Survival of patients with metastatic melanoma and brain metastases in the era of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies: A systematic review

Cancer Treatment Reviews 45 (2016) 38–45

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Systematic or Meta-analysis Studies

Survival of patients with metastatic melanoma and brain metastases in the era of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies: A systematic review Francesco Spagnolo a,⇑, Virginia Picasso b, Matteo Lambertini b, Vincenzo Ottaviano c, Beatrice Dozin d, Paola Queirolo b a

Department of Plastic and Reconstructive Surgery, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy Department of Medical Oncology, U.O. Oncologia Medica 2, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy c Department of Plastic and Reconstructive Surgery, St George’s Hospital, London, UK d Clinical Epidemiology Unit, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy b

a r t i c l e

i n f o

Article history: Received 11 November 2015 Received in revised form 1 March 2016 Accepted 2 March 2016

Keywords: Melanoma Brain metastases Vemurafenib Dabrafenib Ipilimumab Survival

a b s t r a c t Background: The incidence of brain metastases (BM) in melanoma patients is common and associated with poor prognosis. MAP-kinase inhibitors and immunologic checkpoint blockade antibodies led to improved survival of metastatic melanoma patients; however, patients with BM are under-represented or excluded from the majority of clinical trials and the impact of new drugs on their survival is less clear. With the present systematic review, we aimed to analyze outcomes of patients with melanoma BM treated with the new drugs, both in the setting of phase I–II–III clinical trials and in the ‘‘real world”. Methods: An electronic search was performed to identify studies reporting survival outcomes of patients with melanoma BM treated with MAP-kinase inhibitors and/or immunologic checkpoint blockade antibodies, regardless of study design. Results: Twenty-two studies were included for a total of 2153 patients. Median OS was 7.9 months in phase I–II–III trials and 7.7 months in ‘‘real world” studies. In clinical trials, median OS was 7.0 months for patients treated with immunotherapy and 7.9 months for patients treated with BRAF inhibitors. In ‘‘real world” studies, median OS was 4.3 months and 7.7 months for patients treated with immunotherapy and BRAF inhibitors, respectively. Evidence of clinical activity exists for both immunotherapy and MAP-kinase inhibitors. Conclusions: MAP-kinase inhibitors and immunologic checkpoint blockade antibodies have clinical activity and may achieve improved OS in patients with metastatic melanoma and BM. These results support the inclusion of patients with BM in investigations of new agents and new treatment regimens for metastatic melanoma. Ó 2016 Elsevier Ltd. All rights reserved.

Background Before the availability of BRAF/MEK inhibitors and anti-CTLA-4/ PD-1 drugs, median overall survival (OS) for metastatic melanoma was about 6 months, with 25% patients alive at 1 year [1]. The incidence of brain metastases (BM) in melanoma patients is common: 20% of patients have BM at diagnosis of metastatic melanoma and nearly 50% develop BM in the course of the metastatic disease [2–5]. BM are associated with poor prognosis and lack of effective ⇑ Corresponding author at: IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi, 10, 16132 Genova, Italy. Tel.: +39 010 5600384; fax: +39 010 352850. E-mail address: [email protected] (F. Spagnolo). http://dx.doi.org/10.1016/j.ctrv.2016.03.003 0305-7372/Ó 2016 Elsevier Ltd. All rights reserved.

systemic treatments, with a median OS from diagnosis of BM of 2.2–4.7 months [3,6–8]. Retrospective data from several reports suggest that melanoma patients with limited central nervous system (CNS) involvement treated with stereotactic radiotherapy and/ or surgery may achieve better survival [6,7]. Temozolomide and fotemustine, which can cross the blood–brain barrier, were the most widely used systemic treatments for patients with melanoma and BM; however, clinical responses are noted only in 10–15% of patients [8–10]. The introduction of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies led to improved survival of metastatic melanoma patients, with median OS ranging between 10.0 and 25.1 months in Phase 3 studies [11–14]. However, patients with BM are under-represented or excluded from the majority of

F. Spagnolo et al. / Cancer Treatment Reviews 45 (2016) 38–45

clinical trials and the impact of new drugs on survival of patients with metastatic melanoma and BM is less clear. The purpose of this systematic review was to analyze survival outcomes of patients with melanoma BM treated with MAPkinase inhibitors and/or immunologic checkpoint blockade antibodies, both in the setting of prospective phase I–II–III clinical trials and in phase IV and other ‘‘real world” studies. Clinical activity and safety outcomes were also reviewed. Methods Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines were used for the conduct and reporting of this systematic review [15]. Search strategy Studies were identified by a computerized search of the PubMed data-base with the string ‘‘melanoma AND (ipilimumab OR vemurafenib OR dabrafenib OR trametinib OR nivolumab OR pembrolizumab)” and EMBASE with the string ‘‘‘melanoma’/mj AND (‘ipilimumab’/mj OR ‘vemurafenib’/mj OR ‘dabrafenib’/mj OR ‘trametinib’/mj OR ‘nivolumab’/mj OR ‘pembrolizumab’/mj) AND [humans]/lim AND [embase]/lim NOT [medline]/lim AND [<1966–2015]/py” (Fig. 1). The search was performed on the 30th September 2015. Moreover, abstracts published by the ASCO, ESMO and SMR between 2010 and 2015 were reviewed and considered for inclusion if full paper was not published. Reference lists of original articles and review articles were considered as additional sources of information (Fig. 1). No additional studies were identified by an additional search on Cochrane database. Inclusion and exclusion criteria English-language studies which reported any survival outcome (median OS and/or landmark analysis of survival) of patients with

