European Journal of Cancer 58 (2016) 30e37
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ScienceDirect journal homepage: www.ejcancer.com
Original Research
Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer* Masato Karayama a,b, Naoki Inui a,c,*, Tomoyuki Fujisawa a, Noriyuki Enomoto a, Yutaro Nakamura a, Shigeki Kuroishi d, Koshi Yokomura e, Naoki Koshimizu f, Masaki Sato g, Mikio Toyoshima h, Toshihiro Shirai i, Masafumi Masuda j, Takashi Yamada k, Shiro Imokawa l, Takafumi Suda a a
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan b Department of Clinical Oncology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan c Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan d Department of Respiratory Medicine, Ensyu Hospital, 1-1-1 Chuou, Hamamatsu 430-0929, Japan e Department of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara-cho, Hamamatsu 433-8558, Japan f Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda 426-8677, Japan g Department of Respiratory Medicine, Japanese Red Cross Hamamatsu Hospital, 1088-1 Kobayashi, Hamamatsu 434-8533, Japan h Department of Respiratory Medicine, Hamamatsu Rosai Hospital, 25 Shougen-cho, Hamamatsu, Japan i Department of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-ando, Shizuoka 420-0881, Japan j Department of Respiratory Medicine, Shizuoka City Shimizu Hospital, 1231 Miyakami, Shizuoka 424-8636, Japan k Department of Respiratory Medicine, Shizuoka City Hospital, 10-93 Ote-cho, Shizuoka 420-8630, Japan l Department of Respiratory Medicine, Iwata City Hospital, 513-2 Ohkubo, Iwata 438-8550, Japan Received 4 September 2015; received in revised form 15 December 2015; accepted 17 January 2016
Available online xxx
*
The trial was registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN ID 000010002). * Corresponding author: Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Tel.: þ81 53 435 2263; fax: þ81 53 435 2386. E-mail address: [email protected] (N. Inui). http://dx.doi.org/10.1016/j.ejca.2016.01.013 0959-8049/ª 2016 Elsevier Ltd. All rights reserved.
M. Karayama et al. / European Journal of Cancer 58 (2016) 30e37
KEYWORDS Bevacizumab; Carboplatin; Maintenance therapy; Non small cell lung cancer; Pemetrexed
31
Abstract Objectives: Single agent maintenance therapy is widely accepted for advanced nonsquamous non small cell lung cancer (NSCLC). However, there is no consensus on the initial and maintenance phase regimens, and the clinical benefit of adding bevacizumab to cytotoxic drugs in the maintenance phase remains unclear. Methods: Chemotherapy-naı¨ve patients with non-squamous NSCLC were randomly assigned to maintenance therapy with pemetrexed and bevacizumab or pemetrexed alone, after achieving disease control after four cycles of induction therapy with carboplatin (area under the curve Z 6), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg). The primary end-point was 1-year progression-free survival (PFS) rate. Results: One hundred ten patients were enrolled in the study, with 55 patients assigned to the two groups. The mean 1-year PFS rate was 43.9% (95% confidence interval [CI]: 29.6e59.2%) in the combination maintenance group and 35.2% (95% CI: 22.1e51.0%) in the pemetrexed maintenance group, and the difference was not significant (p Z 0.433). Median PFS measured from enrolment was 11.5 months (95% CI: 7.1e19.0) in the combination maintenance group and 7.3 months (95% CI: 5.7e14.1, hazard ratio: 0.73, 95% CI: 0.44e1.19, log-rank p Z 0.198) in the pemetrexed maintenance group. Nasal haemorrhage, hypertension, and proteinuria were significantly more frequent in the combination maintenance group, but they were mild and tolerable. Conclusion: Both maintenance therapy with pemetrexed alone and pemetrexed and bevacizumab in combination were feasible in patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin, pemetrexed, and bevacizumab. According to the selection design, differences in the superiority between these maintenance therapies were not demonstrated. ª 2016 Elsevier Ltd. All rights reserved.
