Original article 239
Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study Pier F. Ferruccia, Ida Minchellab, Massimo Mosconic, Sara Gandinid, Francesco Verrecchiac, Emilia Cocorocchioa, Claudia Passonic, Chiara Paric, Alessandro Testoric, Paola Cocoe and Elisabetta Munzoneb The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/ progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2 ± 13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/ progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall
Introduction Metastatic melanoma (MM) is associated with a poor prognosis (median survival times range from 6 to 10 months [1]). Angiogenesis plays a key role in melanoma progression and metastatic dissemination, and several angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor and interleukin-8 (IL-8), are important mediators in this process [2]. So far, there is no clear consensus for a standard treatment of advanced melanoma, especially for triple-negative [BRAF, C-KIT, NRAS wild type (WT)] MM patients, whose therapeutic options are limited. Regulatory agencies approved dacarbazine (DTIC), IL-2 and ipilimumab for stage IV melanoma [1,3]. For patients with metastatic or unresectable tumours harbouring a BRAFV600 substitution, vemurafenib http://www.clinicaltrials.gov Identifier: NCT01164007. 0960-8931 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/ bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents. Melanoma Res 25:239–245 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Melanoma Research 2015, 25:239–245 Keywords: bevacizumab, combination therapy, dacarbazine, metastatic melanoma, unresectable melanoma, vascular endothelial growth factor a Oncology of Melanoma Unit, bEarly Drug Development for Innovative Therapies Division, cDermatoncological Division, dDepartment of Epidemiology and Biostatistics, European Institute of Oncology, Milan and eRoche S.p.A., Monza, Italy
Correspondence to Pier F. Ferrucci, MD, Oncology of Melanoma Unit, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy Tel: + 39 029 437 1094; fax: + 39 029 437 9230; e-mail: [email protected] Received 12 November 2014 Accepted 5 February 2015
and dabrafenib (BRAF inhibitors) along with trametinib (MEK inhibitor) are available, the latter to be used alone (not in case of previous anti-BRAF therapy) or in combination with dabrafenib [4–7]. Nevertheless, even if BRAF inhibitors resulted in prolonged overall survival (OS), the benefits of this therapy are usually transient, because of the rapid development of resistance [8]. More recently, the first anti-human programmed death receptor-1 antibodies have received accelerated approval by FDA (pembrolizumab and, in December 2014, nivolumab) and EMA (pembrolizumab) for unresectable/MM patients who progressed following ipilimumab or an anti-BRAF inhibitor [9–11], but more data on safety and efficacy are being collected. The chemotherapeutic drug DTIC has been used as a firstline treatment of MM since the 1970s [12]. Throughout the years, DTIC has been shown to improve tumour responses in metastatic patients, but has failed to prolong patients’ DOI: 10.1097/CMR.0000000000000146
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
240 Melanoma Research
2015, Vol 25 No 3
survival [1]. DTIC has been shown to upregulate IL-8 and VEGF transcription in melanoma cells, which may induce resistance to therapy and disease progression [13,14]. We hypothesize that the combined treatment of DTIC with antiangiogenic drugs may potentiate the therapeutic effects of DTIC alone by preventing the onset of such resistance. Bevacizumab is a humanized anti-VEGF antibody that can inhibit blood vessel growth [15]. This antiangiogenic drug is currently used in the treatment of metastatic colon cancer, non-small-cell lung cancer, renal-cell cancer, breast cancer and ovarian cancer [16–20]. Recently, the efficacy of bevacizumab-based therapy has also been shown in MM patients [21–25]. In a phase II trial carried out on 26 MM patients, treatment with bevacizumab, DTIC and daily low-dose interferon-α2a (IFN-α2a) induced an overall rate response (ORR) of 23% and a clinical benefit (CB) of 46% [22]. The median progression-free survival (PFS) and OS were 2.3 and 11.5 months, respectively, and four life-threatening adverse events (AEs) were observed. In a single-arm, open-label, phase II study, the efficacy of bevacizumab and fotemustine as a first-line treatment in 20 MM patients was assessed [23]. CB was observed in 65% of patients, whereas the median PFS was 8.3 months and survival was 20.5 months. Although these efficacy results were encouraging, the safety profile of the combination treatment was less positive. Indeed, 70% of patients experienced high-toxicity AEs (grade 3–4) and five of these patients discontinued treatment for safety reasons. Kim et al. [26] studied the effects of bevacizumab in combination with carboplatin and paclitaxel in 143 MM patients and observed an ORR of 25.5%. PFS and OS were 5.6 and 12.3 months, respectively, with AEs equal to or higher than grade 3 present in 57.4% of patients [26]. Von Moos et al. [27] assessed the efficacy of bevacizumab plus temozolomide in 62 MM patients. In this trial, ORR was 16.1%, PFS was 4.2 months and OS was 9.6 months; the incidence of serious AEs was 32% [27]. These studies show that a combinatorial treatment based on bevacizumab and chemotherapeutic agents may be beneficial to MM patients but also show the need to find a drug combination with an improved safety profile. The aim of the present study was to assess the preliminary antitumour activity of bevacizumab in combination with DTIC and to evaluate the toxicity and safety profile of the combination in previously untreated/unresectable MM patients.
