Abstract
Background
Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear.
Methods
Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle.
Results
Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS.
Conclusion
No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).
Keywords: brain metastases, non-small cell lung cancer, docetaxel plus ramucirumab, sVEGFR-2, VEGF
This clinical trial was designed to evaluate the efficacy and safety of ramucirumab plus docetaxel combination therapy as a treatment for NSCLC with brain metastases.
Lessons Learned.
In this study, median progression-free survival was 3.9 months (95% CI, 1.8-5.3). Intracranial hemorrhage and grade 5 adverse events were not observed.
The statistical power was not sufficient, because enrollment in this study was not reached to the planned number. Further investigation with a larger sample size is needed to determine the tolerability and safety for these populations.
Discussion
Up to 40% of patients with non-small cell lung cancer (NSCLC)will develop de novo metastases during the course of the disease. Although radiotherapy or surgical resection is expected for the local control of brain metastases, chemotherapy shows a marginal anti-tumor effect for brain metastases.
Ramucirumab is a human recombinant IgG1 monoclonal antibody preventing ligand-depended vascular endothelial growth factor receptor-2 (VEGFR-2) receptor activation, which is implicated in tumor progression and metastases. Ramucirumab plus docetaxel combination therapy (DOC/RAM) improves the prognosis in patients with NSCLC progressed after the platinum-based chemotherapy. However, the efficacy and safety for patients with brain metastases remain unclear because patients with untreated brain metastases were excluded from previous studies, and a subset analysis of enrolled patients with treated brain metastases was not performed.
This clinical trial was designed to evaluate the efficacy and safety of DOC/RAM as a treatment for NSCLC with brain metastases. Since the eligible patients were fewer than expected and it was deemed difficult to achieve the planned 65 patients, enrollment was terminated early when 25 patients were enrolled (Table 1). Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3); median iPFS was 4.6 months (95% CI, 2.5-5.9); median OS was 20.9 months (95% CI, 6.6-not possible to estimate) (Fig. 1); the overall response rate (ORR) was 20% (95% CI, 6.8-40.7); disease control rate (DCR) was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher adverse events were neutropenia (10 cases, 40%), leukopenia (5 cases 20%), fatigue (4 cases, 16%) mucositis oral (3 cases, 12%). Intracranial hemorrhage and grade 5 adverse events were not observed in the present study. Furthermore, our exploratory investigation revealed that a high level of sVEGFR-2 at the initiation of treatment tended to be correlated with longer survival in DOC/RAM. However, the sample size was too small and not reached to planned number, so the statistical power was not sufficient in this study.
Table 1.
Patients characteristics.
| Characteristic | n (%) |
|---|---|
| Age, years, median (range) | 67 (44-82) |
| Gender | |
| Male | 16 (64) |
| Female | 9 (36) |
| Histology | |
| Adenocarcinoma | 22 (88) |
| Squamous cell carcinoma | 1 (4) |
| Others | 2 (8) |
| Stage | |
| IV | 21 (84) |
| Postoperative recurrence | 4 (16) |
| CNS lesion | |
| Single | 5 (20) |
| Multiple | 20 (80) |
| Driver mutation | |
| EGFR T790M | 2 (8) |
| EGFR exon 19 del | 6 (24) |
| EGFR L858R | 6 (24) |
| ALK rearrangement | 1 (4) |
| Other | 1 (4) |
| Smoking history | |
| Current or former | 17 (68) |
| Never | 8 (32) |
| Treatment line | |
| 2 | 4 (16) |
| 3 | 10 (40) |
| 4≤ | 11 (44) |
| Previous chemotherapy | |
| Platinum based | 23 (92) |
| EGFR-TKI or ALK-TKI | 13 (52) |
| Anti-angiogenic agents | 14 (56) |
| PD-1/PD-L1 inhibitor | 5 (20) |
| Previous treatment for CNS lesion | |
| SRS | 13 (52) |
| Surgery | 4 (16) |
Abbreviations: ALK, anaplastic lymphoma kinase; CNS, central nervous system; EGFR, epidermal growth factor receptor; SRS, stereotactic radiosurgery; TKI, tyrosine kinase inhibitor.
Figure 1.
Kaplan–Meier survival curves. (A) Progression-free survival (PFS). (B) Intracranial PFS (iPFS). (C) Overall survival (OS).