Introduction Lung cancer is a leading cause of cancer death worldwide [1,2]. In patients with advanced non small cell lung cancer (NSCLC), platinum-based combination chemotherapy has improved survival and quality of life [2,3]. Until recently, patients with advanced NSCLC who completed first-line chemotherapy were followed up without chemotherapy until disease progression, then second-line chemotherapy was administered when the patient exhibited adequate general health and organ function [3]. However, it has been reported that 50% of patients cannot receive secondline chemotherapy mainly because of deteriorating general health [4,5]. To increase the proportion of patients who can receive second-line chemotherapy, maintenance therapy, which is defined as the continuation of chemotherapy without interruption following effective first-line chemotherapy, has emerged as a novel strategy for the treatment of advanced NSCLC [2,6,7]. The high efficacy of first-line chemotherapy and maintaining good performance status are essential to receive maintenance therapy [2,8]. Pemetrexed is a multitargeted antifolate that has demonstrated efficacy for non-squamous NSCLC as first-line therapy combined with platinum agents or second-line therapy in single use [9,10]. In addition, maintenance therapy with pemetrexed after platinum-based chemotherapy
prolonged survival [11,12]. Bevacizumab, an angiogenic inhibitor, is known to stabilise the tumour microenvironment and improve the drug delivery of anti-cancer agents to tumours, which work to enhance the efficacy of chemotherapy [13e16]. Sandler et al. reported that bevacizumab in combination with carboplatin and paclitaxel chemotherapy followed by bevacizumab maintenance prolonged survival compared with carboplatin and paclitaxel [17]. Maintenance therapy with pemetrexed or bevacizumab is widely accepted as a standard therapeutic option for advanced non-squamous NSCLC [2,6,18]. However, there is no consensus regarding the initial therapeutic regimens or the choice of chemotherapeutic agents in the maintenance phase [6,7,18]. In the AVAPERL trial, patients with non-squamous NSCLC who were receiving pemetrexed and bevacizumab maintenance therapy after pemetrexed, cisplatin, and bevacizumab induction therapy had significantly prolonged progression-free survival (PFS), compared with those treated with bevacizumab maintenance therapy [19]. The result confirmed the significance of pemetrexed in maintenance therapy after bevacizumab-containing platinum-based therapy; however, it is unknown whether the addition of bevacizumab to pemetrexed in the maintenance phase improves efficacy. In this study, we evaluated the efficacy and safety of maintenance therapy with pemetrexed alone or pemetrexed and bevacizumab following induction therapy with carboplatin,
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M. Karayama et al. / European Journal of Cancer 58 (2016) 30e37
pemetrexed, and bevacizumab in patients with advanced non-squamous NSCLC. Patients and methods Eligibility Eligible patients were required to be aged 20e75 years and have pathologically confirmed stage IIIB nonsquamous NSCLC, without indication of a definitive radiotherapy, or stage IV or recurrent disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0e1, and no prior history of systemic chemotherapy and targeted therapy. Additional eligibility criteria included adequate haematopoietic, hepatic and renal function (including 1þ of qualitative assessment of urinary protein). Key exclusion criteria included haemoptysis grade II, uncontrolled brain metastasis, active interstitial lung disease, and other uncontrolled complications. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of each participating institution. Each patient gave written informed consent to be included in the study. Study design and treatment This study was a multicentre, open-label, randomised controlled phase II trial. Patients were randomly assigned in a 1:1 ratio to the pemetrexed and bevacizumab maintenance group and the pemetrexed maintenance group. Randomisation was undertaken centrally and stratified by clinical stage, performance status, and endothelial growth factor receptor (EGFR) mutation status before administration of induction chemotherapy. For induction therapy, patients were treated with intravenous pemetrexed 500 mg/m2, intravenous carboplatin at an area under the curve Z 6, and intravenous bevacizumab 15 mg/kg on day 1 of a 21d cycle, for four cycles. Patients who demonstrated complete response, partial response (PR) or stable disease (SD) after four cycles of induction therapy received maintenance therapy. As for the maintenance phase, patients in the pemetrexed and bevacizumab maintenance group received intravenous pemetrexed 500 mg/ m2 and intravenous bevacizumab 15 mg/kg on day 1 of a 21-d cycle. Patients in the pemetrexed maintenance group received intravenous pemetrexed 500 mg/m2 on day 1 of a 21-d cycle. Maintenance therapy was continued until disease progression, unacceptable toxicity, or the patient withdrew consent. During the study period, all patients received prophylactic dexamethasone, folic acid and vitamin B12. Dose reduction was performed based on the occurrence and severity of haematological or non-haematological toxicity. When a dose reduction of more than the permitted range,
necessity for discontinuation of bevacizumab, or a delay of >3 weeks was required, the patient was withdrawn from the study. Tumour response was evaluated with reference to the computed tomography findings every two cycles until completion of treatment and every 2 months thereafter, according to the Response Evaluation Criteria in Solid Tumours version 1.1. Adverse events were graded using the Common Toxicity Criteria (version 4.0). Statistical methods The primary end-point was 1-year PFS rate measured from the date of patient randomisation. The secondary end-points were objective response rate (ORR) and disease control rate (DCR) measured until the end of the induction phase, PFS, overall survival (OS), and safety. PFS and OS were measured from the date of randomisation. Based on the Simon selection design, the number of patients was set to achieve 90% statistical power, assuming an expected 1-year PFS rate of 30% [20] and a threshold rate of 8% [17]. The planned sample size was 55 patients in each group for enrolment after taking dropouts into consideration. The KaplaneMeier method was used to analyse PFS and OS. The log-rank test was used to compare the differences between the two groups. Hazard ratio (HR) was estimated using Cox regression analysis. The Wilcoxon test was used for continuous variables and the Fisher’s exact test for categorised groups. Results Patient characteristics Between January 2011 and May 2014, 110 patients were enroled in the study and randomly assigned to the pemetrexed and bevacizumab maintenance group and the pemetrexed maintenance group (Fig. 1). The median age at enrolment was 65.5 years (range, 39e75 years) and 74 patients (67.3%) were male. All patients, except three, had a histologic diagnosis of adenocarcinoma (97.3%). Thirteen (11.8%) and 95 (86.4%) patients had stage IIIB and IV disease, respectively, and two patients (1.8%) had relapse after radical surgery. Seventeen patients (15.5%) had stable brain metastases that were asymptomatic or had been treated. Baseline demographics at randomisation were well balanced between the two groups (Table 1). The median follow-up time measured from the time of enrolment was 24.1 months (range; 12.7e47.1). Treatment delivery In the induction phase, a median of four cycles (range, 1e4) was administered, and dose reduction and delay in administration were required in 15 (13.6%) and 30
M. Karayama et al. / European Journal of Cancer 58 (2016) 30e37
33
Fig. 1. Study profile.
