Cancer Investigation, 32:144–149, 2014 ISSN: 0735-7907 print / 1532-4192 online C 2014 Informa Healthcare USA, Inc. Copyright DOI: 10.3109/07357907.2014.885984
ORIGINAL ARTICLE
Sequential Treatment with Ipilimumab and BRAF Inhibitors in Patients With Metastatic Melanoma: Data From the Italian Cohort of the Ipilimumab Expanded Access Program
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Paolo Antonio Ascierto,1 Ester Simeone,1 Vanna Chiarion Sileni,2 Michele Del Vecchio,3 Paolo Marchetti,4,5 Gian Carlo Antonini Cappellini,4 Ruggero Ridolfi,6 Francesco de Rosa,6 Francesco Cognetti,7 Virginia Ferraresi,7 Alessandro Testori,8 Paola Queirolo,9 Maria Grazia Bernengo,10 Michele Guida,11 Luca Galli,12 Mario Mandal`a,13 Carolina Cimminiello,14 Gaetana Rinaldi,15 Fabrizio Carnevale-Schianca,16 and Michele Maio17 Melanoma, Cancer Immunotherapy, and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy,1 Melanoma Cancer Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy,2 Medical Oncology, National Cancer Institute, Milan, Italy,3 Dermopathic Institute of the Immaculate IDI-IRCCS, Rome, Italy,4 Medical Oncology, Sant’Andrea Hospital, University Sapienza, Rome, Italy,5 Immunotherapy Unit, Romagna National Cancer Institute, Meldola, Italy,6 Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy,7 Melanoma Division, European Institute of Oncology, Milan, Italy,8 Medical Oncology A, San Martino Hospital-National Institute for Cancer Research, Genoa, Italy,9 University Hospital St John the Baptist, Turin, Italy,10 Medical Oncology Department, National Cancer Research Center, “Giovanni Paolo II”, Bari, Italy,11 Division of Medical Oncology, University Hospital “S. Chiara”, Pisa, Italy,12 Unit of Medical Oncology, “Papa Giovanni XXIII” Hospital, Bergamo, Italy,13 Unit of Immuno-Biotherapy of Melanoma, San Raffaele Hospital, Milan, Italy,14 “Paolo Giaccone” Polyclinic University Hospital, Palermo, Italy,15 Institute of Cancer Research and Treatment, Piedmont Oncology Foundation, Candiolo, Italy,16 Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy17 an inhibitor of mutated BRAF, have both been shown to improve overall survival (OS) in phase 3, randomized trials of patients with advanced melanoma (1–3), and both agents are approved for the treatment of adult patients with advanced melanoma in Europe. In 2013, the BRAF-inhibitor dabrafenib was also approved for the treatment of patients with BRAFV600 -mutated metastatic melanoma. The success of these agents has paved the way for the development of other, similarly acting agents, such as antibodies that target the programed death-1 receptor on T cells (4, 5), and targeted inhibitors of mutated BRAF or downstream MEK that are in advanced clinical development (6, 7). Immunotherapies and targeted agents have very different, but potentially complementary mechanisms of action. Treatment with BRAF inhibitors often results in rapid tumor regression in many patients; however, as with all agents of this class, patients can acquire resistance to therapy and relapse (8–10). Unfortunately, for approximately 40–50% of patients, disease progression upon relapse is very rapid (11). Detection of long-term survival benefits among patients without relapse remains a challenge, partly due to patient crossover in clinical trials. In the registrational phase 3 trial, patients who crossed over to vemurafenib from dacarbazine appeared
Of 93 patients with pretreated, BRAFV600 mutation-positive advanced melanoma who received vemurafenib or dabrafenib before (n = 45) or after (n = 48) treatment with ipilimumab 3 mg/kg, median overall survival (mOS) from first treatment was 9.9 and 14.5 months, respectively. Among patients treated with a BRAF inhibitor first, mOS from the end of BRAF inhibition was 1.2 months for those who did not complete ipilimumab treatment as per protocol, compared with 12.7 months for those who did (p < .001). Prospective, randomized studies are required to determine the optimal sequencing of ipilimumab and BRAF inhibitors in patients with BRAF-mutated metastatic melanoma. Keywords: Cutaneous melanoma, Tumor immunology, Treatment, Molecular biology
INTRODUCTION Recent advances in our understanding of tumor immunology and molecular biology have led to a paradigm shift toward using immunotherapy and targeted agents to treat patients with unresectable or metastatic (advanced) melanoma. Ipilimumab, a modulator of T-cell activity, and vemurafenib,
Correspondence to: Paolo A Ascierto, Melanoma, Cancer Immunotherapy, and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Via Cappella dei Cangiani, 1-80131 Napoli, Italy. email: [email protected] Received 15 November 2013; revised 14 January 2014; accepted 17 January 2013.
