- Email: [email protected]
Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies
original articles
Annals of Oncology 10. Heinrich MC, Maki RG, Corless CL et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 2008; 26(33): 5352–5359. 11. Wardelmann E, Merkelbach-Bruse S, Pauls K et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006; 12(6): 1743–1749.
12. Demetri GD, Jeffers M, Reichardt P et al. Mutational analysis of plasma DNA from patients ( pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes. J Clin Oncol 2013; 31(15): abstr 10503. 13. Growney JD, Li F, Qiu S et al. Dovitinib has anti-tumor activity in gastrointestinal stromal tumor (GIST) cell lines. Cancer Res 2013; 73(8 suppl): abstr 1620.
Annals of Oncology 25: 2277–2284, 2014 doi:10.1093/annonc/mdu441 Published online 10 September 2014
C. Lebbé1*, J. S. Weber2, M. Maio3, B. Neyns4, K. Harmankaya5,†, O. Hamid6, S. J. O’Day7, C. Konto8, L. Cykowski8, M. B. McHenry9 & J. D. Wolchok10 1 Department of Dermatology, APHP, CIC, U976 Hôpital Saint-Louis University Paris Diderot, Paris, France; 2Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA; 3Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 4Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium; 5Department of Dermatology, Medical University of Vienna, Vienna, Austria; 6Melanoma Therapeutics, Translational Research and Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles; 7Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center, Beverly Hills; 8Global Clinical Research; 9Global Biometric Sciences, Bristol-Myers Squibb Company, Wallingford; 10Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
Received 22 April 2014; revised 18 July 2014; accepted 19 August 2014
Background: This report provides a survival update at a follow-up of >5 years (5.5–6 years) for patients with advanced melanoma who previously received ipilimumab in phase II clinical trials. Safety and efficacy data following ipilimumab retreatment are also reported. Patients and methods: Patients who previously received ipilimumab 0.3, 3, or 10 mg/kg in one of six phase II trials (CA184004, CA184-007, CA184-008, CA184-022, MDX010-08, and MDX010-15) were eligible to enroll in the companion study, CA184-025. Upon enrollment, patients initially received ipilimumab retreatment, extended maintenance therapy, or were followed for survival only. Overall survival (OS) rates were evaluated in patients from studies CA184-004, CA184-007, CA184-008, and CA184-022. Safety and best overall response during ipilimumab retreatment at 10 mg/kg were assessed in study CA184-025. Results: Five-year OS rates for previously treated patients who received ipilimumab induction at 0.3, 3, or 10 mg/kg were 12.3%, 12.3%–16.5%, and 15.5%–28.4%, respectively. Five-year OS rates for treatment-naive patients who received ipilimumab induction at 3 or 10 mg/kg were 26.8% and 21.4%–49.5%, respectively. Little to no change in OS was observed from year 5 up to year 6. The objective response rate among retreated patients was 23%. Grade 3/4 immune-related adverse events occurred in 25%, 5.9%, and 13.2% of retreated patients who initially received ipilimumab 0.3, 3, and 10 mg/kg, with the most common being observed in the skin (4.2%, 2.9%, 3.8%) and gastrointestinal tract (12.5%, 2.9%, 3.8%), respectively. Conclusions: At a follow-up of 5–6 years, ipilimumab continues to demonstrate durable, long-term survival in a proportion of patients with advanced melanoma. In some patients, ipilimumab retreatment can re-establish disease control with a safety profile that is comparable with that observed during ipilimumab induction. Further studies are needed to determine the contribution of ipilimumab retreatment to OS. ClinicalTrials.gov: NCT00162123. Key words: advanced melanoma, cytotoxic T-lymphocyte antigen-4, immunotherapy, ipilimumab, long-term survival, survival rate
*Correspondence to: Prof. Celeste Lebbé, APHP Department of Dermatology, CIC, U976 Hôpital Saint-Louis University Paris Diderot, 1 Avenue Claude Vellefaux, Paris 75010, France. Tel: +33-1-42-49-49-49; E-mail: [email protected] †
Present address: Department of Dermatology, Sozialmedizinisches Zentrum Ost, Donauspital, Vienna, Austria.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies
original articles introduction
advanced melanoma patients treated with HD IL-2, 19 of 43 (44%) patient responders survived >5 years [9]. Phase I/II trials conducted at the US National Cancer Institute reported 5-year OS rates of 13%–25% among advanced melanoma patients who received ipilimumab [10]. In phase II clinical trials of ipilimumab in advanced melanoma, eligible patients could enroll in a companion study, CA184-025, in which patients received ipilimumab retreatment or extended maintenance therapy, or were followed for survival only. The primary objective of this report is to provide updated survival data with follow-up of 5.5–6 years for patients enrolled in study CA184-025. A second objective is to provide efficacy and safety data for patients who received ipilimumab retreatment.
patients and methods CA184-025 was a phase II companion study of ipilimumab extended treatment, which included ipilimumab retreatment and continued maintenance therapy, or follow-up for survival only in patients with advanced melanoma who previously received ipilimumab in one of six phase II studies. Details on the parent studies have been published previously [11–16] and are briefly summarized in Table 1.
Table 1. Summary of the phase II parent trials that enrolled patients in study CA184-025 Study design Population Ipilimumab treatment BMS studies CA184-004 [15]
CA184-007 [12]
CA184-008 [13]
CA184-022b [14]
Total Medarex studies MDX010-08 [16]
MDX010-15 [11]
Total Overall total
Randomized, two-dose biomarker study Treatment-naive and previously treated 3 or 10 mg/kg, Q3W × 4 Randomized, open-label, multicenter study Treatment-naive and previously treated 10 mg/kg, Q3W × 4, plus oral budesonide or placebo Single-arm, open-label, multicenter study Previously treated, progressed on prior therapy 10 mg/kg, Q3W × 4 Randomized, double-blind, parallel-group, multicenter, dose-ranging study Previously treated or intolerant of prior therapy 0.3, 3, or 10 mg/kg, Q3W × 4
Randomized, multicenter study Chemotherapy-naïve 3 mg/kg Q4W × 4, with or without dacarbazine Open-label pharmacokinetic and safety study Treatment-naive and previously treated Single- or multiple-dose ipilimumab, up to 20 mg/kg
N a (Parent trials)
N (Study 025)
82
28
115
42
155
67
217
103
569
240
76
2
88
6
164 733
8 248
a
Randomized patients for studies CA184-004, CA184-007, and CA184-022, and treated patients for study CA184-008. Crossover from lower dose groups to 10 mg/kg in CA184-022 was allowed upon disease progression; this occurred in 33% and 42% of patients in the 0.3 and 3 mg/kg dose groups, respectively. Q3W, every 3 weeks. b
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Historically, patients with stage IV melanoma had a median overall survival (OS) of 6–9 months, with ∼10% of patients surviving to 5 years [1]. With recent advances in immunotherapy and targeted therapy, the prognosis of patients with this disease has improved. In particular, emerging evidence from clinical trials suggests that a proportion of advanced melanoma patients treated with ipilimumab experience durable, long-term survival [2, 3]. Ipilimumab is a fully human, IgG1 monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 (CTLA-4) to enhance antitumor immune responses [4, 5]. Ipilimumab significantly improved OS in two phase III, randomized, controlled trials in patients with advanced melanoma [6, 7]. In previously treated patients (MDX010-20), the 2-year OS rate was 21.6% for ipilimumab plus gp100, 23.5% for ipilimumab alone, and 13.7% for gp100 alone [6]. In treatment-naive patients (CA184-024), the 5-year OS rate was 18.2% for ipilimumab plus dacarbazine (DTIC) and 8.8% for DTIC plus placebo [2]. Five-year survival is a clinically meaningful milestone in the treatment of advanced melanoma, after which risk of death is markedly reduced [8]. Five-year survival has been demonstrated in a subset of patients treated with high-dose interleukin-2 (HD IL-2) and ipilimumab [2, 3, 9, 10]. In a pooled analysis of
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year update for study CA184-004 and a 6-year update for studies CA184-007, CA184-008, and CA184-022. Another objective of study CA184-025 was to evaluate the occurrence of new adverse events (AEs) and immune-related adverse events (irAEs) as well as tumor response in patients who received extended ipilimumab treatment. Patient irAEs were managed as per ipilimumab guidelines described in the parent trials [11–16]. Tumor response was evaluated by modified World Health Organization criteria.
