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A real-world study of Afatinib plus ramucirumab in treatment-naïve, EGFR-mutated, non–small cell lung cancer

A real-world study of Afatinib plus ramucirumab in treatment-naïve, EGFR-mutated, non–small cell... Background Recent reports suggested combining ramucirumab with epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors ( TKIs) to overcome EGFR resistance in non–small cell lung cancer (NSCLC). Nonetheless, evidence supporting the activity of afatinib and ramucirumab is lacking. This study investigated the survival benefits and safety profile of afatinib plus ramucirumab in patients with treatment-naïve, EGFR-mutated, metastatic NSCLC. Materials and methods The medical records of patients with EGFR-mutated NSCLC were retrospectively retrieved. Patients who received first-line sequential afatinib followed by ramucirumab and the first-line combination of afatinib plus ramucirumab were included. The Kaplan-Meier was used to estimate the progression-free survival (PFS) of all included patients, patients on sequential afatinib followed by ramucirumab (PFS1), and patients on the up-front combination of afatinib and ramucirumab (PFS2). Results Thirty-three patients were included (25 women; median age: 63 [45–82] years). The median follow-up of the included patients was 17 months (range 6–89 months). the median PFS for the whole cohort was 71 months (95% CI 67.2–74.8) with eight events during the follow-up. The median PFS1 and PFS2 were 71 months (95 CI not defined) and 26 months (95% CI 18.6–33.4), respectively. In terms of OS, the median OS for all patients and patients on sequential treatment was not defined, while the median OS for patients on upfront combination was 30 months (95% CI 20.9–39.1). There was no significant association between EGFR mutation type and PFS1 or PFS2. Conclusions Afatinib plus ramucirumab could improve the PFS of patients with EGFR-positive NSCLC at a predictable safety profile. Our data also suggest a survival benefit of adding ramucirumab to afatinib in patients with uncommon mutations, which should be investigated further. Keywords Afatinib, Ramucirumab, Non–small cell lung cancer, EFGR mutation *Correspondence: Yao-Kuang Wu sub189590@gmail.com Division of Pulmonary Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Rd, Xindian District, 231 New Taipei City, Taiwan © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Huang et al. BMC Cancer (2023) 23:413 Page 2 of 8 Introduction concluded that EGFR resistance is a VEGF-mediated pro- According to GLOBOCAN 2020, lung cancer is the cess, and combined blockade of the VEGFR and EGFR second most common cancer and the leading cause of pathways can overcome EGFR resistance [15]. Ramuci- cancer-related death worldwide [1]. Non–small cell lung rumab is a fully human IgG1 monoclonal antibody that cancer (NSCLC) accounts for nearly 85% of primary lung specifically binds to the extracellular domain of vascular cancer cases. NSCLC ‘tends to metastasize at early stages endothelial growth factor receptor 2 (VEGFR-2) with so that up to 35% of NSCLC patients present with de high affinity, preventing the binding of VEGF ligands novo brain metastasis [2]. Brain metastasis is the major and inhibiting receptor activation [16]. The CNS activity cause of morbidity and mortality in NSCLC patients. of ramucirumab has been demonstrated in clinical stud- Treatment of brain metastasis is a great challenge as the ies [17–20]. The groundbreaking phase III double-blind blood-brain barrier (BBB) prevents the entry of most RELAY trial demonstrated that adding ramucirumab to chemotherapeutics into the brain. erlotinib improved PFS (19.4 vs.12.4 months) in treat- Recent advances in molecular oncology have improved ment-naïve EGFR-mutated metastatic NSCLC [21]. A our understanding of genetic and epigenetic regulations phase Ib trial, which recruited Japanese patients with of NSCLC tumorigenesis and cell survival [3]. Epidermal advanced EGFR-mutated metastatic NSCLC, showed growth factor receptor (EGFR) is a transmembrane gly- a tolerable safety profile of afatinib plus ramucirumab coprotein receptor with an intracellular tyrosine kinase and a median PFS of 9.2 months [22]. Still, the cur- component implicated in cell proliferation and survival rent literature is scarce regarding the benefits of adding regulations. The current evidence shows the significant ramucirumab to first-line EGFR TKIs, such as afatinib, involvement of EGFR overexpression in developing sev- in patients with treatment-naïve NSCLC. Therefore, we eral malignancies, including NSCLC [4]. The frequency conducted this retrospective study to investigate the sur- of EGFR mutations in NSCLC cases shows substantial vival benefits and safety profile of afatinib plus ramuci - ethnic and geographical disparity, with the highest prev- rumab in patients with treatment-naïve, EGFR-mutated alence observed among patients from the Asia-Pacific metastatic, NSCLC. region (range 20–76%). In Taiwan, the frequency of EGFR mutations was estimated to be as high as 76% amongst Materials and methods NSCLC cases [5]. Both deletion within exon 19 (ex19del) The research was approved by the institutional review and leucine to arginine substitution mutation in exon 21 board of the Tzu Chi Hospital, Taiwan. All procedures (Leu858Arg) account for nearly 90% of EGFR mutations were in line with the latest version of the Declaration of in NSCLC patients [6]. These activating EGFR mutations Helsinki, and the report was prepared according to the are responsive to small-molecule EGFR tyrosine kinase STROBE statement [23]. inhibitors (TKIs) [6, 7]. Clinical trials and real-world evidence have estab- Eligibility criteria and data collection lished the efficacy of afatinib, a second-generation EGFR- For this retrospective study, the medical records of