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Sequencing of Ipilimumab and BRAF Inhibitors to have equivalent survival to those who initially started on vemurafenib treatment (12). Because it can take time to build an antitumor immune response, ipilimumab can have a slow onset of activity and tumor responses may evolve over time. In addition, host inflammatory responses or T-cell infiltration can often be mistaken for early disease progression (13). In contrast to targeted therapies, disease control (DC) is often durable, lasting many years in some cases (14). Furthermore, follow-up from phase 2 and 3 trials consistently show a plateau in survival curves for patients treated with ipilimumab that is maintained for an extended period, as evidenced by follow-up of up to 10 years (15). Accumulating data suggest approximately 20% of patients will have longterm survival following treatment with ipilimumab (14–16). The administration of BRAF inhibitors to melanoma cell lines in vitro has been shown to increase the antigenic properties of melanoma cells, resulting in enhanced recognition by antigen-specific T cells (17). This, together with the distinct activity profiles of these agents, provides a strong rationale for a combination or sequencing approach to treatment (11, 12, 18, 19). In theory, using the agents together could result in a high frequency of tumor responses that can be sustained in the long term. Unfortunately, preliminary data from a phase 1 trial suggest the concurrent administration of vemurafenib and ipilimumab may not be feasible due to a high risk of hepatotoxicity, highlighting the need to carefully assess the risk:benefit ratio of new combination strategies within a clinical trial, even when both agents are approved (19). Data on the sequencing of ipilimumab and BRAF inhibitors are scarce, and primarily limited to singleinstitution, retrospective analyses (18, 20, 21). Here, we evaluate the efficacy outcomes of 93 patients enrolled in the ipilimumab expanded access program (EAP) across multiple Italian centers who sequentially received vemurafenib or dabrafenib and ipilimumab, or vice versa.
METHODS Patients and treatment Patients were eligible for analysis if they tested positive for the BRAFV600 mutation and had sequentially received a BRAF inhibitor (vemurafenib or dabrafenib) and ipilimumab, or vice versa. Ipilimumab was available upon physician request for patients aged ≥16 years with life-threatening unresectable Stage III or Stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously over 90 min, every 3 weeks for four doses. For the purposes of this analysis, patients who were unable to complete 3–4 doses of ipilimumab treatment due to progressive disease were defined as having rapid disease progression; whereas those who completed ipilimumab treatment were classed as having slow disease progression. Discontinuation of ipilimumab dosing due to toxicity did not preclude patients from inclusion in this analysis. C 2014 Informa Healthcare USA, Inc. Copyright
Tumor assessments were performed at baseline, prior to starting ipilimumab, and after completion of ipilimumab therapy according to immune-related response criteria (irRC) (13). Patients could have received vemurafenib 960 mg twice daily or dabrafenib 150 mg twice daily. The protocol for the EAP was approved by a local independent ethics committee and all participating patients provided signed informed consent before enrolment. Statistical analysis Patient and disease characteristics were analyzed using descriptive statistics. Discrete variables were expressed as relative frequencies (percentages) and continuous variables as median and range. OS was estimated using Kaplan-Meier analysis and expressed as median values with corresponding two-sided 95% confidence intervals (CIs). Differences between survival curves were evaluated using the log-rank test. Chi-square and Mann-Whitney tests were used to verify the association between baseline factors and the rate of disease progression. RESULTS Patients and treatment In total, 855 patients participated in the EAP between June 2010 and January 2012 across 55 centers in Italy. Of these 855 patients, 469 were tested for the BRAFV600 mutation, of whom 173 (37%) were positive. Among the 173 BRAFmutation positive patients, 93 (54%) had received sequential treatment