Patients and methods Patient population
Patients included in this prospective, open-label, phase II study had clinical evidence of MM, unresectable regional lymphatic disease, and/or extensive in transit recurrent disease, and were chemotherapy-naive for metastatic disease. Other inclusion criteria were as follows: histologically or cytologically proven diagnosis;
Eastern Cooperative Oncology Group Performance Status 0–1; life expectancy of at least 12 weeks; and at least one measurable lesion according to ‘Response Evaluation Criteria in Solid Tumors’. The main exclusion criteria were as follows: previous therapy with IFN-α and/or cytokines; previous treatment with investigational antiangiogenic agents; radiotherapy to any site within 4 weeks before the study; and pregnant or lactating women. The study was carried out in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. The study protocol and the related study documentation were approved by an Independent Ethics Committee. All patients provided written informed consent. Treatment
Patients received DTIC intravenously 800 mg/m2 on day 1 and bevacizumab 10 mg/kg intravenously over 30–90 min on day 1 and day 15 of each 28-day treatment cycle. Treatment was continued on the basis of tumour assessment (every three cycles). Patients with stable disease (SD), complete or partial response (CR or PR) continued treatment until progressive disease (PD), unacceptable toxicity and patient/physician decision. Assessment
Baseline characteristics included a history of melanoma primary disease, concomitant therapies and diseases, medical history and vital signs. Primary and secondary efficacy analysis was based on the intention-to-treat (ITT) population. The primary efficacy parameter was ORR: the proportion of patients who achieved a CR or PR. CB, the proportion of patients who achieved CR or PR or SD, was also assessed. Patients with no tumour assessment after baseline were considered nonresponders. Secondary efficacy parameters included duration of response (DOR), duration of stable disease (DSD), time to progression/PFS (TTP/PFS), time to treatment failure and OS. The safety analysis included AEs and exposure to study treatment. AEs were graded according to the ‘National Cancer Institute Common Toxicity Criteria’ (NCI CTC), version 3.0. AEs related to study medications were followed up until they returned to baseline status or stabilized. Statistical analysis
According to a Simon’s two-stage optimal design [28], ORR up to 10% was considered unacceptable and ORR at least 30% as acceptable for a 5% significance level and 90% power. In the first stage of the study, 18 patients were required: if only up to two patients had experienced an objective response, the trial would have been closed because of poor response; if at least three patients had responded, the trial would have proceeded to the second stage by recruiting 18 more patients to reach a total of 36. With this sample size, assuming a recruitment of two patients per month and follow-up of all patients for a
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
DTIC/bevacizumab for metastatic melanoma Ferrucci et al. 241
minimum of 6 months, the study also had 90% power and a 5% significance level to detect a change in the median OS from 5 months (expected with DTIC alone) [29] to 10 months, and had 65% power (10% significance level) to detect a change in the median OS from 6 to 9 months. ORR was compared with the expected proportion used for sample size calculation (10%) using the one-sample exact binomial test. Statistical significance was assessed with a first type one-sided α error of 5%. A 95% one-sided confidence interval (CI) was provided using the exact binomial method. All secondary endpoints were presented by Kaplan–Meier survival plots and summarized by median and 95% CI. Descriptive statistics were used for safety analysis. All data were analysed using the SAS System for Windows, version 9.2 (SAS Institute Inc., Cary, North Carolina, USA).
patients died during the first-line phase. The median DOR was 16.9 months (95% CI: 5.8–). DSD was calculated for 18 ITT patients: 13 (72.2%) had PD during the first-line period (two with the BRAFV600E mutation); five (27.8%) were censored. None of these patients died during the first-line phase. The median DSD was 12.5 months (95% CI: 5.6–17.7; Fig. 1a). Thirty patients (81.1%) experienced PD during the study period and seven patients (18.92%) were censored. None of these patients died during the first-line phase. The median TTP/PFS was 5.5 months (95% CI: 3.0–10.9; Fig. 1b). Thirty-four patients (91.9%) experienced treatment failure during the first-line period. The median time to treatment failure was 3.1 months (95% CI: 2.6–8.8). During the entire study period, 30 patients (81.1%) died, whereas seven patients (18.9%) were censored. The median OS was 11.4 months (95% CI: 6.5–25.1; Fig. 1c).
Results Baseline characteristics
Safety
The study enrolled 40 patients between June 2006 and May 2012. The majority of patients (75%) discontinued from the first line of the study because of PD (75.0%) and the presence of AEs (12.5%). Table 1 shows the baseline demographic and clinical characteristics. The ITT population included 37 patients, 64.9% men (N = 24) and 35.1% women (N = 13). The mean age of the ITT patients was 54.2 ± 13.1 years (range 31–78) and they had a good performance status (0–1). Thirty-four patients (91.9%) had a surgical resection of the primary tumour at a mean age of 51.6 ± 13.7 years. Seven patients had only one metastatic site, 12 patients showed two metastases and 18 patients presented at least three metastases. The majority of patients (70.3%, N = 26) presented normal lactate dehydrogenase (LDH) levels; 21.6% of patients (N = 8) showed high LDH levels and 8.1% (N = 3) had low values. Finally, analysis of B-RAF and C-KIT mutational status showed that 57.1% (8/14) of the patients carried the BRAFV600E substitution, whereas no C-KIT mutation was identified (data not shown).
Patients were exposed to study treatment for 252.4 ± 245.5 days and followed up for 303.6 ± 343.2 days on average. Compliance with bevacizumab was 90.0 ± 13.4% and compliance with DTIC was 81.7 ± 14.9%. Almost all patients (35/37, 94.6%) experienced at least one AE. The most frequent AEs were gastrointestinal disorders (abdominal pain, upper abdominal pain, constipation, diarrhoea, dyspepsia, nausea, toothache, vomiting; N = 25; 67.6%), respiratory, thoracic and mediastinal disorders (cough, dysphonia, dyspnoea, epistaxis, oropharyngeal pain; N = 16; 43.2%) and general disorders and administration site conditions (asthenia; general physical health deterioration; mucosal inflammation; pyrexia; N = 15; 40.5%). AEs with a toxicity grade ≥ 3 occurred in eight patients (21.6%). Serious AEs were observed in five patients (13.5%). Drug-related AEs occurred in 24 patients (64.9%). At least 17 patients (46.0%) had an AE suspected to be related to chemotherapy and 12 patients (32.4%) had AEs suspected to be related to bevacizumab. The most common haematological AEs were anaemia (N = 4; 10.8%), leucopoenia (N = 5; 13.5%) and thrombocytopenia (N = 5; 13.5%), none of which was related to bevacizumab. Blood chemistry toxicities were serum glutamate pyruvate transaminase (N = 5; 13.5%) and glucose changing from normal to high values (N = 5; 13.5%). High LDH values were found in 12 patients (32.4%) at the end of the study, five of them coming from normal values at baseline. Proteinuria was recorded in four patients (10.8%) and was suspected to be related to bevacizumab. No significant differences were observed in the temporal profiles of body weight, body surface area and sitting pulse rate, as well as systolic and diastolic blood pressure. No new toxicity of bevacizumab occurred as a result of this study. One patient died from cardiac failure unrelated to the study drug and 17 patients died after first-line study discontinuation, but before the first follow-up visit; 13 patients died after the first follow-up visit.