results patients Among 733 patients in the six parent trials (Figure 1), 248 enrolled in study CA184-025: 6 were not eligible for participation, 93 were retreated with ipilimumab upon enrollment (cohort 1), 91 received ipilimumab extended maintenance therapy upon enrollment (cohort 2), and 58 were followed for survival only (cohort 3). A total of 122 patients were retreated in study CA184-025: 93 upon initial enrollment (cohort 1) and 29 of 91 (cohort 2) upon disease progression on extended maintenance therapy. The number of patients who received ipilimumab at an induction dose of 0.3, 3, or 10 mg/kg followed by ipilimumab retreatment at 3 or 10 mg/kg is shown in Figure 1. Most patients (93.4%) were retreated at 10 mg/kg. Three patients initially treated with single-dose or multidose ipilimumab in study MDX010-15 were retreated with ipilimumab in study CA184-025. The median
Enrolled in phase II parent trials N = 733 CA184–004; n = 82 CA184–007; n = 115 CA184–008; n = 155 CA184–022; n = 217 MDX010–08; n = 76 MDX010–15; n = 88
Enrolled in CA184–025 N = 248
Screen failuresa n=6
Cohort 1: Ipilimumab retreatment n = 93
Cohort 2: Ipilimumab extended maintenance n = 91
Cohort 3: Follow-up only n = 58
n = 29
Ipilimumab retreatment n = 122 10b to 10 mg/kg; n = 53 treated 3b to 10 mg/kg; n = 34 treated 0.3b to 10 mg/kg; n = 24 treated 10b to 3 mg/kg; n = 7 treated 3b to 3 mg/kg; n = 1 treated 10 MD to 10 mg/kg; n = 2 treated 20 SD to 10 mg/kg; n = 1 treated
Ipilimumab extended maintenance n = 62 10 mg/kg; n = 45 (33 treated) 3 mg/kg; n = 13 (12 treated) 0.3 mg/kg; n = 4 treated
Figure 1. Flow diagram for patients from phase II parent trials who enrolled in the companion study CA184-025. Upon enrollment in study CA184-025, patients received ipilimumab retreatment (cohort 1) or extended maintenance therapy (cohort 2), or were followed for survival only (cohort 3). aFive patients did not meet study criteria, and one patient failed screening for other reasons. bInduction dose received in the parent trial. MD, multidose; SD, single dose.
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As per study CA184-025 protocol, patients were enrolled into one of three cohorts (Figure 1). Cohort 1 (n = 93) was composed of patients who experienced disease progression in the parent trial and were eligible for retreatment with ipilimumab. Patients were eligible for retreatment if they met core safety criteria and achieved complete response (CR), partial response (PR), or stable disease (SD) (≥3 months) during initial treatment. The exception was study CA184-022, due to the fact that a low-dose (0.3 mg/kg) ipilimumab group was included and ipilimumab dosage was blinded. Patients in any treatment group who experienced disease progression in study CA184022 could enroll in study CA184-025 at any time for retreatment with ipilimumab, provided they met core safety criteria. Cohort 2 (n = 91) was composed of patients who had not progressed on ipilimumab in the parent trial. These patients were treated with ipilimumab extended maintenance therapy in study CA184-025. Cohort 3 (n = 58) was comprised of patients who were either ineligible for the other study cohorts or refused treatment in the other study cohorts but consented to be followed for survival data, with no additional ipilimumab treatment. Patients were followed for survival in either the parent trials or study CA184-025, as described previously [3]. Only patients from studies CA184004, CA184-007, CA184-008, and CA184-022 were included in the survival analysis. Patients from the Medarex (MDX) studies were excluded from the survival analysis because survival follow-up beyond 3 years was not conducted (MDX010-08) or survival was not an end point (MDX010-15). One objective of study CA184-025 was to evaluate median OS and survival rates from the first dose of ipilimumab in the parent trials. The database lock for the current survival analysis was in June 2013. These data provide a 5.5-
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number of retreatment doses among patients initially treated with ipilimumab 0.3, 3, or 10 mg/kg was two, four, and four doses, respectively, with 5, 11, and 20 patients receiving all four doses.
long-term survival analysis
safety outcomes during first ipilimumab retreatment The safety analysis was based on a select group of retreated patients (N = 111) who received ipilimumab induction at 0.3, 3, or 10 mg/kg in a parent trial and who met efficacy and safety criteria for retreatment with ipilimumab at 10 mg/kg in study CA184-025. AEs and irAEs during ipilimumab retreatment at 10 mg/kg are shown in Table 3. As preliminarily reported [17], most patients (75%) initially treated with ipilimumab 0.3 mg/kg experienced irAEs of any grade; 67.6% and 56.6% of patients
tumor response during first ipilimumab retreatment Among 122 patients retreated with ipilimumab in study CA184025, as preliminarily reported [17], seven achieved CR, and 21 achieved PR for a best overall response rate of 23% (95% confidence interval 15.8–31.4). An additional 31 patients achieved SD upon retreatment of a disease control rate (DCR) of 48.4%. Forty-six patients experienced disease progression. Postbaseline tumor assessment was not carried out in 17 patients.
Table 2. Overall survival rates with ipilimumab in phase II trials CA184-004, CA184-007, CA184-008, and CA184-022 Trial
004
008 022b
007
N (prior treatment)
42 Total 14 (TN) 28 (PT) 40 Total 14 (TN) 26 (PT) 155 (PT) 72 (PT) 72 (PT) 73 (PT) 57 Total 32 (TN) 25 (PT) 58 Total 21 (TN) 37 (PT)
Dose (mg/kg)
10
3
10 10 3 0.3 10 + placebo
10 + budesonide
Median OS (months) 11.2a 10.7a 11.4a 12.8a 13.7a 11.5a 10.2 11.4 8.7 8.6 19.3 30.5 14.8 17.7 45.0 8.5
OS rate (%) 1-year 2-year
3-year
4-year
5-year
6-year
45.2 42.9 46.4 52.0 57.1 49.2 47.2 48.6 39.3 39.6 62.4 71.4 50.8 55.9 65.9 49.9
20.1 21.4 19.4 22.7 26.8 20.5 23.3 24.8 19.7 13.8 34.4 42.5 24.2 38.7 57.7 28.4
17.6 21.4 15.5 22.7 26.8 20.5 19.7 21.5 18.2 13.8 32.0 37.7 24.2 36.2 49.5 28.4
17.6 21.4 15.5 17.0 26.8 12.3 18.2 21.5 16.5 12.3 32.0 37.7 24.2 36.2 49.5 28.4
17.6a 21.4a 15.5a 17.0a 26.8a 12.3a 18.2 17.4 14.9 12.3 29.5 33.0 24.2 33.8 49.5 25.3
27.7 35.7 23.2 31.2 35.7 28.7 32.8 29.8 24.2 18.4 41.8 56.6 24.2 41.1 57.7 31.6
a
5.5-year survival data for patients in study CA184-004. Crossover from lower dose groups to 10 mg/kg in CA184-022 was allowed upon disease progression; this occurred in 33% and 42% of patients in the 0.3 and 3 mg/kg dose groups, respectively. OS, overall survival; PT, previously treated; TN, treatment-naive. b
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OS rates and previously reported median OS [3] for patients in studies CA184-004, CA184-007, CA184-008, and CA184-022 are shown in Table 2. Five-year survival rates for previously treated patients in studies CA184-007, CA184-008, and CA184-022 were 12.3% for ipilimumab 0.3 mg/kg, 16.5% for ipilimumab 3 mg/kg, and 18.2%–28.4% for ipilimumab 10 mg/kg. Five-year survival rates for treatment-naive patients in study CA184-007 were 37.7% for the ipilimumab 10 mg/kg plus placebo group and 49.5% for the ipilimumab 10 mg/kg plus budesonide group. Five-year survival rates for previously treated and treatment-naive patients in study CA184-004 were 17.0% for ipilimumab 3 mg/kg and 17.6% for ipilimumab 10 mg/kg. Survival rates at 5 years were similar to those reported at 6 years (5.5 years for CA184-004). Kaplan–Meier survival curves are shown in Figure 2.
initially treated with 3 or 10 mg/kg, respectively, experienced irAEs of any grade. Grade 3 or 4 irAEs were observed in 25%, 5.9%, and 13.2% of patients initially treated with ipilimumab 0.3, 3, and 10 mg/kg, respectively. The most common grade 3 or 4 irAEs affected the gastrointestinal tract and skin; diarrhea, colitis, pruritus, and rash were most frequently reported. Immune-related AEs were managed using established ipilimumab treatment algorithms, including the use of corticosteroids when appropriate [6, 7, 12–14]. There were no deaths attributed to irAEs in any of the retreatment groups. Twenty-seven retreated patients who were evaluated for safety discontinued treatment due to AEs of any cause: 8 (33.3%), 6 (17.6%), and 13 (24.5%) initially received ipilimumab 0.3, 3, or 10 mg/kg. These events were severe (grade 3 or 4) in six (25.0%), three (8.8%), and nine (17.0%) patients in the three dose cohorts, respectively. Four deaths related to gastrointestinal perforation (n = 1); multiorgan failure (n = 2); and cerebral vascular accident, pulmonary embolus, and sepsis (n = 1) were reported. AEs leading to treatment discontinuation were attributed to study drug in five (20.8%), one (2.9%), and six (11.3%) retreated patients who initially received ipilimumab at 0.3, 3, and 10 mg/kg, respectively.