with both treatments and were eligible for analysis, comprising 48 (52%) patients who received BRAF inhibitors upon disease progression with ipilimumab and 45 (48%) patients who received ipilimumab upon disease progression with a BRAF inhibitor. Due to the retrospective nature of this analysis, data are not available on the number of patients who did not cross over to another treatment. Reasons for discontinuation of BRAF inhibitor treatment prior to ipilimumab are unknown. Baseline characteristics, defined as patient characteristics at initiation of first treatment, of the 93 patients are shown in Table 1; characteristics at crossover are not available. Most characteristics were similar between the two groups, although there was a statistically significant difference between the groups for the proportion of patients with elevated lactate dehydrogenase (LDH; p = .03) or brain metastasis (p = .006), both of which were higher in patients who received a BRAF inhibitor as the first part of their sequential treatment. In addition, the proportions of female patients and patients who had received previous therapy for advanced disease were higher in the group who received ipilimumab followed by a BRAF inhibitor, compared with the group who received a BRAF inhibitor first. Efficacy With a median follow-up of 11 months (range: 1–34 months), median OS for patients treated with ipilimumab followed by a BRAF inhibitor was significantly longer than for patients who received ipilimumab upon disease progression with a BRAF inhibitor (Figure 1). Median OS was 14.5 months (95%
P. A. Ascierto et al.
Table 1. Baseline Characteristics at Initiation of First Treatment for Patients Treated Sequentially With BRAF Inhibitors and Ipilimumab
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Characteristic Median age, years Male/female, n (%)/n (%) ECOG PS 0 1 LDH level, n (%)∗
ORIGINAL ARTICLE
Sequential Treatment with Ipilimumab and BRAF Inhibitors in Patients With Metastatic Melanoma: Data From the Italian Cohort of the Ipilimumab Expanded Access Program
Cancer Invest Downloaded from informahealthcare.com by Michigan University on 01/16/15 For personal use only.
Paolo Antonio Ascierto,1 Ester Simeone,1 Vanna Chiarion Sileni,2 Michele Del Vecchio,3 Paolo Marchetti,4,5 Gian Carlo Antonini Cappellini,4 Ruggero Ridolfi,6 Francesco de Rosa,6 Francesco Cognetti,7 Virginia Ferraresi,7 Alessandro Testori,8 Paola Queirolo,9 Maria Grazia Bernengo,10 Michele Guida,11 Luca Galli,12 Mario Mandal`a,13 Carolina Cimminiello,14 Gaetana Rinaldi,15 Fabrizio Carnevale-Schianca,16 and Michele Maio17 Melanoma, Cancer Immunotherapy, and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy,1 Melanoma Cancer Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy,2 Medical Oncology, National Cancer Institute, Milan, Italy,3 Dermopathic Institute of the Immaculate IDI-IRCCS, Rome, Italy,4 Medical Oncology, Sant’Andrea Hospital, University Sapienza, Rome, Italy,5 Immunotherapy Unit, Romagna National Cancer Institute, Meldola, Italy,6 Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy,7 Melanoma Division, European Institute of Oncology, Milan, Italy,8 Medical Oncology A, San Martino Hospital-National Institute for Cancer Research, Genoa, Italy,9 University Hospital St John the Baptist, Turin, Italy,10 Medical Oncology Department, National Cancer Research Center, “Giovanni Paolo II”, Bari, Italy,11 Division of Medical Oncology, University Hospital “S. Chiara”, Pisa, Italy,12 Unit of Medical Oncology, “Papa Giovanni XXIII” Hospital, Bergamo, Italy,13 Unit of Immuno-Biotherapy of Melanoma, San Raffaele Hospital, Milan, Italy,14 “Paolo Giaccone” Polyclinic University Hospital, Palermo, Italy,15 Institute of Cancer Research and Treatment, Piedmont Oncology Foundation, Candiolo, Italy,16 Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy17 an inhibitor of mutated BRAF, have both been shown to improve overall survival (OS) in phase 3, randomized trials of patients with advanced melanoma (1–3), and both agents are approved for the treatment of adult patients with advanced melanoma in Europe. In 2013, the BRAF-inhibitor dabrafenib was also approved for the treatment of patients with BRAFV600 -mutated metastatic melanoma. The success of these agents has paved the way for the development of other, similarly acting agents, such as antibodies