Efficacy Primary efficacy parameter
The best ORR are presented in Table 2. In the ITT population, a response was achieved by seven patients (18.9%): two patients showed CR (both harbouring the BRAFV600E mutation) and five patients achieved PR. Eleven patients achieved SD (four were V600E-positive), which resulted in a CB of 48.6% (18/37). Compared with the expected proportion under null hypothesis, the difference was almost significant (P = 0.071) with a onesided confidence limit of 0.09. Secondary efficacy parameters
DOR (CR or PR) was calculated for seven ITT patients: four patients (57.1%) experienced PD during the firstline period; the rest (N = 3; 42.9%) were censored (alive without an objectively documented PD). None of those
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
242 Melanoma Research
Table 1
2015, Vol 25 No 3
Baseline patient characteristics
Characteristics Total recruitment ITT population Age (years) Median (range) Mean ± SD Sex Males Females ECOG-PS 0 1 Medical conditions Past Active Hypertension Melanoma primary disease history Age at diagnosis (years) Median (range) Mean ± SD Status at first diagnosis Primary operable Regional metastases Metastatic Location at first diagnosis Face/head/scalp Chest/trunk Dorsal/back Arms Legs Feet Vulvar region Unknown Previous treatments (adjuvant or neoadjuvant) Interferon Radiotherapy None N of metastases for each patient 1 2 ≥3 LDH level at baseline High Low Normal
Value [N (%)]
a
40 (100) 37 (92.5) 56 (31–78) 54.2 ± 13.1 24 (64.9) 13 (35.1) 36 (97.3) 1 (2.7) 10 (27.0) 25 (67.6) 10 (27.0)
50 (14–77) 50.4 ± 14.6 34 (91.9) 1 (2.7) 2 (5.4) 4 3 13 4 3 7 1 2
(10.8) (8.1) (35.1) (10.8) (8.1) (18.9) (2.7) (5.4)
8 (21.6) 1 (2.7) 29 (78.4) 7 (18.9) 12 (32.4) 18 (48.6) 8 (21.6) 3 (8.1) 26 (70.3)
ECOG-PS, Eastern Cooperative Oncology Group Performance Status; ITT, intention-to-treat; LDH, lactate dehydrogenase. a Values reported as number of patients and, in parentheses, percentage on total number of patients, unless specified otherwise.
Table 2 Best overall response rates of the ITT population (primary efficacy parameter) Value [N (%)]a CR (best overall response) PR ORR (CR + PR) SD CB (CR + PR + SD) PD Missing assessment
2 5 7 11 18 10 9
(5.4) (13.5) (18.9) (29.7) (48.6) (27.0) (24.3)
CB, clinical benefit; CR, complete response; ITT, intention-to-treat; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. a Values reported as number of patients and, in parentheses, percentage on the total number of patients.
Discussion Despite being used in MM treatment for the past 40 years, patient response to DTIC monotherapy is limited and transient [12]. In addition, treatment with
DTIC may enhance angiogenesis by upregulating the transcription of IL-8 and VEGF [13]. In this study, we aimed to improve ORR in unresectable MM by testing a clinical protocol that combines the antiangiogenic drug bevacizumab with DTIC. Results from this trial show that DTIC/bevacizumab combination therapy can induce longer responses in MM patients than DTIC monotherapy. Our primary objective was to assess the preliminary antitumour activity of bevacizumab and DTIC in terms of ORR (CR and PR) in MM. At the end of the study, seven patients (18.9%) achieved a CR or PR with a median DOR of 16.9 months, which, however, was not significantly different from the null hypothesis (P = 0.071). Yet, a CB was obtained in 18 ITT patients (48.6%); in these patients, a median DSD of 12.5 months was observed, meaning that disease control could be durable, especially in responding patients, such as the two experiencing CR, who are still in CR after almost 5 years. Notably, both of them belong to the group of patients carrying the BRAFV600E allele (n = 8), together with four patients with SD and two with early PD. Recent phase III randomized trials for advanced melanoma have registered ORR to DTIC alone that ranged from 5 to 15% [30–34]. Of note, the median duration of such responses was less than 8 months [33,34], a result much lower than that observed in the present trial. The CB observed in these trials is variable (24–56%). Eighty-one percent of patients who followed our clinical protocol had PD or died from any cause during the study period. However, at the best response rate, only 27% showed PD, a lower percentage than that described in the literature for PD in patients treated with DTIC alone: Middleton et al. [34] described PD in 56% of patients, whereas Schadendorf et al. [32] observed PD in 70.9% of the ITT population. In comparison with the above studies, the median TTP/PFS observed in response to DTIC/bevacizumab was considerably higher (6 months from the first day of treatment administration vs. 3 months). No patient died during the first-line phase. Considering OS, 50% of patients at risk had died at 11.4 months after the start of treatment, 25% had died at 5 months and 25% were still alive at 31 months. The median OS (11.4 months) after combined treatment DTIC/bevacizumab was therefore longer than, or similar to, survival following treatments with only DTIC [33,34]. Treatment was well tolerated. High-toxicity AEs were observed in only eight patients (21.6%). Most of the patients experiencing AEs had gastrointestinal disorders, including constipation and nausea. Although five patients (13.5%) had serious AEs, only one AE (cardiac failure) – not related to the study drug – resulted in death. AEs related to bevacizumab alone were observed in 32.4% of patients, but no new toxicity related to bevacizumab emerged as a result of this study.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
DTIC/bevacizumab for metastatic melanoma Ferrucci et al. 243
Fig. 1
(b)
1
Events Total 13 18
Probability of event free
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
1
Probability of time to progression
(a)
Events Total 30 37
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
0
3
6
9
12
15
18
21
24
27
0
2
4
6
Months since baseline visit Number of 18 patients at risk
17
12
10
8
7
4
(c)
8
10
12 14
16
18
20
22
24
26 28
3
2
1
Months since baseline visit 3
1
0
Number of 37 patients at risk
29
18
15
12
11
8
7
7
5
3
0
Probability of overall survival
1 Events Total 30 37
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Months since baseline visit Number of 37 34 26 23 18 16 14 13 13 10 10 5 4 4 4 4 4 2 1 1 1 0 patients at risk
Kaplan–Meier plots. (a) Duration of response: stable disease (DSD). Median DSD = 12.5 months [95% CI: 5.6–17.7]. (b) Time to progression/ progression-free survival (TTP/PFS). Median TTP/PFS = 5.5 months [95% CI: 3.0–10.9]. (c) Overall survival (OS). Median OS = 11.4 months [95% CI: 6.5–25.1]. CI, confidence interval.