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Proportion alive
A
1.0
3 mg/kg Ipi
0.9
Censored
0.8
10 mg/kg Ipi
0.7
Censored
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
2
4
Patients at risk 40 37 32 27 26 22 20 16 14 13 13 13 12 8 8 8 8 8 8 8 8 3 mg/kg Ipi
8 8 8 8 7 6 6 6 6 6 6 6 6
6 6 6 2 2 1
0
42 37 33 28 24 22 19 16 15 14 12 12 11 9 9 9 9 8 8 8 8
8 8 7 7 7 7 7 7 7 7 7 7 6
6 6 6 3 1 1
0
10 mg/kg Ipi
Proportion alive
B
1.0
Ipi 10 mg/kg+Bude
0.9
Censored
0.8
Ipi 10 mg/kg+Plac
0.7
Censored
0.6 0.5 0.4 0.3 0.2 0.1 0.0
Patients at risk Ipi+Bude Ipi+Plac
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 Months 58 56 52 41 34 32 29 28 25 24 21 19 17 17 17 17 17 17 16 16 16 16 16 15 15 15 15 15 15 15 15 15 15 15 15 15 14 14 13 9 8 5 2 1 0 57 51 47 45 44 38 33 31 29 26 22 20 18 18 17 16 15 15 14 14 14 13 13 13 13 13 13 13 13 13 13 13 13 13 12 12 12 12 8 3 3 1 0 0 0
Figure 2. Kaplan–Meier estimates of overall survival for studies: CA184-004 (A), CA184-007 (B), CA184-008 (C), and CA184-022 (D). Analyses for study CA184-008 include all treated patients, whereas those for studies CA184-004, CA184-007, and CA184-022 include all randomized patients.
discussion These data show that a proportion of advanced melanoma patients achieve durable, long-term survival of ≥5 years with ipilimumab. Five-year survival rates ranged from 12.3% for previously treated patients who received ipilimumab induction at 3 mg/kg to 49.5% for treatment-naive patients who received ipilimumab induction at 10 mg/kg, suggesting that durable, longterm survival may be achieved irrespective of ipilimumab dose or pretreatment status. While OS rates were numerically longer at the 10 mg/kg dose, study CA184-025 was not designed to evaluate differences in OS between ipilimumab dosing groups. Data from an ongoing phase III melanoma trial (CA184-169) should help clarify potential differences in benefit for ipilimumab 3 versus 10 mg/kg dosing. These long-term survival data confirm and extend previously reported survival data from ipilimumab clinical trials [3, 10]. As mentioned previously, 5-year OS rates were 13%–25% in ipilimumab-treated patients with advanced melanoma in phase I/II trials conducted at the National Cancer Institute [10]. Although patients in the phase III study MDX010-20 were not followed for survival beyond 2 years, 5-year survival rates in the phase III
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study CA184-024 were 18.2% for ipilimumab plus DTIC versus 8.8% for DTIC plus placebo [2]. As shown in Figure 2, survival rates reached a plateau beginning at ∼3 years, with 82.6% of patients alive at 3 years surviving to 5 years. This finding is consistent with previously reported data suggesting that a proportion of advanced melanoma patients achieve durable, long-term survival with ipilimumab. In a recent pooled analysis of long-term survival data from 1861 ipilimumab-treated patients with advanced melanoma, a plateau in the OS curve was observed beginning at ∼3 years and extending to ∼10 years [18]. One limitation of the current analysis is the inclusion of patients from multiple parent trials with different patient populations (i.e. previously treated or treatment-naive) and different ipilimumab induction doses (i.e. 0.3, 3, or 10 mg/kg). In addition, a small number of patients received single-dose or multiple-dose ipilimumab (i.e. MDX010-15). A second limitation of this analysis is that not all study sites and eligible patients participated in this companion study, potentially decreasing the reliability of the results [3]. The contribution of ipilimumab retreatment to OS is unknown, and data in this report cannot provide further insight on this issue. However, data from study CA184-025 suggest that a
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6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 Months
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10 mg/kg Ipi Censored
1.0 0.9 0.8
Proportion alive
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84
Proportion alive
D
0.3 mg/kg Ipi
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Censored 3 mg/kg Ipi Censored 10 mg/kg Ipi Censored
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 Months Patients at risk 0.3 mg/kg Ipi 73 61 53 47 38 33 27 24 17 15 14 12 12 12 11 10 10 10 9 9 9 9 9 9 9 8 8 8 8 8 8 8 8 8 8 8 8 8 3 3 1 1 1 0 3 mg/kg Ipi 72 64 54 47 39 30 26 23 22 20 20 18 16 16 16 15 13 13 13 13 13 12 12 12 12 12 12 11 10 10 10 9 9 9 9 9 9 9 5 4 2 0 0 0 10 mg/kg Ipi 72 63 53 45 41 39 31 28 25 22 19 19 18 17 17 17 15 15 15 15 15 13 13 13 12 12 12 12 11 11 11 10 10 9 9 8 8 8 5 3 1 0 0 0
Fig. 2 Continued Table 3. Adverse events and irAEs during ipilimumab retreatment at 10 mg/kg AEs and irAEs, n (%)
Any AE Any irAE Gastrointestinal Dermatologic Hepatic Endocrine Othera
Ipilimumab dose in parent study with retreatment at 10 mg/kg (N = 111) 0.3 mg/kg (n = 24) 3 mg/kg (n = 34) All grades Grade 3/4 All grades Grade 3/4
10 mg/kg (n = 53) All grades
Grade 3/4
24 (100.0) 18 (75.0) 14 (58.3) 10 (41.7) 1 (4.2) 1 (4.2) 1 (4.2)
51 (96.2) 30 (56.6) 11 (20.8) 18 (34.0) 3 (5.7) 3 (5.7) 2 (3.8)
18 (34.0) 7 (13.2) 2 (3.8) 2 (3.8) 2 (3.8) 1 (1.9) 0 (0.0)
10 (41.7) 6 (25.0) 3 (12.5) 1 (4.2) 1 (4.2) 1 (4.2) 0 (0.0)
33 (97.1) 23 (67.6) 7 (20.6) 18 (52.9) 0 (0.0) 2 (5.9) 3 (8.8)
10 (29.4) 2 (5.9) 1 (2.9) 1 (2.9) 0 (0.0) 0 (0.0) 0 (0.0)
Most common (>1%) grade 3/4 “other” irAEs were hypersensitivity and interstitial lung disease; none were grade 5. AE, adverse event; irAE, immune-related adverse event. a
proportion of advanced melanoma patients re-establish disease control with ipilimumab retreatment, as previously shown in the phase III trial MDX010-20 [19] and in an ipilimumab Expanded Access Program (EAP) [17]. In study MDX010-20, the DCR among retreatment-eligible patients was 75% (n = 6/8) for the
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ipilimumab plus placebo group and 65.2% (n = 15/23) for the ipilimumab plus gp100 group [19]. In the Italian EAP, 51 of 855 patients were retreated with ipilimumab at 3 mg/kg, of which 28 (55%) re-established disease control [17]. In the current study, we observed a DCR of 23% among 122 retreated patients.
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Months Patients at risk 10 mg/kg Ipi 155140114 96 83 78 70 65 60 55 52 46 45 42 35 34 33 32 32 31 30 28 27 27 27 27 27 26 26 26 25 25 25 25 24 24 24 24 22 8 3 1 0
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acknowledgements Professional medical writing and editorial assistance was provided by Ward Pedersen and Jennifer DiNieri at StemScientific and was funded by Bristol-Myers Squibb.