TKI, as the first-line treatment of choice for EGFR mut patients with treatment-naïve stage IV NSCLC and lab- mNSCLC patients [8]. Afatinib is a second-generation oratory-confirmed EGFR mutation (ex19del, L858R, or EGFR-TKI that irreversibly blocks the ErbB family of rare mutations, including exon 20 insertions, S768I, or protein-tyrosine kinases. Clinical evidence demon- L861Q), whether they had de novo brain metastases per strated that afatinib can pass the BBB [9]. Two landmark contrast-enhanced magnetic resonance imaging (MRI) or randomized controlled trials (RCTs) (LUX-Lung 3 and not, were retrieved. This study included patients who ini - Lux-Lung 6) demonstrated a significant improvement in tiated treatment with either sequential afatinib (30 mg/d) objective response rate (ORR) and progression-free sur- followed by ramucirumab (10  mg/kg) or front-line com- vival (PFS) with afatinib compared with platinum-based bination of afatinib (30 mg/d) plus ramucirumab (10 mg/ chemotherapy as first-line treatment in EGFR-mutated kg). Data of 33 patients who were treated between March metastatic NSCLC [10–12]. In Taiwan, afatinib is reim- 1, 2016, and April 30, 2022, were retrieved. bursed by the National Health Insurance (NHI) as a Data regarding the demographic characteristics, first-line option for EGFR-mutated metastatic NSCLC tumor stage, EGFR mutation type, treatment regimens, [13]. Unfortunately, data from clinical trials showed response rate, follow-up duration, progression sta- that most patients experience tumor progression after tus, and adverse events were collected. The 7th and 8th 10–14 months [14]. A combination therapy with other editions of TNM staging system were used to classify targeted agents is a viable choice to reduce the rates of patients into stage Iva or Ivb. The Response Evaluation resistance to EGFR-TKI. In 2009, Naumov et al. demon- Criteria in Solid Tumors (RECIST) version 1.1 was used strated that the dual inhibition of EGFR and VEGF abro- to evaluate treatment response, while the adverse events gates the EGFR resistance in NSCLC models. The authors Huang et al. BMC Cancer (2023) 23:413 Page 3 of 8 Table 1 Characteristics of the patients were classified according to the Common Terminology Characteristics Patients Criteria for Adverse Events (CTCAE) version 5.0. (n = 33) The primary endpoint was to investigate the PFS of the Median age (years), n (%) 63 (45–82) combination treatment. Other endpoints included the < 70 26 (78.8%) PFS according to EGFR mutation, ORR (defined as com - ≥ 70 7 (21.2%) plete response rate plus partial response rate), and the Sex, n (%) incidence of treatment-related adverse events. Male 8 (24.2%) Female 25 (75.8%) Statistical analysis Smoking status, n (%) The results were analyzed using SPSS version 28 soft - Non-smoker 31 (93.9%) ware for Windows (IBM Corp. Armonk, NY, USA). Smoker 2 (6.1%) Descriptive statistics were employed according to data Clinical stage , n (%) type. The Kaplan-Meier was used to estimate the PFS of IVA 6 (18.2%) all included patients, patients on sequential afatinib fol- IVB 27 (81.8%) lowed by ramucirumab (PFS1), and patients on up-front ECOG PS, n (%) combination of afatinib and ramucirumab (PFS2). The 0 0 (0.0%) PFS was calculated as the time from treatment initia- 1 33 (100.0%) tion to progression or death from any cause. A log-rank EGFR mutation, n (%) test was used to compare the PFS according to EGFR Del 19 14 (42.4%) mutation status. The chi-square test, Yate’s correction L858R 17 (51.5%) when needed, compared the incidence of adverse events Other 2 (6.1%) between patients who initiated afatinib only and patients Brain metastasis, n (%) 15 (46.5%) No. Brain metastasis, n (%) n = 15 who initiated afatinib plus ramucirumab. The results Single 6 (40%) were considered significant when two-tailed P < 0.05. Multiple 9 (60%) Location of Brain metastasis, n (%) n = 15 Results Cerebellum 1 (6.7%) Patients’ clinical characteristics Cerebellum, Cerebrum 5 (33.3%) Thirty-three patients were included, with female pre - Cerebrum 9 (60%) dominance (n = 25; 75.8%) and a median age of 63 (range Oligo-metastatic, n (%) n = 15 45–82) years. Only two patients (6.1%) were smoker. Single 5 (33.3%) Twenty-seven patients (81.8%) had stage IVB NSCLC. Multiple 2 (13.3%) All patients had an Eastern Cooperative Oncology Group Leptomeningeal metastasis, n (%) 2 (13.3%) performance status (ECOG PS) of 0 or 1. The distribution Symptomatic brain metastasis, n (%) 5 (33.3%) of the EGFR mutations was as follows: ex19del (42.4%), Treatment of brain metastasis, n (%) n = 15 L858R (51.5%), G719 × (3%), and L861Q (3%). Fifteen Surgery 0 patients had brain metastasis, 60% of them had multiple Radiotherapy 13 (86.7%) sites of brain metastasis. One-third of the patients with Treatment, n (%) brain metastasis were symptomatic. Overall, out of the 15 Sequential afatinib followed by ramucirumab 11 (33.3%) patients, 13 (86.7%) received local radiotherapy for brain Upfront combination 22 (66.7%) metastasis before initiating Afatinib or during the course Response, n (%) of treatment. CR and PR 33 In this study, 11 patients administered the sequen- (100.00%) tial regimen (afatinib followed by ramucirumab) and 22 SD 0 (0.00%) patients received upfront combination therapy (afatinib Progressive disease, n (%) plus ramucirumab). In patients who received sequential Yes 5 (15.2%) regimen, the median duration between starting afatinib No 28 (84.8%) and starting ramucirumab was 35 months (range 9–43 Abbreviation: CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; PR, partial response; SD: stable disease months), Table 1. Based on American Joint Committee on Cancer (7th and 8th editions) Rare EGFR mutations, including G719X and L861Q Progression-free survival and overall survival The median follow-up of the included patients was 17 months (range 6–89 