced NSCLC based on the UICC TNM classification (including postoperative or after radical radiotherapy); harboring EGFR L858R mutation; ECOG PS score of 0–2; and received RAM + ERL as the first-line therapy between November 1, 2020 and August 31, 2023. Genetic mutation testing will be conducted at each participating institution. Both tissue samples and blood specimens (plasma samples) are acceptable for analysis. There are no restrictions on the testing methods; both multi-companion diagnostic assays (multi-CDx) and single-gene testing methods such as polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization are permitted. The exclusion criteria will include patients with active double cancers, those harboring exon 19 deletions or other uncommon mutations, and those deemed ineligible by the attending physician. The presence of a measurable lesion is not considered. Regarding RAM + ERL dosage and administration, dose reduction and drug discontinuation were allowed as appropriate depending on age, PS, or the physician’s judgment.

Figure 1.

Schematic of ramucirumab plus erlotinib as a first-line treatment for advanced or recurrent non-small cell lung cancer with EGFR Exon21 L858R mutation (REAL-SPEED).

Statistical design and assessment

The reporting of this study conforms to the ESMO Guidance for Reporting Oncology Real-World evidence (GROW) Statement,⁹ following the EQUATOR Network guidelines. A completed ESMO-GROW checklist is provided in the Supplemental Materials. The study results will also be reported in compliance with the ESMO-GROW guidance. Data will be collected from the electronic medical records of 47 participating institutions. To ensure interoperability among data sources, a standardized case report form (CRF) will be utilized across all sites. Trained clinical research staff at each site will extract raw data using a standardized CRF. The completeness of core variables will be assessed, and missing data will be minimized through a review of source documents. The primary endpoint is the time to treatment failure (TTF), as image evaluation is not performed, and we focus on the effectiveness of RAM + ERL in a clinical setting. TTF is defined as the time from treatment initiation to treatment discontinuation for any reason, including progression disease (PD), toxicity, patient withdrawal, or death. The secondary endpoints are PFS, OS, PFS2, time to discontinuation of any EGFR-TKI (TD-TKI), time to failure of strategy (TFS), objective response rate (ORR), disease control rate (DCR), and safety. PFS is defined as the time from the start of treatment to RECIST-defined PD or clinical PD according to RECIST v1.1.¹⁰ Differences in the assessment of TTF and PFS are presented in Figure 2. OS is defined as the time from the start date of treatment to the date of death. PFS2 is defined as the time from the start of treatment to the second progression of the disease (radiographic aggravation or clinical progression after the start of second-line treatment) or death from any cause, whichever occurs first. Patients who were lost to follow-up or were still on the data cutoff date (December 31, 2023) are censored on the last known-to-be-alive date up to the data cutoff date. TD-TKI is defined as the time from the start of RAM + ERL to the discontinuation of any consecutively administered EGFR-TKI, irrespective of the reason (e.g., adverse drug reactions). Any subsequent treatment with EGFR-TKI, regardless of the number of therapy lines, is considered as continuous if EGFR-TKIs are selected consecutively. If no EGFR-TKIs are used in second-line or later treatments, the only EGFR-TKI administered would be during the first-line RAM plus ERL therapy. In such cases, TD-TKI is equivalent to the TTF of the first-line regimen. If non-EGFR-TKI therapy is selected as second-line treatment, the use of EGFR-TKIs (including RAM + ERL therapy or ERL monotherapy rechallenge) after third-line treatment will not be included at this time.

Figure 2.

Differences between TTF and PFS. Upper: 1st-line Tx (RAM + ERL) was discontinued due to AE despite non-PD, and 2nd-line treatment was initiated. Lower: 1st-line Tx (RAM + ERL) was PD, and 2nd-line therapy was initiated.

TFS is defined as the time from the start of treatment to the day before the start of the second-line treatment. The presence or absence of treatment does not matter. ORR is defined as the proportion of patients with the best response to CR or PR among those with the best overall response to CR, PR, SD, PD, and NE. DCR is defined as the proportion of patients with the best CR, PR, or SD among those with the best overall CR, PR, SD, PD, and NE.

Supplemental Figure 1 illustrates the evaluation procedures for each parameter assessed during treatment. Second-line treatment in the study is defined as systemic chemotherapy following RAM+ ERL discontinuation for any reason, not including palliative radiotherapy or surgical treatment. Furthermore, switching from RAM + ERL to ERL alone (or RAM alone) is not considered second-line treatment, as it is included in the initial treatment. However, RAM + ERL therapy (including ERL alone or RAM alone) during “beyond PD” period is regarded as second-line therapy.⁴ This is intended to pursue a “real-world evaluation” in clinical practice to determine the treatment period during RAM + ERL combination therapy while following the endpoints (PFS, PFS2, and OS) of the RELAY trial. A detailed parameter is set to consider the rechallenge with EGFR-TKIs or the stability period of the disease with drug cessation. For the exploratory endpoints, the effect of RAM + ERL combination therapy on PD-L1 expression and the neutrophil-to-lymphocyte ratio (NLR) will be evaluated. If blood sampling is not available (e.g., due to an insufficient observation period), the case is excluded due to missing data. Moreover, if a re-biopsy is performed after PD, clinical information on resistance-related genetic mutations (such as T790M) will also be collected. For safety, AEs were assessed using Common Terminology Criteria for Adverse Events version 5.0.