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funding Bristol-Myers Squibb (BMS) provided funding to all study sites and institutions to cover investigators’ expenses for undertaking the parent trials.
disclosure CL is a consultant for Roche and has participated in advisory boards for BMS, Roche, GlaxoSmithKline, Amgen, and Novartis. JSW has received honoraria from BMS for advisory boards, and BMS has supported clinical research at his institution. MM is a principal investigator of clinical trials sponsored by BMS. OH is a speaker and consultant for BMS, and he participates in clinical research sponsored by BMS. SJO receives research support from BMS. CK, LC, and MBM are currently employed by BMS. LC and MBM own stock in BMS. JDW is a paid consultant for BMS and receives research support from BMS. BN and KH have declared no conflicts of interest.
references 1. Garbe C, Eigentler TK, Keilholz U et al. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011; 16: 5–24. 2. Maio M, Bondarenko I, Robert C et al. Survival analysis with 5 years of follow-up in a phase III study of ipilimumab and dacarbazine in metastatic melanoma. In Presented at the European Cancer Congress 2013, 27 September–1 October 2013 (Abstr 3704). Amsterdam, The Netherlands 2013. 3. Wolchok JD, Weber JS, Maio M et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol 2013; 24: 2174–2180. 4. Hoos A, Ibrahim R, Korman A et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol 2010; 37: 533–546. 5. Wolchok JD, Hodi FS, Weber JS et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann NY Acad Sci 2013; 1291: 1–13. 6. Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–723. 7. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517–2526. 8. Balch CM, Gershenwald JE, Soong SJ et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27: 6199–6206. 9. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000; 6: S11–S14. 10. Prieto PA, Yang JC, Sherry RM et al. CTLA-4 blockade with ipilimumab: longterm follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 2012; 18: 2039–2047. 11. Weber JS, O’Day S, Urba W et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 2008; 26: 5950–5956. 12. Weber J, Thompson JA, Hamid O et al. A randomized, double-blind, placebocontrolled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 2009; 15: 5591–5598. 13. O’Day SJ, Maio M, Chiarion-Sileni V et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol 2010; 21: 1712–1717. 14. Wolchok JD, Neyns B, Linette G et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11: 155–164.
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Forty-six patients had progressive disease despite ipilimumab retreatment. It has been reported in previous studies that delayed responses with ipilimumab are possible [6]. However, this possibility was not assessed in the current study. The 46 patients who experience disease progression were included in the retreatment group, which was only evaluated for initial tumor response and safety. The rate of retreatment was higher in study CA184-025 than in study MDX010-20 or the Italian EAP (Study CA184-025: 16.6%, 122 of 733 patients; MDX010-20: 4.7%, 32 of 676 patients; EAP: 6%, 51 of 855 patients). This is likely due to differences in parent study protocols and patient eligibility for study CA184-025, in which some patients were retreated at a different dose than that used during induction. In particular, retreated patients in study CA184-025 included those who initially received a low dose of ipilimumab (0.3 mg/kg in study CA184-022), resulting in a disproportionately higher percentage of patients eligible for retreatment. Eligible patients in study MDX010-20 or the EAP were retreated with the same dose and schedule as in the induction phase (i.e. ipilimumab 3 mg/kg every 3 weeks for four doses) [6, 17]. The current analysis provides additional information on the safety profile of ipilimumab retreatment. The most common treatment-related AEs experienced with ipilimumab induction therapy are typically inflammatory in nature [4–7] and are manageable when ipilimumab treatment guidelines are followed [20–22]. In this analysis, the safety profile during ipilimumab retreatment was comparable with that observed during ipilimumab induction in the parent studies [12–14]. Most irAEs affected the skin and gastrointestinal tract, and there were no deaths resulting from irAEs during retreatment. We observed a lower incidence of irAEs among retreated patients who received ipilimumab 3 and 10 mg/kg in a parent trial than in patients who received ipilimumab 0.3 mg/kg. The reason for this apparent difference is unclear, and the data should be interpreted with caution due to small patient numbers. One possibility is that ipilimumab 0.3 mg/kg was insufficient to mitigate CTLA-4 binding to the same extent as the higher doses [23], which may result in greater sensitivity to immune activation upon retreatment. Alternatively, selection bias may explain this observed result since patients with high-grade AEs in the parent study would not have been eligible for retreatment, and serious AEs would have been less common with ipilimumab 0.3 mg/kg. In conclusion, these results demonstrate durable, long-term survival in patients with advanced melanoma who received ipilimumab in phase II clinical trials. This survival analysis represents one of the longest follow-up periods among approved melanoma treatments. This study demonstrates that 5-year survival may be achieved with ipilimumab in a subset of advanced melanoma patients, across a range of doses, and independent of pretreatment status. Ipilimumab retreatment may re-establish disease control in a proportion of eligible patients, but its contribution to OS remains unclear. Additional studies are needed to identify patient populations most likely to experience long-term survival benefit.
original articles 15. Hamid O, Schmidt H, Nissan A et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011; 9: 204. 16. Hersh EM, O’Day SJ, Powderly J et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs 2011; 29: 489–498. 17. Chiarion-Sileni V, Pigozzo J, Ascierto PA et al. Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy. Br J Cancer 2014; 110: 1721–1726. 18. Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. In Presented at the European Cancer Congress 2013, 27 September–1 October 2013 (Abstr 24LBA). Amsterdam, The Netherlands 2013.
Annals of Oncology 19. Robert C, Schadendorf D, Messina M et al. MDX010-20 investigators. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res 2013; 19: 2232–2239. 20. Ibrahim RA, Berman DM, DePril V et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol 2011; 29: Abstr 8583. 21. YERVOY™ (ipilimumab) US Prescribing Information: Risk Evaluation and Mitigation Strategy. Bristol-Myers Squibb Company; 2011; http://www.yervoy.com/hcp/rems. aspx (June 2014, date last accessed). 22. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30: 2691–2697. 23. Feng Y, Roy A, Masson E et al. Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res 2013; 19: 3977–3986.
Association between treatment toxicity and outcomes in oncology clinical trials M. V. Abola1, V. Prasad2 & A. B. Jena3,4* 1
Department of Family Medicine, Case Western Reserve University School of Medicine, Cleveland; 2Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda; 3Department of Health Care Policy, Harvard Medical School, Boston; 4Department of Medicine, Massachusetts General Hospital, Boston, USA
Received 4 July 2014; revised 18 August 2014; accepted 20 August 2014
Background: Whether or not toxicity predicts clinical outcomes has long been a question regarding cancer treatments. While prior studies have focused on specific cancers, therapies, and toxicities, no comprehensive evidence exists on whether treatment toxicity predicts favorable outcomes. Methods: We abstracted treatment toxicity and clinical outcome data from a sample of phase III oncology randomized clinical trials (n = 99 trials). We investigated whether treatments with relatively greater toxicity compared with their controls had relatively higher, lower, or equivocal rates of clinical efficacy, measured by progression-free survival (PFS) and overall survival (OS). Several toxicities were assessed (all grades, grades III/IV, cutaneous rash, gastrointestinal toxicity, and myelosuppression). Results: Toxicity and efficacy were greater among treatments than controls (e.g. 3.5 instances of all-grade toxicity per patient in treatment arms versus 2.8 instances in controls, P < 0.001; mean PFS of 9.1 months across treatment arms versus 7.1 months across controls, P < 0.001; mean OS of 18.6 months across treatment arms versus 16.9 months across controls, P < 0.001). Across trials, greater relative treatment toxicity was strongly associated with greater PFS in treatments versus controls (P < 0.001), but not OS (P = 0.44). Although higher relative rates of myelosuppression and cutaneous rash among treatments were not associated with greater treatment efficacy, greater relative gastrointestinal toxicity among treatments was associated with greater relative PFS compared with controls (P = 0.007). Conclusion: Across trials, treatments with relatively greater all-grade toxicity compared with controls are associated with relatively greater PFS but not OS. Key words: treatment toxicity, clinical trials
introduction Whether or not toxicity of treatment predicts meaningful clinical outcomes has long been a question in cancer medicine, with *Correspondence to: Prof. Anupam B. Jena, Department of Health Care Policy, Harvard Medical School, 180 Longwood Avenue, Boston, MA 02115, USA. Tel: +1-617-4328322; E-mail: [email protected]
available evidence offering mixed conclusions. Across a range of cancers, cytotoxic side-effects such as myelosuppression have been linked to improved outcomes in both the adjuvant and metastatic setting [1–6]. For example in an analysis of patients with advanced nonsmall-cell lung cancer treated with cytotoxic agents, both severe and mild neutropenia were associated with improved survival, leading authors to speculate that the absence
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Annals of Oncology 25: 2284–2289, 2014 doi:10.1093/annonc/mdu444 Published online 5 September 2014
Annals of Oncology 10. Heinrich MC, Maki RG, Corless CL et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 2008; 26(33): 5352–5359. 11. Wardelmann E, Merkelbach-Bruse S, Pauls K et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006; 12(6): 1743–1749.