patients (27.3%), respectively. Ninety-three patients (84.5%) completed four cycles of induction first-line chemotherapy; 55 patients (50.0%) had PR and 29 (26.4%) had SD, yielding an ORR of 50.0% (95% confidence interval (CI): 40.8e59.2%) and a DCR of 76.4% (CI: 67.6e83.3%). Four patients who had a response to induction chemotherapy did not receive subsequent maintenance therapy because of deterioration of performance status and the patient’s decision. As a result, 80 patients received maintenance therapy. For maintenance therapy, patients received a median of 4.5 (range, 1e17) and 5 (range, 1e27) cycles of pemetrexed and pemetrexed and bevacizumab combination, respectively (excluding 10 patients who were still receiving maintenance therapy at the time of data cutoff). The proportion of patients requiring dose reduction was significantly higher in the pemetrexed and bevacizumab maintenance group than the pemetrexed maintenance group (13.3% versus 0%, p Z 0.03). The need for treatment delay was also observed more frequently in the pemetrexed and bevacizumab maintenance group (24.4%) than the pemetrexed maintenance group (14.3%), but the difference was not significant (pZ0.40). Efficacy The mean 1-year PFS rate was 35.2% (95% CI: 22.1e51.0%, Fig. 2) in the pemetrexed maintenance group and 43.9% (95% CI: 29.6e59.2%) in the pemetrexed and bevacizumab maintenance group, and the difference was not significant (p Z 0.433). The median
PFS from enrolment in the pemetrexed and bevacizumab maintenance group was 11.5 months (95% CI: 7.1e19.0) and longer than that in the pemetrexed maintenance group of 7.3 months (95% CI: 5.7e14.1), but the difference was not significant (HR: 0.73, 95% CI: 0.44e1.19, log-rank p Z 0.198). Median OS from enrolment in the pemetrexed maintenance group was 21.3 months (95% CI: 18.6enot estimable) compared with 24.4 months in the pemetrexed and bevacizumab maintenance therapy group (95% CI: 17.0enot estimable, HR: 0.87, 95% CI: 0.49e1.54, p Z 0.64). Safety The major adverse events during the study are listed in Table 2. In the induction phase, the most common haematologic toxicity was neutropenia and thrombocytopaenia. Nausea was the most frequent non-haematologic toxicity. Proteinuria, nasal haemorrhage and hypertension were also frequently observed, but they were tolerable. In the induction therapy and maintenance therapy phases, 18 and 21 patients developed hypertension, respectively; among these patients seven (38.9%) and five (23.8%), respectively, had hypertension as a comorbidity at baseline. In the maintenance phase, the prevalence of haematological adverse events was similar in the two groups, and they were not severe. Nasal haemorrhage, hypertension, and proteinuria were significantly more frequent in the pemetrexed and bevacizumab maintenance group. All adverse events were tolerated and none of the irreversible toxicity was considered to be treatment-related. One patient in the
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M. Karayama et al. / European Journal of Cancer 58 (2016) 30e37
Table 1 Patient characteristics Pemetrexed maintenance group (N Z 55) Age, years 66 (50e75) Sex Male 39 (70.9) Female 16 (29.1) Smoking status Never smoker 13 (23.6) Former smoker 27 (49.1) Current smoker 15 (27.3) Comorbidity Hypertension 8 (14.6) Digestive ulcer 4 (7.3) Cardiovascular 3 (5.5) disease Cerebrovascular 1 (1.8) disease Performance statusa at enrolment 0 48 (87.3) 1 7 (12.7) Stage IIIB 7 (12.7) IV 48 (87.3) Relapse 0 (0) Histology Adenocarcinoma 53 (96.4) Other 2 (3.6) EGFR mutation status Wild type 39 (70.9) Positive mutation 14 (25.5) Not examined 2 (3.6) ALK fusion gene Negative 26 (47.3) Positive 5 (9.0) Not examined 24 (43.7)
Pemetrexed and bevacizumab maintenance group (N Z 55) 65 (39e75) 35 (63.6) 20 (36.4) 19 (34.5) 20 (36.4) 16 (29.1) 8 (14.6) 1 (1.8) 3 (5.5) 1 (1.8)
50 (90.9) 5 (9.1) 6 (10.9) 47 (85.5) 2 (3.6) 54 (98.2) 1 (1.8) 37 (67.3) 15 (27.3) 3 (5.4) 26 (47.3) 2 (3.6) 27 (49.1)
Data are expressed as numbers (percentage) or median (range). EGFR Z epidermal growth factor receptor, ALK Z anaplastic lymphoma kinase. a Performance status was determined according to the Eastern Cooperative Oncology Group Scale.