39

metastatic melanoma and BM who started a treatment with MAPK inhibitors and/or immunologic checkpoint blockade antibodies were included in this review. Studies were included regardless of study design and grouped in phase I to III clinical trials and phase IV plus other ‘‘real world” or safety studies. The following information was extracted from each report: first author and date of publication, study design (with primary endpoint if prospective trial), treatment regimen and line of treatment (i.e. pre-treated or treatment-naïve patients), number of patients with BM, median OS, landmark analysis of survival, median progression-free survival (PFS), overall response rate, disease control rate, intracranial response rate, presence of CNS symptoms, previous BM local treatment, incidence of G3–4 toxicities, discontinuation rate, CNSspecific adverse events (for safety outcomes, we included studies for patients with BM only or reporting outcomes for BM patients separately). Exclusion criteria for study selection were the following: studies with less than 10 patients with BM; retrospective studies where study population was selected and restricted to patients who received a particular local treatment, such as surgery or radiotherapy, or to patients with a specific prognostic marker; studies including both patients with and without BM, when survival data limited to those with BM could not be extracted; studies which included patients who took part to clinical trials or expanded access programmes already included in this systematic review. In one study [16], a three-year follow up paper [17] followed the publication of the original study. Data were extracted from both papers and, when available, the most recent data were reported in this review. Four-year survival data of patients included in a retrospective analysis of an ipilimumab phase II trial included in this review [18] were published in a long-term followup paper by Wolchock and colleagues [19] and reported in this review. Data were independently extracted by 2 investigators (F.S. and V.P.) to ensure homogeneity of collection and to rule out the effect of subjectivity in data gathering and entry. Disagreements were resolved by iteration, discussion, and consensus.

2423 idenfied and screened

2301 excluded aer tle/abstract assessment

studies in PUBMED and EMBASE

103 full-texts excluded n=38

122 arcles assessed for inclusion

4 addional studies from ASCO, ESMO and SMR published abstract

n=39 n=13 n=6 n=5 n=1 n=1

1 addional studies from references on screened arcles

BM excluded or less than 10 paents with BM no survival data could be extracted for paents with brain metastases paents selected upon local treatment no survival outcomes reported paents are part of other included studies commentary on included paper data on paents developing brain metastases while on treatment

22 studies (24 arcles)* included in this systemac review Fig. 1. The PRISMA flowchart summarizing the process for the identification of the eligible studies. *Two articles reported longer follow-up of an included study and were used to extract the available longer follow-up data.

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F. Spagnolo et al. / Cancer Treatment Reviews 45 (2016) 38–45

Statistical analysis Descriptive statistics to obtain median results from summary data were conducted using STATA 12.1 Software. A weighted median according to the number of patients was computed from median OS values reported, when available, in the studies included in this systematic review. Although study populations and treatment regimens were not homogeneous, we assumed that descriptive analyses for the purpose of this review could be carried out separating the group of patients selected for enrolment in clinical trials from the patients of ‘‘real world” studies.

ingly, in studies reporting both intracranial and extracranial response rates, clinical activity was similar for intracranial and extracranial metastases. Safety outcomes are summarized in Table 4. Overall, treatments were well tolerated with a discontinuation rate due to adverse events (AEs) <10% and incidence of G3–4 toxicities ranging from 6% for pembrolizumab to 60% for ipilimumab in combination with fotemustine. Most CNS-specific AEs were considered related to tumor progression rather than study drugs.