The sample size is estimated as 200 patients, considering the Japanese subset with the L858R point mutation in the RELAY study and retrospective studies on OSI in Japan. The RELAY study involved a subset of only 106 Japanese patients who received RAM + ERL combination therapy; however, this number was insufficient to evaluate the treatment efficacy, considering the importance of sequential therapy following EGFR-TKI treatment.⁵

The registration period of this study is divided into two stages as follows:

I. First enrollment period: September 1, 2023–December 31, 2023

II. Second enrollment period: September 1, 2025–December 31, 2025

Following the first enrollment, the analysis will mainly focus on TTF and PFS. After the second enrollment, OS and other endpoints will be examined in detail to determine post-TKI treatment outcomes.

Study analysis

This study aims to assess the efficiency and safety of RAM + ERL combination therapy. TTF, PFS, OS, TFS, and PFS2 will be analyzed using the Kaplan–Meier method. The 95% CI for the median survival time will be calculated using the Brookmeyer–Crowley method. TTF and OS were censored on the day of the data cutoff. Categorical variables will be analyzed using the Chi-square test or Fisher’s exact test. Normally and non-normally distributed continuous variables will be analyzed using the Student’s t test and Mann–Whitney U test, respectively. Finally, the clinical endpoints—PD-L1 expression and NLR—will be analyzed. EZR software version 1.36 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) will be used for statistical analyses.

This study is conducted in accordance with the Declaration of Helsinki (revised in 2013) and is approved by the Teikyo University Ethical Review Board for Medical and Health Research Involving Human Subjects (approval number: 22-183-3). The requirement for informed consent for this study is waived by the Ethical Review Board owing to its retrospective design. To ensure confidentiality, only anonymized data are used for analysis.

Discussion

This is the first retrospective study to assess the efficacy and safety of RAM + ERL for advanced L858R mutation-positive NSCLC in a real-world setting. Considering the lower effectiveness of OSI for the L858R mutation subtype in the FLAURA trial, RAM + ERL may be an efficient alternative treatment.

In the global phase III trials of OSI (FLAURA, AURA3, and ADAURA), the HR for PFS by each exon type (Ex19del vs L858R) tended to be higher for L858R (Supplemental Table 1),^3,11,12 indicating shorter PFS with L858R than with Ex19del. In contrast, the HR for PFS for each exon type was almost the same in global phase III trials of combination therapy with ERL and an angiogenesis inhibitor (RELAY, NEJ026, CTONG1509; Supplemental Table 2),^2,13,14 with no difference in efficacy between Ex19del and L858R.

Aligning with the FLAURA study, several clinical observational studies have consistently reported shorter PFS and OS with OSI in patients with L858R mutation-positive NSCLC compared to those with Ex19del mutations (Supplemental Table 3).^8,15–18 However, despite the promising results of RAM + ERL in the RELAY trial, real-world data regarding both PFS and OS for patients with the L858R mutation remain lacking. Therefore, evaluating the clinical efficacy of RAM + ERL for this subgroup in a real-world setting is of significant importance.

Notably, the AEs associated with EGFR-TKIs are critical for sequential therapy. Moreover, corresponding to the higher risk of interstitial pneumonitis related to EGFR-TKIs in Asians than in non-Asians, the FLAURA trial reported a higher incidence of interstitial pneumonia and discontinuation rate due to all AEs in Japanese patients.^3,19,20 RAM + ERL may be promising as sequential treatment following EGFR-TKI treatment.