In summary, no clinical concerns were identified with treatment with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations.
| Trial Information | |
|---|---|
| Disease | Lung cancer—NSCLC |
| Stage of disease/treatment | Metastatic/advanced |
| Prior therapy | A history of 1 or more regimen of chemotherapy |
| Type of study | Phase II single arm |
| Primary endpoint | Progression-free survival (PFS) |
| Secondary endpoints | Intracranial progression-free survival (iPFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), safety |
| Investigator’s analysis | Correlative endpoints not met but clinical activity observed |
Additional Details of Endpoints or Study Design
Eligibility Criteria
Eligibility criteria were as follows: (a) histologically or cytologically confirmed to have recurrence or advanced stage NSCLC; (b) asymptomatic metastatic brain tumor fulfilling the following conditions; patients after stereotactic radiosurgery (SRS) such as gamma knife radiosurgery 2 weeks or more before the beginning of protocol treatment, neurological symptoms and general condition are stable after SRS on the day of the beginning of protocol treatment, untreated brain metastasis are accepted only when they are asymptomatic and when the physician in charge judges it unnecessary to perform SRS before chemotherapy; (c) history of at least 1 regimen of chemotherapy, preoperative/postoperative adjuvant chemotherapy or chemoradiotherapy are also included; (d) performance status (ECOG) is 0-1; (e) aged 20 years and older; (f) adequate organ and bone marrow function as defined below: neutrophil count ≥1500/mm3; platelet count ≥100 000/mm3; hemoglobin ≥9.0 g/dL; AST or ALT ≤3 or ≤5 ×ULN (if there is liver metastasis); serum bilirubin ≤1.5 mg/dL; serum creatinine ≤1.5 × ULN or creatinine clearance ≥40 mL/minute; PT-INR ≤1.5, APTT prolonged within 5 s above the upper limit of the normal range; urinary protein ≤1+ or ≤1000 mg/day in 24-h pooled urine; (g) survive for at least 3 months; (h) following period are needed after previous treatment at the beginning of protocol treatment: chemotherapy, immune checkpoint inhibitors (at least 4 weeks), EGFR-TKI (1 day), chest radiation (at least 28 days), radiation of areas other than the chest (at least 7 days), surgery including thoracic drainage (at least 4 weeks); (i) women of reproductive age who can practice appropriate contraceptive measures from during to 4 months after the last ramucirumab administration and must be tested negative for pregnancy at least 1 week before registration; (j) no active double cancers; and (k) patients who have provided written consent in person.
Exclusion Criteria
Exclusion criteria were as follows: (a) patients who have not received any prior systemic chemotherapy; (b) surgery within 28 days, or intravenous device placement within 7 days, before providing consent; (c) symptomatic brain metastasis or those undergoing treatment by irradiation of the whole brain or surgery for brain metastases (SRS alone is allowed); (d) meningeal dissemination; (e) intratumoral bleeding of brain metastasis or other bleeding from the central nervous system within 21 days; (f) cavity formation in an intracranial or extracranial tumor or invasion to large vessels; (g) poorly controlled congenital or acquired clotting disorders; (h) developed cardiovascular, cerebrovascular disorders, deep vein thrombosis (DVT), pulmonary embolism, other severe thromboembolism within 6 months; (i) serious hemorrhagic complication within 6 months (grade 1≤ bleeding of the central nervous system; grade 3≤ gastrointestinal bleeding or hemoptysis; or hemorrhagic event of any grade within 14 days under the heparin anticoagulation); (j) gastrointestinal perforation within 6 months or have a risk of perforation (gastrointestinal invasion/metastasis); (k) Child-Pugh B or severer liver cirrhosis, hepatic encephalopathy, or hepatic ascites requiring therapeutic intervention; (l) poorly controlled hypertension (systolic pressure remaining at ≥160 mmHg or diastolic pressure remaining at ≥100 mmHg for 4 weeks or longer); (m) unhealed wounds or ulcerated lesions; or with a history of fracture within 28 days; (n) pregnant, breast-feeding, or may be pregnant; (o) poorly controlled metabolic disorders (diabetes mellitus); (p) active or uncontrolled infections; (q) regularly administered non-steroidal anti-inflammatory drugs (NSAIDs: indomethacin, ibuprofen, naproxen, or their analogs) or antiplatelet agents (aspirin, dipyridamole, ticlopidine, clopidogrel, or their analogs); (r) complications that have a high medical risk or may cause life-threatening events; (s) inappropriate as participants in this study.