Discussion Results Twenty-two studies were included in our analysis for a total of 2153 patients with metastatic melanoma and BM treated with MAP-kinase inhibitors and/or immune checkpoint blockade antibodies: 8 phase I–II trials (including a retrospective analysis of data from a phase II trial) (n = 490; 148 treated with immunotherapy and 342 with MAP-kinase inhibitors) and 14 ‘‘real world” or safety studies (n = 1663; 566 treated with immunotherapy and 1097 with MAP-kinase inhibitors), the majority of which were retrospective analyses of the Expanded Access Programmes of ipilimumab. No randomized phase III trials were identified; no prospective trial included in this review had survival as primary endpoint. Study populations were heterogeneous and included patients pre-treated or treatment-naïve for metastatic melanoma, with or without CNS symptoms and who received or who had not received a local treatment for their BM at baseline. Treatment regimens included MAP-kinase inhibitors vemurafenib and dabrafenib as single agents, ipilimumab at 3 and 10 mg/kg and pembrolizumab 10 mg/kg. We did not identify any study reporting survival outcomes for the combination of BRAF and MEK inhibitors. Survival and clinical activity outcomes from the studies included in this review are summarized in Table 1 [2,16–24] and Table 2 [25–38]. Median OS was 7.9 months (IQR 7.0–8.3) in phase I–II trials and 7.7 months (IQR 5.6–7.7) in ‘‘real world” studies. In clinical trials, median OS was 7.0 months (IQR 7.0–12.7) for patients treated with immunotherapy and 7.9 months (IQR 7.1–8.3) for patients treated with MAP-kinase inhibitors. In ‘‘real world” studies, median OS was 4.3 months (IQR 4.3–7.0) and 7.7 months (IQR 7.7–7.7) for patients treated with immunotherapy and MAP-kinase inhibitors, respectively. Median OS ranged 3.7–14.0 months in trials with selected patients and 3.3–9.3 months in ‘‘real world” studies, with 1-year survival ranging 12–54% and 11–20%, respectively. The lowest values of median OS were observed for patients with symptomatic BM treated with ipilimumab. Some long-term survival data were available for patients treated with ipilimumab: Di Giacomo et al. reported a 3-year survival rate of 27.8% for patients with BM treated with ipilimumab and fotemustine [16,17] and Wolchock et al. reported that 3 out of 12 patients with BM included in a phase II study of ipilimumab 10 mg/kg with or without budesonide were alive after 4 years [18,19]. Seven studies, which included both patients with and without BM, analyzed survival outcomes according to presence or absence of BM (Table 3): three studies reported similar OS for patients with and without BM [16,32,34], whilst four studies showed a statistically significant association between shorter OS and presence of BM [22,25,26,37]. Evidence of clinical activity in BM exist for both immunotherapy and MAP-kinase inhibitors; however, similar to that observed with extra-cranial disease, intracranial response rates are higher for BRAF inhibitors than ipilimumab (see Tables 1 and 2). Interest-

Melanoma BM are historically associated with poor prognosis and patients with BM have been excluded or have been underrepresented in most clinical trials, including the phase III studies which led to the approval of the new agents for the treatment of metastatic melanoma. Four phase II trials were designed specifically for patients with metastatic melanoma and BM [2,21,23,24], showing that vemurafenib, dabrafenib, ipilimumab and pembrolizumab have intracranial clinical activity, but no study with survival as primary endpoint has been conducted so far with an adequate representation of patients with BM. Median OS data available from phase I and II trials (7.9 months) and from analyses in a ‘‘real world” setting (7.7 months) indicate that BRAF inhibitors and ipilimumab might achieve improved survival in patients with BM compared to the historical survival benchmark of 6.2 months for metastatic melanoma overall [1] and 2.2–4.7 months for patients with BM [3,6–8]. The overall beneficial effects on survival of the new drugs in the clinical practice seem to be consistent with the one observed in clinical trials. The analysis of median OS according to type of treatment (BRAF inhibitors vs. ipilimumab) suggests that unselected BM patients treated with ipilimumab may have the worst survival. Nevertheless, the highest values of median OS were observed for selected patients with pre-treated and asymptomatic BM treated with ipilimumab [17,18]. CNS symptoms are historically associated with worse prognosis [3,6,7]. The studies included in our review show that BRAFi may achieve intracranial disease control also in patients with symptomatic BM [20,27,28], whilst patients with CNS symptoms seem to have poor outcomes when treated with immunotherapy [23]. These results suggest that targeted therapies may be a better option than ipilimumab in BRAF V600 mutant melanoma patients with symptomatic BM and warrant further prospective evaluation in clinical trials. Some long-term follow-up data are available for patients treated with immunotherapy [16–19], suggesting that long-term survival may also be achieved in patients with BM, though it must be acknowledged that these data come from a small number of patients (20 in the ipilimumab plus fotemustine phase II study and 12 in the ipilimumab with or without budesonide phase II study). Studies including both patients with and without BM which analyzed survival outcomes according to presence or absence of BM showed discordant results (Table 3) [16,22,25,26,32,34,37], highlighting the need of further investigation in this setting. Recent studies, including registration clinical trials, demonstrated the superior efficacy of combination therapy compared with monotherapy. Combined BRAF and MEK inhibition outperformed BRAF inhibitors as single agents in three randomized clinical trials [39] and nivolumab in combination with ipilimumab achieved increased PFS and response rate compared to nivolumab and ipilimumab as single agents [40]. Superior efficacy may also be achieved in patients with BM; unfortunately, no survival data were available for this subset of patients, though some clinical trials are ongoing (Table 5): specifically designed phase 2 studies are

Table 1 Survival and clinical activity outcomes from phase I–II clinical trials. Author and date of publication [Ref.]

