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A randomized, phase II study of vandetanib maintenance for advanced or metastatic non-small-cell lung cancer following first-line platinum-doublet chemotherapy
Lung Cancer 82 (2013) 455–460
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A randomized, phase II study of vandetanib maintenance for advanced or metastatic non-small-cell lung cancer following first-line platinum-doublet chemotherapy夽 Jin Seok Ahn a,1 , Ki Hyeong Lee b,1 , Jong-Mu Sun a , Keunchil Park a , Eun-Suk Kang c , Eun Kyung Cho d , Dae Ho Lee e , Sang-We Kim e , Gyeong-Won Lee f , Jin-Hyoung Kang g , Jong-Seok Lee h , Jae-Won Lee i , Myung-Ju Ahn a,∗ a
Department of Medicine, Samsung Medical Center, Sungkyunkwan University, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea c Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea d Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea e Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea f Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea g Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea h Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea i Department of Statistics, Korea University, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 16 April 2013 Received in revised form 23 August 2013 Accepted 31 August 2013 Keywords: Vandetanib Maintenance Chemotherapy Lung cancer Progression-free survival Target therapy
a b s t r a c t Background: This randomized, phase II study investigated whether benefit could be obtained by giving vandetanib, an oral inhibitor of vascular endothelial and epithelial growth factor receptor, as a maintenance treatment in non-small cell lung cancer (NSCLC). Methods: Patients were randomly assigned to either vandetanib or placebo after completion of 4 cycles of first-line chemotherapy. A progression-free survival (PFS) rate at 3 months was selected as the primary endpoint. We set a maximum PFS rate at 3 months to 30% (null hypothesis), and a minimum PFS rate at 3 months to 50% (alternative hypothesis). Results: At the interim analysis, 9 of 24 patients in the vandetanib arm were progression-free at 3 months, whereas 7 of 24 in the placebo arm were progression-free. The placebo arm was closed at the first stage. The vandetanib arm proceeded to the second stage, and recruited a total of 75 patients. At the second stage, 28 out of 63 evaluable patients receiving vandetanib achieved PFS at 3 months. The alternative hypothesis that the PFS rate at 3 months is at least 50% was accepted. The median PFS was 2.7 months (95% CI, 1.9–4.4 months) in the vandetanib arm and 1.7 months (95% CI, 0.9–2.6 months) in the placebo arm. The most common adverse events in patients receiving vandetanib were rash (77.3%) and diarrhea (60.0%). Conclusions: Maintenance therapy with vandetanib for patients with NSCLC after standard platinum doublet chemotherapy is well tolerated and may prolong PFS compared with placebo, and needs additional investigation. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
夽 Presented in part at the 2011 World Lung Cancer Conference, July 3–7, Amsterdam, Netherlands; at the 2010 Asia Pacific Lung Cancer Conference, December 2–4, Seoul, Republic of Korea. ∗ Corresponding author at: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel.: +82 2 3410 3438; fax: +82 2 3410 1754. E-mail address: [email protected] (M.-J. Ahn). 1 These authors contributed equally to this work. 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.08.027
About 85% of all lung cancers are non-small cell lung cancer (NSCLC), with approximately 40% of patients presenting with metastatic disease. Meta-analysis showed increased quality of life and improvement of overall survival (OS) in patients treated with platinum-doublet chemotherapy [1], but the improvement was modest and reached a plateau [2]. Current guidelines recommend four to six cycles of platinum-based chemotherapy for stage IIIB and IV NSCLC patients [3]. However, most patients eventually experience progression and need second- or third-line chemotherapy.
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Maintenance therapy after first-line chemotherapy is emerging as an attractive therapeutic option. Maintenance therapy with docetaxel, gemcitabine, or pemetrexed has improved progressionfree survival (PFS) [4–6]. In addition, pemetrexed and erlotinib after four cycles of platinum doublet showed statistically significant prolongation of OS, although there is concern that not enough patients in the placebo arm received any second-line chemotherapy [5,7]. The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways are clinically validated targets in NSCLC. Bevacizumab, an anti-VEGF monoclonal antibody, showed improved efficacy in stage IIIB and IV NSCLC when combined with paclitaxel/carboplatin [8], although the efficacy of bevacizumab as monotherapy remains to be established. Gefitinib and erlotinib, EGFR tyrosine kinase inhibitors (TKIs), and cetuximab, anti-EGFR monoclonal antibody have shown efficacy in NSCLC. Gefitinib was noninferior to docetaxel in terms of OS as second-line therapy [9]. Erlotinib resulted in a significant survival benefit in second- or third-line therapy compared to placebo [10]. Addition of cetuximab to platinum-based chemotherapy also prolonged survival [11]. Combination therapies have been reported with these novel agents. Pre-clinical and clinical data suggested that the combination of bevacizumab and erlotinib might improve the efficacy of NSCLC treatment [12]. This potential was demonstrated in the BETA trial in the second-line therapy [13] and ATLAS trial in the maintenance therapy [14,15]. PFS was significantly improved for patients treated with bevacizumab and erlotinib in both trials. Vandetanib is an oral inhibitor of VEGFR, EGFR, and RET (rearranged during transfection) signaling [16]. Vandetanib monotherapy (300 mg/d) in a phase II trial demonstrated an overall response rate of 13.2% in patients with previously treated advanced NSCLC [17]. Recently, vandetanib has demonstrated antitumor activity in a series of phase III trials in patients with previously treated, advanced NSCLC, both as a single agent and in combination with chemotherapy [18–20]. Therefore, it is a reasonable approach that vandetanib as a less toxic molecular-targeted agent with both EGFR and VEGFR blocking activity can be added in patients who do not progress after completion of first-line cytotoxic chemotherapy. This approach might prolong PFS and eventually OS without experiences of cumulative toxicities. This study investigated whether benefit could be obtained by giving vandetanib as a maintenance treatment after standard platinum-doublet chemotherapy regimen in patients with locally advanced or metastatic NSCLC.