pemetrexed maintenance group died from sudden cardiac arrest during maintenance, but a causal relationship with therapy was unknown. Discussion In maintenance therapy, the choice of chemotherapeutic agents is important. In this randomised phase II study, we evaluated the efficacy and safety of maintenance therapy with pemetrexed alone and combination maintenance therapy with pemetrexed and bevacizumab following four cycles of carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous NSCLC. Pemetrexed is the sole drug that has demonstrated clinical benefit in both continuation and switch maintenance therapy [11,12]. As continuation maintenance therapy, pemetrexed after induction therapy with
cisplatin and pemetrexed demonstrated a median PFS of 4.4 months compared with that of 2.8 months in the placebo group [11]. In the present study, median PFS in the pemetrexed maintenance group was 7.3 months. Currently, continuation maintenance with pemetrexed is standard in chemotherapy for advanced non-squamous NSCLC [2,6,18] and our data from the pemetrexed maintenance group supported the efficacy of pemetrexed continuation maintenance therapy, even if it followed first-line chemotherapy with carboplatin, pemetrexed, and bevacizumab. Bevacizumab inhibits new and recurrent tumour vessel growth [13e16]. In addition, bevacizumab is thought to normalise the vasculature surrounding tumours and improve drug delivery, which work to enhance the efficacy of combined cytotoxic agents [14e16]. Clinically, add-on bevacizumab in the induction phase can improve the DCR of first-line chemotherapy and increase the number of patients who can receive maintenance therapy [17]. Okamoto et al. showed that 55% of patients received maintenance therapy after carboplatin and pemetrexed induction therapy [21]. In the present study, where bevacizumab was added to identical carboplatin and pemetrexed induction therapy, 80 patients (72.7%) could receive maintenance therapy. At present, continuing bevacizumab is recommended in patients who experienced disease control after bevacizumab-containing induction chemotherapy. The antiangiogenic effect of bevacizumab is assumed to be reversible and cessation of bevacizumab causes regrowth of tumour vessels [13,22], which supports the idea that continuation of bevacizumab after initial therapy is necessary to maintain anti-tumour effects. However, the significance of continuing bevacizumab in the maintenance phase remains unclear. This is because bevacizumab has been evaluated in regimens in which bevacizumab is consecutively administered during the induction and maintenance phases in clinical trials. No study has directly compared continuing and interrupting bevacizumab in maintenance therapy with cytotoxic drugs; therefore, it is unknown whether continuation of bevacizumab actually provides clinical benefit in maintenance therapy when combined with cytotoxic agents beyond the initial induction phase. In the present study, we evaluated maintenance therapy with pemetrexed alone and pemetrexed and bevacizumab combination. Both maintenance strategies were feasible but no difference was demonstrated. Clinically, continuation of bevacizumab increased bevacizumab-specific adverse events, although they were mild and treatable. In our study, these adverse events were frequently observed in the pemetrexed and bevacizumab maintenance group. In contrast, the pemetrexed and bevacizumab maintenance group showed a non-significant longer median PFS of 11.5 months. Patel et al. performed a phase II study in 50
M. Karayama et al. / European Journal of Cancer 58 (2016) 30e37
35
Fig. 2. Progression-free survival. Progression-free survival (PFS) was estimated from enrolment of the study using the KaplaneMeier method. The median PFS in the pemetrexed maintenance group (dotted line) and the pemetrexed and bevacizumab maintenance group (solid line) was 7.3 months and 11.5 months, respectively. CI, confidence interval.
patients to evaluate the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by pemetrexed and bevacizumab maintenance therapy [20]. The median PFS was 7.8 months and the median
OS was 14.1 months. In PointBreak, identical maintenance therapy with pemetrexed and bevacizumab demonstrated a significantly longer PFS than maintenance therapy with bevacizumab after carboplatin,
Table 2 Adverse events during the induction and maintenance phases
Haematologic toxicity Leucopenia Neutropenia Anaemia Thrombocytopaenia Non-haematologic toxicity ALT/AST increased Nausea Vomiting Constipation Fatigue Febrile neutropenia Oral mucositis Nasal haemorrhage Gastrointestinal haemorrhage Haemoptysis Hypertension Proteinuria Digestive perforation Pneumonitis Cardiac arrest
Pemetrexed maintenance group
Pemetrexed and bevacizumab maintenance group
Induction phase
Induction phase
Maintenance phase
Maintenance phase
Any
Grade III
Any
Grade III
Any
Grade III
Any
Grade III
36 35 28 31
(65.5) (63.6) (50.9) (56.4)
12 18 5 17
10 10 11 6
(28.6) (28.6) (31.4) (17.1)
