Article Tools
ORIGINAL REPORTS
Melanoma
Article Tools
Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma
Abstract
The addition of nivolumab (anti–programmed death-1 antibody) to ipilimumab (anti–cytotoxic T-cell lymphocyte–associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen.
This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome.
Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy.
Ipilimumab is a fully human monoclonal antibody to cytotoxic T-lymphocyte–associated protein 4 antigen1 and was the first therapy to demonstrate a survival improvement in patients with metastatic melanoma in a randomized trial.2,3 Nivolumab is a fully human, anti–programmed death-1 (PD-1) checkpoint inhibitor that selectively blocks the interaction of the PD-1 receptor with PD ligands 1 and 24 and has shown increased efficacy in patients with metastatic melanoma compared with ipilimumab monotherapy both alone and in combination with ipilimumab.5-7 Ipilimumab and nivolumab as monotherapies and in combination are approved by the US Food and Drug Administration and the European Commission for the treatment of patients with advanced melanoma.
The phase II CheckMate 0696,7 and phase III CheckMate 0675,8 trials demonstrated an improved objective response rate (ORR) and progression-free survival (PFS) for nivolumab plus ipilimumab compared with ipilimumab alone but with a higher frequency of adverse events (AEs). Specifically, treatment-related grade 3/4 AEs were 54% and 55% with nivolumab plus ipilimumab versus 20% and 27% with ipilimumab alone in CheckMate 069 and 067, respectively.5,7 Despite a higher frequency of AEs, AEs that led to treatment discontinuation with nivolumab plus ipilimumab combination therapy, and the requirements of immunosuppressive agents such as corticosteroids to reverse toxicity in most of these patients, previous post hoc analyses demonstrated consistent efficacy in patients who discontinued because of AEs compared with all patients.7,9
AEs observed during treatment with ipilimumab or nivolumab are believed to have an immune-related etiology consistent with their mechanism of action. The most common events occur in the skin, GI, endocrine, hepatic, pulmonary, and renal systems; therefore, these categories have been designated for specific reporting of immune checkpoint AEs (ie, select AEs).5,7,8,10 Guidelines for the management of these AEs are well established and include interruption or discontinuation of the immune checkpoint inhibitor and administration of symptomatic therapy and immune-modulating agents (IMs).6,10-12 We performed a pooled analysis across melanoma studies to further characterize the safety profile and the outcomes of select AE management for the approved dose and schedule of the nivolumab plus ipilimumab regimen.
The analysis population included all patients treated with at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 (induction phase) followed by nivolumab 3 mg/kg every 2 weeks (continuation phase) in the following clinical trials:
Phase Ib open-label dose-escalation study in patients with pretreated or untreated unresectable or metastatic melanoma (CA209-004 cohort 8; ClinicalTrials.gov identifier: NCT01024231; n = 41; database lock, July 2015)13
Phase II randomized study in patients with untreated, unresectable, or metastatic melanoma (CheckMate 069; ClinicalTrials.gov identifier: NCT01927419; n = 94; database lock, August 2015)6,7
Phase III randomized study in patients with untreated unresectable or metastatic melanoma (CheckMate 067; ClinicalTrials.gov identifier: NCT01844505; n = 313; database lock, February 2015)5
Patients were treated until disease progression or unacceptable toxicity. Patients in CA209-004 could enter the continuation phase without completing all four induction doses, whereas patients in CheckMate 069 and 067 had to complete all four induction doses before continuing onto nivolumab alone.
Patients with preexisting autoimmune disease were excluded from all studies, except conditions not expected to recur in the absence of an external trigger and for resolved childhood asthma/atopy (CA209-004); vitiligo and type 1 diabetes (all studies); and residual hypothyroidism that only required hormone replacement therapy and psoriasis that did not require systemic treatment (CheckMate 067 and 069).
All pooled safety analyses were based on treatment-related AEs. The analyses reported here are overall frequency of AEs and select AEs, proportion of patients with AEs and select AEs over time, times to onset and resolution of select AEs, and use of IMs to manage select AEs. Select AEs are those with presumed immune-related etiology that may be mitigated by early recognition and potential management with immunosuppression and for which multiple event terms may be used to describe a single type. Time to resolution analyses were based on Kaplan-Meier estimates. Probability of AE incidence was demonstrated by use of a vector analysis method to determine the incidence rate of AEs over time for study period days 1 to 620. For each study day, a vector was defined to obtain the cumulative number of unique patients who experienced AEs that started at or before that study day and ended at or after that study day. Probability of AE incidence (cumulative number of unique patients with AEs / total number of patients) for each study day was plotted against the study day to show AE incidence over time.
AEs were coded by using the Medical Dictionary for Regulatory Activities version 15.1 for CA209-004 and version 16.1 for CheckMate 069 and 067. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0 [CA209-004] and version 4.0 [CheckMate 069 and 067]). Statistical analyses were conducted with SAS 9.2 software (SAS Institute, Cary, NC).