Study design (primary endpoint)

Treatment regimen

Previous systemic therapy

Number of BM patients

Median OS months

Median PFSa months

6Month survival

1-Year survival

2-Year survival

3-Year survival

4-Year survival

ORR (DCR)a

OIRR

CNS symptoms

BM pretreated

Dummer [20]

Pilot study

Vemurafenib 960 mg twice a day

83%

24

5.3

3.9

NR

NR

NR

NR

NR

42% (80%)

37%

100%

100%

Kefford [21]

Multicenter, phase II study (OIR)

Vemurafenib 960 mg twice a day

NR

146b Cohort 1: 90 Cohort 2: 56

7.1

3.7

NR

NR

NR

NR

NR

NR

21%

NR

0%

9.5

3.9

NR

NR

NR

NR

NR

NR

NR

172c Cohort A: 74 V600E 15 V600K Cohort B: 65 V600E 18 V600K

8.3 4.1

4.0 2.0

61% 27%

NR

NR

NR

NR

39% 7%

7.9 5.5

4.2 4.0

61% 41%

NR

NR

NR

NR

38% (80%) 0% (47%) 31% (83%) 28% (50%)

Multicenter, phase II study (OIRR)

Dabrafenib 150 mg twice a day

NR

NR

31% 22%

0%

100%

Di Giacomo [16,17]

Phase II study (irDCR)

Ipilimumab 10 mg/kg + fotemustine 100 mg/m2

49%

20

12.7

3.4

NR

54%

39%

28%

NR

40% (50%)

NR

0%

35%

Zimmer [22]

Multicenter, phase II study

Ipilimumab 3 mg/kg q21 (4 doses)

100%

26

NR

NR

NR

12%

4%

NR

NR

NR

NR

0%

NR

Margolin [23]

Multicenter, phase II study (DCR)

Ipilimumab 10 mg/kg (induction + maintenance)

72d Cohort A: 51 Cohort B: 21

7.0

2.7

55%

31%

26%

NR

NR

10% (25%)

16%

0%

41%

3.7

1.3

38%

19%

10%

NR

NR

5% (10%)

5%

100%

48%

78% 71%

Weber [18,19]

Retrospective analysis of data from a phase II trial

Ipilimumab 10 mg/kg q21 (4 doses) ± budesonide

58%

12

14.0

NR

NR

NR

NR

NR

25%

NR

NR

0%

8%

Kluger 2015 [24]

Phase II study (OIRR)

Pembrolizumab 10 mg/ kg every 2 weeks

78%

18

NR

NR

67%

NR

NR

NR

NR

22% (NR)

22%

NR

0%

F. Spagnolo et al. / Cancer Treatment Reviews 45 (2016) 38–45

Long [2]

100%

BM: brain metastases; OS: overall survival; PFS: progression-free survival; ORR: overall response rate; DCR: disease control rate; OIRR: overall intracranial response rate; CNS: central nervous system; NR: not reported; irDCR: immune-related disease control rate. a Immune-related criteria when applicable. b Two cohorts: cohort 1 (90 previously untreated brain metastases) and cohort 2 (56 previously treated brain metastases). c Two cohorts: cohort A (89 no previous local treatment for brain metastases) and cohort B (83 progressive brain metastases after previous local treatments). d Two cohorts: cohort A (51 neurologically asymptomatic and not receiving corticosteroid treatment at study entry) and cohort B (21 symptomatic and on a stable dose of corticosteroids).

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42

Table 2 Survival and clinical activity outcomes from ‘‘real world” studies. Study design

Treatment regimen

Previous systemic therapy

Number of BM patients

Median OS months

Median PFSa months

6Month survival

1-Year survival

2-Year survival

ORR (DCR)a

OIRR

CNS symptoms

BM pretreated

Larkin [25]

Prospective, open-label, multicenter, vemurafenib safety study

Vemurafenib 960 mg twice a day

50%

750

7.7

3.8

NR

NR

NR

24% (82%)

NR

0%

NR

Fennira [26]

Single-center, retrospective analysis of patients treated with vemurafenib within French EAP

Vemurafenib 960 mg twice a day

72%

20

4.3

3.1

NR

NR

NR

50% (NR)

NR

40%

25%

Gibney [27]

Retrospective, observational study

Vemurafenib 960 mg twice a day

44%

283

NR

NR

85.6%

59%

NR

46% (66%)

48%

Active BM (not treated or with evidence of progression)

39%

Harding [28]

Retrospective, observational study

Vemurafenib 960 mg twice a day

33%

27

7.5

4.1

NR

30%

NR

70% (NR)

50%

Active BM

56%

Lau [29]

Retrospective analysis of dabrafenib named patient programme

Dabrafenib 150 mg twice a day

NR

17

5.6

4.6

NR

NR

NR

41% (71%)