3 (8.6) 3 (8.6) 0 0
26 31 29 26
(47.3) (56.4) (52.7) (47.3)
8 14 6 8
(14.6) (24.5) (10.9) (14.6)
9 11 21 11
(20.0) (24.4) (46.7) (24.4)
2 3 3 1
20 37 13 22 17 0 8 9 5 2 11 10 1 1 0
(36.4) (62.3) (23.6) (40.0) (30.9)
0 6 2 1 0 0 0 0 2 0 2 0 1 0 0
10 9 0 6 9 0 2 1 0 1 6 5 0 1 1
(28.6) (25.7)
0 0 0 0 1 1 0 0 0 0 0 0 0 1 1
15 31 14 13 17 3 4 11 1 0 7 18 0 0 0
(27.3) (56.4) (25.5) (23.6) (30.9) (5.5) (7.3) (20.0) (1.8)
1 6 1 0 0 3 0 0 0 0 1 0 0 0 0
(1.8) (10.9) (1.8)
16 17 2 6 13 0 1 9 1 1 15 20 1 2 0
(35.6) (37.8) (4.4) (13.3) (28.9)
0 1 1 0 1 3 0 0 0 0 7 1 1 1 0
(14.6) (16.4) (9.1) (3.6) (20.0) (18.2) (1.8) (1.8)
(21.8) (32.7) (9.1) (30.9)
(10.9) (3.6) (1.8)
(3.6) (3.6) (1.8)
(17.1) (25.7) (5.7) (2.9) (2.9) (17.1) (14.3) (2.9) (2.9)
(2.9) (2.9)
(2.9) (2.9)
(12.7) (32.7)
(5.5)
(1.8)
(2.2) (20.0) (2.2) (2.2) (33.3) (44.4) (2.2) (4.4)
The data compiled involved adverse events occurring in 2% of patients during the induction and maintenance phases. ALT: alanine aminotransferase, AST: aspartate aminotransferase. Values are expressed as numbers (percentage). a p
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Original Research
Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer* Masato Karayama a,b, Naoki Inui a,c,*, Tomoyuki Fujisawa a, Noriyuki Enomoto a, Yutaro Nakamura a, Shigeki Kuroishi d, Koshi Yokomura e, Naoki Koshimizu f, Masaki Sato g, Mikio Toyoshima h, Toshihiro Shirai i, Masafumi Masuda j, Takashi Yamada k, Shiro Imokawa l, Takafumi Suda a a
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan b Department of Clinical Oncology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan c Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan d Department of Respiratory Medicine, Ensyu Hospital, 1-1-1 Chuou, Hamamatsu 430-0929, Japan e Department of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara-cho, Hamamatsu 433-8558, Japan f Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda 426-8677, Japan g Department of Respiratory Medicine, Japanese Red Cross Hamamatsu Hospital, 1088-1 Kobayashi, Hamamatsu 434-8533, Japan h Department of Respiratory Medicine, Hamamatsu Rosai Hospital, 25 Shougen-cho, Hamamatsu, Japan i Department of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-ando, Shizuoka 420-0881, Japan j Department of Respiratory Medicine, Shizuoka City Shimizu Hospital, 1231 Miyakami, Shizuoka 424-8636, Japan k Department of Respiratory Medicine, Shizuoka City Hospital, 10-93 Ote-cho, Shizuoka 420-8630, Japan l Department of Respiratory Medicine, Iwata City Hospital, 513-2 Ohkubo, Iwata 438-8550, Japan Received 4 September 2015; received in revised form 15 December 2015; accepted 17 January 2016
Available online xxx
*
The trial was registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN ID 000010002). * Corresponding author: Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Tel.: þ81 53 435 2263; fax: þ81 53 435 2386. E-mail address: [email protected] (N. Inui). http://dx.doi.org/10.1016/j.ejca.2016.01.013 0959-8049/ª 2016 Elsevier Ltd. All rights reserved.
M. Karayama et al. / European Journal of Cancer 58 (2016) 30e37
KEYWORDS Bevacizumab; Carboplatin; Maintenance therapy; Non small cell lung cancer; Pemetrexed
31
Abstract Objectives: Single agent maintenance therapy is widely accepted for advanced nonsquamous non small cell lung cancer (NSCLC). However, there is no consensus on the initial and maintenance phase regimens, and the clinical benefit of adding bevacizumab to cytotoxic drugs in the maintenance phase remains unclear. Methods: Chemotherapy-naı¨ve patients with non-squamous NSCLC were randomly assigned to maintenance therapy with pemetrexed and bevacizumab or pemetrexed alone, after achieving disease control after four cycles of induction therapy with carboplatin (area under the curve Z 6), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg). The primary end-point was 1-year progression-free survival (PFS) rate. Results: One hundred ten patients were enrolled in the study, with 55 patients assigned to the two groups. The mean 1-year PFS rate was 43.9% (95% confidence interval [CI]: 29.6e59.2%) in the combination maintenance group and 35.2% (95% CI: 22.1e51.0%) in the pemetrexed maintenance group, and the difference was not significant (p Z 0.433). Median PFS measured from enrolment was 11.5 months (95% CI: 7.1e19.0) in the combination maintenance group and 7.3 months (95% CI: 5.7e14.1, hazard ratio: 0.73, 95% CI: 0.44e1.19, log-rank p Z 0.198) in the pemetrexed maintenance group. Nasal haemorrhage, hypertension, and proteinuria were significantly more frequent in the combination maintenance group, but they were mild and tolerable. Conclusion: Both maintenance therapy with pemetrexed alone and pemetrexed and bevacizumab in combination were feasible in patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin, pemetrexed, and bevacizumab. According to the selection design, differences in the superiority between these maintenance therapies were not demonstrated. ª 2016 Elsevier Ltd. All rights reserved.
