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Keywords:

  • bevacizumab;
  • carboplatin;
  • chemotherapy;
  • maintenance;
  • non–small cell lung cancer;
  • S-1

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

A previous phase 3 trial demonstrated noninferiority in terms of overall survival for combined S-1 (an oral fluoropyrimidine) and carboplatin compared with combined paclitaxel and carboplatin as first-line treatment for advanced non–small cell lung cancer (NSCLC). In the current study, the authors evaluated the efficacy and safety of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab in chemotherapy-naive patients with advanced nonsquamous NSCLC.

METHODS

Patients received carboplatin (area under the concentration-time curve, 5 mg mL−1 per minute) and bevacizumab (15 mg/kg) on day 1 plus oral S-1 (80 mg/m2 per day) on days 1 through 14 every 21 days for up to 6 cycles. For patients without disease progression, S-1 and bevacizumab were continued until disease progression or unacceptable toxicity developed.

RESULTS

Forty-eight patients were enrolled in the phase 2 study; of these, 35 patients (72.9%) completed at least 4 cycles. Most toxicities of grade ≥3 were hematologic, and no increase in relative incidence associated with maintenance with S-1 and bevacizumab was observed. The objective response rate was 54.2% (95% confidence interval, 39.2%-68.6%), and the median progression-free survival was 6.8 months (95% confidence interval, 4.3-8.2 months).

CONCLUSIONS

The regimen of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab was active and feasible as first-line treatment for advanced nonsquamous NSCLC. Cancer 2013;119:2275–2281. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Lung cancer is the leading cause of death related to cancer worldwide, with non–small cell lung cancer (NSCLC) accounting for 85% of lung cancer cases.[1] For individuals with advanced or metastatic NSCLC, platinum-based chemotherapy is the mainstay of first-line treatment[2, 3] on the basis of the moderate improvement in survival and quality of life it affords compared with best supportive care alone.[4]

A phase 3 study, the Eastern Cooperative Oncology Group (ECOG) E4599 trial, demonstrated that bevacizumab, a humanized monoclonal antibody specific for vascular endothelial growth factor,[5] given with paclitaxel and carboplatin resulted in significant improvements in the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with paclitaxel and carboplatin alone in individuals with advanced nonsquamous NSCLC.[6] A Japanese phase 2 study also indicated that bevacizumab in combination with paclitaxel and carboplatin improved the ORR and PFS compared with paclitaxel and carboplatin alone.[7] In a confirmatory phase 3 study (the Avastin in Lung [AVAiL] trial), the addition of bevacizumab to cisplatin and gemcitabine resulted in a significant improvements in the ORR and PFS.[8, 9] These observations provide a rationale for combining bevacizumab with platinum-doublet chemotherapy in individuals with advanced nonsquamous NSCLC.

S-1 (TS-1; Taiho Pharmaceutical Company Ltd., Tokyo, Japan) is an oral fluoropyrimidine agent that consists of tegafur (a prodrug of 5-fluorouracil), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate.[10] It has demonstrated activity and acceptable tolerability in phase 2 studies of patients with advanced NSCLC.[11] Our previous phase 3 study demonstrated the noninferiority in terms of OS as well as a favorable toxicity profile for S-1 and carboplatin compared with standard paclitaxel-carboplatin as first-line treatment for patients with advanced NSCLC.[12] Thus, our results indicated that the combination of S-1 and carboplatin is a valid option for the first-line treatment of such patients.

In addition to the enhanced efficacy of cytotoxic chemotherapy observed with bevacizumab, preclinical studies indicate that the combination of bevacizumab with 5-fluorouracil derivatives results in increased antitumor activity.[13, 14] Therefore, we have now performed a multicenter phase 2 study to evaluate the efficacy and safety of S-1 and carboplatin in combination with bevacizumab followed by maintenance therapy with S-1 and bevacizumab alone in chemotherapy-naive patients with advanced nonsquamous NSCLC.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Eligibility