12. Demetri GD, Jeffers M, Reichardt P et al. Mutational analysis of plasma DNA from patients ( pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes. J Clin Oncol 2013; 31(15): abstr 10503. 13. Growney JD, Li F, Qiu S et al. Dovitinib has anti-tumor activity in gastrointestinal stromal tumor (GIST) cell lines. Cancer Res 2013; 73(8 suppl): abstr 1620.
Annals of Oncology 25: 2277–2284, 2014 doi:10.1093/annonc/mdu441 Published online 10 September 2014
C. Lebbé1*, J. S. Weber2, M. Maio3, B. Neyns4, K. Harmankaya5,†, O. Hamid6, S. J. O’Day7, C. Konto8, L. Cykowski8, M. B. McHenry9 & J. D. Wolchok10 1 Department of Dermatology, APHP, CIC, U976 Hôpital Saint-Louis University Paris Diderot, Paris, France; 2Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA; 3Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 4Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium; 5Department of Dermatology, Medical University of Vienna, Vienna, Austria; 6Melanoma Therapeutics, Translational Research and Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles; 7Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center, Beverly Hills; 8Global Clinical Research; 9Global Biometric Sciences, Bristol-Myers Squibb Company, Wallingford; 10Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
Received 22 April 2014; revised 18 July 2014; accepted 19 August 2014
Background: This report provides a survival update at a follow-up of >5 years (5.5–6 years) for patients with advanced melanoma who previously received ipilimumab in phase II clinical trials. Safety and efficacy data following ipilimumab retreatment are also reported. Patients and methods: Patients who previously received ipilimumab 0.3, 3, or 10 mg/kg in one of six phase II trials (CA184004, CA184-007, CA184-008, CA184-022, MDX010-08, and MDX010-15) were eligible to enroll in the companion study, CA184-025. Upon enrollment, patients initially received ipilimumab retreatment, extended maintenance therapy, or were followed for survival only. Overall survival (OS) rates were evaluated in patients from studies CA184-004, CA184-007, CA184-008, and CA184-022. Safety and best overall response during ipilimumab retreatment at 10 mg/kg were assessed in study CA184-025. Results: Five-year OS rates for previously treated patients who received ipilimumab induction at 0.3, 3, or 10 mg/kg were 12.3%, 12.3%–16.5%, and 15.5%–28.4%, respectively. Five-year OS rates for treatment-naive patients who received ipilimumab induction at 3 or 10 mg/kg were 26.8% and 21.4%–49.5%, respectively. Little to no change in OS was observed from year 5 up to year 6. The objective response rate among retreated patients was 23%. Grade 3/4 immune-related adverse events occurred in 25%, 5.9%, and 13.2% of retreated patients who initially received ipilimumab 0.3, 3, and 10 mg/kg, with the most common being observed in the skin (4.2%, 2.9%, 3.8%) and gastrointestinal tract (12.5%, 2.9%, 3.8%), respectively. Conclusions: At a follow-up of 5–6 years, ipilimumab continues to demonstrate durable, long-term survival in a proportion of patients with advanced melanoma. In some patients, ipilimumab retreatment can re-establish disease control with a safety profile that is comparable with that observed during ipilimumab induction. Further studies are needed to determine the contribution of ipilimumab retreatment to OS. ClinicalTrials.gov: NCT00162123. Key words: advanced melanoma, cytotoxic T-lymphocyte antigen-4, immunotherapy, ipilimumab, long-term survival, survival rate
*Correspondence to: Prof. Celeste Lebbé, APHP Department of Dermatology, CIC, U976 Hôpital Saint-Louis University Paris Diderot, 1 Avenue Claude Vellefaux, Paris 75010, France. Tel: +33-1-42-49-49-49; E-mail: [email protected] †
Present address: Department of Dermatology, Sozialmedizinisches Zentrum Ost, Donauspital, Vienna, Austria.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies
original articles introduction
advanced melanoma patients treated with HD IL-2, 19 of 43 (44%) patient responders survived >5 years [9]. Phase I/II trials conducted at the US National Cancer Institute reported 5-year OS rates of 13%–25% among advanced melanoma patients who received ipilimumab [10]. In phase II clinical trials of ipilimumab in advanced melanoma, eligible patients could enroll in a companion study, CA184-025, in which patients received ipilimumab retreatment or extended maintenance therapy, or were followed for survival only. The primary objective of this report is to provide updated survival data with follow-up of 5.5–6 years for patients enrolled in study CA184-025. A second objective is to provide efficacy and safety data for patients who received ipilimumab retreatment.
patients and methods CA184-025 was a phase II companion study of ipilimumab extended treatment, which included ipilimumab retreatment and continued maintenance therapy, or follow-up for survival only in patients with advanced melanoma who previously received ipilimumab in one of six phase II studies. Details on the parent studies have been published previously [11–16] and are briefly summarized in Table 1.
Table 1. Summary of the phase II parent trials that enrolled patients in study CA184-025 Study design Population Ipilimumab treatment BMS studies CA184-004 [15]
CA184-007 [12]
CA184-008 [13]
CA184-022b [14]
Total Medarex studies MDX010-08 [16]
MDX010-15 [11]
Total Overall total
Randomized, two-dose biomarker study Treatment-naive and previously treated 3 or 10 mg/kg, Q3W × 4 Randomized, open-label, multicenter study Treatment-naive and previously treated 10 mg/kg, Q3W × 4, plus oral budesonide or placebo Single-arm, open-label, multicenter study Previously treated, progressed on prior therapy 10 mg/kg, Q3W × 4 Randomized, double-blind, parallel-group, multicenter, dose-ranging study Previously treated or intolerant of prior therapy 0.3, 3, or 10 mg/kg, Q3W × 4
Randomized, multicenter study Chemotherapy-naïve 3 mg/kg Q4W × 4, with or without dacarbazine Open-label pharmacokinetic and safety study Treatment-naive and previously treated Single- or multiple-dose ipilimumab, up to 20 mg/kg
N a (Parent trials)
N (Study 025)
82
28
115
42
155
67
217
103
569
240
76
2
88
6
164 733
8 248
a
Randomized patients for studies CA184-004, CA184-007, and CA184-022, and treated patients for study CA184-008. Crossover from lower dose groups to 10 mg/kg in CA184-022 was allowed upon disease progression; this occurred in 33% and 42% of patients in the 0.3 and 3 mg/kg dose groups, respectively. Q3W, every 3 weeks. b
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Historically, patients with stage IV melanoma had a median overall survival (OS) of 6–9 months, with ∼10% of patients surviving to 5 years [1]. With recent advances in immunotherapy and targeted therapy, the prognosis of patients with this disease has improved. In particular, emerging evidence from clinical trials suggests that a proportion of advanced melanoma patients treated with ipilimumab experience durable, long-term survival [2, 3]. Ipilimumab is a fully human, IgG1 monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 (CTLA-4) to enhance antitumor immune responses [4, 5]. Ipilimumab significantly improved OS in two phase III, randomized, controlled trials in patients with advanced melanoma [6, 7]. In previously treated patients (MDX010-20), the 2-year OS rate was 21.6% for ipilimumab plus gp100, 23.5% for ipilimumab alone, and 13.7% for gp100 alone [6]. In treatment-naive patients (CA184-024), the 5-year OS rate was 18.2% for ipilimumab plus dacarbazine (DTIC) and 8.8% for DTIC plus placebo [2]. Five-year survival is a clinically meaningful milestone in the treatment of advanced melanoma, after which risk of death is markedly reduced [8]. Five-year survival has been demonstrated in a subset of patients treated with high-dose interleukin-2 (HD IL-2) and ipilimumab [2, 3, 9, 10]. In a pooled analysis of
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year update for study CA184-004 and a 6-year update for studies CA184-007, CA184-008, and CA184-022. Another objective of study CA184-025 was to evaluate the occurrence of new adverse events (AEs) and immune-related adverse events (irAEs) as well as tumor response in patients who received extended ipilimumab treatment. Patient irAEs were managed as per ipilimumab guidelines described in the parent trials [11–16]. Tumor response was evaluated by modified World Health Organization criteria.