NR

0%

59%

Queirolo [30]

Retrospective analysis of the Italian ipilimumab EAP

Ipilimumab 3 mg/kg every 3 weeks for four treatments with re-induction, if eligible

100%

146

4.3

3.1

NR

20%

NR

12% (27%)

NR

0%

4%

Konstantinou [31]

Retrospective six-centers analysis of the French ipilimumab EAP

Ipilimumab 3 mg/kg every 3 weeks for four treatments with re-induction, if eligible

100%

38

3.3

NR

NR

10.5%

NR

8% (21%)

5%

21%

47%

Alexander [32]

Single-center, retrospective analysis of patients treated with ipilimumab within Australian EAP

Ipilimumab 3 mg/kg every 3 weeks for four treatments with re-induction, if eligible

100%

44

9.3

3.0

NR

NR

NR

NR

NR

0%

NR

Altomonte [33]

Retrospective analysis of the Italian ipilimumab EAP

Ipilimumab 10 mg/kg induction + maintenance

100%

11

4.0

NR

NR

NR

NR

NR

NR

0%

NR

Chasset [34]

Retrospective single-center analysis of the French ipilimumab EAP

Ipilimumab 3 mg/kg every 3 weeks for four treatments with re-induction, if eligible

100%

23

7

NR

NR

NR

NR

17% (30%)

NR

35%

65%

Berrocal [35]

Retrospective analysis of the Spanish ipilimumab EAP

Ipilimumab 3 mg/kg every 3 weeks for four treatments with re-induction, if eligible

100%

28

4

NR

NR

NR

NR

11% (18%)

NR

0%

NR

Patt [36]

Retrospective, observational study

Ipilimumab 3 mg/kg every 3 weeks for four treatments

0%

54

7.0

NR

NR

NR

NR

NR

NR

0%

NR

Eigentler [37]

Retrospective analysis of the German ipilimumab EAP

Ipilimumab 3 mg/kg every 3 weeks for four treatments with re-induction, if eligible

100%

57

4.9

NR

NR

NR

NR

NR

NR

0%

NR

Heller [38]

Retrospective analysis of ipilimumab EAP

Ipilimumab 10 mg/kg

100%

165

NR

NR

NR

20%

NR

NR

NR

0%

NR

BM: brain metastases; OS: overall survival; PFS: progression-free survival; ORR: overall response rate; DCR: disease control rate; OIRR: overall intracranial response rate; CNS: central nervous system; NR: not reported; irDCR: immune-related disease control rate. a Immune-related criteria when applicable.

F. Spagnolo et al. / Cancer Treatment Reviews 45 (2016) 38–45

Author and date of publication [Ref.]

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F. Spagnolo et al. / Cancer Treatment Reviews 45 (2016) 38–45 Table 3 Differences in OS according to presence of brain metastases. Author and date of publication [Ref.]

Number of patients with BM

Number of patients without BM

Treatment

Fennira [26] Larkin [25] Di Giacomo [16]

20 750 20

30 2409 66

Chasset [34]

23

Alexander [32] Eigentler [37] Zimmer [22]

44 57 26

Median OS

Differences in OS according to presence of BM

With BM

Without BM

Yes/ no

Test (p-value)

4.3 7.7 13.4

13.3 15.5 13.3

Yes Yes No

Multivariate Cox modela (p < 0.0001) NR NR

22

Vemurafenib Vemurafenib Ipilimumab + fotemustine Ipilimumab

7.0

11.0

No

60 139 57

Ipilimumab Ipilimumab Ipilimumab

9.3 4.9 12%b

10.6 10.1 51%b

No Yes Yes

Cox proportional hazards regression HR: 1.70 (p = 0.11) Log-rank test (p = 0.91) Log-rank test (p = 0.008) NR (p < 0.0001)

BM: brain metastases; OS: overall survival; NR: not reported. a A multivariate Cox model for OS was obtained by including predefined variables: presence of brain metastases, treatment received before vemurafenib and LDH levels. b 1-Year survival.

Table 4 Safety outcomes from studies including only patients with BM (or reporting outcomes for BM patients separately).

a

Incidence of G3–4 toxicities

Discontinuation rate due to AEs

CNS-specific AEs Rate

Type

Treatmentrelated

24

17%

4%

NR

NR

NR

Vemurafenib 960 mg twice a day Vemurafenib 960 mg twice a day

750 27

49% NR

6% 0%

NR NR

NR NR

NR NR

Vemurafenib 960 mg twice a day

146

51%

5%

NR

NR

NR

Long 2012 [2]

Dabrafenib 150 mg twice a day

172

22%

2%

6%

Intracranial hemorrhage

No

Di Giacomo 2015 [16]

Ipilimumab 10 mg/kg + fotemustine

20

60%

NR

25%

Intracranial hemorrhage, headache and seizures

No

Margolin 2012 [23]