Eligible patients were required be aged ≥20 years and to have histologically or cytologically confirmed stage IIIB or IV nonsquamous NSCLC (diagnosed according to the seventh edition of the International Union Against Cancer cancer staging manual) or recurrence of this condition after surgery. The patients also were required to have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1); adequate hematologic, hepatic, and renal function; an ECOG performance status of 0 or 1; and no tumor invasion into the trachea, main bronchi, or major vessels. Exclusion criteria included hemoptysis (>2.5 mL of red blood per episode), radiologic evidence of tumor invasion or tumor abutting of major blood vessels, evidence of a brain metastasis >1 cm, current or recent use of full-dose anticoagulants, medically uncontrolled hypertension or a history of thrombotic or hemorrhagic disorders, interstitial pneumonia recognized on a chest x-ray, supporting radiation therapy occupying the pulmonary region in the 3 months before enrollment, and major surgery within 28 days before enrollment. The study was performed according to good clinical practices and ethical principles outlined in the Declaration of Helsinki. The study protocol was approved by the institutional review board at each participating center, and all patients signed written informed consent forms before enrollment. The trial has been registered under University Medical Hospital Information Network (UMIN) Clinical Trials Registry Identifier UMIN 000003698.

Study Design and Treatment

The study was designed as a prospective, multicenter, single-arm phase 2 trial of first-line combination therapy with S-1, carboplatin, and bevacizumab followed by continuous maintenance therapy with S-1 and bevacizumab. The primary endpoint was treatment efficacy measured as the ORR in patients who received at least 1 course of the initial combination therapy. OS, PFS, the disease control ratio, and adverse events also were evaluated as secondary endpoints.

Patients received S-1 orally at a dose of 80 mg/m2 per day on days 1 through 14 as well as carboplatin at a dose calculated to produce an area under the concentration-time curve of 5 mg mL−1 per minute and bevacizumab at a dose of 15 mg/kg as an intravenous infusion on day 1. The combination therapy was repeated every 21 days for up to 4 to 6 cycles unless there was evidence of disease progression or intolerance of the study treatment. After 4 to 6 cycles of treatment with S-1, carboplatin, and bevacizumab, patients who attained a complete response (CR), a partial response (PR), or stable disease (SD) continued to receive cycles of maintenance therapy with S-1 and bevacizumab every 21 days until they had evidence of disease progression or developed unacceptable toxicity. Administration of S-1 during the maintenance phase was interrupted if patients developed grade 4 neutropenia, a platelet count <50,000/μL, a serum creatinine concentration ≥1.5 mg/dL, a serum total bilirubin concentration ≥2.0 mg/dL, a putative infection with fever of at least 38°C, or severe diarrhea or stomatitis (grade 2 or higher). Treatment with S-1 and bevacizumab was resumed if the neutrophil count was ≥1500/μL, the platelet count was ≥100,000/μL, the serum total bilirubin concentration was <1.5 mg/dL, there was no infection with fever of at least 38°C, and diarrhea or stomatitis was grade 1 or lower.

Subsequent cycles of treatment were withheld until the following criteria were satisfied: neutrophil count, ≥1500/μL; platelet count, ≥100,000/μL; performance status, 0 to 2; serum total bilirubin concentration, ≤1.5 mg/dL; weight loss, grade 2 or lower abnormal electrolytes, peripheral nerve damage, and hepatotoxicity (based on aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels); grade 3 or lower hypertension; grade 2 or lower proteinuria; grade 0 hemoptysis or bleeding; and no infection with fever of at least 38°C. The study therapy was stopped if grade 2 or higher hemoptysis developed or if bleeding persisted after treatment of hemorrhage. Patients also were to be removed from the study if the next treatment cycle had not started within 42 days of the previous dosing as a result of toxicity.

Baseline and Treatment Assessments

Baseline evaluations included medical history, physical examination, electrocardiogram, ECOG performance status, and laboratory analyses. Computed tomography (CT) scans of the chest and abdomen, magnetic resonance imaging (MRI) studies of the brain, and bone scintigraphy or positron emission tomography (PET)-CT studies were performed for tumor assessment within 28 days of initiation of the study treatment. CT scans of the chest and abdomen were repeated every 2 cycles, brain MRI studies were repeated every 3 months or on the appearance of any neurologic symptoms, and bone scintigraphy or PET-CT studies were performed every 6 months or on the appearance of any bone-related symptoms. All treatment responses were defined according to RECIST version 1.1. If a patient had a documented a CR or a PR, then the respective response had to be confirmed 4 weeks later. A patient was considered to have SD if their response was confirmed and sustained for at least 6 weeks. PFS was calculated from the date of enrollment to the date of confirmation of progressive disease or the date of death from any cause. PFS from the start of maintenance therapy was calculated by subtracting the period of the initial combination therapy from overall PFS. OS was calculated from the date of initial treatment to the date of death from any cause. For patients with unknown death status, OS was censored at the last date the patient was known to be alive. Patients were assessed for toxicity according version 4.0 of the National Cancer Institute Common Toxicity Criteria.