2. Patients and methods 2.1. Patients This study (study code: NCT00777179) included patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC at the time of original diagnosis who completed 4 cycles of gemcitabine (1000 mg/m2 /day on day 1 and 8) and cisplatin (70 mg/m2 /day on day 1) every 3 weeks and have shown responses or stable disease (SD) by Response Evaluation Criteria In Solid Tumors (RECIST) [21]. Patients should be age of 18 years or older and WHO performance status of 0–1. The allowable maximum interval between the last day of the final 4th chemotherapy cycle and randomization was 21 days. Patients with prior treatment with EGFR-targeted or angiogenesis-targeted treatment, or any unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 2 from previous anticancer therapy were ineligible. All patients provided written informed consent. The study was approved by Institutional Review Boards at every participating
institution and was done in accordance with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice. 2.2. Study design This study was a multicenter, randomized, double-blind, placebo-controlled, phase II study comparing vandetanib plus best supportive care to placebo plus best supportive care as a maintenance treatment in patients with locally advanced or metastatic NSCLC, who have received and responded to prior platinumdoublet chemotherapy. Patients with a complete response (CR), partial response (PR), or SD after completion of 4 cycles of standard chemotherapy were randomly assigned to either vandetanib or placebo. Randomization scheme was stratified by center. Patients received 300 mg/day of vandetanib or placebo orally until disease progression, unacceptable toxicity, death or patient’s withdrawal of consent. Response assessment with CT scans using RECIST was performed every 4 weeks until 12 weeks following randomization, and then every 8 weeks during the rest of study period. 2.3. Serum sample collection for biomarker analysis Blood serum samples were collected at baseline, frozen, and stored at −70 to −80 ◦ C until analysis. We analyzed the serum samples blinded to clinical outcome. Hepatocyte growth factor (HGF), phosphatidylinositol-glycan biosynthesis class F protein (PIGF), vascular endothelial growth factor (VEGF), VEGF receprtor-2 (VEGFR-2), matrix metalloproteinase-9 (MMP-9), soluble intercellular adhesion molecule (sICAM), hypoxia-inducible factor-1 (HIF-1), interleukin-8 (IL-8), and IL-12 were analyzed. HGF, PIGF, VEGFR-2, MMP-9, sICAM and HIF-1 were analyzed by enzyme-linked immunosorbent assay kits from R&D Systems (Minneapolis, MN). VEGF, IL-8 and IL-12 were analyzed using microbead array kits from Milipore, all per the manufacturers’ instructions. Each sample was analyzed in duplicate. 2.4. Endpoints and statistical analysis Sample size determination was based on the optimal two-stage design by Simon [22]. A PFS rate at 3 months was selected as the primary endpoint for this study. We set a maximum PFS rate at 3 months to declare that ‘treatment is not better than observation only’ to 30% (P0 ), and a minimum PFS rate at 3 months to declare that ‘treatment is better than observation only’ to 50% (P1 ). The choice of these values was based on the previous studies with observation only. However, patients were randomized to receive either vandetanib or placebo in this trial because the assumptions made regarding the historical control need to be confirmed. It was designed for 5% significance level and 90% power in each group independently. For each treatment, interim analysis was planned when 24 PFSevaluable patients were accrued and the 24th PFS-evaluable patient in each arm was followed for a minimum of 3 months. If there were at least 9 patients who remain progression-free at 3 months, then we would proceed to the second stage. Otherwise, we should stop the trial at the first stage and accept the null hypothesis. At the second stage, 39 additional PFS-evaluable patients would be accrued to each arm and the final analysis would be conducted with a total of 63 PFS-evaluable patients. If at least 25 patients remained progression-free at 3 months, we would reject the null hypothesis in favor of the alternative hypothesis. Otherwise, we should accept the null hypothesis. Efficacy data from this study were analyzed on an intention-to-treat (ITT) basis. In addition, a per protocol (PP) analysis excluding significant protocol deviators was also carried out.
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Secondary endpoints were PFS, OS, objective response rate, duration of response, safety and tolerability. The response was evaluated from the point of randomization. Adverse events were graded according to NCI CTCAE version 3.0. Descriptive statistics used means, medians, or proportions with their appropriate measures of distribution. Exploratory endpoint was to investigate the correlation of baseline levels of circulating protein biomarkers with prognosis. The transformation of logarithm to biomarker was used to satisfy the normality assumption. Univariate and multivariate regression analyses using the Cox proportional hazards model were conducted on PFS. All p values are two-sided. We considered P < 0.05 to be significant. 3. Results 3.1. Patient disposition and characteristics
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Table 1 Patient characteristics at study baseline. Vandetanib (n = 75)
Placebo (n = 42)
Total (n = 117)
Median age, years (range)
61 (33–76)
60.5 (29–70)
61 (29–76)
Sex, n (%) Male Female
47 (62.7) 28 (37.3)
28 (66.7) 14 (33.3)
75 (64.1) 42 (35.9)
WHO PS, n (%) 0 1
20 (26.7) 55 (73.3)
10 (23.8) 32 (76.2)
30 (25.6) 87 (74.4)
Smoking history, n (%) Non-smoker Ex-smoker Smoker
28 (37.3) 19 (25.3) 28 (37.3)
14 (33.3) 13 (31.0) 15 (35.7)
42 (35.9) 32 (27.4) 43 (36.8)
Histology, n (%) Adenocarcinoma Squamous cell carcinoma Other
56 (74.7) 11 (14.7) 8 (10.7)
31 (73.8) 9 (21.4) 2 (4.8)
87 (74.4) 20 (17.1) 10 (8.5)
Disease stage, n (%) IIIB IV
15 (20.0) 60 (80.0)
12 (28.6) 30 (71.4)
27 (23.1) 90 (76.9)
Response to previous therapy, n (%) 44 (58.7) Partial response 31 (41.3) Stable disease
30 (71.4) 12 (28.6)
74 (63.3) 43 (36.8)
Between November 2008 and December 2009, 127 patients from 7 centers in Korea were screened and 118 were randomized in the trial. Only the vandetanib arm met the criteria for proceeding to stage 2. The trial flow is illustrated in Fig. 1. The ITT population comprised 117 patients (vandetanib, n = 75; placebo, n = 42); one patient in the vandetanib group withdrew consent before receiving treatment. The PP population consisted of 107 patients (vandetanib, n = 69; placebo, n = 38). Demographic baseline characteristics were well balanced between treatment groups (Table 1). Median age was 61 years (range, 29–76 years). The proportion of patients who achieved PR at the screening in placebo arm was higher, but this was not statistically significant.
3–282 days) in patients receiving placebo. The percentage of patients receiving treatment for more than 3 months was 40% in the vandetanib arm and 21% in the placebo arm. Disease progression was the main reason for patients not receiving treatment for more than 3 months.