months). The PFS was determined for all patients who received either upfront combination or sequential treatment with afatinib and ramucirumab Huang et al. BMC Cancer (2023) 23:413 Page 4 of 8 (n = 33 patients); the median PFS for the whole cohort female aged 77 years who presented with stage IVA ade- was 71 months (95% CI 67.2–74.8) with eight events dur- nocarcinoma and metastatic pleural effusion. She had ing the follow-up (Fig.  1A). The median PFS1 and PFS2 L861Q positive mutation. She initially started on 30  mg were 71 months (95 CI not defined) and 26 months (95% afatinib and then received 10  mg/kg ramucirumab two CI 18.6–33.4), respectively (Fig.  1B). In terms of OS, years later. She has an ongoing response with a notable the median OS for all patients and patients on sequen- PFS of > 56 months. The second patient was a 65 years tial treatment was not defined, while the median OS for old female with a stage IVB disease who started 30  mg patients on upfront combination was 30 months (95% CI afatinib in 2018. Three years later, she received 10  mg/ 20.9–39.1), Fig.  1C. Figure  2 shows the swimmer plot of kg ramucirumab. The patient had G719X mutation and the 33 patients. showed an ongoing PFS of > 52 months. Association between EGFR mutations and treatment Adverse events outcomes The adverse events caused by each type of treatment There was no significant association between EGFR regimens were analyzed. Despite being frequent among mutation type and PFS1 (P = 0.171; Fig. 3A). The median patients, the presentation of diarrhea (P = 0.602) and par- PFS1 of patients with L858R and ex19del was undefined. onychia (P = 0.801) had no significant difference between Likewise, there was no significant association between patients who were first treated with sequential regiment EGFR mutation type and PFS2 (P = 0.803; Fig.  3B). The and patients treated with up-front combination (Table 2). median PFS2 of patients with L858R was 26 months (95% CI 18.4–33.6), while the estimate was not defined for Discussion patients with ex19del mutation. Ramucirumab represents a viable option to overcome In the present study, two patients presented with EGFR resistance in patients with EGFR-mutated meta- uncommon EGFR mutations. The first patient was a static NSCLC. The phase III RELAY trial found that Fig. 1 (A) Kaplan-Meier estimates of progression-free survival (mPFS = 71 mon) of all patients who received either upfront combination or sequential treatment with afatinib and ramucirumab (n = 33 patients); (B) Kaplan-Meier estimates of progression-free survival in patients received sequential (blue; mPFS 71 mon; n = 11) and upfront combination therapy (green; mPFS 30 mon; n = 22). PFS, progression-free survival; (C) Kaplan-Meier estimates of overall survival in patients received sequential (blue; mOS not defined mon; n = 11) and upfront combination therapy (green; mOS 30 mon; n = 22) Huang et al. BMC Cancer (2023) 23:413 Page 5 of 8 Fig. 2 Swimmer plot of the 33 patients. Kaplan-Meier estimates of progression-free survival of patients with L858R and ex19del EGFR mutations (A) patients starting sequential regimen; (B) patients starting up-front combination ramucirumab addition to erlotinib improves disease con- EGFR-TKIs [26]. The survival benefits of afatinib in trol in patients with EGFR-mutated metastatic NSCLC patients with uncommon EGFR mutations are well estab- [21]. In addition, the safety profile of ramucirumab plus lished, and it is currently approved for patients with any erlotinib was demonstrated in several trials [21, 22]. EGFR mutation. According to a subgroup analysis from However, studies are yet to determine the clinical efficacy LUX-Lung 2, 3, and 6 trials, patients harboring G719X and safety profile of upfront ramucirumab plus EGFR- and L861Q mutations had a median PFS of 13.8 and 8.2 TKI combination in NSCLC patients. The present study months, respectively [27]. Two patients presented with found that the median PFS of the EGFR-mutated patients uncommon EGFR mutations in the present retrospec- on ramucirumab plus afatinib, whether the combination tive chart review. The patient with L861Q mutation had was initiated concurrently or sequentially, was 71 months a notable PFS of > 56 months, while the patient with (95% CI not defined). Besides, the median PFS for G719X mutation showed an ongoing PFS of > 52 months. patients who initiated sequential treatment and upfront Although immature, our data suggest a further survival combination were 71 months (95% CI not defined) and benefit of adding ramucirumab to afatinib in patients 26 months (95% CI 18.6–33.4), respectively. Further- with uncommon mutations. Future studies are recom- more, no significant difference in PFS was observed mended to assess the survival benefits of ramucirumab among patients with different EGFR mutations. To our plus afatinib in patients with uncommon mutations. knowledge, this is the first study that outlines the efficacy Several other EGFR-TKI have been trialed in patients of afatinib plus ramucirumab in treatment-naïve patients with EGFR-mutated metastatic NSCLC (such as dacomi- with EGFR mutation. Of note, the median PFS observed tinib and erlotinib) but with a high incidence and severity in our cohort was notably longer than the median PFS of adverse events [6]. In our study, dermatitis and paro- reported in pivotal clinical trials and observational stud- nychia were frequent among patients, although no sig- ies. In the LUX-Lung 3, 6, and 7 trials, EGFR-mutated nificant difference was found between patients who were patients with brain metastasis on first-line afatinib had first treated with afatinib compared with patients treated a median PFS ranging from 7.2 to 8.2 months [11, 12, with afatinib and ramucirumab. Diarrhea was frequent in 24]. Similar figures were reported in real-world studies both groups as