Statistical Analysis

We assumed that an ORR of 50% for the study regimen in eligible patients would indicate potential usefulness, whereas an ORR of 30% would be the lower limit of interest. On the basis of these assumptions, our study was designed to have a power of 80% and a 1-sided level of type I error of 0.05, resulting in a requirement for 45 patients. A Simon 2-stage design (MiniMax) was adopted. Nineteen patients were to be initially assessed for response, and if more than 6 patients manifested a PR or a CR, then 26 additional patients would be added to the assessment. Efficacy and safety analyses were planned for patients who received at least 1 cycle of the treatment. PFS and OS were analyzed using the Kaplan-Meier method to estimate the median points with 95% confidence intervals (CIs).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Patient Characteristics

Between April 2010 and October 2011, a total of 48 patients with recurrent or newly diagnosed, advanced nonsquamous NSCLC were enrolled at 3 participating centers. The baseline characteristics of all assigned patients are provided in Table 1. The median age for the treated patients was 65.5 years (range, 35-77 years), 33 patients (68.8%) were men, 42 patients (87.5%) had adenocarcinoma histology, 40 patients (83.3%) had stage IV disease, and 16 patients (33.3%) were never-smokers. Epidermal growth factor receptor mutation status was evaluated in 42 patients (87.5%), and 4 individuals had activating mutations identified.

Table 1. Baseline Characteristics of the Study Patients, n = 48
CharacteristicNo. of Patients (%)
  1. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status.

Age: Median [range], y65.5 [35-77]
Sex 
Men33 (68.8)
Women15 (31.3)
ECOG PS 
015 (31.3)
133 (68.8)
Disease stage 
IIIB3 (6.3)
IV40 (83.3)
Recurrence5 (10.4)
Histology 
Adenocarcinoma42 (87.5)
Large cell carcinoma1 (2.1)
Others5 (10.4)
Smoking status 
Never-smoker16 (33.3)
Former or current smoker32 (66.7)

Treatment Delivery

Patient disposition is illustrated in Figure 1. Overall, 35 patients (72.9%) completed at least 4 cycles of S-1 and carboplatin combined with bevacizumab, and 29 patients (60.4%) were shifted to subsequent maintenance therapy with S-1 and bevacizumab and received a median of 4 cycles (range, 1-18 cycles). In the initial combination phase, 13 of 48 patients (27.1%) experienced dose reductions, and 34 patients (70.8%) experienced a treatment delay because of adverse events, mostly related to myelosuppression. Among the 29 patients who received maintenance therapy with S-1 and bevacizumab, 2 individuals (6.9%) underwent a dose reduction, and 20 individuals (69%) had a treatment delay.

image

Figure 1. This is a Consolidated Standards of Reporting Trials (CONSORT) diagram for the current study.

Download figure to PowerPoint

Efficacy

Forty-eight patients were deemed eligible for evaluation of treatment response. Twenty-six patients attained a PR, and no patients attained a CR, yielding an ORR of 54.2% (95% CI, 39.2%-68.6%) (Table 2). Eleven patients (22.9%) had SD, yielding a disease control ratio (CR + PR + SD) of 77.1% (95% CI, 67.2%-88%). Eleven patients (22.9%) had progressive disease as their best response. At a median follow-up of 13.9 months (range, 2.0-27.5 months), the median PFS was 6.8 months (95% CI, 4.3-8.2 months) (Fig. 2), and the median OS was 22.8 months (lower limit of 95% CI, 13.1 months). Thirty-seven patients (77.1%) received subsequent chemotherapy regimens as poststudy treatment.

Table 2. Treatment Outcomes for the Study Patients,, n = 48
OutcomeNo. of Patients (%)
  1. Abbreviations: CI, confidence interval.

Complete response0 (0)
Partial response26 (54.2)
Stable disease11 (22.9)
Progressive disease11 (22.9)
Overall response rate [95% CI], %54.2 [39.2-68.6]
Disease control rate [95% CI], %77.1 [67.2-88]
image

Figure 2. This Kaplan-Meier curve illustrates progression-free survival (PFS). CI indicates confidence interval.