that target the programed death-1 receptor on T cells (4, 5), and targeted inhibitors of mutated BRAF or downstream MEK that are in advanced clinical development (6, 7). Immunotherapies and targeted agents have very different, but potentially complementary mechanisms of action. Treatment with BRAF inhibitors often results in rapid tumor regression in many patients; however, as with all agents of this class, patients can acquire resistance to therapy and relapse (8–10). Unfortunately, for approximately 40–50% of patients, disease progression upon relapse is very rapid (11). Detection of long-term survival benefits among patients without relapse remains a challenge, partly due to patient crossover in clinical trials. In the registrational phase 3 trial, patients who crossed over to vemurafenib from dacarbazine appeared
Of 93 patients with pretreated, BRAFV600 mutation-positive advanced melanoma who received vemurafenib or dabrafenib before (n = 45) or after (n = 48) treatment with ipilimumab 3 mg/kg, median overall survival (mOS) from first treatment was 9.9 and 14.5 months, respectively. Among patients treated with a BRAF inhibitor first, mOS from the end of BRAF inhibition was 1.2 months for those who did not complete ipilimumab treatment as per protocol, compared with 12.7 months for those who did (p < .001). Prospective, randomized studies are required to determine the optimal sequencing of ipilimumab and BRAF inhibitors in patients with BRAF-mutated metastatic melanoma. Keywords: Cutaneous melanoma, Tumor immunology, Treatment, Molecular biology
INTRODUCTION Recent advances in our understanding of tumor immunology and molecular biology have led to a paradigm shift toward using immunotherapy and targeted agents to treat patients with unresectable or metastatic (advanced) melanoma. Ipilimumab, a modulator of T-cell activity, and vemurafenib,
Correspondence to: Paolo A Ascierto, Melanoma, Cancer Immunotherapy, and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Via Cappella dei Cangiani, 1-80131 Napoli, Italy. email: [email protected] Received 15 November 2013; revised 14 January 2014; accepted 17 January 2013.
Cancer Invest Downloaded from informahealthcare.com by Michigan University on 01/16/15 For personal use only.
Sequencing of Ipilimumab and BRAF Inhibitors to have equivalent survival to those who initially started on vemurafenib treatment (12). Because it can take time to build an antitumor immune response, ipilimumab can have a slow onset of activity and tumor responses may evolve over time. In addition, host inflammatory responses or T-cell infiltration can often be mistaken for early disease progression (13). In contrast to targeted therapies, disease control (DC) is often durable, lasting many years in some cases (14). Furthermore, follow-up from phase 2 and 3 trials consistently show a plateau in survival curves for patients treated with ipilimumab that is maintained for an extended period, as evidenced by follow-up of up to 10 years (15). Accumulating data suggest approximately 20% of patients will have longterm survival following treatment with ipilimumab (14–16). The administration of BRAF inhibitors to melanoma cell lines in vitro has been shown to increase the antigenic properties of melanoma cells, resulting in enhanced recognition by antigen-specific T cells (17). This, together with the distinct activity profiles of these agents, provides a strong rationale for a combination or sequencing approach to treatment (11, 12, 18, 19). In theory, using the agents together could result in a high frequency of tumor responses that can be sustained in the long term. Unfortunately, preliminary data from a phase 1 trial suggest the concurrent administration of vemurafenib and ipilimumab may not be feasible due to a high risk of hepatotoxicity, highlighting the need to carefully assess the risk:benefit ratio of new combination strategies within a clinical trial, even when both agents are approved (19). Data on the sequencing of ipilimumab and BRAF inhibitors are scarce, and primarily limited to singleinstitution, retrospective analyses (18, 20, 21). Here, we evaluate the efficacy outcomes of 93 patients enrolled in the ipilimumab expanded access program (EAP) across multiple Italian centers who sequentially received vemurafenib or dabrafenib and ipilimumab, or vice versa.