Endpoints
The primary endpoint was PFS. Secondary endpoints were iPFS, OS, ORR, DCR, and safety. Exploratory endpoints were the evaluation of the relationships of plasma VEGF before, during, and at the end of protocol treatment and the change in the serum soluble VEGFR-2 level with the efficacy.
Statistical Analysis
In PFS and OS analyses, survival functions and annual survival rates were calculated using the Kaplan–Meier method, with CI for the median survival time being estimated using the method of Brookmeyer and Crowley, and the standard error for annual survival rates being estimated using Greenwood’s method. ORR and 2-sided 90% CI were calculated using Wilson’s method.
Rationale for the Sample Size
From data of JVCG phase II study in patients treated by ramucirumab plus docetaxel, median PFS and median OS were reported to be 5.22 months (95% CI, 3.52-6.97) and 15.15 months (95% CI, 12.45-26.55 months), respectively. On the other hand, life expectancy for patients with brain metastases is poor, with a median OS of only 3.4-4.5 months following chemotherapy or radiotherapy [7-9].
As mentioned earlier, the threshold median PFS and expected median PFS of patients with brain metastases who have a history of systemic chemotherapy are estimated to 3.0and 5.3 months, respectively. In this condition, when a 2-sided significant level of 5% and the power of the test of 80% are assumed from one sample non-parametric tests for a median survival time, 56 subjects are required. Considering allowing for dropouts, 65 subjects were planned to enroll.
Ethics
The present study was approved by the Institutional Review Boards of all sites, conducted in accordance with the principles of the Declaration of Helsinki, and registered at the University Hospital Medical Information Network in Japan and the Japan Registry of Clinical Trials under registration numbers UMIN000024551 and jRCTs071180048, respectively. All patients provided written informed consent before the initiation of any study-related procedures.
| Drug Information | |
|---|---|
| Generic/working name | Ramucirumab |
| Company name | Eli Lily |
| Drug type | Monoclonal antibody |
| Drug class | VEGFR-2 |
| Dose | 10 mg/kg |
| Unit | mg |
| Route | i.v. |
| Schedule of administration | Administered with docetaxel on day 1 of 21-day cycles until disease progression or a discontinuation criterion was met. |
| Generic/working name | Docetaxel |
| Company name | Sanofi Aventis |
| Drug type | Biological |
| Drug class | Taxane |
| Dose | 60 mg/kg |
| Unit | mg |
| Route | i.v. |
| Schedule of administration | Administered with ramucirumab on day 1 of 21-day cycles until disease progression or a discontinuation criterion was met. |
| Patient Characteristics | |
|---|---|
| Number of patients, male | 16 |
| Number of patients, female | 9 |
| Stage | IV: 21, postoperative recurrence: 4 |
| Age, median (range) | 67 (44-82) years |
| Number of prior systemic therapies: median (range) | 1: 4, 2: 10, 3≤: 11 |
| Performance status: ECOG | 0: 9 (36.0) 1: 16 (64.0) 2: 0 (0) 3: 0 (0) 4: 0 (0) |
| Cancer types or histologic subtypes | Adenocarcinoma, 22; squamous cell carcinoma, 1; other, 2 |
| Primary Assessment Method: PFS | |
|---|---|
| Number of patients screened | 25 |
| Number of patients enrolled | 25 |
| Number of patients evaluable for toxicity | 25 |
| Number of patients evaluated for efficacy | 25 |
| Evaluation method | RECIST 1.1 |
| Median duration assessments, PFS | 3.9 months (CI: 1.8-5.3) |
| Outcome notes | The 6-month PFS rate was 21.1% (95% CI, 7.7-38.9), and the 1-year PFS rate was 8.4% (95% CI, 1.5-23.6) (Fig. 1A) |
| Secondary Assessment Method: Intracranial PFS | |
|---|---|
| Number of patients screened | 25 |
| Number of patients enrolled | 25 |
| Number of patients evaluable for toxicity | 25 |
| Number of patients evaluated for efficacy | 25 |
| Evaluation method | Kaplan–Meier method |
| Outcome notes | Median iPFS was 4.6 months (95% CI, 2.5-5.9), the 6-month iPFS rate was 29.2% (95% CI, 12.2-48.7), and the 1-year iPFS rate was 9.7% (95% CI, 1.7-26.5) (Fig. 1B) |