Bevacizumab has been tested in MM treatment either as a monotherapy [24] or in association with chemotherapeutic agents, with promising results [22,23,25–27]. The outcomes of our clinical trial confirm the findings of these studies and point towards bevacizumab as a potential agent that could lengthen the DOR (both patients in CR after almost 5 years presented the V600E substitution, as well as four with SD) and OS when associated with DTIC. In addition, the drug combination tested in the present trial showed a better safety profile than other combinatorial treatments based on bevacizumab. In a phase II trial of bevacizumab with DTIC and IFN-α, grade 3–4 AEs occurred in 38.5% of MM patients [22]. A study by Del Vecchio et al. [23] showed that fotemustine and bevacizumab induced favourable responses rates (15% ORR; 65% CB) as well as long PFS and OS times (8.3 and 20.5 months, respectively), but observed AEs of grade 3/4 in 70% of patients. Similarly, the study carried
out by Kim et al. [26] described high-toxicity AEs in 57.4% of MM patients treated with bevacizumab combined with carboplatin and paclitaxel. In a multicentre phase II trial assessing the efficacy of bevacizumab in combination with temozolomide, serious AEs occurred in 32% of MM patients [27]. Our clinical protocol shows equivalent efficacy results with less toxicity (21.6 vs. 38.5% and 70 and 57.4%) and fewer incidences of serious AEs (13.5 vs. 32%). Since our study started in 2006, new treatments have been approved for MM [35]. In phase III randomized clinical trials, the anticytotoxic T-lymphocyte antigen-4 monoclonal antibody ipilimumab has been shown to improve the survival of MM patients treated previously with chemotherapy and whose disease had progressed and, in combination with DTIC, to increase survival times in untreated MM patients [36,37]. In addition,
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
244 Melanoma Research
2015, Vol 25 No 3
targeted therapies against BRAF mutations, which are present in 50% of melanomas, have also been approved recently [3]. In a phase III randomized clinical trial enrolling untreated MM patients, the BRAF inhibitor vemurafenib was shown to induce response rates of 48% against 5% observed in the DTIC arm [4]. Dabrafenib, another inhibitor of BRAF mutations, improved PFS in patients with MM in comparison with DTIC (5.1 vs. 2.1 months) [38]. However, for BRAF WT and nonresponding MM patients, better clinical options are needed. In two recent studies, chemotherapy regimens combined with bevacizumab have been shown to improve responses in sub-sets of patients, such as LDH high and BRAF WT MM patients [26,27]. In contrast, although the sample size was small, our results indicate that patients with the BRAF mutation are more likely to respond to Bevacizumab, as reported recently in the adjuvant setting [39]. In this new and broadened therapeutic scenario, the role of DTIC/bevacizumab combination therapy in MM has clearly changed; however, our results indicate that this drug combination may still be an option that should be evaluated in particular subgroups of patients. A further randomized phase III trial will help clarify and confirm these findings.
9
10
11
12
13
14
15
16
17
18
Acknowledgements The authors thank S. Mogavero, PhD, and R. Carvalhosa, PhD (Primula Multimedia S.r.L. Pisa, Italy) for writing and editorial assistance, which was funded by Roche.
19
20
This work was supported by F. Hoffmann-La Roche Ltd (ML18727).
21
Conflicts of interest
22
P.F.F. and A.T. have participated in advisory boards sponsored by GSK, BMS and Roche. P.C. is an employee of Roche. For the remaining authors there are no conflicts of interest.
References 1
2 3
4
5
6
7
8
Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011; 16:5–24. Streit M, Detmar M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene 2003; 22:3172–3179. Tentori L, Lacal PM, Graziani G. Challenging resistance mechanisms to therapies for metastatic melanoma. Trends Pharmacol Sci 2013; 34:656–666. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507–2516. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367:1694–1703. Menzies AM, Long GV. Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Clin Cancer Res 2014; 20:2035–2043. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372:30–39. Trunzer K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE, et al. Pharmacodynamic effects and mechanisms of resistance to
23
24
25
26
27
28 29
vemurafenib in patients with metastatic melanoma. J Clin Oncol 2013; 31:1767–1774. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumabrefractory or -naive melanoma. J Clin Oncol 2013; 31:4311–4318. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:134–144. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014; 32:1020–1030. Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res 2000; 19:21–34. Lev DC, Ruiz M, Mills L, McGary EC, Price JE, Bar-Eli M. Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther 2003; 2:753–763. Lev DC, Onn A, Melinkova VO, Miller C, Stone V, Ruiz M, et al. Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol 2004; 22:2092–2100. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3:391–400. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–2342. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542–2550. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349:427–434. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357:2666–2676. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365:2473–2483. Varker KA, Biber JE, Kefauver C, Jensen R, Lehman A, Young D, et al. A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma. Ann Surg Oncol 2007; 14:2367–2376. Vihinen PP, Hernberg M, Vuoristo MS, Tyynelä K, Laukka M, Lundin J, et al. A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-alpha2a as first line treatment in metastatic melanoma. Melanoma Res 2010; 20:318–325. Del Vecchio M, Mortarini R, Canova S, Di Guardo L, Pimpinelli N, Sertoli MR, et al. Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors. Clin Cancer Res 2010; 16:5862–5872. Schuster C, Eikesdal HP, Puntervoll H, Geisler J, Geisler S, Heinrich D, et al. Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension. PLoS One 2012; 7:e38364. Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, et al. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer 2013; 119:586–592. Kim KB, Sosman JA, Fruehauf JP, Linette GP, Markovic SN, McDermott DF, et al. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol 2012; 30:34–41. Von Moos R, Seifert B, Simcock M, Goldinger SM, Gillessen S, Ochsenbein A, et al. Swiss Group for Clinical Cancer Research (SAKK). First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07). Ann Oncol 2012; 23:531–536. Koyama T, Chen H. Proper inference from Simon’s two-stage designs. Stat Med 2008; 27:3145–3154. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 2004; 22:1118–1125.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
DTIC/bevacizumab for metastatic melanoma Ferrucci et al. 245
30
Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17:2745–2751. 31 Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006; 24:4738–4745. 32 Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, et al. DC study group of the DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 2006; 17:563–570. 33 McDermott DF, Sosman JA, Gonzalez R, Hodi FS, Linette GP, Richards J, et al. Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol 2008; 26:2178–2185. 34 Middleton M, Hauschild A, Thomson D, Anderson R, Burdette-Radoux S, Gehlsen K, et al. Results of a multicenter randomized study to evaluate the
35
36
37
38
39
safety and efficacy of combined immunotherapy with interleukin-2, interferon{alpha}2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma. Ann Oncol 2007; 18:1691–1697. Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann Oncol 2012; 23 (Suppl 8):viii15–viii21. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711–723. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364:2517–2526. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, openlabel, phase 3 randomised controlled trial. Lancet 2012; 380:358–365. Corrie PG, Marshall A, Dunn JA, Middleton MR, Nathan PD, Gore M, et al. Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. Lancet Oncol 2014; 15:620–630.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study Pier F. Ferruccia, Ida Minchellab, Massimo Mosconic, Sara Gandinid, Francesco Verrecchiac, Emilia Cocorocchioa, Claudia Passonic, Chiara Paric, Alessandro Testoric, Paola Cocoe and Elisabetta Munzoneb The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/ progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2 ± 13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/ progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall
Introduction Metastatic melanoma (MM) is associated with a poor prognosis (median survival times range from 6 to 10 months [1]). Angiogenesis plays a key role in melanoma progression and metastatic dissemination, and several angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor and interleukin-8 (IL-8), are important mediators in this process [2]. So far, there is no clear consensus for a standard treatment of advanced melanoma, especially for triple-negative [BRAF, C-KIT, NRAS wild type (WT)] MM patients, whose therapeutic options are limited. Regulatory agencies approved dacarbazine (DTIC), IL-2 and ipilimumab for stage IV melanoma [1,3]. For patients with metastatic or unresectable tumours harbouring a BRAFV600 substitution, vemurafenib http://www.clinicaltrials.gov Identifier: NCT01164007. 0960-8931 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/ bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents. Melanoma Res 25:239–245 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Melanoma Research 2015, 25:239–245 Keywords: bevacizumab, combination therapy, dacarbazine, metastatic melanoma, unresectable melanoma, vascular endothelial growth factor a Oncology of Melanoma Unit, bEarly Drug Development for Innovative Therapies Division, cDermatoncological Division, dDepartment of Epidemiology and Biostatistics, European Institute of Oncology, Milan and eRoche S.p.A., Monza, Italy
Correspondence to Pier F. Ferrucci, MD, Oncology of Melanoma Unit, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy Tel: + 39 029 437 1094; fax: + 39 029 437 9230; e-mail: [email protected] Received 12 November 2014 Accepted 5 February 2015
and dabrafenib (BRAF inhibitors) along with trametinib (MEK inhibitor) are available, the latter to be used alone (not in case of previous anti-BRAF therapy) or in combination with dabrafenib [4–7]. Nevertheless, even if BRAF inhibitors resulted in prolonged overall survival (OS), the benefits of this therapy are usually transient, because of the rapid development of resistance [8]. More recently, the first anti-human programmed death receptor-1 antibodies have received accelerated approval by FDA (pembrolizumab and, in December 2014, nivolumab) and EMA (pembrolizumab) for unresectable/MM patients who progressed following ipilimumab or an anti-BRAF inhibitor [9–11], but more data on safety and efficacy are being collected. The chemotherapeutic drug DTIC has been used as a firstline treatment of MM since the 1970s [12]. Throughout the years, DTIC has been shown to improve tumour responses in metastatic patients, but has failed to prolong patients’ DOI: 10.1097/CMR.0000000000000146
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
240 Melanoma Research
2015, Vol 25 No 3
survival [1]. DTIC has been shown to upregulate IL-8 and VEGF transcription in melanoma cells, which may induce resistance to therapy and disease progression [13,14]. We hypothesize that the combined treatment of DTIC with antiangiogenic drugs may potentiate the therapeutic effects of DTIC alone by preventing the onset of such resistance. Bevacizumab is a humanized anti-VEGF antibody that can inhibit blood vessel growth [15]. This antiangiogenic drug is currently used in the treatment of metastatic colon cancer, non-small-cell lung cancer, renal-cell cancer, breast cancer and ovarian cancer [16–20]. Recently, the efficacy of bevacizumab-based therapy has also been shown in MM patients [21–25]. In a phase II trial carried out on 26 MM patients, treatment with bevacizumab, DTIC and daily low-dose interferon-α2a (IFN-α2a) induced an overall rate response (ORR) of 23% and a clinical benefit (CB) of 46% [22]. The median progression-free survival (PFS) and OS were 2.3 and 11.5 months, respectively, and four life-threatening adverse events (AEs) were observed. In a single-arm, open-label, phase II study, the efficacy of bevacizumab and fotemustine as a first-line treatment in 20 MM patients was assessed [23]. CB was observed in 65% of patients, whereas the median PFS was 8.3 months and survival was 20.5 months. Although these efficacy results were encouraging, the safety profile of the combination treatment was less positive. Indeed, 70% of patients experienced high-toxicity AEs (grade 3–4) and five of these patients discontinued treatment for safety reasons. Kim et al. [26] studied the effects of bevacizumab in combination with carboplatin and paclitaxel in 143 MM patients and observed an ORR of 25.5%. PFS and OS were 5.6 and 12.3 months, respectively, with AEs equal to or higher than grade 3 present in 57.4% of patients [26]. Von Moos et al. [27] assessed the efficacy of bevacizumab plus temozolomide in 62 MM patients. In this trial, ORR was 16.1%, PFS was 4.2 months and OS was 9.6 months; the incidence of serious AEs was 32% [27]. These studies show that a combinatorial treatment based on bevacizumab and chemotherapeutic agents may be beneficial to MM patients but also show the need to find a drug combination with an improved safety profile. The aim of the present study was to assess the preliminary antitumour activity of bevacizumab in combination with DTIC and to evaluate the toxicity and safety profile of the combination in previously untreated/unresectable MM patients.