Ipilimumab 10 mg/kg (induction + maintenance)

72

NR

10%

4%a

Headache, intracranial hemorrhage

Possible

Weber 2011 [18]

Ipilimumab 10 mg/kg every 3 weeks for up to four doses ± budesonide (pre-treated and treatment-naïve)

16

NR

NR

31%

Headache, cerebral edema, seizures, confusion

NR

Queirolo 2014 [30]

Ipilimumab 3 mg/kg every 3 weeks for four treatments

146

10%

5%

7%

Intracranial hemorrhage, headache and seizure

Yes (1%)

Konstantinou 2014 [31]

Ipilimumab 3 mg/kg every 3 weeks for four treatments

38

NR

8%

21%

Peri-tumoral edema

Possible

Heller 2011 [38]

Ipilimumab 10 mg/kg

23%

NR

2%a

Intracranial hemorrhage and convulsion

Yes

Kluger 2015 [24]

Pembrolizumab 10 mg/kg every 2 weeks

6%

NR

11%

Seizures

No

Author and date of publication [Ref.]

Treatment regimen

Dummer 2014 [20] Larkin 2014 [25] Harding 2013 [28] Kefford 2013 [21]

Vemurafenib 960 mg twice a day

Number of patients with BM

165

18

(Only grade 3–4).

evaluating the efficacy and safety of combined BRAF and MEK inhibition (NCT01978236 and NCT02039947 for dabrafenib in combination with trametinib; NCT02230306 and NCT02537600 for vemurafenib in combination with cobimetinib) and combined anti-CTLA-4 and anti-PD-1 therapy (NCT02320058 and NCT02374242) in patients with metastatic melanoma and BM. Aggressive loco-regional treatment of melanoma BM with surgery, radiotherapy and radiosurgery may have an impact on survival [42]; unfortunately, the lack of details about pre-treatment modalities of BM in most of the included studies limits our understanding of this important topic. Remarkably, several retrospective studies suggested the possibility of improved survival and local control of BM when stereotactic radiosurgery was administered either before, during or after anti-CTLA-4 and anti-PD-1 drugs,

with little impact on toxicity [41,43]. Phase 2 clinical trials are ongoing to prospectively assess the role of stereotactic radiosurgery and its possible synergistic effect with immunotherapy (Table 4). Despite the use of ipilimumab in BM patients was hypothesized to possibly cause neurological complications due to inflammation in the brain [23,30], both immunotherapy and targeted therapies seem to be as safe in patients with BM as in those without CNS involvement. The incidence of G3–4 toxicities in the studies included in our review (Table 4) was similar to that observed in the overall population of phase III trials and safety studies (i.e. 46% for vemurafenib, 30–34% for dabrafenib, 10% for pembrolizumab and 20–27% for ipilimumab), as well as the discontinuation rates due to AEs (i.e. 6% for vemurafenib, 5% for dabrafenib,

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F. Spagnolo et al. / Cancer Treatment Reviews 45 (2016) 38–45

Table 5 Open interventional clinical trials investigating systemic treatments for patients with metastatic melanoma and brain metastases. Name of study

Treatment(s)

Phase

Status

NCT

GEM STUDY: Radiation And Yervoy in patients with melanoma and brain metastases (GRAY-B)

Ipilimumab + whole-brain radiotherapy 30 Gy in 10 fractions

II

Recruiting

NCT02115139

Anti-PD 1 Brain Collaboration for patients with melanoma brain metastases (ABC)

Nivolumab Nivolumab + ipilimumab

II

Recruiting

NCT02374242

MK-3475 in melanoma and NSCLC patients with brain metastases

Pembrolizumab

II

Recruiting

NCT02085070

Dabrafenib/trametinib, BRAF or BRAF AND MEK Pre-op with BRAF and MEK Post-op, phase IIB, melanoma with brain mets, biomarkers and metabolites

Dabrafenib Dabrafenib + trametinib

II

Recruiting

NCT01978236

A study of abemaciclib (LY2835219) in participants with breast cancer, non-small cell lung cancer, or melanoma that has spread to the brain

Abemaciclib (CDK inhibitor)

II

Recruiting

NCT02308020

Ipilimumab induction in patients with melanoma brain metastases receiving stereotactic radiosurgery

Ipilimumab followed by stereotactic radiosurgery Stereotactic radiosurgery followed by ipilimumab

II

Recruiting

NCT02097732

SRS (stereotactic radiosurgery) plus ipilimumab

Ipilimumab + stereotactic radiosurgery

I

Recruiting

NCT01950195

A study of fotemustine (FTM) Vs FTM and ipilimumab (IPI) or IPI and nivolumab in melanoma brain metastasis (NIBIT-M2)

Fotemustine Fotemustine + ipilimumab Ipilimumab + nivolumab

III

Recruiting

NCT02460068

A phase I trial of WP1066 in patients with central nervous system (CNS) melanoma and recurrent glioblastoma multiforme (GBM)