Introduction Lung cancer is a leading cause of cancer death worldwide [1,2]. In patients with advanced non small cell lung cancer (NSCLC), platinum-based combination chemotherapy has improved survival and quality of life [2,3]. Until recently, patients with advanced NSCLC who completed first-line chemotherapy were followed up without chemotherapy until disease progression, then second-line chemotherapy was administered when the patient exhibited adequate general health and organ function [3]. However, it has been reported that 50% of patients cannot receive secondline chemotherapy mainly because of deteriorating general health [4,5]. To increase the proportion of patients who can receive second-line chemotherapy, maintenance therapy, which is defined as the continuation of chemotherapy without interruption following effective first-line chemotherapy, has emerged as a novel strategy for the treatment of advanced NSCLC [2,6,7]. The high efficacy of first-line chemotherapy and maintaining good performance status are essential to receive maintenance therapy [2,8]. Pemetrexed is a multitargeted antifolate that has demonstrated efficacy for non-squamous NSCLC as first-line therapy combined with platinum agents or second-line therapy in single use [9,10]. In addition, maintenance therapy with pemetrexed after platinum-based chemotherapy
prolonged survival [11,12]. Bevacizumab, an angiogenic inhibitor, is known to stabilise the tumour microenvironment and improve the drug delivery of anti-cancer agents to tumours, which work to enhance the efficacy of chemotherapy [13e16]. Sandler et al. reported that bevacizumab in combination with carboplatin and paclitaxel chemotherapy followed by bevacizumab maintenance prolonged survival compared with carboplatin and paclitaxel [17]. Maintenance therapy with pemetrexed or bevacizumab is widely accepted as a standard therapeutic option for advanced non-squamous NSCLC [2,6,18]. However, there is no consensus regarding the initial therapeutic regimens or the choice of chemotherapeutic agents in the maintenance phase [6,7,18]. In the AVAPERL trial, patients with non-squamous NSCLC who were receiving pemetrexed and bevacizumab maintenance therapy after pemetrexed, cisplatin, and bevacizumab induction therapy had significantly prolonged progression-free survival (PFS), compared with those treated with bevacizumab maintenance therapy [19]. The result confirmed the significance of pemetrexed in maintenance therapy after bevacizumab-containing platinum-based therapy; however, it is unknown whether the addition of bevacizumab to pemetrexed in the maintenance phase improves efficacy. In this study, we evaluated the efficacy and safety of maintenance therapy with pemetrexed alone or pemetrexed and bevacizumab following induction therapy with carboplatin,
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pemetrexed, and bevacizumab in patients with advanced non-squamous NSCLC. Patients and methods Eligibility Eligible patients were required to be aged 20e75 years and have pathologically confirmed stage IIIB nonsquamous NSCLC, without indication of a definitive radiotherapy, or stage IV or recurrent disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0e1, and no prior history of systemic chemotherapy and targeted therapy. Additional eligibility criteria included adequate haematopoietic, hepatic and renal function (including 1þ of qualitative assessment of urinary protein). Key exclusion criteria included haemoptysis grade II, uncontrolled brain metastasis, active interstitial lung disease, and other uncontrolled complications. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of each participating institution. Each patient gave written informed consent to be included in the study. Study design and treatment This study was a multicentre, open-label, randomised controlled phase II trial. Patients were randomly assigned in a 1:1 ratio to the pemetrexed and bevacizumab maintenance group and the pemetrexed maintenance group. Randomisation was undertaken centrally and stratified by clinical stage, performance status, and endothelial growth factor receptor (EGFR) mutation status before administration of induction chemotherapy. For induction therapy, patients were treated with intravenous pemetrexed 500 mg/m2, intravenous carboplatin at an area under the curve Z 6, and intravenous bevacizumab 15 mg/kg on day 1 of a 21d cycle, for four cycles. Patients who demonstrated complete response, partial response (PR) or stable disease (SD) after four cycles of induction therapy received maintenance therapy. As for the maintenance phase, patients in the pemetrexed and bevacizumab maintenance group received intravenous pemetrexed 500 mg/ m2 and intravenous bevacizumab 15 mg/kg on day 1 of a 21-d cycle. Patients in the pemetrexed maintenance group received intravenous pemetrexed 500 mg/m2 on day 1 of a 21-d cycle. Maintenance therapy was continued until disease progression, unacceptable toxicity, or the patient withdrew consent. During the study period, all patients received prophylactic dexamethasone, folic acid and vitamin B12. Dose reduction was performed based on the occurrence and severity of haematological or non-haematological toxicity. When a dose reduction of more than the permitted range,
necessity for discontinuation of bevacizumab, or a delay of >3 weeks was required, the patient was withdrawn from the study. Tumour response was evaluated with reference to the computed tomography findings every two cycles until completion of treatment and every 2 months thereafter, according to the Response Evaluation Criteria in Solid Tumours version 1.1. Adverse events were graded using the Common Toxicity Criteria (version 4.0). Statistical methods The primary end-point was 1-year PFS rate measured from the date of patient randomisation. The secondary end-points were objective response rate (ORR) and disease control rate (DCR) measured until the end of the induction phase, PFS, overall survival (OS), and safety. PFS and OS were measured from the date of randomisation. Based on the Simon selection design, the number of patients was set to achieve 90% statistical power, assuming an expected 1-year PFS rate of 30% [20] and a threshold rate of 8% [17]. The planned sample size was 55 patients in each group for enrolment after taking dropouts into consideration. The KaplaneMeier method was used to analyse PFS and OS. The log-rank test was used to compare the differences between the two groups. Hazard ratio (HR) was estimated using Cox regression analysis. The Wilcoxon test was used for continuous variables and the Fisher’s exact test for categorised groups. Results Patient characteristics Between January 2011 and May 2014, 110 patients were enroled in the study and randomly assigned to the pemetrexed and bevacizumab maintenance group and the pemetrexed maintenance group (Fig. 1). The median age at enrolment was 65.5 years (range, 39e75 years) and 74 patients (67.3%) were male. All patients, except three, had a histologic diagnosis of adenocarcinoma (97.3%). Thirteen (11.8%) and 95 (86.4%) patients had stage IIIB and IV disease, respectively, and two patients (1.8%) had relapse after radical surgery. Seventeen patients (15.5%) had stable brain metastases that were asymptomatic or had been treated. Baseline demographics at randomisation were well balanced between the two groups (Table 1). The median follow-up time measured from the time of enrolment was 24.1 months (range; 12.7e47.1). Treatment delivery In the induction phase, a median of four cycles (range, 1e4) was administered, and dose reduction and delay in administration were required in 15 (13.6%) and 30
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33
Fig. 1. Study profile.