Patients and methods Patient population
Patients included in this prospective, open-label, phase II study had clinical evidence of MM, unresectable regional lymphatic disease, and/or extensive in transit recurrent disease, and were chemotherapy-naive for metastatic disease. Other inclusion criteria were as follows: histologically or cytologically proven diagnosis;
Eastern Cooperative Oncology Group Performance Status 0–1; life expectancy of at least 12 weeks; and at least one measurable lesion according to ‘Response Evaluation Criteria in Solid Tumors’. The main exclusion criteria were as follows: previous therapy with IFN-α and/or cytokines; previous treatment with investigational antiangiogenic agents; radiotherapy to any site within 4 weeks before the study; and pregnant or lactating women. The study was carried out in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. The study protocol and the related study documentation were approved by an Independent Ethics Committee. All patients provided written informed consent. Treatment
Patients received DTIC intravenously 800 mg/m2 on day 1 and bevacizumab 10 mg/kg intravenously over 30–90 min on day 1 and day 15 of each 28-day treatment cycle. Treatment was continued on the basis of tumour assessment (every three cycles). Patients with stable disease (SD), complete or partial response (CR or PR) continued treatment until progressive disease (PD), unacceptable toxicity and patient/physician decision. Assessment
Baseline characteristics included a history of melanoma primary disease, concomitant therapies and diseases, medical history and vital signs. Primary and secondary efficacy analysis was based on the intention-to-treat (ITT) population. The primary efficacy parameter was ORR: the proportion of patients who achieved a CR or PR. CB, the proportion of patients who achieved CR or PR or SD, was also assessed. Patients with no tumour assessment after baseline were considered nonresponders. Secondary efficacy parameters included duration of response (DOR), duration of stable disease (DSD), time to progression/PFS (TTP/PFS), time to treatment failure and OS. The safety analysis included AEs and exposure to study treatment. AEs were graded according to the ‘National Cancer Institute Common Toxicity Criteria’ (NCI CTC), version 3.0. AEs related to study medications were followed up until they returned to baseline status or stabilized. Statistical analysis
According to a Simon’s two-stage optimal design [28], ORR up to 10% was considered unacceptable and ORR at least 30% as acceptable for a 5% significance level and 90% power. In the first stage of the study, 18 patients were required: if only up to two patients had experienced an objective response, the trial would have been closed because of poor response; if at least three patients had responded, the trial would have proceeded to the second stage by recruiting 18 more patients to reach a total of 36. With this sample size, assuming a recruitment of two patients per month and follow-up of all patients for a
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
DTIC/bevacizumab for metastatic melanoma Ferrucci et al. 241
minimum of 6 months, the study also had 90% power and a 5% significance level to detect a change in the median OS from 5 months (expected with DTIC alone) [29] to 10 months, and had 65% power (10% significance level) to detect a change in the median OS from 6 to 9 months. ORR was compared with the expected proportion used for sample size calculation (10%) using the one-sample exact binomial test. Statistical significance was assessed with a first type one-sided α error of 5%. A 95% one-sided confidence interval (CI) was provided using the exact binomial method. All secondary endpoints were presented by Kaplan–Meier survival plots and summarized by median and 95% CI. Descriptive statistics were used for safety analysis. All data were analysed using the SAS System for Windows, version 9.2 (SAS Institute Inc., Cary, North Carolina, USA).
patients died during the first-line phase. The median DOR was 16.9 months (95% CI: 5.8–). DSD was calculated for 18 ITT patients: 13 (72.2%) had PD during the first-line period (two with the BRAFV600E mutation); five (27.8%) were censored. None of these patients died during the first-line phase. The median DSD was 12.5 months (95% CI: 5.6–17.7; Fig. 1a). Thirty patients (81.1%) experienced PD during the study period and seven patients (18.92%) were censored. None of these patients died during the first-line phase. The median TTP/PFS was 5.5 months (95% CI: 3.0–10.9; Fig. 1b). Thirty-four patients (91.9%) experienced treatment failure during the first-line period. The median time to treatment failure was 3.1 months (95% CI: 2.6–8.8). During the entire study period, 30 patients (81.1%) died, whereas seven patients (18.9%) were censored. The median OS was 11.4 months (95% CI: 6.5–25.1; Fig. 1c).
Results Baseline characteristics
Safety
The study enrolled 40 patients between June 2006 and May 2012. The majority of patients (75%) discontinued from the first line of the study because of PD (75.0%) and the presence of AEs (12.5%). Table 1 shows the baseline demographic and clinical characteristics. The ITT population included 37 patients, 64.9% men (N = 24) and 35.1% women (N = 13). The mean age of the ITT patients was 54.2 ± 13.1 years (range 31–78) and they had a good performance status (0–1). Thirty-four patients (91.9%) had a surgical resection of the primary tumour at a mean age of 51.6 ± 13.7 years. Seven patients had only one metastatic site, 12 patients showed two metastases and 18 patients presented at least three metastases. The majority of patients (70.3%, N = 26) presented normal lactate dehydrogenase (LDH) levels; 21.6% of patients (N = 8) showed high LDH levels and 8.1% (N = 3) had low values. Finally, analysis of B-RAF and C-KIT mutational status showed that 57.1% (8/14) of the patients carried the BRAFV600E substitution, whereas no C-KIT mutation was identified (data not shown).
Patients were exposed to study treatment for 252.4 ± 245.5 days and followed up for 303.6 ± 343.2 days on average. Compliance with bevacizumab was 90.0 ± 13.4% and compliance with DTIC was 81.7 ± 14.9%. Almost all patients (35/37, 94.6%) experienced at least one AE. The most frequent AEs were gastrointestinal disorders (abdominal pain, upper abdominal pain, constipation, diarrhoea, dyspepsia, nausea, toothache, vomiting; N = 25; 67.6%), respiratory, thoracic and mediastinal disorders (cough, dysphonia, dyspnoea, epistaxis, oropharyngeal pain; N = 16; 43.2%) and general disorders and administration site conditions (asthenia; general physical health deterioration; mucosal inflammation; pyrexia; N = 15; 40.5%). AEs with a toxicity grade ≥ 3 occurred in eight patients (21.6%). Serious AEs were observed in five patients (13.5%). Drug-related AEs occurred in 24 patients (64.9%). At least 17 patients (46.0%) had an AE suspected to be related to chemotherapy and 12 patients (32.4%) had AEs suspected to be related to bevacizumab. The most common haematological AEs were anaemia (N = 4; 10.8%), leucopoenia (N = 5; 13.5%) and thrombocytopenia (N = 5; 13.5%), none of which was related to bevacizumab. Blood chemistry toxicities were serum glutamate pyruvate transaminase (N = 5; 13.5%) and glucose changing from normal to high values (N = 5; 13.5%). High LDH values were found in 12 patients (32.4%) at the end of the study, five of them coming from normal values at baseline. Proteinuria was recorded in four patients (10.8%) and was suspected to be related to bevacizumab. No significant differences were observed in the temporal profiles of body weight, body surface area and sitting pulse rate, as well as systolic and diastolic blood pressure. No new toxicity of bevacizumab occurred as a result of this study. One patient died from cardiac failure unrelated to the study drug and 17 patients died after first-line study discontinuation, but before the first follow-up visit; 13 patients died after the first follow-up visit.