well. Our results were in accordance with (median PFS = 8.2 months) [25]. Thus, our data suggest those reported by Paz-Ares et al., who also found that that ramucirumab improves the PFS of first-line EGFR- diarrhea (12.5%) was a frequent adverse event [28]. By TKI. These run in line with previous reports showing an contrast, other studies have reported hypertension and improvement in PFS amongst patients receiving first- renal failure as the most frequent adverse events, which generation EGFR-TKIs plus ramucirumab [21]. Further could not be managed with dose adjustments or support- experimental evidence is needed to elucidate the poten- ive care [21]. tial synergistic mechanisms of action of the combination While the present study provides novel findings regard - therapy. ing the benefit of afatinib plus ramucirumab for patients Uncommon EGFR mutations can present in 10% of with EGFR-mutated metastatic NSCLC, we acknowledge the NSCLC patients and show variable responses to that the study has certain limitations. The study’s findings Huang et al. BMC Cancer (2023) 23:413 Page 6 of 8 Fig. 3 Kaplan-Meier estimates of progression-free survival of patients with L858R and ex19del EGFR mutations (A) patients starting sequential regimen; (B) patients starting up-front combination Table 2 Presence or absence of adverse events are based on retrospective data collection, introducing Adverse Events (N = 33) Sequential Up-front P- reporting bias, and limiting the control of the outcomes (n = 11) combination val- reporting and definitions. In addition, the sample size of (n = 22) ue the included patients was relatively small, and the follow- Diarrhea 8 (72.7%) 14 (63.6%) 0.602 up period was short to attain a measurable median PFS. Dermatitis 11 (100%) 22 (100%) -- We could not assess the impact of long-term response to Paronychia 7 (63.6%) 13 (59.1%) 0.801 afatinib monotherapy on the survival benefit of combi - Nausea & Vomiting 1 (9.1%) 0 (0%) 0.151 nation therapy due to the small sample size. Besides, the Mucositis 0 (0%) 0 (0%) -- causal relationship between treatment regimen and sur- Hepatitis 0 (0%) 0 (0%) -- vival benefit could not be established due to the lack of a Hemorrhagic events 0 (0%) 0 (0%) -- control group. Renal dysfunction 0 (0%) 0 (0%) -- Huang et al. BMC Cancer (2023) 23:413 Page 7 of 8 Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Conclusions 2021;71:209–49. https://doi.org/10.3322/caac.21660. 2. Lei L, Wang WX, Wang D, Lin L, Zhu YC, Wang H, Wang LP, Zhuang W, Fang MY, This real-world cohort study demonstrated that afatinib Wan B, et al. A real-world study in advanced non-small cell lung cancer with plus ramucirumab could improve the PFS of patients de novo brain metastasis. J Cancer. 2021;12:1467–73. https://doi.org/10.7150/ with EGFR-mutated metastatic NSCLC. The survival jca.51411. 3. Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor benefit was notable for the combination of afatinib and (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010;2:48–51. ramucirumab, at a predictable safety profile for both 4. Inamura K, Ninomiya H, Ishikawa Y, Matsubara O. Is the epidermal drugs. Additional data collected among a large popula- growth factor receptor status in lung cancers reflected in clinico - pathologic features? Arch Pathol Lab Med. 2010;134:66–72. https://doi. tion remains necessary to better address the advantages org/10.5858/2008-0586-rar1.1. of afatinib plus ramucirumab and optimize their clinical 5. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small- applications. Although immature, our data suggest a fur- cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5:2892–911. ther survival benefit of adding ramucirumab to afatinib 6. Hsu WH, Yang JC, Mok TS, Loong HH. Overview of current systemic man- in patients with uncommon mutations. Future stud- agement of EGFR-mutant NSCLC. Ann Oncol. 2018;29:i3–i9. https://doi. ies are recommended to assess the survival benefits of org/10.1093/annonc/mdx702. 7. Kim ES, Melosky B, Park K, Yamamoto N, Yang JC. EGFR tyrosine kinase inhibi- ramucirumab plus afatinib in patients with uncommon tors for EGFR mutation-positive non-small-cell lung cancer: outcomes in mutations. asian populations. Future Oncol. 2021;17:2395–408. https://doi.org/10.2217/ fon-2021-0195. Acknowledgements 8. Takeda M, Nakagawa K. First- and second-generation EGFR-TKIs are all The editorial assistance was provided to the authors by Nova Journal Experts. replaced to Osimertinib in Chemo-Naive EGFR mutation-positive Non- Small Cell Lung Cancer? Int J Mol Sci. 2019;20. https://doi.org/10.3390/ Authors’ contributions ijms20010146. Chun-Yao Huang: Conception/Design; Provision of study material or patients; 9. Hochmair M. Medical treatment options for patients with epidermal growth Collection and/or assembly of data; Data analysis and interpretation; factor receptor mutation-positive non-small cell lung cancer suffering Manuscript writing; Final approval of manuscriptHui-Li Huang: Collection from brain metastases and/or leptomeningeal disease. Target Oncol. and/or assembly of data; Data analysis and interpretation; Final approval 2018;13:269–85. of manuscriptChou-Chin Lan: Provision of study material or patients; Final 10. Karachaliou N, Fernandez-Bruno M, Bracht JWP, Rosell R. EGFR first- and approval of manuscriptYi-Chih Huang: Provision of study material or patients; second-generation TKIs-there is still place for them in EGFR-mutant NSCLC Final approval of manuscriptYao-Kuang Wu: Conception/Design; Provision of patients. 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Preventing and treating brain metastases with three first-line EGFR- Springer Nature remains neutral with regard to jurisdictional claims in tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

A real-world study of Afatinib plus ramucirumab in treatment-naïve, EGFR-mutated, non–small cell lung cancer