patients (27.3%), respectively. Ninety-three patients (84.5%) completed four cycles of induction first-line chemotherapy; 55 patients (50.0%) had PR and 29 (26.4%) had SD, yielding an ORR of 50.0% (95% confidence interval (CI): 40.8e59.2%) and a DCR of 76.4% (CI: 67.6e83.3%). Four patients who had a response to induction chemotherapy did not receive subsequent maintenance therapy because of deterioration of performance status and the patient’s decision. As a result, 80 patients received maintenance therapy. For maintenance therapy, patients received a median of 4.5 (range, 1e17) and 5 (range, 1e27) cycles of pemetrexed and pemetrexed and bevacizumab combination, respectively (excluding 10 patients who were still receiving maintenance therapy at the time of data cutoff). The proportion of patients requiring dose reduction was significantly higher in the pemetrexed and bevacizumab maintenance group than the pemetrexed maintenance group (13.3% versus 0%, p Z 0.03). The need for treatment delay was also observed more frequently in the pemetrexed and bevacizumab maintenance group (24.4%) than the pemetrexed maintenance group (14.3%), but the difference was not significant (pZ0.40). Efficacy The mean 1-year PFS rate was 35.2% (95% CI: 22.1e51.0%, Fig. 2) in the pemetrexed maintenance group and 43.9% (95% CI: 29.6e59.2%) in the pemetrexed and bevacizumab maintenance group, and the difference was not significant (p Z 0.433). The median
PFS from enrolment in the pemetrexed and bevacizumab maintenance group was 11.5 months (95% CI: 7.1e19.0) and longer than that in the pemetrexed maintenance group of 7.3 months (95% CI: 5.7e14.1), but the difference was not significant (HR: 0.73, 95% CI: 0.44e1.19, log-rank p Z 0.198). Median OS from enrolment in the pemetrexed maintenance group was 21.3 months (95% CI: 18.6enot estimable) compared with 24.4 months in the pemetrexed and bevacizumab maintenance therapy group (95% CI: 17.0enot estimable, HR: 0.87, 95% CI: 0.49e1.54, p Z 0.64). Safety The major adverse events during the study are listed in Table 2. In the induction phase, the most common haematologic toxicity was neutropenia and thrombocytopaenia. Nausea was the most frequent non-haematologic toxicity. Proteinuria, nasal haemorrhage and hypertension were also frequently observed, but they were tolerable. In the induction therapy and maintenance therapy phases, 18 and 21 patients developed hypertension, respectively; among these patients seven (38.9%) and five (23.8%), respectively, had hypertension as a comorbidity at baseline. In the maintenance phase, the prevalence of haematological adverse events was similar in the two groups, and they were not severe. Nasal haemorrhage, hypertension, and proteinuria were significantly more frequent in the pemetrexed and bevacizumab maintenance group. All adverse events were tolerated and none of the irreversible toxicity was considered to be treatment-related. One patient in the
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Table 1 Patient characteristics Pemetrexed maintenance group (N Z 55) Age, years 66 (50e75) Sex Male 39 (70.9) Female 16 (29.1) Smoking status Never smoker 13 (23.6) Former smoker 27 (49.1) Current smoker 15 (27.3) Comorbidity Hypertension 8 (14.6) Digestive ulcer 4 (7.3) Cardiovascular 3 (5.5) disease Cerebrovascular 1 (1.8) disease Performance statusa at enrolment 0 48 (87.3) 1 7 (12.7) Stage IIIB 7 (12.7) IV 48 (87.3) Relapse 0 (0) Histology Adenocarcinoma 53 (96.4) Other 2 (3.6) EGFR mutation status Wild type 39 (70.9) Positive mutation 14 (25.5) Not examined 2 (3.6) ALK fusion gene Negative 26 (47.3) Positive 5 (9.0) Not examined 24 (43.7)
Pemetrexed and bevacizumab maintenance group (N Z 55) 65 (39e75) 35 (63.6) 20 (36.4) 19 (34.5) 20 (36.4) 16 (29.1) 8 (14.6) 1 (1.8) 3 (5.5) 1 (1.8)
50 (90.9) 5 (9.1) 6 (10.9) 47 (85.5) 2 (3.6) 54 (98.2) 1 (1.8) 37 (67.3) 15 (27.3) 3 (5.4) 26 (47.3) 2 (3.6) 27 (49.1)
Data are expressed as numbers (percentage) or median (range). EGFR Z epidermal growth factor receptor, ALK Z anaplastic lymphoma kinase. a Performance status was determined according to the Eastern Cooperative Oncology Group Scale.