3.2. Treatment exposure
3.3. Efficacy
The median duration of treatment exposure was 59 days (range, 2–401 days) in patients receiving vandetanib and 54 days (range,
At the interim analysis, 9 of 24 patients in the vandetanib arm were progression-free at 3 months, whereas 7 of 24 in the placebo
Fig. 1. Trial flow.
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Fig. 2. Kaplan–Meier curve for progression-free survival and overall survival by treatment arm.
arm were progression-free. The placebo arm was closed at the first stage since the null hypothesis that the PFS rate at 3 months is at most 30% was not rejected. The enrollment was not interrupted before interim analysis, thus additional 14 patients were randomized to the placebo arm. The blinding for these additional patients in the placebo arm was maintained until the PFS at 3 months could be evaluated. In contrast, the vandetanib arm proceeded to the second stage according to the two-stage design, and recruited a total of 75 patients. At the second stage, 28 out of 63 evaluable patients receiving vandetanib achieved PFS at 3 months. Therefore, the alternative hypothesis that the PFS rate at 3 months is at least 50% was accepted. The median duration of follow-up in the study was 12.1 months for vandetanib patients and 17.0 months for placebo patients. The median PFS was 2.7 months (95% CI, 1.9–4.4 months) in the vandetanib arm and 1.7 months (95% CI, 0.9–2.6 months) in the placebo arm, respectively (ITT population: odds ratio [OR] = 0.667 [95% CI, 0.44–1.01], P = 0.062; PP population: OR = 0.642 [95% CI, 0.42–0.92], P = 0.042) (Fig. 2). The median OS was 15.6 months (95% CI, 9.6 months to not reached) in the vandetanib arm and 20.8 months (95% CI, 15.2 months to not reached) in the placebo arm, respectively. The objective response rate was 18.7% in the vandetanib arm (all PRs) compared with 2.4% in the placebo arm (one PR) (ITT population: OR = 9.410 [95% CI, 1.12–74.35], P = 0.012). The median duration of response was 9.2 months (95% CI, 6.5–9.4 months) for vandetanib patients with an objective response.
3.4. Safety Adverse events (AEs) with any grade occurred in 72 patients (96.0%) in the vandetanib arm and 37 patients (88.1%) in the placebo arm, respectively, but were usually mild (Table 2). The most common AEs in patients receiving vandetanib were rash (77.3%), diarrhea (60.0%) and cough (50.7%); cough (54.8%) was also the most common AE in the placebo arm. Three patients in the vandetanib arm experienced asymptomatic QTc prolongation that required dose modification. In the vandetanib group, AEs ≥grade 3 experienced by more than two patients were rash (13.3%, n = 10), pneumonia (9.3%, n = 7), dyspnea (6.7%, n = 5) and hypertension (6.7%, n = 5). In patients receiving vandetanib, there were six grade 4 AEs (two cases of pneumonia and one case each of ileal perforation, dyspnea, rash and Stevens-Johnson syndrome), and three grade 5 events (one case each of pneumonia, sepsis and dyspnea). All grade 3 or 4 AEs were resolved following dose interruption/reduction without clinical sequelae.
The most commonly reported serious adverse event (SAE) in patients receiving vandetanib was pneumonia (16.0%, n = 12). SAEs leading to death were reported in five patients in the vandetanib arm (pneumonia [n = 4]; sepsis [n = 1]). However, none of the cases was considered to be treatment related. In the vandetanib arm, 17 patients (22.7%) discontinued treatment owing to toxicity, most commonly rash (n = 7). 3.5. Serum biomarker Baseline serum samples were available from 115 (98%) of 117 patients in the trial. On univariate analysis, sICAM (P = 0.0208) and IL-8 (P = 0.0168) were significant biomarkers associated with PFS (Table 3). The higher of baseline sICAM or IL-8, the shorter was PFS. When markers of P-value less than 0.2, and clinical factors of treatment arm (vandetanib vs placebo) and response from first-line chemotherapy (PR vs. SD) were included on multivariate Table 2 Adverse events (occurring in ≥10 patients in the vandetanib arm). Vandetanib (n = 75)
Rash Diarrhea Cough Productive cough Anorexia Pruritus Dyspnea Insomnia Hypertension Nausea Chest pain Dry skin
Placebo (n = 42)
All grades
Grade ≥3
All grades
58 (77.3) 45 (60.0) 38 (50.7) 29 (38.7) 29 (38.7) 23 (30.7) 19 (25.3) 14 (18.7) 13 (17.3) 13 (17.3) 12 (16.0) 10 (13.3)
10 (13.3)a 2 (2.7) 2 (2.7) 0 0 1 (1.3) 5 (6.7)b 0 5 (6.7) 1 (1.3) 0 0
11 (26.2) 4 (9.5) 23 (54.8) 15 (35.7) 7 (16.7) 7 (16.7) 5 (11.9) 2 (4.8) 0 6 (14.3) 5 (11.9) 0
Grade ≥3 0 0 0 0 0 0 0 0 0 0 0 0
Data presented as n (%). MedDRA, Medical Dictionary for Regulatory Activities. a Includes one grade 4 event. b includes one grade 4 event and one grade 5 event (death). Table 3 Univariate analysis of circulating protein biomarkers at baseline. Plasma biomarkers
Cox P-value
Regression estimate
HGF PIGF VEGF VEGFR-2 MMP-9 sICAM IHF-1 IL-8 IL-12
0.2322 0.3020 0.4000 0.7541 0.1125 0.0208 0.3477 0.0168 0.9176
0.438 0.044 0.044 −0.174 0.214 0.494 −0.082 0.101 −0.008
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Fig. 3. Kaplan–Meier curve for progression-free survival by interleukin-8 level.