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Abstract

Background Recent reports suggested combining ramucirumab with epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors ( TKIs) to overcome EGFR resistance in non–small cell lung cancer (NSCLC). Nonetheless, evidence supporting the activity of afatinib and ramucirumab is lacking. This study investigated the survival benefits and safety profile of afatinib plus ramucirumab in patients with treatment-naïve, EGFR-mutated, metastatic NSCLC. Materials and methods The medical records of patients with EGFR-mutated NSCLC were retrospectively retrieved. Patients who received first-line sequential afatinib followed by ramucirumab and the first-line combination of afatinib plus ramucirumab were included. The Kaplan-Meier was used to estimate the progression-free survival (PFS) of all included patients, patients on sequential afatinib followed by ramucirumab (PFS1), and patients on the up-front combination of afatinib and ramucirumab (PFS2). Results Thirty-three patients were included (25 women; median age: 63 [45–82] years). The median follow-up of the included patients was 17 months (range 6–89 months). the median PFS for the whole cohort was 71 months (95% CI 67.2–74.8) with eight events during the follow-up. The median PFS1 and PFS2 were 71 months (95 CI not defined) and 26 months (95% CI 18.6–33.4), respectively. In terms of OS, the median OS for all patients and patients on sequential treatment was not defined, while the median OS for patients on upfront combination was 30 months (95% CI 20.9–39.1). There was no significant association between EGFR mutation type and PFS1 or PFS2. Conclusions Afatinib plus ramucirumab could improve the PFS of patients with EGFR-positive NSCLC at a predictable safety profile. Our data also suggest a survival benefit of adding ramucirumab to afatinib in patients with uncommon mutations, which should be investigated further. Keywords Afatinib, Ramucirumab, Non–small cell lung cancer, EFGR mutation *Correspondence: Yao-Kuang Wu sub189590@gmail.com Division of Pulmonary Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Rd, Xindian District, 231 New Taipei City, Taiwan © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Huang et al. BMC Cancer (2023) 23:413 Page 2 of 8 Introduction concluded that EGFR resistance is a VEGF-mediated pro- According to GLOBOCAN 2020, lung cancer is the cess, and combined blockade of the VEGFR and EGFR second most common cancer and the leading cause of pathways can overcome EGFR resistance [15]. Ramuci- cancer-related death worldwide [1]. Non–small cell lung rumab is a fully human IgG1 monoclonal antibody that cancer (NSCLC) accounts for nearly 85% of primary lung specifically binds to the extracellular domain of vascular cancer cases. NSCLC ‘tends to metastasize at early stages endothelial growth factor receptor 2 (VEGFR-2) with so that up to 35% of NSCLC patients present with de high affinity, preventing the binding of VEGF ligands novo brain metastasis [2]. Brain metastasis is the major and inhibiting receptor activation [16]. The CNS activity cause of morbidity and mortality in NSCLC patients. of ramucirumab has been demonstrated in clinical stud- Treatment of brain metastasis is a great challenge as the ies [17–20]. The groundbreaking phase III double-blind blood-brain barrier (BBB) prevents the entry of most RELAY trial demonstrated that adding ramucirumab to chemotherapeutics into the brain. erlotinib improved PFS (19.4 vs.12.4 months) in treat- Recent advances in molecular oncology have improved ment-naïve EGFR-mutated metastatic NSCLC [21]. A our understanding of genetic and epigenetic regulations phase Ib trial, which recruited Japanese patients with of NSCLC tumorigenesis and cell survival [3]. Epidermal advanced EGFR-mutated metastatic NSCLC, showed growth factor receptor (EGFR) is a transmembrane gly- a tolerable safety profile of afatinib plus ramucirumab coprotein receptor with an intracellular tyrosine kinase and a median PFS of 9.2 months [22]. Still, the cur- component implicated in cell proliferation and survival rent literature is scarce regarding the benefits of adding regulations. The current evidence shows the significant ramucirumab to first-line EGFR TKIs, such as afatinib, involvement of EGFR overexpression in developing sev- in patients with treatment-naïve NSCLC. Therefore, we eral malignancies, including NSCLC [4]. The frequency conducted this retrospective study to investigate the sur- of EGFR mutations in NSCLC cases shows substantial vival benefits and safety profile of afatinib plus ramuci - ethnic and geographical disparity, with the highest prev- rumab in patients with treatment-naïve, EGFR-mutated alence observed among patients from the Asia-Pacific metastatic, NSCLC. region (range 20–76%). In Taiwan, the frequency of EGFR mutations was estimated to be as high as 76% amongst Materials and methods NSCLC cases [5]. Both deletion within exon 19 (ex19del) The research was approved by the institutional review and leucine to arginine substitution mutation in exon 21 board of the Tzu Chi Hospital, Taiwan. All procedures (Leu858Arg) account for nearly 90% of EGFR mutations were in line with the latest version of the Declaration of in NSCLC patients [6]. These activating EGFR mutations Helsinki, and the report was prepared according to the are responsive to small-molecule EGFR tyrosine kinase STROBE statement [23]. inhibitors (TKIs) [6, 7]. Clinical trials and real-world evidence have estab- Eligibility criteria and data collection lished the efficacy of afatinib, a second-generation EGFR- For this retrospective study, the medical records of TKI, as the first-line treatment of choice for EGFR mut patients with treatment-naïve stage IV NSCLC and lab- mNSCLC patients [8]. Afatinib is a second-generation