METHODS Patients and treatment Patients were eligible for analysis if they tested positive for the BRAFV600 mutation and had sequentially received a BRAF inhibitor (vemurafenib or dabrafenib) and ipilimumab, or vice versa. Ipilimumab was available upon physician request for patients aged ≥16 years with life-threatening unresectable Stage III or Stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously over 90 min, every 3 weeks for four doses. For the purposes of this analysis, patients who were unable to complete 3–4 doses of ipilimumab treatment due to progressive disease were defined as having rapid disease progression; whereas those who completed ipilimumab treatment were classed as having slow disease progression. Discontinuation of ipilimumab dosing due to toxicity did not preclude patients from inclusion in this analysis. C 2014 Informa Healthcare USA, Inc. Copyright
Tumor assessments were performed at baseline, prior to starting ipilimumab, and after completion of ipilimumab therapy according to immune-related response criteria (irRC) (13). Patients could have received vemurafenib 960 mg twice daily or dabrafenib 150 mg twice daily. The protocol for the EAP was approved by a local independent ethics committee and all participating patients provided signed informed consent before enrolment. Statistical analysis Patient and disease characteristics were analyzed using descriptive statistics. Discrete variables were expressed as relative frequencies (percentages) and continuous variables as median and range. OS was estimated using Kaplan-Meier analysis and expressed as median values with corresponding two-sided 95% confidence intervals (CIs). Differences between survival curves were evaluated using the log-rank test. Chi-square and Mann-Whitney tests were used to verify the association between baseline factors and the rate of disease progression. RESULTS Patients and treatment In total, 855 patients participated in the EAP between June 2010 and January 2012 across 55 centers in Italy. Of these 855 patients, 469 were tested for the BRAFV600 mutation, of whom 173 (37%) were positive. Among the 173 BRAFmutation positive patients, 93 (54%) had received sequential treatment with both treatments and were eligible for analysis, comprising 48 (52%) patients who received BRAF inhibitors upon disease progression with ipilimumab and 45 (48%) patients who received ipilimumab upon disease progression with a BRAF inhibitor. Due to the retrospective nature of this analysis, data are not available on the number of patients who did not cross over to another treatment. Reasons for discontinuation of BRAF inhibitor treatment prior to ipilimumab are unknown. Baseline characteristics, defined as patient characteristics at initiation of first treatment, of the 93 patients are shown in Table 1; characteristics at crossover are not available. Most characteristics were similar between the two groups, although there was a statistically significant difference between the groups for the proportion of patients with elevated lactate dehydrogenase (LDH; p = .03) or brain metastasis (p = .006), both of which were higher in patients who received a BRAF inhibitor as the first part of their sequential treatment. In addition, the proportions of female patients and patients who had received previous therapy for advanced disease were higher in the group who received ipilimumab followed by a BRAF inhibitor, compared with the group who received a BRAF inhibitor first. Efficacy With a median follow-up of 11 months (range: 1–34 months), median OS for patients treated with ipilimumab followed by a BRAF inhibitor was significantly longer than for patients who received ipilimumab upon disease progression with a BRAF inhibitor (Figure 1). Median OS was 14.5 months (95%
P. A. Ascierto et al.
Table 1. Baseline Characteristics at Initiation of First Treatment for Patients Treated Sequentially With BRAF Inhibitors and Ipilimumab
Cancer Invest Downloaded from informahealthcare.com by Michigan University on 01/16/15 For personal use only.
Characteristic Median age, years Male/female, n (%)/n (%) ECOG PS 0 1 LDH level, n (%)∗