Download figure to PowerPoint

Safety Analysis

All 48 patients who received the study treatment were deemed eligible for safety analysis. The major adverse events for each treatment phase (initial and maintenance phases) are listed in Table 3. During treatment with the combination of S-1, carboplatin, and bevacizumab, grade 3 and higher hematologic toxicities included neutropenia (31.3%), thrombocytopenia (16.7%), anemia (10.5%), and leukopenia (8.3%). Among the 29 patients who continued with S-1 plus bevacizumab during the maintenance phase, 4 patients (13.8%) had grade 3 neutropenia, and 1 patient (3.4%) had grade 3 anemia during the period. Most nonhematologic adverse events were of mild to moderate intensity (grade 1 or 2); those that were grade 3 or higher during the initial phase of the study treatment included hypertension (8.3%), appetite loss (6.3%), diarrhea (6.3%), fatigue (2.1%), and intestinal perforation (2.1%); whereas those during the maintenance phase included proteinuria (6.9%), mucositis (3.4%), and diarrhea (3.4%). There were no clinically relevant bleeding events during either treatment phase for any patient, and there were no treatment-related deaths.

Table 3. Incidence of Adverse Events in the Study Patients
 No. of Patients (%)
 Initial Treatment Phase, n = 48Maintenance Phase, n = 29
Adverse EventAll GradesGrade 3Grade 4All GradesGrade 3Grade 4
  1. Abbreviations: AEs, adverse events.

Hematologic AEs      
Leukopenia43 (89.6)4 (8.3)0 (0)17 (58.6)0 (0)0 (0)
Neutropenia44 (91.7)12 (25)3 (6.3)16 (55.2)4 (13.8)0 (0)
Anemia37 (77.1)2 (4.2)3 (6.3)25 (86.2)1 (3.4)0 (0)
Thrombocytopenia43 (89.6)5 (10.4)3 (6.3)11 (37.9)0 (0)0 (0)
Nonhematologic AEs      
Fatigue36 (75)1 (2.1)0 (0)14 (48.3)0 (0)0 (0)
Appetite loss31 (64.6)3 (6.3)0 (0)12 (41.4)0 (0)0 (0)
Proteinuria25 (52.1)0 (0)0 (0)9 (31)2 (6.9)0 (0)
Nausea21 (43.8)0 (0)0 (0)9 (31)0 (0)0 (0)
Mucositis17 (35.4)0 (0)0 (0)9 (31)1 (3.4)0 (0)
Hypertension14 (29.2)4 (8.3)0 (0)5 (17.2)0 (0)0 (0)
Diarrhea11 (22.9)3 (6.3)0 (0)4 (13.8)1 (3.4)0 (0)
Hemoptysis6 (12.5)0 (0)0 (0)1 (3.4)0 (0)0 (0)
Intestinal perforation2 (4.2)0 (0)1 (1.1)1 (3.4)0 (0)0 (0)
Interstitial pneumonia0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

This multicenter phase 2 study is the first to evaluate the efficacy and safety of a new regimen, S-1 and carboplatin combined with bevacizumab followed by maintenance S-1 and bevacizumab, for first-line treatment of patients with advanced nonsquamous NSCLC. We observed that the combination was active, with an ORR of 54.2% (95% CI, 39.2%-68.6%), which met the primary objective of the study. At a median follow-up of 13.9 months, the median PFS was 6.8 months, and the median OS was 22.8 months. Our previous phase 3 study demonstrated that the combination of S-1 and carboplatin was not inferior relative to a standard paclitaxel-carboplatin regimen in terms of OS for chemotherapy-naive patients with advanced NSCLC.[12] The ORR for S-1 and carboplatin, however, was significantly lower than that for paclitaxel-carboplatin (20.4% vs 29%; P = .019). This difference in ORR also was apparent for patients who had nonsquamous NSCLC (18.8% vs 27.6%; P = .027).[15] It is believed that bevacizumab is targets the tumor vasculature, reducing interstitial pressure and increasing vessel permeability, thereby resulting in enhanced tumor sensitivity to cytotoxic chemotherapy.[16, 17] Although there are limitations to comparisons of results among different studies, the ORR (54.2%) obtained in the current trial is indicative of increased antitumor activity of S-1 and carboplatin with the addition of bevacizumab.