oratory-confirmed EGFR mutation (ex19del, L858R, or EGFR-TKI that irreversibly blocks the ErbB family of rare mutations, including exon 20 insertions, S768I, or protein-tyrosine kinases. Clinical evidence demon- L861Q), whether they had de novo brain metastases per strated that afatinib can pass the BBB [9]. Two landmark contrast-enhanced magnetic resonance imaging (MRI) or randomized controlled trials (RCTs) (LUX-Lung 3 and not, were retrieved. This study included patients who ini - Lux-Lung 6) demonstrated a significant improvement in tiated treatment with either sequential afatinib (30 mg/d) objective response rate (ORR) and progression-free sur- followed by ramucirumab (10  mg/kg) or front-line com- vival (PFS) with afatinib compared with platinum-based bination of afatinib (30 mg/d) plus ramucirumab (10 mg/ chemotherapy as first-line treatment in EGFR-mutated kg). Data of 33 patients who were treated between March metastatic NSCLC [10–12]. In Taiwan, afatinib is reim- 1, 2016, and April 30, 2022, were retrieved. bursed by the National Health Insurance (NHI) as a Data regarding the demographic characteristics, first-line option for EGFR-mutated metastatic NSCLC tumor stage, EGFR mutation type, treatment regimens, [13]. Unfortunately, data from clinical trials showed response rate, follow-up duration, progression sta- that most patients experience tumor progression after tus, and adverse events were collected. The 7th and 8th 10–14 months [14]. A combination therapy with other editions of TNM staging system were used to classify targeted agents is a viable choice to reduce the rates of patients into stage Iva or Ivb. The Response Evaluation resistance to EGFR-TKI. In 2009, Naumov et al. demon- Criteria in Solid Tumors (RECIST) version 1.1 was used strated that the dual inhibition of EGFR and VEGF abro- to evaluate treatment response, while the adverse events gates the EGFR resistance in NSCLC models. The authors Huang et al. BMC Cancer (2023) 23:413 Page 3 of 8 Table 1 Characteristics of the patients were classified according to the Common Terminology Characteristics Patients Criteria for Adverse Events (CTCAE) version 5.0. (n = 33) The primary endpoint was to investigate the PFS of the Median age (years), n (%) 63 (45–82) combination treatment. Other endpoints included the < 70 26 (78.8%) PFS according to EGFR mutation, ORR (defined as com - ≥ 70 7 (21.2%) plete response rate plus partial response rate), and the Sex, n (%) incidence of treatment-related adverse events. Male 8 (24.2%) Female 25 (75.8%) Statistical analysis Smoking status, n (%) The results were analyzed using SPSS version 28 soft - Non-smoker 31 (93.9%) ware for Windows (IBM Corp. Armonk, NY, USA). Smoker 2 (6.1%) Descriptive statistics were employed according to data Clinical stage , n (%) type. The Kaplan-Meier was used to estimate the PFS of IVA 6 (18.2%) all included patients, patients on sequential afatinib fol- IVB 27 (81.8%) lowed by ramucirumab (PFS1), and patients on up-front ECOG PS, n (%) combination of afatinib and ramucirumab (PFS2). The 0 0 (0.0%) PFS was calculated as the time from treatment initia- 1 33 (100.0%) tion to progression or death from any cause. A log-rank EGFR mutation, n (%) test was used to compare the PFS according to EGFR Del 19 14 (42.4%) mutation status. The chi-square test, Yate’s correction L858R 17 (51.5%) when needed, compared the incidence of adverse events Other 2 (6.1%) between patients who initiated afatinib only and patients Brain metastasis, n (%) 15 (46.5%) No. Brain metastasis, n (%) n = 15 who initiated afatinib plus ramucirumab. The results Single 6 (40%) were considered significant when two-tailed P < 0.05. Multiple 9 (60%) Location of Brain metastasis, n (%) n = 15 Results Cerebellum 1 (6.7%) Patients’ clinical characteristics Cerebellum, Cerebrum 5 (33.3%) Thirty-three patients were included, with female pre - Cerebrum 9 (60%) dominance (n = 25; 75.8%) and a median age of 63 (range Oligo-metastatic, n (%) n = 15 45–82) years. Only two patients (6.1%) were smoker. Single 5 (33.3%) Twenty-seven patients (81.8%) had stage IVB NSCLC. Multiple 2 (13.3%) All patients had an Eastern Cooperative Oncology Group Leptomeningeal metastasis, n (%) 2 (13.3%) performance status (ECOG PS) of 0 or 1. The distribution Symptomatic brain metastasis, n (%) 5 (33.3%) of the EGFR mutations was as follows: ex19del (42.4%), Treatment of brain metastasis, n (%) n = 15 L858R (51.5%), G719 × (3%), and L861Q (3%). Fifteen Surgery 0 patients had brain metastasis, 60% of them had multiple Radiotherapy 13 (86.7%) sites of brain metastasis. One-third of the patients with Treatment, n (%) brain metastasis were symptomatic. Overall, out of the 15 Sequential afatinib followed by ramucirumab 11 (33.3%) patients, 13 (86.7%) received local radiotherapy for brain Upfront combination 22 (66.7%) metastasis before initiating Afatinib or during the course Response, n (%) of treatment. CR and PR 33 In this study, 11 patients administered the sequen- (100.00%) tial regimen (afatinib followed by ramucirumab) and 22 SD 0 (0.00%) patients received upfront combination therapy (afatinib Progressive disease, n (%) plus ramucirumab). In patients who received sequential Yes 5 (15.2%) regimen, the median duration between starting afatinib No 28 (84.8%) and starting ramucirumab was 35 months (range 9–43 Abbreviation: CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; PR, partial response; SD: stable disease months), Table 1. Based on American Joint Committee on Cancer (7th and 8th editions) Rare EGFR mutations, including G719X and L861Q Progression-free survival and overall survival The median follow-up of the included patients was 17 months (range 6–89 months). The PFS was determined for all patients who received either upfront combination or sequential treatment with afatinib and ramucirumab Huang et al. BMC Cancer (2023) 23:413 Page 4 of 8 (n = 33 patients); the median PFS for the whole cohort female aged 77 years who presented with stage IVA ade- was 71 months (95% CI 67.2–74.8) with eight events dur- nocarcinoma and metastatic pleural effusion. She had ing the follow-up (Fig.  1A). The median PFS1 and PFS2 L861Q positive mutation. She initially started on 30  mg were 71 months (95 CI not defined) and 26 months (95% afatinib and then received 10  mg/kg ramucirumab two CI 18.6–33.4), respectively (Fig.  1B). In terms of OS, years later. She has an ongoing response with a notable the median OS for all patients and patients on sequen- PFS of > 56 months. The second patient was a 65 years tial treatment was not defined, while the median OS for old female with a stage IVB disease who started 30  mg patients on upfront combination was 30 months (95% CI afatinib in 2018. Three years later, she received 10  mg/ 20.9–39.1), Fig.  1C. Figure  2 shows the swimmer plot of kg ramucirumab. The patient had G719X mutation and the 33 patients. showed an ongoing PFS of > 52 months. Association between EGFR mutations and treatment Adverse events outcomes The adverse events caused by each type of treatment There was no significant association between EGFR regimens were analyzed. Despite being frequent among mutation type and PFS1 (P = 0.171; Fig. 3A). The median patients, the presentation of diarrhea (P = 0.602) and par- PFS1 of patients with L858R and ex19del was undefined. onychia (P = 0.801) had no significant difference between Likewise, there was no significant association between patients who were first treated with sequential regiment EGFR mutation type and PFS2 (P = 0.803; Fig.  3B). The and patients treated with up-front combination (Table 2). median PFS2 of patients with L858R was 26 months (95% CI 18.4–33.6), while the estimate was not defined for Discussion patients with ex19del mutation. Ramucirumab represents a viable option to overcome In the present study, two patients presented with EGFR resistance in patients with EGFR-mutated meta- uncommon EGFR mutations. The first patient was a static NSCLC. The phase III RELAY trial found that Fig. 1 (A) Kaplan-Meier estimates of progression-free survival (mPFS = 71 mon) of all patients who received either upfront combination or sequential treatment with afatinib and ramucirumab (n = 33 patients); (B) Kaplan-Meier estimates of progression-free survival in patients received sequential (blue; mPFS 71 mon; n = 11) and upfront combination therapy (green; mPFS 30 mon; n = 22). PFS, progression-free survival; (C) Kaplan-Meier estimates of overall survival in patients received sequential (blue; mOS not defined mon; n = 11) and upfront combination therapy (green; mOS 30 mon; n = 22) Huang et al. BMC Cancer (2023) 23:413 Page 5 of 8 Fig. 2 Swimmer plot of the 33 patients. Kaplan-Meier estimates of progression-free survival of patients with L858R and ex19del EGFR mutations (A) patients starting sequential regimen; (B) patients starting up-front combination ramucirumab addition to erlotinib improves disease con- EGFR-TKIs [26]. The survival benefits of afatinib in trol in patients with EGFR-mutated metastatic NSCLC patients with uncommon EGFR mutations are well estab- [21]. In addition, the safety profile of ramucirumab plus lished, and it is currently approved for patients with any erlotinib was demonstrated in several trials [21, 22]. EGFR mutation. According to a subgroup analysis from However, studies are yet to determine the clinical efficacy LUX-Lung 2, 3, and 6 trials, patients harboring G719X and safety profile of upfront ramucirumab plus EGFR- and L861Q mutations had a median PFS of 13.8 and 8.2 TKI combination in NSCLC patients. The present study months, respectively [27]. Two patients presented with found that the median PFS of the EGFR-mutated patients uncommon EGFR mutations in the present retrospec- on ramucirumab plus afatinib, whether the combination tive chart review. The patient with L861Q mutation had was initiated concurrently or sequentially, was 71 months a notable PFS of > 56 months, while the patient with (95% CI not defined). Besides, the median PFS for G719X mutation showed an ongoing PFS of > 52 months. patients who initiated sequential treatment and upfront Although immature, our data suggest a further survival combination were 71 months (95% CI not defined) and benefit of adding ramucirumab to afatinib in patients 26 months (95% CI 18.6–33.4), respectively. Further- with uncommon mutations. Future studies are recom- more, no significant difference in PFS was observed mended to assess the survival benefits of ramucirumab among patients with different EGFR mutations. To our plus afatinib in patients with uncommon mutations. knowledge, this is the first study that outlines the efficacy Several other EGFR-TKI have been trialed in patients of afatinib plus ramucirumab in treatment-naïve patients with EGFR-mutated metastatic NSCLC (such as dacomi- with EGFR mutation. Of note, the median PFS observed tinib and erlotinib) but with a high incidence and severity in our cohort was notably longer than the median PFS of adverse events [6]. In our study, dermatitis and paro- reported in pivotal clinical trials and observational stud- nychia were frequent among patients, although no sig- ies. In the LUX-Lung 3, 6, and 7 trials, EGFR-mutated nificant difference was found between patients who were patients with brain metastasis on first-line afatinib had first treated with afatinib compared with patients treated a median PFS ranging from 7.2 to 8.2 months [11, 12, with afatinib and ramucirumab. Diarrhea was frequent in 24]. Similar figures were reported in real-world studies both groups as well. Our results were in accordance with (median PFS = 8.2 months) [25]. Thus, our data suggest those reported by Paz-Ares et al., who also found that that ramucirumab