results patients Among 733 patients in the six parent trials (Figure 1), 248 enrolled in study CA184-025: 6 were not eligible for participation, 93 were retreated with ipilimumab upon enrollment (cohort 1), 91 received ipilimumab extended maintenance therapy upon enrollment (cohort 2), and 58 were followed for survival only (cohort 3). A total of 122 patients were retreated in study CA184-025: 93 upon initial enrollment (cohort 1) and 29 of 91 (cohort 2) upon disease progression on extended maintenance therapy. The number of patients who received ipilimumab at an induction dose of 0.3, 3, or 10 mg/kg followed by ipilimumab retreatment at 3 or 10 mg/kg is shown in Figure 1. Most patients (93.4%) were retreated at 10 mg/kg. Three patients initially treated with single-dose or multidose ipilimumab in study MDX010-15 were retreated with ipilimumab in study CA184-025. The median
Enrolled in phase II parent trials N = 733 CA184–004; n = 82 CA184–007; n = 115 CA184–008; n = 155 CA184–022; n = 217 MDX010–08; n = 76 MDX010–15; n = 88
Enrolled in CA184–025 N = 248
Screen failuresa n=6
Cohort 1: Ipilimumab retreatment n = 93
Cohort 2: Ipilimumab extended maintenance n = 91
Cohort 3: Follow-up only n = 58
n = 29
Ipilimumab retreatment n = 122 10b to 10 mg/kg; n = 53 treated 3b to 10 mg/kg; n = 34 treated 0.3b to 10 mg/kg; n = 24 treated 10b to 3 mg/kg; n = 7 treated 3b to 3 mg/kg; n = 1 treated 10 MD to 10 mg/kg; n = 2 treated 20 SD to 10 mg/kg; n = 1 treated
Ipilimumab extended maintenance n = 62 10 mg/kg; n = 45 (33 treated) 3 mg/kg; n = 13 (12 treated) 0.3 mg/kg; n = 4 treated
Figure 1. Flow diagram for patients from phase II parent trials who enrolled in the companion study CA184-025. Upon enrollment in study CA184-025, patients received ipilimumab retreatment (cohort 1) or extended maintenance therapy (cohort 2), or were followed for survival only (cohort 3). aFive patients did not meet study criteria, and one patient failed screening for other reasons. bInduction dose received in the parent trial. MD, multidose; SD, single dose.
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As per study CA184-025 protocol, patients were enrolled into one of three cohorts (Figure 1). Cohort 1 (n = 93) was composed of patients who experienced disease progression in the parent trial and were eligible for retreatment with ipilimumab. Patients were eligible for retreatment if they met core safety criteria and achieved complete response (CR), partial response (PR), or stable disease (SD) (≥3 months) during initial treatment. The exception was study CA184-022, due to the fact that a low-dose (0.3 mg/kg) ipilimumab group was included and ipilimumab dosage was blinded. Patients in any treatment group who experienced disease progression in study CA184022 could enroll in study CA184-025 at any time for retreatment with ipilimumab, provided they met core safety criteria. Cohort 2 (n = 91) was composed of patients who had not progressed on ipilimumab in the parent trial. These patients were treated with ipilimumab extended maintenance therapy in study CA184-025. Cohort 3 (n = 58) was comprised of patients who were either ineligible for the other study cohorts or refused treatment in the other study cohorts but consented to be followed for survival data, with no additional ipilimumab treatment. Patients were followed for survival in either the parent trials or study CA184-025, as described previously [3]. Only patients from studies CA184004, CA184-007, CA184-008, and CA184-022 were included in the survival analysis. Patients from the Medarex (MDX) studies were excluded from the survival analysis because survival follow-up beyond 3 years was not conducted (MDX010-08) or survival was not an end point (MDX010-15). One objective of study CA184-025 was to evaluate median OS and survival rates from the first dose of ipilimumab in the parent trials. The database lock for the current survival analysis was in June 2013. These data provide a 5.5-
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number of retreatment doses among patients initially treated with ipilimumab 0.3, 3, or 10 mg/kg was two, four, and four doses, respectively, with 5, 11, and 20 patients receiving all four doses.
long-term survival analysis
safety outcomes during first ipilimumab retreatment The safety analysis was based on a select group of retreated patients (N = 111) who received ipilimumab induction at 0.3, 3, or 10 mg/kg in a parent trial and who met efficacy and safety criteria for retreatment with ipilimumab at 10 mg/kg in study CA184-025. AEs and irAEs during ipilimumab retreatment at 10 mg/kg are shown in Table 3. As preliminarily reported [17], most patients (75%) initially treated with ipilimumab 0.3 mg/kg experienced irAEs of any grade; 67.6% and 56.6% of patients
tumor response during first ipilimumab retreatment Among 122 patients retreated with ipilimumab in study CA184025, as preliminarily reported [17], seven achieved CR, and 21 achieved PR for a best overall response rate of 23% (95% confidence interval 15.8–31.4). An additional 31 patients achieved SD upon retreatment of a disease control rate (DCR) of 48.4%. Forty-six patients experienced disease progression. Postbaseline tumor assessment was not carried out in 17 patients.
Table 2. Overall survival rates with ipilimumab in phase II trials CA184-004, CA184-007, CA184-008, and CA184-022 Trial
004
008 022b
007
N (prior treatment)
42 Total 14 (TN) 28 (PT) 40 Total 14 (TN) 26 (PT) 155 (PT) 72 (PT) 72 (PT) 73 (PT) 57 Total 32 (TN) 25 (PT) 58 Total 21 (TN) 37 (PT)
Dose (mg/kg)
10
3
10 10 3 0.3 10 + placebo
10 + budesonide
Median OS (months) 11.2a 10.7a 11.4a 12.8a 13.7a 11.5a 10.2 11.4 8.7 8.6 19.3 30.5 14.8 17.7 45.0 8.5
OS rate (%) 1-year 2-year
3-year
4-year
5-year
6-year
45.2 42.9 46.4 52.0 57.1 49.2 47.2 48.6 39.3 39.6 62.4 71.4 50.8 55.9 65.9 49.9
20.1 21.4 19.4 22.7 26.8 20.5 23.3 24.8 19.7 13.8 34.4 42.5 24.2 38.7 57.7 28.4
17.6 21.4 15.5 22.7 26.8 20.5 19.7 21.5 18.2 13.8 32.0 37.7 24.2 36.2 49.5 28.4
17.6 21.4 15.5 17.0 26.8 12.3 18.2 21.5 16.5 12.3 32.0 37.7 24.2 36.2 49.5 28.4
17.6a 21.4a 15.5a 17.0a 26.8a 12.3a 18.2 17.4 14.9 12.3 29.5 33.0 24.2 33.8 49.5 25.3
27.7 35.7 23.2 31.2 35.7 28.7 32.8 29.8 24.2 18.4 41.8 56.6 24.2 41.1 57.7 31.6
a
5.5-year survival data for patients in study CA184-004. Crossover from lower dose groups to 10 mg/kg in CA184-022 was allowed upon disease progression; this occurred in 33% and 42% of patients in the 0.3 and 3 mg/kg dose groups, respectively. OS, overall survival; PT, previously treated; TN, treatment-naive. b
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OS rates and previously reported median OS [3] for patients in studies CA184-004, CA184-007, CA184-008, and CA184-022 are shown in Table 2. Five-year survival rates for previously treated patients in studies CA184-007, CA184-008, and CA184-022 were 12.3% for ipilimumab 0.3 mg/kg, 16.5% for ipilimumab 3 mg/kg, and 18.2%–28.4% for ipilimumab 10 mg/kg. Five-year survival rates for treatment-naive patients in study CA184-007 were 37.7% for the ipilimumab 10 mg/kg plus placebo group and 49.5% for the ipilimumab 10 mg/kg plus budesonide group. Five-year survival rates for previously treated and treatment-naive patients in study CA184-004 were 17.0% for ipilimumab 3 mg/kg and 17.6% for ipilimumab 10 mg/kg. Survival rates at 5 years were similar to those reported at 6 years (5.5 years for CA184-004). Kaplan–Meier survival curves are shown in Figure 2.
initially treated with 3 or 10 mg/kg, respectively, experienced irAEs of any grade. Grade 3 or 4 irAEs were observed in 25%, 5.9%, and 13.2% of patients initially treated with ipilimumab 0.3, 3, and 10 mg/kg, respectively. The most common grade 3 or 4 irAEs affected the gastrointestinal tract and skin; diarrhea, colitis, pruritus, and rash were most frequently reported. Immune-related AEs were managed using established ipilimumab treatment algorithms, including the use of corticosteroids when appropriate [6, 7, 12–14]. There were no deaths attributed to irAEs in any of the retreatment groups. Twenty-seven retreated patients who were evaluated for safety discontinued treatment due to AEs of any cause: 8 (33.3%), 6 (17.6%), and 13 (24.5%) initially received ipilimumab 0.3, 3, or 10 mg/kg. These events were severe (grade 3 or 4) in six (25.0%), three (8.8%), and nine (17.0%) patients in the three dose cohorts, respectively. Four deaths related to gastrointestinal perforation (n = 1); multiorgan failure (n = 2); and cerebral vascular accident, pulmonary embolus, and sepsis (n = 1) were reported. AEs leading to treatment discontinuation were attributed to study drug in five (20.8%), one (2.9%), and six (11.3%) retreated patients who initially received ipilimumab at 0.3, 3, and 10 mg/kg, respectively.