| Secondary Assessment Method: OS | |
|---|---|
| Number of patients screened | 25 |
| Number of patients enrolled | 25 |
| Number of patients evaluable for toxicity | 25 |
| Number of patients evaluated for efficacy | 25 |
| Evaluation method | Kaplan–Meier method |
| Median duration assessment, OS | 20.9 months (6.6-not possible to estimate) |
| Outcome notes | The 6-month OS rate was 82.0% (95% CI, 58.8-92.8), the 1-year OS rate was 50.1% (95% CI, 28.3-68.5), and the 2-year OS rate was 37.6% (95% CI, 13.4-62.0) (Fig. 1C) |
| Secondary Assessment Method: ORR, DCR | |
|---|---|
| Number of patients screened | 25 |
| Number of patients enrolled | 25 |
| Number of patients evaluable for toxicity | 25 |
| Number of patients evaluated for efficacy | 25 |
| Evaluation method | RECIST 1.1 |
| Response assessment, CR | 0 (0%) |
| Response assessment, PR | 5 (20%) |
| Response assessment, SD | 12 (48%) |
| Response assessment, PD | 8 (32%) |
| Outcome notes | ORR was 20% (95% CI, 6.8-40.7) and DCR was 68% (95% CI, 46.5-85.1). |
| Secondary Assessment Method: Safety | |
|---|---|
| Number of patients screened | 25 |
| Number of patients enrolled | 25 |
| Number of patients evaluable for toxicity | 25 |
| Number of patients evaluated for efficacy | 25 |
| Evaluation method | NCI-CTCAE v.4.0 |
| Outcome notes | In the present study, grade 3 or higher treatment-emergent hematological toxicities included neutropenia in 10 cases (40%), leukopenia in 5 (20%), febrile neutropenia in 2 (8%), and anemia in 1 (4%). Grade 3 or higher treatment-emergent non-hematological toxicities were as follows: fatigue in 4 cases (16%), mucositis oral in 3 (12%), anorexia in 2 (8%), hypoalbuminemia, peripheral edema, nausea, and pneumonitis in 1 each (4%). Grade 3 or higher treatment-emergent adverse events of special interest for ramucirumab plus docetaxel combination therapy were as follows: gastrointestinal hemorrhage in 2 cases (8%) and epistaxis and hematuria in 1 each (4%). Intracranial hemorrhage and grade 5 adverse events were not observed in the present study (Table 2) |
| Assessment, Analysis, and Discussion | |
|---|---|
| Completion | Study terminated prior to completion |
| Investigator’s assessment | Registration was stopped early due to enrollment issues |
VEGF-A/VEGFR-2 signaling plays an essential role in the formation of brain metastases via tumor neovascularization.1 Pre-clinical research revealed that angiogenesis via the VEGF pathway was involved in the formation of brain metastases.2 Thus, chemotherapy with the anti-VEGF antibody achieved favorable outcomes in patients with NSCLC with metastatic brain tumors in several clinical studies.3,4 Ramucirumab is a human recombinant IgG1 monoclonal antibody that specifically binds to the extracellular domain of VEGF receptor-2 (VEGFR-2) with high affinity and is expected to enhance the therapeutic effect of concomitant cytotoxic anticancer agents.5
Although patients with asymptomatic brain metastases were eligible for the REVEL study, there were still little data including the efficacy of the combination of ramucirumab and docetaxel for patients with NSCLC with brain metastases. Therefore, we conducted a prospective study to investigate the efficacy and safety of ramucirumab plus docetaxel for patients with NSCLC with brain metastases. The obtained results showed that the median PFS for ramucirumab plus docetaxel combination therapy in patients with NSCLC with brain metastases was 3.9 months (Fig. 1A), which was slightly shorter than 4.5 months in the REVEL trial and 5 months in the JVCG trial.6,7 Although these studies also included asymptomatic cases of brain metastases, the present study focused on patients with brain metastases, which may have resulted in shorter PFS.8,9 On the other hand, the median OS in our cohort was 20.9 months (Fig. 1C), which was longer than 10.5 months in the REVEL study. However, it may reflect the following background factors: half of the patients in this study have driver mutations; and patients with untreated brain metastases who were excluded in the REVEL trial are only 32% of this study.