improves the PFS of first-line EGFR- diarrhea (12.5%) was a frequent adverse event [28]. By TKI. These run in line with previous reports showing an contrast, other studies have reported hypertension and improvement in PFS amongst patients receiving first- renal failure as the most frequent adverse events, which generation EGFR-TKIs plus ramucirumab [21]. Further could not be managed with dose adjustments or support- experimental evidence is needed to elucidate the poten- ive care [21]. tial synergistic mechanisms of action of the combination While the present study provides novel findings regard - therapy. ing the benefit of afatinib plus ramucirumab for patients Uncommon EGFR mutations can present in 10% of with EGFR-mutated metastatic NSCLC, we acknowledge the NSCLC patients and show variable responses to that the study has certain limitations. The study’s findings Huang et al. BMC Cancer (2023) 23:413 Page 6 of 8 Fig. 3 Kaplan-Meier estimates of progression-free survival of patients with L858R and ex19del EGFR mutations (A) patients starting sequential regimen; (B) patients starting up-front combination Table 2 Presence or absence of adverse events are based on retrospective data collection, introducing Adverse Events (N = 33) Sequential Up-front P- reporting bias, and limiting the control of the outcomes (n = 11) combination val- reporting and definitions. In addition, the sample size of (n = 22) ue the included patients was relatively small, and the follow- Diarrhea 8 (72.7%) 14 (63.6%) 0.602 up period was short to attain a measurable median PFS. Dermatitis 11 (100%) 22 (100%) -- We could not assess the impact of long-term response to Paronychia 7 (63.6%) 13 (59.1%) 0.801 afatinib monotherapy on the survival benefit of combi - Nausea & Vomiting 1 (9.1%) 0 (0%) 0.151 nation therapy due to the small sample size. Besides, the Mucositis 0 (0%) 0 (0%) -- causal relationship between treatment regimen and sur- Hepatitis 0 (0%) 0 (0%) -- vival benefit could not be established due to the lack of a Hemorrhagic events 0 (0%) 0 (0%) -- control group. Renal dysfunction 0 (0%) 0 (0%) -- Huang et al. BMC Cancer (2023) 23:413 Page 7 of 8 Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Conclusions 2021;71:209–49. https://doi.org/10.3322/caac.21660. 2. Lei L, Wang WX, Wang D, Lin L, Zhu YC, Wang H, Wang LP, Zhuang W, Fang MY, This real-world cohort study demonstrated that afatinib Wan B, et al. A real-world study in advanced non-small cell lung cancer with plus ramucirumab could improve the PFS of patients de novo brain metastasis. J Cancer. 2021;12:1467–73. https://doi.org/10.7150/ with EGFR-mutated metastatic NSCLC. The survival jca.51411. 3. Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor benefit was notable for the combination of afatinib and (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010;2:48–51. ramucirumab, at a predictable safety profile for both 4. Inamura K, Ninomiya H, Ishikawa Y, Matsubara O. Is the epidermal drugs. Additional data collected among a large popula- growth factor receptor status in lung cancers reflected in clinico - pathologic features? Arch Pathol Lab Med. 2010;134:66–72. https://doi. tion remains necessary to better address the advantages org/10.5858/2008-0586-rar1.1. of afatinib plus ramucirumab and optimize their clinical 5. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small- applications. Although immature, our data suggest a fur- cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5:2892–911. ther survival benefit of adding ramucirumab to afatinib 6. Hsu WH, Yang JC, Mok TS, Loong HH. Overview of current systemic man- in patients with uncommon mutations. Future stud- agement of EGFR-mutant NSCLC. Ann Oncol. 2018;29:i3–i9. https://doi. ies are recommended to assess the survival benefits of org/10.1093/annonc/mdx702. 7. Kim ES, Melosky B, Park K, Yamamoto N, Yang JC. EGFR tyrosine kinase inhibi- ramucirumab plus afatinib in patients with uncommon tors for EGFR mutation-positive non-small-cell lung cancer: outcomes in mutations. asian populations. Future Oncol. 2021;17:2395–408. https://doi.org/10.2217/ fon-2021-0195. Acknowledgements 8. Takeda M, Nakagawa K. First- and second-generation EGFR-TKIs are all The editorial assistance was provided to the authors by Nova Journal Experts. replaced to Osimertinib in Chemo-Naive EGFR mutation-positive Non- Small Cell Lung Cancer? Int J Mol Sci. 2019;20. https://doi.org/10.3390/ Authors’ contributions ijms20010146. Chun-Yao Huang: Conception/Design; Provision of study material or patients; 9. Hochmair M. Medical treatment options for patients with epidermal growth Collection and/or assembly of data; Data analysis and interpretation; factor receptor mutation-positive non-small cell lung cancer suffering Manuscript writing; Final approval of manuscriptHui-Li Huang: Collection from brain metastases and/or leptomeningeal disease. Target Oncol. and/or assembly of data; Data analysis and interpretation; Final approval 2018;13:269–85. of manuscriptChou-Chin Lan: Provision of study material or patients; Final 10. Karachaliou N, Fernandez-Bruno M, Bracht JWP, Rosell R. EGFR first- and approval of manuscriptYi-Chih Huang: Provision of study material or patients; second-generation TKIs-there is still place for them in EGFR-mutant NSCLC Final approval of manuscriptYao-Kuang Wu: Conception/Design; Provision of patients. 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Preventing and treating brain metastases with three first-line EGFR- Springer Nature remains neutral with regard to jurisdictional claims in tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced published maps and institutional affiliations.

Journal

BMC Cancer – Springer Journals

Published: May 8, 2023

Keywords: Afatinib; Ramucirumab; Non–small cell lung cancer; EFGR mutation

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