Although PD-L1 expression is also important for determining antitumor agents, data on treatment for EGFR-mutant NSCLC with positive PD-L1 expression remain lacking. EGFR-TKIs, mainly OSI, exhibit low effectiveness against this lung cancer type; however, the reason underlying this resistance remains unclear.^8,18,21–23 Novel treatment strategies are required to improve clinical outcomes in lung cancer patients with PD-L1 expression. High PD-L1 expression in lung adenocarcinoma correlates with missense and nonsense mutations in the TP53 gene.²⁴ TP53 co-mutations serve as negative prognostic factors and are associated with poor response to EGFR-TKI monotherapy, including OSI.^25,26 In the RELAY study, patients with baseline TP53 mutations showed longer PFS with RAM + ERL than with placebo + ERL, regardless of the EGFR mutation subtype.^25,27 The RANGE study reported improved OS in patients with high PD-L1 expression treated with RAM for platinum-refractory urothelial carcinoma.²⁸ A preclinical study also showed that PD-L1 promotes angiogenesis and metastasis in ovarian cancer via VEGFR2 signaling.²⁹ These findings support the potential efficacy of RAM + ERL combination therapy. PD-L1 expression is upregulated via various mechanisms, including the activation of oncogenes. Recently, the yes-associated protein (YAP) oncogene was identified as an important mediator of the Hippo pathway in several clinical studies.^8,22,23 YAP oncogene regulates PD-L1 expression³⁰ and is involved in resistance to EGFR-TKI^31,32 and tumor angiogenesis.^33,34 Therefore, using an angiogenic inhibitor to treat EGFR-mutant NSCLC expressing PD-L1 is a reasonable approach.

Angiogenesis inhibitors affect the tumor microenvironment (TME).³⁵ VEGF suppresses cytotoxic T lymphocyte induction and promotes the proliferation of immunosuppressive cells, including regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, via the VEGF receptor 2.³⁶ This proliferation is inhibited by blocking VEGF-A/VEGFR-2.³⁷ Moreover, several clinical studies have demonstrated a lower frequency of resistance to treatment with VEGF/VEGFR antibody and EGFR-TKI combination therapy than treatment with EGFR-TKI monotherapy.^2,13,38 Therefore, the combination therapy involving EGFR-TKI and an angiogenesis inhibitor may exhibit a positive effect on the TME.

Several clinical trials have reported prolonged PFS following treatment with a combination of ERL and the angiogenesis inhibitor bevacizumab, although it did not improve OS.^{13,14,39–42} However, <1% of participants had received anti-PD-1/PD-L1 inhibitors when these trials were conducted.^14,41 Considering the effectiveness of immune checkpoint inhibitors on TME following treatment with RAM, our study might complement the clinical trials of ERL plus bevacizumab.

This study has several limitations. First, the single-arm, retrospective design may introduce selection bias and limit control of confounding factors. Second, variations in clinical practices—such as treatment decisions and imaging schedules—across institutions could affect the consistency of endpoints. Third, the sample size is determined by feasibility rather than statistical power, which may limit the generalizability of the results. Nonetheless, this study aims to provide valuable real-world insights into RAM + ERL therapy for Japanese patients with EGFR L858R-mutated NSCLC, an area with limited clinical evidence.

Conclusion

RAM + ERL may be beneficial for Japanese patients with the L858R mutation. However, large-scale real-world data remain unavailable and must be reported promptly.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251344010 – Supplemental material for Ramucirumab and erlotinib combination as first-line treatment for advanced or recurrent non-small cell lung cancer harboring EGFR Exon21 L858R mutation: a multicenter retrospective observational cohort study in Japan (REAL-SPEED)

Supplemental material, sj-docx-1-tam-10.1177_17588359251344010 for Ramucirumab and erlotinib combination as first-line treatment for advanced or recurrent non-small cell lung cancer harboring EGFR Exon21 L858R mutation: a multicenter retrospective observational cohort study in Japan (REAL-SPEED) by Masashi Ishihara, Takahisa Kawamura, Yukiko Namba, Yuki Takeyasu, Yukihiro Hasegawa, Yuki Sato, Yoshiki Negi, Tomohiro Oba, Toshiyuki Sumi, Hirokuni Hirata, Hidemitsu Funabashi, Yuko Oya, Hajime Kikuchi, Naoko Katsurada, Takeshi Nakatani, Keiko Tanimura, Taku Nakagawa, Naoya Takeda, Takahiro Asami, Osamu Honjo, Hiromi Nagashima, Takumi Yamaura, Norihiko Hata, Miyako Kitazono, Naoya Nishioka, Akihiro Tamiya, Yuichi Sakamori, Ryota Shigaki, Kyoichi Kaira, Ryoichi Honda, Takashi Matsui, Eriko Suzuki, Kentaro Ito, Kojiro Otsuka, Naoto Takase, Yusuke Murakami, Kazuhiko Matsuno, Sumito Inoue, Akira Kisohara, Sojiro Kusumoto, Hiroe Aoshima, Yumiko Kakizaki, Akihito Kubo, Akito Hata, Nobuhisa Ishikawa, Kosuke Hamai, Nobuhiro Kanaji, Toshihiro Misumi, Noriyuki Matsutani and Nobuhiko Seki in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

The authors express their gratitude to Editage () for editing a draft of this article funded by Eli Lilly Japan K.K. (Kobe, Japan).

Declarations

ORCID iDs

Masashi Ishihara

Yoshiki Negi

Supplemental material

Supplemental material for this article is available online.

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