analysis, IL-8 and treatment arm remained as significant factors for PFS (Fig. 3). 4. Discussion The results of this study demonstrated that maintenance therapy with vandetanib after standard platinum-doublet chemotherapy is active. Although this is a phase II study and a direct comparison between the vandetanib arm and the placebo arm was not carried out, the results seem to favor vandetatinb maintenance. Angiogenic inhibition is one of the targeted approaches to the treatment of advanced NSCLC. Among them, the anti-VEGF monoclonal antibody bevacizumab represents the most successful targeted therapy. Two landmark trials of ECOG 4599 [8] and AVAil [23] have shown the first evidence of an improvement in outcomes using chemotherapy combined with bevacizumab as first-line chemotherapy until progression. Therefore, it is not clear to determine from these two trials whether the survival benefit in bevacizumab arms might have come from the maintenance phase of the treatment. In contrast, vandetanib in this study was administered only as maintenance phase and demonstrated prolongation of PFS. To our knowledge, this might be the first study demonstrating that angiogenic targeted agent can improve clinical outcomes when given as maintenance therapy. Recently, a randomized phase III trial from the Cancer and Leukemia Group B (CALGB 30607) was designed [24]. In this study, patients receive 4 cycles of platinum-doublet chemotherapy, and responding and stable patients are randomized to receive sequential sunitinib 37.5 mg daily or placebo. This study will directly address the potential benefit from maintenance therapy of sunitinib, a multi-targeted antiangiogenic drug. Although recombinant enzyme assays have shown that vandetanib is a potent inhibitor of VEGFR-2 tyrosine kinase activity (IC50 , 40 nM), it also inhibits EGFR tyrosine kinase at submicromolar level (IC50 , 500 nM) [16]. A randomized phase III trial comparing vandetanib with erlotinib in unselected patients with previously treated advanced NSCLC did not show superiority of vandetanib in PFS, but both agents showed equivalent PFS and OS in a preplanned noninferiority analysis [20]. In SATURN trial, maintenance therapy with erlotinib significantly prolonged PFS compared with placebo (12.3 weeks versus 11.1 weeks) [7]. The median PFS of 12.3 weeks in the erlotinib group of SATURN trial is comparable with the median PFS of 11.7 weeks (2.7 months) in the vandetanib group of the present study. However, the patient population of this study had somewhat higher proportion of women, nonsmokers and adenocarcinoma compared with SATURN study, and totally consisted of Korean ethnicity. Thus, patients in this study are expected to have high probability of harboring EGFR mutation. We could collect the result of EGFR gene mutation test in 37 patients. Among them, 15
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patients (40.5%) had the EGFR mutation. However, it is not yet confirmed whether EGFR mutation status is a predictive biomarker for vandetanib [25]. Patients receiving vandetanib had favorable safety profiles. The most common adverse events were rash and diarrhea, which was consistent with previous phase II studies [17,26] and the recent phase III study of vandetanib in NSCLC [20]. These toxicities are likely related to the EGFR inhibitory effects of vandetanib, having also been observed with other EGFR inhibitors. All grades of hypertension were reported in 17.3% and grade 3 or 4 hypertension occurred in 6.7% of patients, which was also similar to previous studies. Mild hemoptysis was reported in only 1 patient. SAEs reported as leading to death were pneumonia (n = 4) and sepsis (n = 1). All of them were not associated with treatment but with disease progression. About one fourth of patients (23%) discontinued vandetanib due to toxicity, which was higher than that reported in the recent phase III trial (14%) [20]. Until now, there are no definitive molecular biomarkers available for predicting response with antiangiogenic agents including vandetanib. Although low baseline circulating VEGF may be associated with PFS advantage in patients with advanced NSCLC receiving vandetanib in randomized phase II study, we did not find any correlation of basal level of VEGF with clinical outcomes. Instead, baseline serum IL-8 level was associated with shorter PFS in this study. There is evidence that chronic inflammation is involved in the development and progression of cancer [27–29]. IL-8 is produced by NSCLC cells in vitro and in vivo and has been shown to contribute to tumor-induced angiogenesis in vivo [30]. Therefore, IL-8 may play a role in enhancing tumor cell proliferation, tumor cell motility and adhesion [31]. The baseline levels of certain cytokines have been associated with OS in some tumor types. High plasma and serum IL-8 has been associated with shorter survival of patients with chronic lymphocytic leukemia and squamous cell head and neck carcinoma [32,33]. In NSCLC patients treated by radiotherapy, higher baseline serum and bronchoalveolar lavage fluid IL-8 and serum VEGF levels were associated with shorter survival [34]. However, in a larger prospective cohort study, serum IL-8 level was not associated with survival, in which IL-6 and IL-12 serum concentrations were associated with significantly poorer survival [35]. These inconsistent findings indicate that further research is warranted to better understand the prognostic or predictive value of blood angiogenic factors and serum cytokines and should be validated in large prospective studies. In summary, although this is a randomized, phase II trial done with the limited number of patients, this study showed that maintenance therapy with vandetanib alone for patients with NSCLC after standard platinum-doublet chemotherapy prolonged PFS rate at 3 months compared with placebo, with manageable toxicities. Vandetanib maintenance warrants further investigation. Conflicts of interest statement Funding source: This study was sponsored by AstraZeneca. Financial disclosure: Keunchil Park has received honoraria from AstraZeneca, is currently receiving consulting fee from Roche, EliLilly and Pfizer, and is on the speaker’s bureau for Roche and Merck. For the remaining authors, none were declared. References [1] Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617–25. [2] Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–8.