In a safety analysis, there was no intracranial hemorrhage, including bleeding from metastatic tumors, and only expected adverse events were observed (Table 2). However, highly unstable lesions, such as symptomatic CNS (central nervous system) metastases and intracranial tumors with cavity formation, were excluded from the present study. Previous studies showed that bevacizumab combined with chemotherapy was effective for symptomatic brain metastases; however, there is still insufficient clinical evidence for ramucirumab plus docetaxel combination therapy, which needs to be carefully evaluated in further studies.10,11
Table 2.
Adverse events of worst grade per patients.
| Name | Grade 1 (%) | Grade 2 (%) | Grade 3 (%) | Grade 4 (%) | Grade 5 (%) | All grades (%) |
|---|---|---|---|---|---|---|
| Neutropenia | — | 1 (4%) | 4 (16%) | 6 (24%) | — | 11 (44%) |
| Anemia | 1 (4%) | 4 (16%) | 1 (4%) | — | — | 6 (24%) |
| Leucopenia | — | 1 (4%) | 2 (8%) | 2 (8%) | — | 5 (20%) |
| Fatigue | — | 2 (8%) | 2 (8%) | — | — | 4 (16%) |
| Hypoalbuminemia | 1 (4%) | 1 (4%) | 1 (4%) | — | — | 3 (12%) |
| Mucositis oral | — | 1 (4%) | 2 (8%) | — | — | 3 (12%) |
| Anorexia | — | 1 (4%) | 2 (8%) | — | — | 3 (12%) |
| Dizziness | — | 2 (8%) | — | — | — | 2 (8%) |
| Febrile neutropenia | — | — | — | 1 (4%) | — | 1 (4%) |
| Epistaxis | — | — | 1 (4%) | — | — | 1 (4%) |
| Gastrointestinal hemorrhage | — | — | 1 (4%) | — | — | 1 (4%) |
| Constipation | — | 1 (4%) | — | — | — | 1 (4%) |
| Palmar—plantar erythrodysesthesia syndrome | — | 1 (4%) | — | — | — | 1 (4%) |
| Nail loss | — | 1 (4%) | — | — | — | 1 (4%) |
| Proteinuria | — | 1 (4%) | — | — | — | 1 (4%) |
| Renal failure | 1 (4%) | — | — | — | — | 1 (4%) |
| Nausea | 1 (4%) | — | — | — | — | 1 (4%) |
| Aspartate aminotransferase increased | 1 (4%) | — | — | — | — | 1 (4%) |
Although many clinical trials have been conducted to date, predictive biomarkers for the efficacy of antiangiogenic agents have not yet been identified. A lower concentration of VEGF before treatment was previously associated with a favorable outcome in chemotherapy with bevacizumab,12-14 whereas another study indicated that VEGF concentrations did not correlate with the treatment outcomes of bevacizumab.4,15 Similarity, predictive biomarkers for the treatment efficacy of the anti-VEGFR-2 antibody ramucirumab have been investigated in several clinical studies. In metastatic colorectal cancer, higher VEGF-D levels were associated with poor OS in combination therapy with ramucirumab and chemotherapy,16 whereas another clinical trial on recurrent gastric cancer did not show a correlation between VEGF-D levels and treatment outcomes.17 Therefore, we investigated the impact of plasma VEGF and serum sVEGFR-2 levels on ramucirumab plus docetaxel combination therapy as an exploratory endpoint in the present study. Among the 25 enrolled patients, serum sVEGFR-2 and plasma VEGF levels were measured at the initiation of treatment in 18 patients and at the discontinuation of treatment in 12 patients. The median level of sVEGFR-2 was 8015 pg/mL (range: 3990-10 500 pg/mL) at the initiation of treatment and had significantly decreased by the discontinuation of treatment. The median level of VEGF was 64.5 pg/mL (range: 20-354 pg/mL) at the initiation of treatment and had significantly increased by the discontinuation of treatment (Fig. 2A, 2B). To evaluate the impact of pre-treatment levels of sVEGFR-2 and VEGF on the effects of ramucirumab plus docetaxel combination therapy, patients were divided into high- and low-level groups according to the median values of sVEGFR-2 and VEGF (n = 9 per group), and PFS and tumor responses were compared between the 2 groups. Median PFS in the sVEGFR-2-High and sVEGFR-2-Low groups were 5.9 and 3.0 months, respectively (Fig. 3A). Median PFS in the VEGF-High and VEGF-Low groups were 4.5 and 3.9 months, respectively (Fig. 3B). Best overall responses in the sVEGFR-2-High and sVEGFR-2-Low groups were 33% (3 PR, 3 SD, and 3 PD) and 0% (6 SD and 3 PD), respectively (Fig. 3C). Best overall responses in VEGF-High and VEGF-Low were 22% (2 PR, 5 SD, and 2 PD) and 11% (1 PR, 4 SD, and 4 PD), respectively (Fig. 3D). These results suggested that patients with lower sVEGFR-2 levels at baseline had slightly shorter times to progression, which was similar to that in a previous study.18
Figure 2.