Our trial also indicates a favorable toxicity profile for the study treatment. All toxicities were manageable with symptomatic treatment and dose reduction or interruption. In our previous phase 3 study, the combination of S-1 and carboplatin was associated with significantly lower rates of neutropenia, leukopenia, and febrile neutropenia compared with paclitaxel and carboplatin.[12] Consistent with these results, most patients enrolled in the current study had only mild hematologic toxicities, and no cases of febrile neutropenia occurred. Thus, no obvious exacerbation of chemotherapy-induced myelosuppression by the addition of bevacizumab to S-1 and carboplatin was apparent. There also was no increase in the relative incidence of hematologic toxicities associated with maintenance therapy with S-1 and bevacizumab. With regard to nonhematologic toxicities, there were no grade 3 or 4 toxicities encountered in >10% of patients throughout the study treatment. Mild or moderate fatigue and gastrointestinal adverse effects were the most frequent nonhematologic toxicities, consistent with findings from previous studies with combined S-1 and carboplatin.[12] Hypertension and proteinuria have been associated with bevacizumab administration[6, 8] and also were observed in the current study. Two patients experienced grade 3 proteinuria in the maintenance period; however, both cases were fully reversible without dose reduction or cessation of treatment. Because clinically significant (grade ≥3) hemoptysis was observed in 0.9% to 1.9% of patients who received bevacizumab in the ECOG E4599 and AVAiL trials,[6, 8] the lack of fatal bleeding events and treatment-related deaths in the current study also is noteworthy. Patients with brain metastases have been excluded from most clinical trials of bevacizumab for fear of intracranial hemorrhage.[6, 8] However, recent data suggest that the risk of developing intracranial hemorrhage is independent of bevacizumab therapy in patients with NSCLC who have brain metastases.[18] Conversely, another study suggested that intracranial hemorrhage is more likely to become clinically symptomatic in larger (>2 cm) brain metastases.[19] On the basis of these data, patients with brain metastases that measured <1 cm were eligible for the current study. Indeed, 2 patients who had asymptomatic, small (<1 cm) brain metastases were enrolled in the study, but no intracranial hemorrhage was observed.

Bevacizumab is used in the maintenance setting for patients with advanced nonsquamous NSCLC on the basis of the results from the ECOG E4599 and AVAiL trials, in which bevacizumab monotherapy after induction therapy with bevacizumab plus platinum doublets was administered until patients developed disease progression.[6, 8] More recently, a large phase 3 trial (PARAMOUNT) demonstrated that maintenance therapy with pemetrexed after induction therapy with pemetrexed and cisplatin resulted in a significant improvement in PFS and OS.[20] Furthermore, an ongoing ECOG phase 3 trial is comparing bevacizumab alone, pemetrexed alone, and the pemetrexed-bevacizumab combination for maintenance therapy after initial therapy with paclitaxel, carboplatin, and bevacizumab (National Clinical Trials identifier NCT01107626). Thus, extensive efforts are under way to examine the effects of the combination of bevacizumab and chemotherapy during the maintenance phase of treatment for advanced nonsquamous NSCLC. On the basis of the low level of toxicity accumulation for S-1,[21] we explored the efficacy and feasibility of continued maintenance therapy with S-1 and bevacizumab in the current study. The favorable tolerability profile of maintenance with S-1 and bevacizumab after induction therapy with S-1, carboplatin, and bevacizumab is reflected in out observation that 60% of patients were able to continue on S-1 and bevacizumab for a median of 4 cycles (range, 1-18 cycles). Among the 29 patients who received maintenance therapy with S-1 and bevacizumab, the median PFS of 8.2 months (95% CI, 7.4-9.6 months) from the beginning of induction treatment is encouraging and compares favorably with that of 6.9 months reported in the PARAMOUNT study for maintenance with pemetrexed monotherapy. Despite the limitations to comparisons of results from different studies, these data may stimulate further interest in the clinically relevant efficacy of maintenance therapy with S-1 and bevacizumab.

In conclusion, here, we have presented results from the first phase 2 study of combined S-1, carboplatin, and bevacizumab followed by maintenance therapy with S-1 and bevacizumab. Although our study was not randomized, the promising efficacy and favorable toxicity profile of the study treatment justify further development of regimens that contain S-1 and bevacizumab. A large randomized phase 3 trial comparing single-agent S-1 with docetaxel in previously treated patients with advanced NSCLC in Asian countries is currently under way (JPRN-JapicCTI-101155). We believe that further randomized trials are warranted comparing S-1, carboplatin, and bevacizumab with the current standard of care (paclitaxel, carboplatin, and bevacizumab) in previously untreated patients with advanced nonsquamous NSCLC.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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