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[18] de Boer RH, Arrieta O, Yang CH, Gottfried M, Chan V, Raats J, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-smallcell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 2011;29:1067–74. [19] Herbst RS, Sun Y, Eberhardt WE, Germonpre P, Saijo N, Zhou C, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010;11:619–26. [20] Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011;29:1059–66. [21] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16. [22] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10. [23] Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227–34. [24] ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). June 6. Identifier NCT00693992, Sunitinib as maintenance therapy in treating patients with stage III or stage IV non-small cell lung cancer previously treated with combination chemotherapy; 2008. Available from: http://clinicaltrials.gov/ct2/show/NCT00693992 [accessed 19.11.11]. [25] Johnson BE, Ryan AJ, Heymach J, Stephens C, Kennedy SJ, Langmuir PB, et al. Tumor biomarker analyses from the phase III ZODIAC study of docetaxel (D) plus or minus vandetanib (VAN) in second-line advanced NSCLC. ASCO Meeting Abstr 2010;28:7516. [26] Natale RB, Bodkin D, Govindan R, Sleckman BG, Rizvi NA, Capo A, et al. Vandetanib versus gefitinib in patients with advanced non-small-cell lung cancer: results from a two-part, double-blind, randomized phase ii study. J Clin Oncol 2009;27:2523–9. [27] Ballaz S, Mulshine JL. The potential contributions of chronic inflammation to lung carcinogenesis. Clin Lung Cancer 2003;5:46–62. [28] Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–7. [29] Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer 2003;3:276–85. [30] Yatsunami J, Tsuruta N, Ogata K, Wakamatsu K, Takayama K, Kawasaki M, et al. Interleukin-8 participates in angiogenesis in non-small cell, but not small cell carcinoma of the lung. Cancer Lett 1997;120:101–8. [31] Nacinovic-Duletic A, Stifter S, Dvornik S, Skunca Z, Jonjic N. Correlation of serum IL-6, IL-8 and IL-10 levels with clinicopathological features and prognosis in patients with diffuse large B-cell lymphoma. Int J Lab Hematol 2008;30:230–9. [32] Druzgal CH, Chen Z, Yeh NT, Thomas GR, Ondrey FG, Duffey DC, et al. A pilot study of longitudinal serum cytokine and angiogenesis factor levels as markers of therapeutic response and survival in patients with head and neck squamous cell carcinoma. Head Neck 2005;27:771–84. [33] Wierda WG, Johnson MM, Do KA, Manshouri T, Dey A, O‘Brien S, et al. Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukaemia. Br J Haematol 2003;120:452–6. [34] Crohns M, Saarelainen S, Laine S, Poussa T, Alho H, Kellokumpu-Lehtinen P. Cytokines in bronchoalveolar lavage fluid and serum of lung cancer patients during radiotherapy – association of interleukin-8 and VEGF with survival. Cytokine 2010;50:30–6. [35] Enewold L, Mechanic LE, Bowman ED, Zheng YL, Yu Z, Trivers G, et al. Serum concentrations of cytokines and lung cancer survival in African Americans and Caucasians. Cancer Epidemiol Biomarkers Prev 2009;18:215–22.
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
A randomized, phase II study of vandetanib maintenance for advanced or metastatic non-small-cell lung cancer following first-line platinum-doublet chemotherapy夽 Jin Seok Ahn a,1 , Ki Hyeong Lee b,1 , Jong-Mu Sun a , Keunchil Park a , Eun-Suk Kang c , Eun Kyung Cho d , Dae Ho Lee e , Sang-We Kim e , Gyeong-Won Lee f , Jin-Hyoung Kang g , Jong-Seok Lee h , Jae-Won Lee i , Myung-Ju Ahn a,∗ a
Department of Medicine, Samsung Medical Center, Sungkyunkwan University, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea c Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea d Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea e Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea f Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea g Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea h Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea i Department of Statistics, Korea University, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 16 April 2013 Received in revised form 23 August 2013 Accepted 31 August 2013 Keywords: Vandetanib Maintenance Chemotherapy Lung cancer Progression-free survival Target therapy
a b s t r a c t Background: This randomized, phase II study investigated whether benefit could be obtained by giving vandetanib, an oral inhibitor of vascular endothelial and epithelial growth factor receptor, as a maintenance treatment in non-small cell lung cancer (NSCLC). Methods: Patients were randomly assigned to either vandetanib or placebo after completion of 4 cycles of first-line chemotherapy. A progression-free survival (PFS) rate at 3 months was selected as the primary endpoint. We set a maximum PFS rate at 3 months to 30% (null hypothesis), and a minimum PFS rate at 3 months to 50% (alternative hypothesis). Results: At the interim analysis, 9 of 24 patients in the vandetanib arm were progression-free at 3 months, whereas 7 of 24 in the placebo arm were progression-free. The placebo arm was closed at the first stage. The vandetanib arm proceeded to the second stage, and recruited a total of 75 patients. At the second stage, 28 out of 63 evaluable patients receiving vandetanib achieved PFS at 3 months. The alternative hypothesis that the PFS rate at 3 months is at least 50% was accepted. The median PFS was 2.7 months (95% CI, 1.9–4.4 months) in the vandetanib arm and 1.7 months (95% CI, 0.9–2.6 months) in the placebo arm. The most common adverse events in patients receiving vandetanib were rash (77.3%) and diarrhea (60.0%). Conclusions: Maintenance therapy with vandetanib for patients with NSCLC after standard platinum doublet chemotherapy is well tolerated and may prolong PFS compared with placebo, and needs additional investigation. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
夽 Presented in part at the 2011 World Lung Cancer Conference, July 3–7, Amsterdam, Netherlands; at the 2010 Asia Pacific Lung Cancer Conference, December 2–4, Seoul, Republic of Korea. ∗ Corresponding author at: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel.: +82 2 3410 3438; fax: +82 2 3410 1754. E-mail address: [email protected] (M.-J. Ahn). 1 These authors contributed equally to this work. 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.08.027
About 85% of all lung cancers are non-small cell lung cancer (NSCLC), with approximately 40% of patients presenting with metastatic disease. Meta-analysis showed increased quality of life and improvement of overall survival (OS) in patients treated with platinum-doublet chemotherapy [1], but the improvement was modest and reached a plateau [2]. Current guidelines recommend four to six cycles of platinum-based chemotherapy for stage IIIB and IV NSCLC patients [3]. However, most patients eventually experience progression and need second- or third-line chemotherapy.
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Maintenance therapy after first-line chemotherapy is emerging as an attractive therapeutic option. Maintenance therapy with docetaxel, gemcitabine, or pemetrexed has improved progressionfree survival (PFS) [4–6]. In addition, pemetrexed and erlotinib after four cycles of platinum doublet showed statistically significant prolongation of OS, although there is concern that not enough patients in the placebo arm received any second-line chemotherapy [5,7]. The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways are clinically validated targets in NSCLC. Bevacizumab, an anti-VEGF monoclonal antibody, showed improved efficacy in stage IIIB and IV NSCLC when combined with paclitaxel/carboplatin [8], although the efficacy of bevacizumab as monotherapy remains to be established. Gefitinib and erlotinib, EGFR tyrosine kinase inhibitors (TKIs), and cetuximab, anti-EGFR monoclonal antibody have shown efficacy in NSCLC. Gefitinib was noninferior to docetaxel in terms of OS as second-line therapy [9]. Erlotinib resulted in a significant survival benefit in second- or third-line therapy compared to placebo [10]. Addition of cetuximab to platinum-based chemotherapy also prolonged survival [11]. Combination therapies have been reported with these novel agents. Pre-clinical and clinical data suggested that the combination of bevacizumab and erlotinib might improve the efficacy of NSCLC treatment [12]. This potential was demonstrated in the BETA trial in the second-line therapy [13] and ATLAS trial in the maintenance therapy [14,15]. PFS was significantly improved for patients treated with bevacizumab and erlotinib in both trials. Vandetanib is an oral inhibitor of VEGFR, EGFR, and RET (rearranged during transfection) signaling [16]. Vandetanib monotherapy (300 mg/d) in a phase II trial demonstrated an overall response rate of 13.2% in patients with previously treated advanced NSCLC [17]. Recently, vandetanib has demonstrated antitumor activity in a series of phase III trials in patients with previously treated, advanced NSCLC, both as a single agent and in combination with chemotherapy [18–20]. Therefore, it is a reasonable approach that vandetanib as a less toxic molecular-targeted agent with both EGFR and VEGFR blocking activity can be added in patients who do not progress after completion of first-line cytotoxic chemotherapy. This approach might prolong PFS and eventually OS without experiences of cumulative toxicities. This study investigated whether benefit could be obtained by giving vandetanib as a maintenance treatment after standard platinum-doublet chemotherapy regimen in patients with locally advanced or metastatic NSCLC.