WP1066 (Stat3 inhibitor)

I

Not yet recruiting

NCT01904123

Study to evaluate treatment of dabrafenib plus trametinib in subjects with BRAF mutation-positive melanoma that has metastasized to the brain

Dabrafenib + trametinib

II

Recruiting

NCT02039947

Phase II study of cobimetinib in combination with vemurafenib in active melanoma brain metastases (CoBRIM-B)

Vemurafenib + cobimetinib

II

Not yet recruiting

NCT02230306

Buparlisib in melanoma patients suffering from brain metastases (BUMPER)

Buparlisib (pan-PI3K inhibitor)

II

Recruiting

NCT02452294

Vemurafenib and cobimetinib combination in BRAF mutated melanoma with brain metastasis (CONVERCE)

Vemurafenib + cobimetinib

II

Not yet recruiting

NCT02537600

A multi-center phase 2 open-label study to evaluate safety and efficacy in subjects with melanoma metastatic to the brain treated with nivolumab in combination with ipilimumab followed by nivolumab monotherapy (CheckMate 204)

Nivolumab + ipilimumab

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Recruiting

NCT02320058

Clinicaltrials.gov accessed 30 September 2015 (search string: melanoma AND brain).

4–7% for pembrolizumab and 10% for ipilimumab) [14,25,40,44,45]. Some limitations of our analysis should be acknowledged, mostly due to the heterogeneity of the included studies in terms of designs, populations and treatment regimens; in addition, the majority of ‘‘real world” studies data were obtained from retrospective analyses. No study included in the review had survival as primary endpoint. Median OS was not reported in every study. Finally, in the ‘‘real world” group of studies, it should be noted that almost half of the patients were from a single study (vemurafenib safety study) [29]. Despite these limitations, the results of our review suggest that improved survival may also be achieved in patients with BM and support the inclusion of this large subset of patients in investigations of new agents and new treatment regimens for metastatic melanoma. Conflict of interest statement All authors have no financial interest in any of the products, devices, or drugs mentioned in this article. FS received lecture fees from Bristol-Myers Squibb, Novartis and Roche; VP received lecture fees from Bristol-Myers Squibb; PQ received lecture fees and served on advisory board for Bristol-Myers Squibb, Novartis, Roche and MSD. References [1] Korn EL, Liu P-Y, Lee SJ, Chapman J-AW, Niedzwiecki D, Suman VJ, et al. Metaanalysis of phase II cooperative group trials in metastatic stage IV melanoma to

[2]

[3]

[4]

[5] [6]

[7]

[8]

[9]

[10]

[11]

[12]

determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 2008;26:527–34. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:1087–95. Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu W-J, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 2011;117:1687–96. Sampson JH, Carter JH, Friedman AH, Seigler HF. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998;88:11–20. Bafaloukos D, Gogas H. The treatment of brain metastases in melanoma patients. Cancer Treat Rev 2004;30(6):515–20. Fife KM, Colman MH, Stevens GN, Firth IC, Moon D, Shannon KF, et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 2004;22:1293–300. Vecchio S, Spagnolo F, Merlo DF, Signori A, Acquati M, Pronzato P, et al. The treatment of melanoma brain metastases before the advent of targeted therapies: associations between therapeutic choice, clinical symptoms and outcome with survival. Melanoma Res 2014;24. Agarwala SS, Kirkwood JM, Gore M, Dreno B, Thatcher N, Czarnetski B, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004;22:2101–7. Margolin K, Atkins M, Thompson J, Ernstoff M, Weber J, Flaherty L, et al. Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. J Cancer Res Clin Oncol 2002;128:214–8. 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;22:1118–25. 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;363:711–23. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutationpositive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014;15:323–32.