Efficacy Primary efficacy parameter
The best ORR are presented in Table 2. In the ITT population, a response was achieved by seven patients (18.9%): two patients showed CR (both harbouring the BRAFV600E mutation) and five patients achieved PR. Eleven patients achieved SD (four were V600E-positive), which resulted in a CB of 48.6% (18/37). Compared with the expected proportion under null hypothesis, the difference was almost significant (P = 0.071) with a onesided confidence limit of 0.09. Secondary efficacy parameters
DOR (CR or PR) was calculated for seven ITT patients: four patients (57.1%) experienced PD during the firstline period; the rest (N = 3; 42.9%) were censored (alive without an objectively documented PD). None of those
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
242 Melanoma Research
Table 1
2015, Vol 25 No 3
Baseline patient characteristics
Characteristics Total recruitment ITT population Age (years) Median (range) Mean ± SD Sex Males Females ECOG-PS 0 1 Medical conditions Past Active Hypertension Melanoma primary disease history Age at diagnosis (years) Median (range) Mean ± SD Status at first diagnosis Primary operable Regional metastases Metastatic Location at first diagnosis Face/head/scalp Chest/trunk Dorsal/back Arms Legs Feet Vulvar region Unknown Previous treatments (adjuvant or neoadjuvant) Interferon Radiotherapy None N of metastases for each patient 1 2 ≥3 LDH level at baseline High Low Normal
Value [N (%)]
a
40 (100) 37 (92.5) 56 (31–78) 54.2 ± 13.1 24 (64.9) 13 (35.1) 36 (97.3) 1 (2.7) 10 (27.0) 25 (67.6) 10 (27.0)
50 (14–77) 50.4 ± 14.6 34 (91.9) 1 (2.7) 2 (5.4) 4 3 13 4 3 7 1 2
(10.8) (8.1) (35.1) (10.8) (8.1) (18.9) (2.7) (5.4)
8 (21.6) 1 (2.7) 29 (78.4) 7 (18.9) 12 (32.4) 18 (48.6) 8 (21.6) 3 (8.1) 26 (70.3)
ECOG-PS, Eastern Cooperative Oncology Group Performance Status; ITT, intention-to-treat; LDH, lactate dehydrogenase. a Values reported as number of patients and, in parentheses, percentage on total number of patients, unless specified otherwise.
Table 2 Best overall response rates of the ITT population (primary efficacy parameter) Value [N (%)]a CR (best overall response) PR ORR (CR + PR) SD CB (CR + PR + SD) PD Missing assessment
2 5 7 11 18 10 9
(5.4) (13.5) (18.9) (29.7) (48.6) (27.0) (24.3)
CB, clinical benefit; CR, complete response; ITT, intention-to-treat; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. a Values reported as number of patients and, in parentheses, percentage on the total number of patients.
Discussion Despite being used in MM treatment for the past 40 years, patient response to DTIC monotherapy is limited and transient [12]. In addition, treatment with
DTIC may enhance angiogenesis by upregulating the transcription of IL-8 and VEGF [13]. In this study, we aimed to improve ORR in unresectable MM by testing a clinical protocol that combines the antiangiogenic drug bevacizumab with DTIC. Results from this trial show that DTIC/bevacizumab combination therapy can induce longer responses in MM patients than DTIC monotherapy. Our primary objective was to assess the preliminary antitumour activity of bevacizumab and DTIC in terms of ORR (CR and PR) in MM. At the end of the study, seven patients (18.9%) achieved a CR or PR with a median DOR of 16.9 months, which, however, was not significantly different from the null hypothesis (P = 0.071). Yet, a CB was obtained in 18 ITT patients (48.6%); in these patients, a median DSD of 12.5 months was observed, meaning that disease control could be durable, especially in responding patients, such as the two experiencing CR, who are still in CR after almost 5 years. Notably, both of them belong to the group of patients carrying the BRAFV600E allele (n = 8), together with four patients with SD and two with early PD. Recent phase III randomized trials for advanced melanoma have registered ORR to DTIC alone that ranged from 5 to 15% [30–34]. Of note, the median duration of such responses was less than 8 months [33,34], a result much lower than that observed in the present trial. The CB observed in these trials is variable (24–56%). Eighty-one percent of patients who followed our clinical protocol had PD or died from any cause during the study period. However, at the best response rate, only 27% showed PD, a lower percentage than that described in the literature for PD in patients treated with DTIC alone: Middleton et al. [34] described PD in 56% of patients, whereas Schadendorf et al. [32] observed PD in 70.9% of the ITT population. In comparison with the above studies, the median TTP/PFS observed in response to DTIC/bevacizumab was considerably higher (6 months from the first day of treatment administration vs. 3 months). No patient died during the first-line phase. Considering OS, 50% of patients at risk had died at 11.4 months after the start of treatment, 25% had died at 5 months and 25% were still alive at 31 months. The median OS (11.4 months) after combined treatment DTIC/bevacizumab was therefore longer than, or similar to, survival following treatments with only DTIC [33,34]. Treatment was well tolerated. High-toxicity AEs were observed in only eight patients (21.6%). Most of the patients experiencing AEs had gastrointestinal disorders, including constipation and nausea. Although five patients (13.5%) had serious AEs, only one AE (cardiac failure) – not related to the study drug – resulted in death. AEs related to bevacizumab alone were observed in 32.4% of patients, but no new toxicity related to bevacizumab emerged as a result of this study.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
DTIC/bevacizumab for metastatic melanoma Ferrucci et al. 243
Fig. 1
(b)
1
Events Total 13 18
Probability of event free
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
1
Probability of time to progression
(a)
Events Total 30 37
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
0
3
6
9
12
15
18
21
24
27
0
2
4
6
Months since baseline visit Number of 18 patients at risk
17
12
10
8
7
4
(c)
8
10
12 14
16
18
20
22
24
26 28
3
2
1
Months since baseline visit 3
1
0
Number of 37 patients at risk
29
18
15
12
11
8
7
7
5
3
0
Probability of overall survival
1 Events Total 30 37
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Months since baseline visit Number of 37 34 26 23 18 16 14 13 13 10 10 5 4 4 4 4 4 2 1 1 1 0 patients at risk
Kaplan–Meier plots. (a) Duration of response: stable disease (DSD). Median DSD = 12.5 months [95% CI: 5.6–17.7]. (b) Time to progression/ progression-free survival (TTP/PFS). Median TTP/PFS = 5.5 months [95% CI: 3.0–10.9]. (c) Overall survival (OS). Median OS = 11.4 months [95% CI: 6.5–25.1]. CI, confidence interval.