2. Patients and methods 2.1. Patients This study (study code: NCT00777179) included patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC at the time of original diagnosis who completed 4 cycles of gemcitabine (1000 mg/m2 /day on day 1 and 8) and cisplatin (70 mg/m2 /day on day 1) every 3 weeks and have shown responses or stable disease (SD) by Response Evaluation Criteria In Solid Tumors (RECIST) [21]. Patients should be age of 18 years or older and WHO performance status of 0–1. The allowable maximum interval between the last day of the final 4th chemotherapy cycle and randomization was 21 days. Patients with prior treatment with EGFR-targeted or angiogenesis-targeted treatment, or any unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 2 from previous anticancer therapy were ineligible. All patients provided written informed consent. The study was approved by Institutional Review Boards at every participating
institution and was done in accordance with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice. 2.2. Study design This study was a multicenter, randomized, double-blind, placebo-controlled, phase II study comparing vandetanib plus best supportive care to placebo plus best supportive care as a maintenance treatment in patients with locally advanced or metastatic NSCLC, who have received and responded to prior platinumdoublet chemotherapy. Patients with a complete response (CR), partial response (PR), or SD after completion of 4 cycles of standard chemotherapy were randomly assigned to either vandetanib or placebo. Randomization scheme was stratified by center. Patients received 300 mg/day of vandetanib or placebo orally until disease progression, unacceptable toxicity, death or patient’s withdrawal of consent. Response assessment with CT scans using RECIST was performed every 4 weeks until 12 weeks following randomization, and then every 8 weeks during the rest of study period. 2.3. Serum sample collection for biomarker analysis Blood serum samples were collected at baseline, frozen, and stored at −70 to −80 ◦ C until analysis. We analyzed the serum samples blinded to clinical outcome. Hepatocyte growth factor (HGF), phosphatidylinositol-glycan biosynthesis class F protein (PIGF), vascular endothelial growth factor (VEGF), VEGF receprtor-2 (VEGFR-2), matrix metalloproteinase-9 (MMP-9), soluble intercellular adhesion molecule (sICAM), hypoxia-inducible factor-1 (HIF-1), interleukin-8 (IL-8), and IL-12 were analyzed. HGF, PIGF, VEGFR-2, MMP-9, sICAM and HIF-1 were analyzed by enzyme-linked immunosorbent assay kits from R&D Systems (Minneapolis, MN). VEGF, IL-8 and IL-12 were analyzed using microbead array kits from Milipore, all per the manufacturers’ instructions. Each sample was analyzed in duplicate. 2.4. Endpoints and statistical analysis Sample size determination was based on the optimal two-stage design by Simon [22]. A PFS rate at 3 months was selected as the primary endpoint for this study. We set a maximum PFS rate at 3 months to declare that ‘treatment is not better than observation only’ to 30% (P0 ), and a minimum PFS rate at 3 months to declare that ‘treatment is better than observation only’ to 50% (P1 ). The choice of these values was based on the previous studies with observation only. However, patients were randomized to receive either vandetanib or placebo in this trial because the assumptions made regarding the historical control need to be confirmed. It was designed for 5% significance level and 90% power in each group independently. For each treatment, interim analysis was planned when 24 PFSevaluable patients were accrued and the 24th PFS-evaluable patient in each arm was followed for a minimum of 3 months. If there were at least 9 patients who remain progression-free at 3 months, then we would proceed to the second stage. Otherwise, we should stop the trial at the first stage and accept the null hypothesis. At the second stage, 39 additional PFS-evaluable patients would be accrued to each arm and the final analysis would be conducted with a total of 63 PFS-evaluable patients. If at least 25 patients remained progression-free at 3 months, we would reject the null hypothesis in favor of the alternative hypothesis. Otherwise, we should accept the null hypothesis. Efficacy data from this study were analyzed on an intention-to-treat (ITT) basis. In addition, a per protocol (PP) analysis excluding significant protocol deviators was also carried out.
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Secondary endpoints were PFS, OS, objective response rate, duration of response, safety and tolerability. The response was evaluated from the point of randomization. Adverse events were graded according to NCI CTCAE version 3.0. Descriptive statistics used means, medians, or proportions with their appropriate measures of distribution. Exploratory endpoint was to investigate the correlation of baseline levels of circulating protein biomarkers with prognosis. The transformation of logarithm to biomarker was used to satisfy the normality assumption. Univariate and multivariate regression analyses using the Cox proportional hazards model were conducted on PFS. All p values are two-sided. We considered P < 0.05 to be significant. 3. Results 3.1. Patient disposition and characteristics
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Table 1 Patient characteristics at study baseline. Vandetanib (n = 75)
Placebo (n = 42)
Total (n = 117)
Median age, years (range)
61 (33–76)
60.5 (29–70)
61 (29–76)
Sex, n (%) Male Female
47 (62.7) 28 (37.3)
28 (66.7) 14 (33.3)
75 (64.1) 42 (35.9)
WHO PS, n (%) 0 1
20 (26.7) 55 (73.3)
10 (23.8) 32 (76.2)
30 (25.6) 87 (74.4)
Smoking history, n (%) Non-smoker Ex-smoker Smoker
28 (37.3) 19 (25.3) 28 (37.3)
14 (33.3) 13 (31.0) 15 (35.7)
42 (35.9) 32 (27.4) 43 (36.8)
Histology, n (%) Adenocarcinoma Squamous cell carcinoma Other
56 (74.7) 11 (14.7) 8 (10.7)
31 (73.8) 9 (21.4) 2 (4.8)
87 (74.4) 20 (17.1) 10 (8.5)
Disease stage, n (%) IIIB IV
15 (20.0) 60 (80.0)
12 (28.6) 30 (71.4)
27 (23.1) 90 (76.9)
Response to previous therapy, n (%) 44 (58.7) Partial response 31 (41.3) Stable disease
30 (71.4) 12 (28.6)
74 (63.3) 43 (36.8)
Between November 2008 and December 2009, 127 patients from 7 centers in Korea were screened and 118 were randomized in the trial. Only the vandetanib arm met the criteria for proceeding to stage 2. The trial flow is illustrated in Fig. 1. The ITT population comprised 117 patients (vandetanib, n = 75; placebo, n = 42); one patient in the vandetanib group withdrew consent before receiving treatment. The PP population consisted of 107 patients (vandetanib, n = 69; placebo, n = 38). Demographic baseline characteristics were well balanced between treatment groups (Table 1). Median age was 61 years (range, 29–76 years). The proportion of patients who achieved PR at the screening in placebo arm was higher, but this was not statistically significant.
