The efficacy and safety of ramucirumab plus docetaxel in older patients with advanced non-small cell lung cancer.

Abstract Background Ramucirumab plus docetaxel (RAM+DOC) is expected to prolong survival in patients with advanced non‐small cell lung cancer (NSCLC); however, the efficacy and safety for older patients remains unknown. The objective of this study was to evaluate the efficacy and safety of RAM+DOC in patients 75 years and older. Methods We retrospectively reviewed consecutive patients with advanced NSCLC who had received RAM+DOC treatment at three institutions. We compared the efficacy and safety in patients 75 years and older to those under 75 years of age. Results A total of 114 patients were identified. The median progression‐free survival, time to treatment failure and overall survival was 3.6 (95% CI: 0.4–6.7), 3.1 (95% CI: 2.4–3.9) and 11.2 months (95% CI: 5.6–16.8) in the older group (N = 23), and 4.2 (95% CI: 3.3–5.0), 3.4 (95% CI: 3.3–5.0) and 12.2 months (95% CI: 9.1–15.4) in the younger group (N = 91), respectively. Survival curves were similar for each group, while the objective response rate was 30.4% (95% CI: 13.2–52.9%) in older patients and 35.2% (95% CI, 25.4–45.9%) for the younger group. A total of 22 older patients (95.7%) and 73 (80.2%) younger patients received primary prophylactic pegylated‐granulocyte‐colony stimulating factor (PEG‐G‐CSF). Four older patients (17.3%) and 14 younger patients (15.3%) discontinued RAM+DOC due to adverse events. Conclusions RAM+DOC is expected to be efficacious and tolerable in older patients when supported with prophylactic PEG‐G‐CSF therapy. Key points Significant findings of the study ・PFS, OS, and ORR in older patients were similar to those under 75 years of age. ・Safety of RAM+DOC was well tolerated in older patients with prophylactic PEG‐G‐CSF. ・Prophylactic PEG‐G‐CSF with RAM+DOC may contribute to better efficacy. What this study adds ・This study suggests that RAM+DOC with prophylactic PEG‐G‐CSF is expected to be a useful option in older patients with advanced NSCLC.

generally recommended regardless of age; therefore, cytotoxic agents are still indicated in those with driver oncogene alterations after targeted therapy. In a recent pooled analysis of older patients with advanced NSCLC with programmed death-ligand 1 (PD-L1) positive tumors, immune checkpoint inhibitors (ICI) improved overall survival (OS) compared with cytotoxic chemotherapy, with a more favorable safety profile. 1 However, whether older patients derive similar benefits or can tolerate ICIs in clinical practice is uncertain. Although recent studies have shown efficacy for carboplatinbased platinum doublets in older patients, [2][3][4][5] docetaxel monotherapy is a standard of care for chemotherapy-naïve older patients with advanced NSCLC. 6 Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody that specifically binds to the vascular endothelial growth factor (VEGF) receptor-2 extracellular domain with high affinity, preventing binding of all VEGF ligands and receptor activation. 7 In the REVEL trial, ramucirumab plus docetaxel (RAM+DOC) improved objective response rates (ORR), progression-free survival (PFS) and OS compared with docetaxel monotherapy as a second-line treatment in patients with advanced NSCLC. 8 Moreover, in the JVCG trial, a similarly designed Japanese randomized phase II trial, second-line RAM+DOC improved PFS to that seen in the REVEL trial with a manageable safety profile. 9 RAM+DOC is expected to prolong survival in patients with advanced NSCLC; however, the efficacy and safety in older patients is still unknown. Therefore, in this study, we retrospectively evaluated the efficacy and safety of RAM +DOC in patients 75 years and older.

Patient selection
This retrospective study was conducted across three institutions in Japan (St. Marianna University School of Medicine, Yokohama City Seibu Hospital and Matsusaka Municipal Hospital). We reviewed electronic data from consecutive patients with advanced NSCLC who received RAM+DOC from June 2016 to December 2018. Clinical data assessments included: patient characteristics; histology; clinical stage (UICC eighth edition); Eastern Cooperative Oncology Group performance status (ECOG PS); the number of prior treatments; prior bevacizumab or ICI therapies; usage of prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF); treatment outcomes and adverse events. This study was approved by the institutional review board of each institution.

Definition of older patients
We defined older patients as those 75 years and older according to guidelines from the Japan Lung Cancer Society. 10 Although many studies and subgroup analyses in Western countries have assessed older patients as 70 years and older, we regard patients aged 70 to 75 years as treatable with platinum-based chemotherapy in Japan.

Drug administration
Intravenous ramucirumab (10 mg/kg) plus docetaxel (60 mg/ m 2 ) were administered every three weeks until disease progression or unacceptable toxicity. The use of primary and secondary prophylactic PEG-G-CSF and dose modification were at the discretion of the attending physicians.

Treatment assessment
The data cutoff was April 2019. Efficacy endpoints were PFS, time to treatment failure (TTF), OS, ORR, and the disease control rate (DCR). Endpoints for safety included the incidence of grade ≥ 3 neutropenia and febrile neutropenia,

Patient characteristics
A total of 114 patients (older, 23; younger, 91) were identified for efficacy and safety analyses. The main characteristics for each group are shown in Table 1, and a more detailed comparison of characteristics are displayed in Tables S1A and   B. Among the older group, 47.8% were female, 52.2% were never smokers and 39.1% were diagnosed with squamous cell carcinoma. The use of RAM+DOC for early-line (prior treatments = 0-1) was most prevalent in the older group (39.1%), while the use of late-line (prior treatments = ≥3) was higher for the younger group (42.9%). In the older group, over half of the patients (56.5%) were administered RAM+DOC after ICI treatment.