Bevacizumab has been tested in MM treatment either as a monotherapy [24] or in association with chemotherapeutic agents, with promising results [22,23,25–27]. The outcomes of our clinical trial confirm the findings of these studies and point towards bevacizumab as a potential agent that could lengthen the DOR (both patients in CR after almost 5 years presented the V600E substitution, as well as four with SD) and OS when associated with DTIC. In addition, the drug combination tested in the present trial showed a better safety profile than other combinatorial treatments based on bevacizumab. In a phase II trial of bevacizumab with DTIC and IFN-α, grade 3–4 AEs occurred in 38.5% of MM patients [22]. A study by Del Vecchio et al. [23] showed that fotemustine and bevacizumab induced favourable responses rates (15% ORR; 65% CB) as well as long PFS and OS times (8.3 and 20.5 months, respectively), but observed AEs of grade 3/4 in 70% of patients. Similarly, the study carried
out by Kim et al. [26] described high-toxicity AEs in 57.4% of MM patients treated with bevacizumab combined with carboplatin and paclitaxel. In a multicentre phase II trial assessing the efficacy of bevacizumab in combination with temozolomide, serious AEs occurred in 32% of MM patients [27]. Our clinical protocol shows equivalent efficacy results with less toxicity (21.6 vs. 38.5% and 70 and 57.4%) and fewer incidences of serious AEs (13.5 vs. 32%). Since our study started in 2006, new treatments have been approved for MM [35]. In phase III randomized clinical trials, the anticytotoxic T-lymphocyte antigen-4 monoclonal antibody ipilimumab has been shown to improve the survival of MM patients treated previously with chemotherapy and whose disease had progressed and, in combination with DTIC, to increase survival times in untreated MM patients [36,37]. In addition,
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
244 Melanoma Research
2015, Vol 25 No 3
targeted therapies against BRAF mutations, which are present in 50% of melanomas, have also been approved recently [3]. In a phase III randomized clinical trial enrolling untreated MM patients, the BRAF inhibitor vemurafenib was shown to induce response rates of 48% against 5% observed in the DTIC arm [4]. Dabrafenib, another inhibitor of BRAF mutations, improved PFS in patients with MM in comparison with DTIC (5.1 vs. 2.1 months) [38]. However, for BRAF WT and nonresponding MM patients, better clinical options are needed. In two recent studies, chemotherapy regimens combined with bevacizumab have been shown to improve responses in sub-sets of patients, such as LDH high and BRAF WT MM patients [26,27]. In contrast, although the sample size was small, our results indicate that patients with the BRAF mutation are more likely to respond to Bevacizumab, as reported recently in the adjuvant setting [39]. In this new and broadened therapeutic scenario, the role of DTIC/bevacizumab combination therapy in MM has clearly changed; however, our results indicate that this drug combination may still be an option that should be evaluated in particular subgroups of patients. A further randomized phase III trial will help clarify and confirm these findings.
9
10
11
12
13
14
15
16
17
18
Acknowledgements The authors thank S. Mogavero, PhD, and R. Carvalhosa, PhD (Primula Multimedia S.r.L. Pisa, Italy) for writing and editorial assistance, which was funded by Roche.
19
20
This work was supported by F. Hoffmann-La Roche Ltd (ML18727).
21
Conflicts of interest
22
P.F.F. and A.T. have participated in advisory boards sponsored by GSK, BMS and Roche. P.C. is an employee of Roche. For the remaining authors there are no conflicts of interest.
References 1
2 3
4
5
6
7
8
Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011; 16:5–24. Streit M, Detmar M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene 2003; 22:3172–3179. Tentori L, Lacal PM, Graziani G. Challenging resistance mechanisms to therapies for metastatic melanoma. Trends Pharmacol Sci 2013; 34:656–666. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507–2516. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367:1694–1703. Menzies AM, Long GV. Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Clin Cancer Res 2014; 20:2035–2043. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372:30–39. Trunzer K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE, et al. Pharmacodynamic effects and mechanisms of resistance to
23
24
25
26
27
28 29
vemurafenib in patients with metastatic melanoma. J Clin Oncol 2013; 31:1767–1774. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumabrefractory or -naive melanoma. J Clin Oncol 2013; 31:4311–4318. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:134–144. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014; 32:1020–1030. Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res 2000; 19:21–34. Lev DC, Ruiz M, Mills L, McGary EC, Price JE, Bar-Eli M. Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther 2003; 2:753–763. Lev DC, Onn A, Melinkova VO, Miller C, Stone V, Ruiz M, et al. Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol 2004; 22:2092–2100. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3:391–400. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–2342. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542–2550. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349:427–434. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357:2666–2676. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365:2473–2483. Varker KA, Biber JE, Kefauver C, Jensen R, Lehman A, Young D, et al. A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma. Ann Surg Oncol 2007; 14:2367–2376. Vihinen PP, Hernberg M, Vuoristo MS, Tyynelä K, Laukka M, Lundin J, et al. A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-alpha2a as first line treatment in metastatic melanoma. Melanoma Res 2010; 20:318–325. Del Vecchio M, Mortarini R, Canova S, Di Guardo L, Pimpinelli N, Sertoli MR, et al. Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors. Clin Cancer Res 2010; 16:5862–5872. Schuster C, Eikesdal HP, Puntervoll H, Geisler J, Geisler S, Heinrich D, et al. Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension. PLoS One 2012; 7:e38364. Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, et al. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer 2013; 119:586–592. Kim KB, Sosman JA, Fruehauf JP, Linette GP, Markovic SN, McDermott DF, et al. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol 2012; 30:34–41. Von Moos R, Seifert B, Simcock M, Goldinger SM, Gillessen S, Ochsenbein A, et al. Swiss Group for Clinical Cancer Research (SAKK). First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07). Ann Oncol 2012; 23:531–536. Koyama T, Chen H. Proper inference from Simon’s two-stage designs. Stat Med 2008; 27:3145–3154. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 2004; 22:1118–1125.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
DTIC/bevacizumab for metastatic melanoma Ferrucci et al. 245
30
Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17:2745–2751. 31 Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006; 24:4738–4745. 32 Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, et al. DC study group of the DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 2006; 17:563–570. 33 McDermott DF, Sosman JA, Gonzalez R, Hodi FS, Linette GP, Richards J, et al. Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol 2008; 26:2178–2185. 34 Middleton M, Hauschild A, Thomson D, Anderson R, Burdette-Radoux S, Gehlsen K, et al. Results of a multicenter randomized study to evaluate the
35
36
37
38
39
safety and efficacy of combined immunotherapy with interleukin-2, interferon{alpha}2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma. Ann Oncol 2007; 18:1691–1697. Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann Oncol 2012; 23 (Suppl 8):viii15–viii21. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711–723. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364:2517–2526. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, openlabel, phase 3 randomised controlled trial. Lancet 2012; 380:358–365. Corrie PG, Marshall A, Dunn JA, Middleton MR, Nathan PD, Gore M, et al. Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. Lancet Oncol 2014; 15:620–630.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