3–282 days) in patients receiving placebo. The percentage of patients receiving treatment for more than 3 months was 40% in the vandetanib arm and 21% in the placebo arm. Disease progression was the main reason for patients not receiving treatment for more than 3 months.
3.2. Treatment exposure
3.3. Efficacy
The median duration of treatment exposure was 59 days (range, 2–401 days) in patients receiving vandetanib and 54 days (range,
At the interim analysis, 9 of 24 patients in the vandetanib arm were progression-free at 3 months, whereas 7 of 24 in the placebo
Fig. 1. Trial flow.
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Fig. 2. Kaplan–Meier curve for progression-free survival and overall survival by treatment arm.
arm were progression-free. The placebo arm was closed at the first stage since the null hypothesis that the PFS rate at 3 months is at most 30% was not rejected. The enrollment was not interrupted before interim analysis, thus additional 14 patients were randomized to the placebo arm. The blinding for these additional patients in the placebo arm was maintained until the PFS at 3 months could be evaluated. In contrast, the vandetanib arm proceeded to the second stage according to the two-stage design, and recruited a total of 75 patients. At the second stage, 28 out of 63 evaluable patients receiving vandetanib achieved PFS at 3 months. Therefore, the alternative hypothesis that the PFS rate at 3 months is at least 50% was accepted. The median duration of follow-up in the study was 12.1 months for vandetanib patients and 17.0 months for placebo patients. The median PFS was 2.7 months (95% CI, 1.9–4.4 months) in the vandetanib arm and 1.7 months (95% CI, 0.9–2.6 months) in the placebo arm, respectively (ITT population: odds ratio [OR] = 0.667 [95% CI, 0.44–1.01], P = 0.062; PP population: OR = 0.642 [95% CI, 0.42–0.92], P = 0.042) (Fig. 2). The median OS was 15.6 months (95% CI, 9.6 months to not reached) in the vandetanib arm and 20.8 months (95% CI, 15.2 months to not reached) in the placebo arm, respectively. The objective response rate was 18.7% in the vandetanib arm (all PRs) compared with 2.4% in the placebo arm (one PR) (ITT population: OR = 9.410 [95% CI, 1.12–74.35], P = 0.012). The median duration of response was 9.2 months (95% CI, 6.5–9.4 months) for vandetanib patients with an objective response.
3.4. Safety Adverse events (AEs) with any grade occurred in 72 patients (96.0%) in the vandetanib arm and 37 patients (88.1%) in the placebo arm, respectively, but were usually mild (Table 2). The most common AEs in patients receiving vandetanib were rash (77.3%), diarrhea (60.0%) and cough (50.7%); cough (54.8%) was also the most common AE in the placebo arm. Three patients in the vandetanib arm experienced asymptomatic QTc prolongation that required dose modification. In the vandetanib group, AEs ≥grade 3 experienced by more than two patients were rash (13.3%, n = 10), pneumonia (9.3%, n = 7), dyspnea (6.7%, n = 5) and hypertension (6.7%, n = 5). In patients receiving vandetanib, there were six grade 4 AEs (two cases of pneumonia and one case each of ileal perforation, dyspnea, rash and Stevens-Johnson syndrome), and three grade 5 events (one case each of pneumonia, sepsis and dyspnea). All grade 3 or 4 AEs were resolved following dose interruption/reduction without clinical sequelae.
The most commonly reported serious adverse event (SAE) in patients receiving vandetanib was pneumonia (16.0%, n = 12). SAEs leading to death were reported in five patients in the vandetanib arm (pneumonia [n = 4]; sepsis [n = 1]). However, none of the cases was considered to be treatment related. In the vandetanib arm, 17 patients (22.7%) discontinued treatment owing to toxicity, most commonly rash (n = 7). 3.5. Serum biomarker Baseline serum samples were available from 115 (98%) of 117 patients in the trial. On univariate analysis, sICAM (P = 0.0208) and IL-8 (P = 0.0168) were significant biomarkers associated with PFS (Table 3). The higher of baseline sICAM or IL-8, the shorter was PFS. When markers of P-value less than 0.2, and clinical factors of treatment arm (vandetanib vs placebo) and response from first-line chemotherapy (PR vs. SD) were included on multivariate Table 2 Adverse events (occurring in ≥10 patients in the vandetanib arm). Vandetanib (n = 75)
Rash Diarrhea Cough Productive cough Anorexia Pruritus Dyspnea Insomnia Hypertension Nausea Chest pain Dry skin
Placebo (n = 42)
All grades
Grade ≥3
All grades
58 (77.3) 45 (60.0) 38 (50.7) 29 (38.7) 29 (38.7) 23 (30.7) 19 (25.3) 14 (18.7) 13 (17.3) 13 (17.3) 12 (16.0) 10 (13.3)
10 (13.3)a 2 (2.7) 2 (2.7) 0 0 1 (1.3) 5 (6.7)b 0 5 (6.7) 1 (1.3) 0 0
11 (26.2) 4 (9.5) 23 (54.8) 15 (35.7) 7 (16.7) 7 (16.7) 5 (11.9) 2 (4.8) 0 6 (14.3) 5 (11.9) 0
Grade ≥3 0 0 0 0 0 0 0 0 0 0 0 0
Data presented as n (%). MedDRA, Medical Dictionary for Regulatory Activities. a Includes one grade 4 event. b includes one grade 4 event and one grade 5 event (death). Table 3 Univariate analysis of circulating protein biomarkers at baseline. Plasma biomarkers
Cox P-value
Regression estimate
HGF PIGF VEGF VEGFR-2 MMP-9 sICAM IHF-1 IL-8 IL-12
0.2322 0.3020 0.4000 0.7541 0.1125 0.0208 0.3477 0.0168 0.9176
0.438 0.044 0.044 −0.174 0.214 0.494 −0.082 0.101 −0.008
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Fig. 3. Kaplan–Meier curve for progression-free survival by interleukin-8 level.