Efficacy analysis
At data cutoff (April 2019), the median follow-up was 9.1 months. One older patient (4.3%) and eight younger patients (8.7%) received continuous RAM+DOC treatment. The median number of cycles of RAM+DOC was four for each group. The median PFS, TTF, and OS was 3.6 months   Table 2).

Use of prophylactic PEG-G-CSF and initial dose adjustment
In older patients, 22 (95.7%) received primary prophylactic PEG-G-CSF, whereas 73 patients (80.2%) received PEG-G-CSF in the younger group. One older patient (4.3%) and 13 younger patients (14.3%) received secondary prophylactic PEG-G-CSF (Fig 2). The use of prophylactic PEG-G-CSF, especially for primary use, was associated with better outcomes for PFS and OS (Fig 3). Multivariate analysis identified the use of primary prophylactic PEG-G-CSF as an independent favorable factor for PFS and OS (Tables S2  and S3). Six older patients (26.0%) and five younger patients (5.5%) required a reduction of docetaxel (50 mg/ m 2 ) at the initial course, while one older (4.3%) and two younger patients (2.1%) required a reduction of ramucirumab (8 mg/kg) at the initial course.

Safety analysis
In the older group, three patients (13.0%) required a reduction in dosage for regimens after the initial course, whereas, 13 patients (14.3%) received a reduction in the younger group. Four older patients (17.3%) discontinued RAM+DOC due to adverse events which included; one interstitial pneumonia, one anorexia, one diarrhea and one edematous disorder. In the younger group, 14 patients (15.3%) discontinued treatment. Five older patients  (21.7%) and 23 younger patients (25.2%) developed Grade ≥ 3 neutropenia. One older patient (4.3%) and nine younger patients (9.8%) required secondary prophylactic PEG-G-CSF support after developing febrile neutropenia (FN). In each group, one patient died during RAM+DOC treatment. Key safety data are shown in Table 3.

Discussion
This is the first report to investigate the efficacy and safety of RAM+DOC and primary prophylactic PEG-G-CSF focused on older patients with advanced NSCLC. In this study, RAM+DOC was efficacious and well tolerated in older patients. RAM+DOC had been considered a highrisk regimen since the incidence of FN is higher with RAM +DOC (34.2%) than with placebo-docetaxel (19.8%) in a Japanese phase II study. 9 However, in our study, it is notable that most patients in the older group received primary prophylactic PEG-G-CSF without developing FN. Recent studies report that prophylactic PEG-G-CSF not only reduces FN incidences, 12 but was able to maintain dose intensity and improve the prognosis in adjuvant treatments for breast cancer. 13 In our study, the use of PEG-G-CSF might have influenced better efficacy, especially in primary prophylactic PEG-G-CSF, which is consistent with a previous study. 13 Therefore, primary prophylactic PEG-G-CSF is considered an important option for better efficacy and safety, but appropriate dose reduction at the initial course and after the initial course is needed in some cases. The Japan Lung Cancer Society guidelines do not recommend RAM+DOC for patients aged 75 years and older due to the lack of efficacy and safety data. 10 In subgroup analysis of age in the REVEL trial, 14 the hazard ratio model using quintile age groupings adjusted for significant prognostic factors showed OS and PFS hazard ratios favored ramucirumab treatment over the control arm in all age groups. However, this study did not evaluate patients aged 75 and older. Furthermore, in the JVCG trial, 9 patients aged 75 years and older were rarely enrolled, resulting in a lack of clinical trial data for older patients. In recent retrospective studies which included some patients aged 75 years and older treated with RAM+DOC, there were no instances of FN after receiving prophylactic PEG-G-CSF support, whereas FN developed in patients not receiving PEG-G-CSF. 15,16 In consideration of our results, the administration of PEG-G-CSF seemed to be essential therapy for RAM+DOC, especially in older patients. Therefore, RAM +DOC with prophylactic PEG-G-CSF support may be a useful strategy for patients, regardless of age.
The DRAGON study, 17 a multicenter, prospective, single-arm, phase II trial of RAM+DOC with primary prophylactic PEG-G-CSF support for chemotherapy-naive older patients with advanced NSCLC is ongoing in Japan. This study will further shed light on the efficacy and safety of RAM+DOC with primary prophylactic PEG-G-CSF support without dose reductions at the initial course.
There were several limitations to this study. First, this was a relatively small retrospective study and further evaluation with larger cohorts is required. Second, this study did not compare the efficacy and safety in older patients receiving docetaxel monotherapy alone; therefore, further comparison studies are needed. Third, the administration of RAM+DOC as an early-line treatment was most prevalent in older patients, which might have affected the favorable OS in this group. Finally, the standard dose of docetaxel in Japan (60 mg/m 2 ) is lower than that of the international standard dose (75 mg/m 2 ); therefore, we could not assess the efficacy and safety of the higher dose in this study. However, considering docetaxel at 75 mg/m 2 was associated with a higher rate of neutropenia in East Asian patients, the lower dose of docetaxel at 60 mg/m 2 was similar to the rate of neutropenia in the REVEL study for non-Asian patients.
In conclusion, RAM+DOC is expected to be efficacious and tolerable in older patients with prophylactic PEG-G-CSF support. Prophylactic PEG-G-CSF support may impact not only safety, but efficacy in patients treated with RAM+DOC.

Supporting Information
Additional Supporting Informationmay be found in the online version of this article at the publisher's website: Table S1A. Patient characteristics Table S1B. EGFR-TKI treatment in patients harboring EGFR mutation Table S2. Predictors of PFS analyzed by Cox regression model in all patients  Table S3. Predictors of OS analyzed by Cox regression model in all patients.