pemetrexed maintenance group died from sudden cardiac arrest during maintenance, but a causal relationship with therapy was unknown. Discussion In maintenance therapy, the choice of chemotherapeutic agents is important. In this randomised phase II study, we evaluated the efficacy and safety of maintenance therapy with pemetrexed alone and combination maintenance therapy with pemetrexed and bevacizumab following four cycles of carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous NSCLC. Pemetrexed is the sole drug that has demonstrated clinical benefit in both continuation and switch maintenance therapy [11,12]. As continuation maintenance therapy, pemetrexed after induction therapy with
cisplatin and pemetrexed demonstrated a median PFS of 4.4 months compared with that of 2.8 months in the placebo group [11]. In the present study, median PFS in the pemetrexed maintenance group was 7.3 months. Currently, continuation maintenance with pemetrexed is standard in chemotherapy for advanced non-squamous NSCLC [2,6,18] and our data from the pemetrexed maintenance group supported the efficacy of pemetrexed continuation maintenance therapy, even if it followed first-line chemotherapy with carboplatin, pemetrexed, and bevacizumab. Bevacizumab inhibits new and recurrent tumour vessel growth [13e16]. In addition, bevacizumab is thought to normalise the vasculature surrounding tumours and improve drug delivery, which work to enhance the efficacy of combined cytotoxic agents [14e16]. Clinically, add-on bevacizumab in the induction phase can improve the DCR of first-line chemotherapy and increase the number of patients who can receive maintenance therapy [17]. Okamoto et al. showed that 55% of patients received maintenance therapy after carboplatin and pemetrexed induction therapy [21]. In the present study, where bevacizumab was added to identical carboplatin and pemetrexed induction therapy, 80 patients (72.7%) could receive maintenance therapy. At present, continuing bevacizumab is recommended in patients who experienced disease control after bevacizumab-containing induction chemotherapy. The antiangiogenic effect of bevacizumab is assumed to be reversible and cessation of bevacizumab causes regrowth of tumour vessels [13,22], which supports the idea that continuation of bevacizumab after initial therapy is necessary to maintain anti-tumour effects. However, the significance of continuing bevacizumab in the maintenance phase remains unclear. This is because bevacizumab has been evaluated in regimens in which bevacizumab is consecutively administered during the induction and maintenance phases in clinical trials. No study has directly compared continuing and interrupting bevacizumab in maintenance therapy with cytotoxic drugs; therefore, it is unknown whether continuation of bevacizumab actually provides clinical benefit in maintenance therapy when combined with cytotoxic agents beyond the initial induction phase. In the present study, we evaluated maintenance therapy with pemetrexed alone and pemetrexed and bevacizumab combination. Both maintenance strategies were feasible but no difference was demonstrated. Clinically, continuation of bevacizumab increased bevacizumab-specific adverse events, although they were mild and treatable. In our study, these adverse events were frequently observed in the pemetrexed and bevacizumab maintenance group. In contrast, the pemetrexed and bevacizumab maintenance group showed a non-significant longer median PFS of 11.5 months. Patel et al. performed a phase II study in 50
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Fig. 2. Progression-free survival. Progression-free survival (PFS) was estimated from enrolment of the study using the KaplaneMeier method. The median PFS in the pemetrexed maintenance group (dotted line) and the pemetrexed and bevacizumab maintenance group (solid line) was 7.3 months and 11.5 months, respectively. CI, confidence interval.
patients to evaluate the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by pemetrexed and bevacizumab maintenance therapy [20]. The median PFS was 7.8 months and the median
OS was 14.1 months. In PointBreak, identical maintenance therapy with pemetrexed and bevacizumab demonstrated a significantly longer PFS than maintenance therapy with bevacizumab after carboplatin,
Table 2 Adverse events during the induction and maintenance phases
Haematologic toxicity Leucopenia Neutropenia Anaemia Thrombocytopaenia Non-haematologic toxicity ALT/AST increased Nausea Vomiting Constipation Fatigue Febrile neutropenia Oral mucositis Nasal haemorrhage Gastrointestinal haemorrhage Haemoptysis Hypertension Proteinuria Digestive perforation Pneumonitis Cardiac arrest
Pemetrexed maintenance group
Pemetrexed and bevacizumab maintenance group
Induction phase
Induction phase
Maintenance phase
Maintenance phase
Any
Grade III
Any
Grade III
Any
Grade III
Any
Grade III
36 35 28 31
(65.5) (63.6) (50.9) (56.4)
12 18 5 17
10 10 11 6
(28.6) (28.6) (31.4) (17.1)
3 (8.6) 3 (8.6) 0 0
26 31 29 26
(47.3) (56.4) (52.7) (47.3)
8 14 6 8
(14.6) (24.5) (10.9) (14.6)
9 11 21 11
(20.0) (24.4) (46.7) (24.4)
2 3 3 1
20 37 13 22 17 0 8 9 5 2 11 10 1 1 0
(36.4) (62.3) (23.6) (40.0) (30.9)
0 6 2 1 0 0 0 0 2 0 2 0 1 0 0
10 9 0 6 9 0 2 1 0 1 6 5 0 1 1
(28.6) (25.7)
0 0 0 0 1 1 0 0 0 0 0 0 0 1 1
15 31 14 13 17 3 4 11 1 0 7 18 0 0 0
(27.3) (56.4) (25.5) (23.6) (30.9) (5.5) (7.3) (20.0) (1.8)
1 6 1 0 0 3 0 0 0 0 1 0 0 0 0
(1.8) (10.9) (1.8)
16 17 2 6 13 0 1 9 1 1 15 20 1 2 0
(35.6) (37.8) (4.4) (13.3) (28.9)
0 1 1 0 1 3 0 0 0 0 7 1 1 1 0
(14.6) (16.4) (9.1) (3.6) (20.0) (18.2) (1.8) (1.8)
(21.8) (32.7) (9.1) (30.9)
(10.9) (3.6) (1.8)
(3.6) (3.6) (1.8)
(17.1) (25.7) (5.7) (2.9) (2.9) (17.1) (14.3) (2.9) (2.9)
(2.9) (2.9)
(2.9) (2.9)
(12.7) (32.7)
(5.5)
(1.8)
(2.2) (20.0) (2.2) (2.2) (33.3) (44.4) (2.2) (4.4)
The data compiled involved adverse events occurring in 2% of patients during the induction and maintenance phases. ALT: alanine aminotransferase, AST: aspartate aminotransferase. Values are expressed as numbers (percentage). a p