analysis, IL-8 and treatment arm remained as significant factors for PFS (Fig. 3). 4. Discussion The results of this study demonstrated that maintenance therapy with vandetanib after standard platinum-doublet chemotherapy is active. Although this is a phase II study and a direct comparison between the vandetanib arm and the placebo arm was not carried out, the results seem to favor vandetatinb maintenance. Angiogenic inhibition is one of the targeted approaches to the treatment of advanced NSCLC. Among them, the anti-VEGF monoclonal antibody bevacizumab represents the most successful targeted therapy. Two landmark trials of ECOG 4599 [8] and AVAil [23] have shown the first evidence of an improvement in outcomes using chemotherapy combined with bevacizumab as first-line chemotherapy until progression. Therefore, it is not clear to determine from these two trials whether the survival benefit in bevacizumab arms might have come from the maintenance phase of the treatment. In contrast, vandetanib in this study was administered only as maintenance phase and demonstrated prolongation of PFS. To our knowledge, this might be the first study demonstrating that angiogenic targeted agent can improve clinical outcomes when given as maintenance therapy. Recently, a randomized phase III trial from the Cancer and Leukemia Group B (CALGB 30607) was designed [24]. In this study, patients receive 4 cycles of platinum-doublet chemotherapy, and responding and stable patients are randomized to receive sequential sunitinib 37.5 mg daily or placebo. This study will directly address the potential benefit from maintenance therapy of sunitinib, a multi-targeted antiangiogenic drug. Although recombinant enzyme assays have shown that vandetanib is a potent inhibitor of VEGFR-2 tyrosine kinase activity (IC50 , 40 nM), it also inhibits EGFR tyrosine kinase at submicromolar level (IC50 , 500 nM) [16]. A randomized phase III trial comparing vandetanib with erlotinib in unselected patients with previously treated advanced NSCLC did not show superiority of vandetanib in PFS, but both agents showed equivalent PFS and OS in a preplanned noninferiority analysis [20]. In SATURN trial, maintenance therapy with erlotinib significantly prolonged PFS compared with placebo (12.3 weeks versus 11.1 weeks) [7]. The median PFS of 12.3 weeks in the erlotinib group of SATURN trial is comparable with the median PFS of 11.7 weeks (2.7 months) in the vandetanib group of the present study. However, the patient population of this study had somewhat higher proportion of women, nonsmokers and adenocarcinoma compared with SATURN study, and totally consisted of Korean ethnicity. Thus, patients in this study are expected to have high probability of harboring EGFR mutation. We could collect the result of EGFR gene mutation test in 37 patients. Among them, 15
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patients (40.5%) had the EGFR mutation. However, it is not yet confirmed whether EGFR mutation status is a predictive biomarker for vandetanib [25]. Patients receiving vandetanib had favorable safety profiles. The most common adverse events were rash and diarrhea, which was consistent with previous phase II studies [17,26] and the recent phase III study of vandetanib in NSCLC [20]. These toxicities are likely related to the EGFR inhibitory effects of vandetanib, having also been observed with other EGFR inhibitors. All grades of hypertension were reported in 17.3% and grade 3 or 4 hypertension occurred in 6.7% of patients, which was also similar to previous studies. Mild hemoptysis was reported in only 1 patient. SAEs reported as leading to death were pneumonia (n = 4) and sepsis (n = 1). All of them were not associated with treatment but with disease progression. About one fourth of patients (23%) discontinued vandetanib due to toxicity, which was higher than that reported in the recent phase III trial (14%) [20]. Until now, there are no definitive molecular biomarkers available for predicting response with antiangiogenic agents including vandetanib. Although low baseline circulating VEGF may be associated with PFS advantage in patients with advanced NSCLC receiving vandetanib in randomized phase II study, we did not find any correlation of basal level of VEGF with clinical outcomes. Instead, baseline serum IL-8 level was associated with shorter PFS in this study. There is evidence that chronic inflammation is involved in the development and progression of cancer [27–29]. IL-8 is produced by NSCLC cells in vitro and in vivo and has been shown to contribute to tumor-induced angiogenesis in vivo [30]. Therefore, IL-8 may play a role in enhancing tumor cell proliferation, tumor cell motility and adhesion [31]. The baseline levels of certain cytokines have been associated with OS in some tumor types. High plasma and serum IL-8 has been associated with shorter survival of patients with chronic lymphocytic leukemia and squamous cell head and neck carcinoma [32,33]. In NSCLC patients treated by radiotherapy, higher baseline serum and bronchoalveolar lavage fluid IL-8 and serum VEGF levels were associated with shorter survival [34]. However, in a larger prospective cohort study, serum IL-8 level was not associated with survival, in which IL-6 and IL-12 serum concentrations were associated with significantly poorer survival [35]. These inconsistent findings indicate that further research is warranted to better understand the prognostic or predictive value of blood angiogenic factors and serum cytokines and should be validated in large prospective studies. In summary, although this is a randomized, phase II trial done with the limited number of patients, this study showed that maintenance therapy with vandetanib alone for patients with NSCLC after standard platinum-doublet chemotherapy prolonged PFS rate at 3 months compared with placebo, with manageable toxicities. Vandetanib maintenance warrants further investigation. Conflicts of interest statement Funding source: This study was sponsored by AstraZeneca. Financial disclosure: Keunchil Park has received honoraria from AstraZeneca, is currently receiving consulting fee from Roche, EliLilly and Pfizer, and is on the speaker’s bureau for Roche and Merck. For the remaining authors, none were declared. References [1] Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617–25. [2] Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–8.
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