Serum sVEGFR-2 (A) and plasma VEGF (B) levels compared between the value at treatment initiation and discontinuation using the paired t-test. P-value bars apply to the changes in median for each respective biomarker between initiation and discontinuation.
Figure 3.
Kaplan–Meier curves of PFS according to pre-treatment levels of sVEGFR2 (A) and VEGF (B). Tumor responses according to pre-treatment levels of sVEGFR2 (C) and VEGF (D). Abbreviations: sVEGFR, soluble vascular endothelial growth factor receptor-2; VEGF, vascular endothelial growth factor; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; PR, partial response; SD, stable disease; PD, progression disease.
The soluble form of VEGFR-2 has an affinity for VEGF as a receptor but competes with transmembrane VEGFR-2 as a regulatory decoy function of VEGF-A because of the lack of the effector domain of tyrosine kinases.19 Therefore, tumor progression and angiogenesis may be suppressed by the downregulation of VEGF-A/VEGFR-2 signal transduction because of competition with the soluble form of VEGFR-2. This hypothesis is consistent with the present results suggested that patients highly expressing sVEGFR-2 and treated with ramucirumab plus docetaxel combination therapy showed slightly more favorable outcomes. However, this was not limited to ramucirumab-containing treatment, and may be associated with the overall prognosis of patients with NSCLC.
The present study has several limitations. First, this was an open-label, single-arm study. In addition, the sample size was too small in this study, which may lead to the occurrence of type 2 errors and insufficient statistical power. Second, treatment efficacy and safety for symptomatic brain metastases remain unclear because eligibility was limited to patients with asymptomatic brain metastases. Moreover, SRS for intracranial lesions preceding protocol treatment may have influenced disease progression. Regarding the exploratory analysis of VEGF and sVEGFR-2 levels, the collected sample was small, and not contained control value from a healthy population or patients with brain metastases not treated with ramucirumab.
In summary, no clinical concerns were identified with a combination of docetaxel and ramucirumab for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety for these population.
Contributor Information
Keiko Tanimura, Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Junji Uchino, Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Hideharu Kimura, Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan.
Osamu Hiranuma, Department of Respiratory Medicine, Otsu City Hospital, Otsu, Japan.
Yusuke Chihara, Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Uji, Japan.
Shigeru Tanzawa, Division of Medical Oncology, Department of Internal Medicine, Teikyo University Hospital, Tokyo, Japan.
Chieko Takumi, Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
Toshiyuki Kita, Department of Respiratory Medicine, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan.
Koji Inoue, Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan.
Koichi Minato, Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Japan.
Shinnosuke Takemoto, Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Akira Nakao, Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka, Japan.
Kenichi Yoshimura, Future Medical Center, Hiroshima University Hospital, Hiroshima, Japan.
Koichi Takayama, Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Funding
This study was sponsored by Eli Lilly, Japan.
Conflict of Interest
Shigeru Tanzawa reported research funding from AstraZeneca. Kenichi Yoshimura reported honoraria from Eli Lilly. Koichi Takayama reported research funding from Taiho Pharmaceutical Co., Ono Pharmaceutical Co., Eli Lilly Co., Fukuda Denshi Co., Teijin Co., and Chugai-Roche Co.; honoraria from Ono Pharmaceutical Co., Bristol Myers Squibb Co., AstraZeneca Co., Boehringer-Ingelheim Co., MSD Co., and Chugai-Roche Co.; scientific advisory board for Ono Pharmaceutical Co.; and Delegate of Japan Lung Cancer Society. The other authors indicated no financial relationships.
Data Availability
The data underlying this article will be shared on reasonable request to the corresponding author.
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Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.