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Proportion alive
A
1.0
3 mg/kg Ipi
0.9
Censored
0.8
10 mg/kg Ipi
0.7
Censored
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
2
4
Patients at risk 40 37 32 27 26 22 20 16 14 13 13 13 12 8 8 8 8 8 8 8 8 3 mg/kg Ipi
8 8 8 8 7 6 6 6 6 6 6 6 6
6 6 6 2 2 1
0
42 37 33 28 24 22 19 16 15 14 12 12 11 9 9 9 9 8 8 8 8
8 8 7 7 7 7 7 7 7 7 7 7 6
6 6 6 3 1 1
0
10 mg/kg Ipi
Proportion alive
B
1.0
Ipi 10 mg/kg+Bude
0.9
Censored
0.8
Ipi 10 mg/kg+Plac
0.7
Censored
0.6 0.5 0.4 0.3 0.2 0.1 0.0
Patients at risk Ipi+Bude Ipi+Plac
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 Months 58 56 52 41 34 32 29 28 25 24 21 19 17 17 17 17 17 17 16 16 16 16 16 15 15 15 15 15 15 15 15 15 15 15 15 15 14 14 13 9 8 5 2 1 0 57 51 47 45 44 38 33 31 29 26 22 20 18 18 17 16 15 15 14 14 14 13 13 13 13 13 13 13 13 13 13 13 13 13 12 12 12 12 8 3 3 1 0 0 0
Figure 2. Kaplan–Meier estimates of overall survival for studies: CA184-004 (A), CA184-007 (B), CA184-008 (C), and CA184-022 (D). Analyses for study CA184-008 include all treated patients, whereas those for studies CA184-004, CA184-007, and CA184-022 include all randomized patients.
discussion These data show that a proportion of advanced melanoma patients achieve durable, long-term survival of ≥5 years with ipilimumab. Five-year survival rates ranged from 12.3% for previously treated patients who received ipilimumab induction at 3 mg/kg to 49.5% for treatment-naive patients who received ipilimumab induction at 10 mg/kg, suggesting that durable, longterm survival may be achieved irrespective of ipilimumab dose or pretreatment status. While OS rates were numerically longer at the 10 mg/kg dose, study CA184-025 was not designed to evaluate differences in OS between ipilimumab dosing groups. Data from an ongoing phase III melanoma trial (CA184-169) should help clarify potential differences in benefit for ipilimumab 3 versus 10 mg/kg dosing. These long-term survival data confirm and extend previously reported survival data from ipilimumab clinical trials [3, 10]. As mentioned previously, 5-year OS rates were 13%–25% in ipilimumab-treated patients with advanced melanoma in phase I/II trials conducted at the National Cancer Institute [10]. Although patients in the phase III study MDX010-20 were not followed for survival beyond 2 years, 5-year survival rates in the phase III
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study CA184-024 were 18.2% for ipilimumab plus DTIC versus 8.8% for DTIC plus placebo [2]. As shown in Figure 2, survival rates reached a plateau beginning at ∼3 years, with 82.6% of patients alive at 3 years surviving to 5 years. This finding is consistent with previously reported data suggesting that a proportion of advanced melanoma patients achieve durable, long-term survival with ipilimumab. In a recent pooled analysis of long-term survival data from 1861 ipilimumab-treated patients with advanced melanoma, a plateau in the OS curve was observed beginning at ∼3 years and extending to ∼10 years [18]. One limitation of the current analysis is the inclusion of patients from multiple parent trials with different patient populations (i.e. previously treated or treatment-naive) and different ipilimumab induction doses (i.e. 0.3, 3, or 10 mg/kg). In addition, a small number of patients received single-dose or multiple-dose ipilimumab (i.e. MDX010-15). A second limitation of this analysis is that not all study sites and eligible patients participated in this companion study, potentially decreasing the reliability of the results [3]. The contribution of ipilimumab retreatment to OS is unknown, and data in this report cannot provide further insight on this issue. However, data from study CA184-025 suggest that a
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6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 Months
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10 mg/kg Ipi Censored
1.0 0.9 0.8
Proportion alive
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84
Proportion alive
D
0.3 mg/kg Ipi
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Censored 3 mg/kg Ipi Censored 10 mg/kg Ipi Censored
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 Months Patients at risk 0.3 mg/kg Ipi 73 61 53 47 38 33 27 24 17 15 14 12 12 12 11 10 10 10 9 9 9 9 9 9 9 8 8 8 8 8 8 8 8 8 8 8 8 8 3 3 1 1 1 0 3 mg/kg Ipi 72 64 54 47 39 30 26 23 22 20 20 18 16 16 16 15 13 13 13 13 13 12 12 12 12 12 12 11 10 10 10 9 9 9 9 9 9 9 5 4 2 0 0 0 10 mg/kg Ipi 72 63 53 45 41 39 31 28 25 22 19 19 18 17 17 17 15 15 15 15 15 13 13 13 12 12 12 12 11 11 11 10 10 9 9 8 8 8 5 3 1 0 0 0
Fig. 2 Continued Table 3. Adverse events and irAEs during ipilimumab retreatment at 10 mg/kg AEs and irAEs, n (%)
Any AE Any irAE Gastrointestinal Dermatologic Hepatic Endocrine Othera
Ipilimumab dose in parent study with retreatment at 10 mg/kg (N = 111) 0.3 mg/kg (n = 24) 3 mg/kg (n = 34) All grades Grade 3/4 All grades Grade 3/4
10 mg/kg (n = 53) All grades
Grade 3/4
24 (100.0) 18 (75.0) 14 (58.3) 10 (41.7) 1 (4.2) 1 (4.2) 1 (4.2)
51 (96.2) 30 (56.6) 11 (20.8) 18 (34.0) 3 (5.7) 3 (5.7) 2 (3.8)
18 (34.0) 7 (13.2) 2 (3.8) 2 (3.8) 2 (3.8) 1 (1.9) 0 (0.0)
10 (41.7) 6 (25.0) 3 (12.5) 1 (4.2) 1 (4.2) 1 (4.2) 0 (0.0)
33 (97.1) 23 (67.6) 7 (20.6) 18 (52.9) 0 (0.0) 2 (5.9) 3 (8.8)
10 (29.4) 2 (5.9) 1 (2.9) 1 (2.9) 0 (0.0) 0 (0.0) 0 (0.0)
Most common (>1%) grade 3/4 “other” irAEs were hypersensitivity and interstitial lung disease; none were grade 5. AE, adverse event; irAE, immune-related adverse event. a
proportion of advanced melanoma patients re-establish disease control with ipilimumab retreatment, as previously shown in the phase III trial MDX010-20 [19] and in an ipilimumab Expanded Access Program (EAP) [17]. In study MDX010-20, the DCR among retreatment-eligible patients was 75% (n = 6/8) for the
| Lebbé et al.
ipilimumab plus placebo group and 65.2% (n = 15/23) for the ipilimumab plus gp100 group [19]. In the Italian EAP, 51 of 855 patients were retreated with ipilimumab at 3 mg/kg, of which 28 (55%) re-established disease control [17]. In the current study, we observed a DCR of 23% among 122 retreated patients.
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Months Patients at risk 10 mg/kg Ipi 155140114 96 83 78 70 65 60 55 52 46 45 42 35 34 33 32 32 31 30 28 27 27 27 27 27 26 26 26 25 25 25 25 24 24 24 24 22 8 3 1 0
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acknowledgements Professional medical writing and editorial assistance was provided by Ward Pedersen and Jennifer DiNieri at StemScientific and was funded by Bristol-Myers Squibb.