F. Spagnolo et al. / Cancer Treatment Reviews 45 (2016) 38–45 [13] Hauschild A. An update on BREAK-3, a phase III, randomized trial: dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM) [abstract]. J Clin Oncol 2013;31 (Suppl.) [abstr. 9013]. [14] Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAFmutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015;386(9992):444–51. [15] Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6 e1000097. [16] Di Giacomo AM, Ascierto PA, Pilla L, Santinami M, Ferrucci PF, Giannarelli D, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol 2012;13:879–86. [17] Di Giacomo AM, Ascierto PA, Queirolo P, Pilla L, Ridolfi R, Santinami M, et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann Oncol 2014. [18] Weber JS, Amin A, Minor D, Siegel J, Berman D, O’Day SJ. Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial. Melanoma Res 2011;21:530–4. [19] Wolchok JD, Weber JS, Maio M, Neyns B, Harmankaya K, Chin K, et al. Fouryear survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol 2013;24:2174–80. [20] Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, et al. Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer 2014;50:611–21. [21] Kefford RF, Maio M, Arance A, Nathan P, Blank C, Avril MF, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, singlearm, phase 2, multicenter study [abstract]. Pigment Cell Melanoma Res 2013;26(Suppl.):965. [22] Zimmer L, Eigentler TK, Vaubel JM, Mohr P, Jradi Z, Kiecker F, et al. Open-label, multicenter, single-arm phase II study (DeCOG-trial) to further evaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and rare subgroups [abstract]. J Clin Oncol 2014;32(Suppl.):5s [abstr. 9031]. [23] Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13:459–65. [24] Kluger HM, Goldberg SB, Sznol M, Tsiouris J, Vortmeyer A, Jilaveanu L, et al. Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases [abstract]. J Clin Oncol 2015;33(Suppl.) [abstr. 9009]. [25] Larkin J, Del Vecchio M, Ascierto PA, Krajsova I, Schachter J, Neyns B, et al. Vemurafenib in patients with BRAFV600 mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014;15:436–44. [26] Fennira F, Pagès C, Schneider P, Sidina I, Viguier M, Basset-Seguin N, et al. Vemurafenib in the French temporary authorization for use metastatic melanoma cohort: a single-centre trial. Melanoma Res 2014;24:75–82. [27] Gibney GT, Gauthier G, Ayas C, Galebach P, Wu EQ, Abhyankar S, et al. Treatment patterns and outcomes in BRAF V600E-mutant melanoma patients with brain metastases receiving vemurafenib in the real-world setting. Cancer Med 2015;4(8):1205–13. [28] Harding JJ, Catalanotti F, Munhoz RR, Cheng DT, Yaqubie A, Kelly N, et al. A retrospective evaluation of vemurafenib as treatment for BRAF-mutant melanoma brain metastases. Oncologist 2015;20:789–97.

45

[29] Lau DK, Andrews MC, Turner N, Azad AA, Davis ID, Cebon JS. A single-centre experience of patients with metastatic melanoma enrolled in a dabrafenib named patient programme. Melanoma Res 2014;24:144–9. [30] Queirolo P, Spagnolo F, Ascierto P, Simeone E, Marchetti P, Scoppola A, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neurooncol 2014;118:109–16. [31] Konstantinou MP, Dutriaux C, Gaudy-Marqueste C, Mortier L, Bedane C, Girard C, et al. Ipilimumab in melanoma patients with brain metastasis: a retrospective multicentre evaluation of thirty-eight patients. Acta Derm Venereol 2014;94:45–9. [32] Alexander M, Mellor JD, McArthur G, Kee D. Ipilimumab in pretreated patients with unresectable or metastatic cutaneous, uveal and mucosal melanoma. Med J Aust 2014;201:49–53. [33] Altomonte M, Di Giacomo A, Queirolo P, Ascierto P, Spagnolo F, Bajetta E, et al. Clinical experience with ipilimumab 10 mg/kg in patients with melanoma treated at Italian centres as part of a European expanded access programme. J Exp Clin Cancer Res 2013;32:82. [34] Chasset F, Pages C, Biard L, Roux J, Sidina I, Madelaine I, et al. Single-center study under a French Temporary Authorization for Use (TAU) protocol for ipilimumab in metastatic melanoma: negative impact of baseline corticosteroids. Eur J Dermatol 2015;25:36–44. [35] Berrocal A, Arance A, Lopez Martin JA, Soriano V, Muñoz E, Alonso L, et al. Ipilimumab for advanced melanoma: experience from the Spanish Expanded Access Program. Melanoma Res 2014;24:577–83. [36] Patt D, Rembert D, Bhor M, Bhowmik D, Rao S. A real-world observational study of patients with advanced melanoma receiving first-line ipilimumab in a community practice setting. J Cancer Ther 2014;5:1049–58. [37] Eigentler TK, Schlaak M, Hassel JC, Loquai C, Stoffels I, Gutzmer R, et al. Effectiveness and tolerability of ipilimumab: experiences from 198 patients included in a named-patient program in various daily-practice settings and multiple institutions. J Immunother 2014;37:374–81. [38] Heller KN, Pavlick AC, Hodi FS, Thompson JA, Margolin KA, Lawrence DP, et al. Safety and survival analysis of ipilimumab therapy in patients with stable asymptomatic brain metastases [abstract]. J Clin Oncol 2011;29(Suppl.) [abstr. 8581]. [39] Queirolo P, Picasso V, Spagnolo F. Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma. Cancer Treat Rev 2015;41:519–26. [40] Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23–34. [41] Ajithkumar T, Parkinson C, Fife K, Corrie P, Jefferies S. Evolving treatment options for melanoma brain metastases. Lancet Oncol 2015;16:e486–97. [42] Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosisspecific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012;30:419–25. [43] Ahmed KA, Stallworth DG, Kim Y, Johnstone PA, Harrison LB, Caudell JJ, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol 2016;27:434–41. [44] Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877–88. [45] Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372(26):2521–32.