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funding Bristol-Myers Squibb (BMS) provided funding to all study sites and institutions to cover investigators’ expenses for undertaking the parent trials.
disclosure CL is a consultant for Roche and has participated in advisory boards for BMS, Roche, GlaxoSmithKline, Amgen, and Novartis. JSW has received honoraria from BMS for advisory boards, and BMS has supported clinical research at his institution. MM is a principal investigator of clinical trials sponsored by BMS. OH is a speaker and consultant for BMS, and he participates in clinical research sponsored by BMS. SJO receives research support from BMS. CK, LC, and MBM are currently employed by BMS. LC and MBM own stock in BMS. JDW is a paid consultant for BMS and receives research support from BMS. BN and KH have declared no conflicts of interest.
references 1. Garbe C, Eigentler TK, Keilholz U et al. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011; 16: 5–24. 2. Maio M, Bondarenko I, Robert C et al. Survival analysis with 5 years of follow-up in a phase III study of ipilimumab and dacarbazine in metastatic melanoma. In Presented at the European Cancer Congress 2013, 27 September–1 October 2013 (Abstr 3704). Amsterdam, The Netherlands 2013. 3. Wolchok JD, Weber JS, Maio M et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol 2013; 24: 2174–2180. 4. Hoos A, Ibrahim R, Korman A et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol 2010; 37: 533–546. 5. Wolchok JD, Hodi FS, Weber JS et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann NY Acad Sci 2013; 1291: 1–13. 6. Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–723. 7. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517–2526. 8. Balch CM, Gershenwald JE, Soong SJ et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27: 6199–6206. 9. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000; 6: S11–S14. 10. Prieto PA, Yang JC, Sherry RM et al. CTLA-4 blockade with ipilimumab: longterm follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 2012; 18: 2039–2047. 11. Weber JS, O’Day S, Urba W et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 2008; 26: 5950–5956. 12. Weber J, Thompson JA, Hamid O et al. A randomized, double-blind, placebocontrolled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 2009; 15: 5591–5598. 13. O’Day SJ, Maio M, Chiarion-Sileni V et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol 2010; 21: 1712–1717. 14. Wolchok JD, Neyns B, Linette G et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11: 155–164.
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Forty-six patients had progressive disease despite ipilimumab retreatment. It has been reported in previous studies that delayed responses with ipilimumab are possible [6]. However, this possibility was not assessed in the current study. The 46 patients who experience disease progression were included in the retreatment group, which was only evaluated for initial tumor response and safety. The rate of retreatment was higher in study CA184-025 than in study MDX010-20 or the Italian EAP (Study CA184-025: 16.6%, 122 of 733 patients; MDX010-20: 4.7%, 32 of 676 patients; EAP: 6%, 51 of 855 patients). This is likely due to differences in parent study protocols and patient eligibility for study CA184-025, in which some patients were retreated at a different dose than that used during induction. In particular, retreated patients in study CA184-025 included those who initially received a low dose of ipilimumab (0.3 mg/kg in study CA184-022), resulting in a disproportionately higher percentage of patients eligible for retreatment. Eligible patients in study MDX010-20 or the EAP were retreated with the same dose and schedule as in the induction phase (i.e. ipilimumab 3 mg/kg every 3 weeks for four doses) [6, 17]. The current analysis provides additional information on the safety profile of ipilimumab retreatment. The most common treatment-related AEs experienced with ipilimumab induction therapy are typically inflammatory in nature [4–7] and are manageable when ipilimumab treatment guidelines are followed [20–22]. In this analysis, the safety profile during ipilimumab retreatment was comparable with that observed during ipilimumab induction in the parent studies [12–14]. Most irAEs affected the skin and gastrointestinal tract, and there were no deaths resulting from irAEs during retreatment. We observed a lower incidence of irAEs among retreated patients who received ipilimumab 3 and 10 mg/kg in a parent trial than in patients who received ipilimumab 0.3 mg/kg. The reason for this apparent difference is unclear, and the data should be interpreted with caution due to small patient numbers. One possibility is that ipilimumab 0.3 mg/kg was insufficient to mitigate CTLA-4 binding to the same extent as the higher doses [23], which may result in greater sensitivity to immune activation upon retreatment. Alternatively, selection bias may explain this observed result since patients with high-grade AEs in the parent study would not have been eligible for retreatment, and serious AEs would have been less common with ipilimumab 0.3 mg/kg. In conclusion, these results demonstrate durable, long-term survival in patients with advanced melanoma who received ipilimumab in phase II clinical trials. This survival analysis represents one of the longest follow-up periods among approved melanoma treatments. This study demonstrates that 5-year survival may be achieved with ipilimumab in a subset of advanced melanoma patients, across a range of doses, and independent of pretreatment status. Ipilimumab retreatment may re-establish disease control in a proportion of eligible patients, but its contribution to OS remains unclear. Additional studies are needed to identify patient populations most likely to experience long-term survival benefit.
original articles 15. Hamid O, Schmidt H, Nissan A et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011; 9: 204. 16. Hersh EM, O’Day SJ, Powderly J et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs 2011; 29: 489–498. 17. Chiarion-Sileni V, Pigozzo J, Ascierto PA et al. Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy. Br J Cancer 2014; 110: 1721–1726. 18. Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. In Presented at the European Cancer Congress 2013, 27 September–1 October 2013 (Abstr 24LBA). Amsterdam, The Netherlands 2013.
Annals of Oncology 19. Robert C, Schadendorf D, Messina M et al. MDX010-20 investigators. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res 2013; 19: 2232–2239. 20. Ibrahim RA, Berman DM, DePril V et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol 2011; 29: Abstr 8583. 21. YERVOY™ (ipilimumab) US Prescribing Information: Risk Evaluation and Mitigation Strategy. Bristol-Myers Squibb Company; 2011; http://www.yervoy.com/hcp/rems. aspx (June 2014, date last accessed). 22. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30: 2691–2697. 23. Feng Y, Roy A, Masson E et al. Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res 2013; 19: 3977–3986.
Association between treatment toxicity and outcomes in oncology clinical trials M. V. Abola1, V. Prasad2 & A. B. Jena3,4* 1
Department of Family Medicine, Case Western Reserve University School of Medicine, Cleveland; 2Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda; 3Department of Health Care Policy, Harvard Medical School, Boston; 4Department of Medicine, Massachusetts General Hospital, Boston, USA
Received 4 July 2014; revised 18 August 2014; accepted 20 August 2014
Background: Whether or not toxicity predicts clinical outcomes has long been a question regarding cancer treatments. While prior studies have focused on specific cancers, therapies, and toxicities, no comprehensive evidence exists on whether treatment toxicity predicts favorable outcomes. Methods: We abstracted treatment toxicity and clinical outcome data from a sample of phase III oncology randomized clinical trials (n = 99 trials). We investigated whether treatments with relatively greater toxicity compared with their controls had relatively higher, lower, or equivocal rates of clinical efficacy, measured by progression-free survival (PFS) and overall survival (OS). Several toxicities were assessed (all grades, grades III/IV, cutaneous rash, gastrointestinal toxicity, and myelosuppression). Results: Toxicity and efficacy were greater among treatments than controls (e.g. 3.5 instances of all-grade toxicity per patient in treatment arms versus 2.8 instances in controls, P < 0.001; mean PFS of 9.1 months across treatment arms versus 7.1 months across controls, P < 0.001; mean OS of 18.6 months across treatment arms versus 16.9 months across controls, P < 0.001). Across trials, greater relative treatment toxicity was strongly associated with greater PFS in treatments versus controls (P < 0.001), but not OS (P = 0.44). Although higher relative rates of myelosuppression and cutaneous rash among treatments were not associated with greater treatment efficacy, greater relative gastrointestinal toxicity among treatments was associated with greater relative PFS compared with controls (P = 0.007). Conclusion: Across trials, treatments with relatively greater all-grade toxicity compared with controls are associated with relatively greater PFS but not OS. Key words: treatment toxicity, clinical trials
introduction Whether or not toxicity of treatment predicts meaningful clinical outcomes has long been a question in cancer medicine, with *Correspondence to: Prof. Anupam B. Jena, Department of Health Care Policy, Harvard Medical School, 180 Longwood Avenue, Boston, MA 02115, USA. Tel: +1-617-4328322; E-mail: [email protected]
available evidence offering mixed conclusions. Across a range of cancers, cytotoxic side-effects such as myelosuppression have been linked to improved outcomes in both the adjuvant and metastatic setting [1–6]. For example in an analysis of patients with advanced nonsmall-cell lung cancer treated with cytotoxic agents, both severe and mild neutropenia were associated with improved survival, leading authors to speculate that the absence
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Annals of Oncology 25: 2284–2289, 2014 doi:10.1093/annonc/mdu444 Published online 5 September 2014