A total of 448 treated patients were included in this analysis. Baseline demographics and disease characteristics were typical for an advanced melanoma clinical trial population (Data Supplement). Among all treated patients, the median number of doses of nivolumab received was four (range, one to 50) and of ipilimumab, four (range, one to four), with 47% of patients continuing onto nivolumab maintenance. Median study follow-up was 13.2 months (range, 0.1 to 24.0 months). At the time of analysis, 73.4% of patients had discontinued treatment for reasons of study drug toxicity (40.0%), disease progression (21.4%), unrelated AE (4.5%), patient request (2.2%), death (1.3%), clinical benefit (1.1%), or other (1.1%). In addition, < 1% of patients each discontinued for poor or noncompliance and study criteria not met, not reported, or withdrawal of consent.
Almost all treated patients (94.9%) experienced treatment-related AEs, including 55.4% of patients who experienced grade 3/4 treatment-related AEs (Table 1). The Data Supplement lists all grade 3/4 treatment-related AEs and any grade AEs reported in ≥ 5% of patients. More than one-third of patients (35.7%) had any grade treatment-related AEs that led to discontinuation (Table 1). Figure 1 shows the proportion of patients who experienced treatment-related grade 3/4 AEs over time as a plot of AE incidence on any given day during the study period. Peaks in grade 3/4 AE burden were observed at approximately days 50 and 90.
|
Fig 1. Proportion of patients with treatment-related grade 3/4 adverse events over time. The percentage at each time point shows the number of patients who experienced at least one grade 3/4 adverse event divided by all treated patients (N = 448).
Treatment-related select AEs were reported by 87.5% of patients, including 41.5% with grade 3/4 events (Table 1). The proportions of patients who experienced treatment-related select grade 3/4 AEs over time are shown by organ system in Figure 2. Median time to onset of grade 3/4 treatment-related select AEs was fastest for skin at 3 weeks (range, 0.1 to 55.0 weeks) followed by GI at 7 weeks (range, 0.6 to 48.9 weeks; Fig 3). Most treatment-related select AEs resolved, except for endocrinopathies, which frequently required long-term hormone replacement therapy. Median time to resolution of grade 3/4 AEs was < 5 weeks, excluding endocrinopathies (Fig 4). Overall, 370 (82.6%) of 448 patients and 293 (74.7%) of 392 patients experienced one or more treatment-related select AEs and were managed with IMs; the most common treatments were systemic corticosteroids (75.0% and 65.3%, respectively) and topical corticosteroids (31.3% and 28.8%, respectively). In addition, in those with treatment-related select AEs, infliximab was used to treat 23 (5.9%) of 392 patients for GI AEs and one (0.3%) patient for hepatic AEs; mycophenolic acid was used to treat three (0.8%) patients for hepatic AEs. IM use for management of select AEs is shown by organ system in the Data Supplement.
Fig 2. Proportion of patients with treatment-related grade 3/4 select adverse events (AEs) over time by organ category. (A) More common select AEs. (B) Less common select AEs. The percentage at each time point shows the number of patients who experienced at least one grade 3/4 AE divided by all treated patients (N = 448).
Fig 3. Time to onset of grade 3/4 treatment-related select adverse events. Colored boxes indicate interquartile range (IQR; Q1, Q3); center vertical line indicates median; outer vertical lines indicate range (minimum to maximum [min-max]). Median times to resolution for all-grade treatment-related select adverse events were as follows: 2.0 weeks (range, 0.1 to 66.9 weeks) for skin, 5.0 weeks (range, 0.1 to 63.6 weeks) for GI, 6.1 weeks (range, 0.1 to 49.7 weeks) for hepatic, 7.4 weeks (range, 0.1 to 46.1 weeks) for endocrine, 10.6 weeks (range, 2.9 to 47.7 weeks) for pulmonary, and 10.2 weeks (range, 2.3 to 63.9 weeks) for renal systems.
Fig 4. Time to resolution of grade 3/4 treatment-related select adverse events (AEs). Resolution is shown over time in patients whose AEs had not yet resolved; at time 0, 100% of patients had not had a resolution. Median times to resolution for all-grade AEs were as follows: 10.9 weeks (range, 0.1 to 101.3+ weeks) for skin, 3.0 weeks (range, 0.1 to 78.7+ weeks) for GI, 4.6 weeks (range, 0.1 to 53.1+ weeks) for hepatic, 42.7 weeks (range, 0.4 to 93.9+) for endocrine, 6.1 weeks (range, 0.3 to 46.9+ weeks) for pulmonary, and 1.9 weeks (range, 0.3 to 42.6+ weeks) for renal systems. IM, immune-modulating agent; NA, not available.
The majority of patients with grade 2 to 4 treatment-related select AEs experienced events in one (41.5%) or two (23.2%) organ systems (Data Supplement). Among patients who had select AEs in two organ systems, the most common combinations were skin and hepatic (18.3%) or skin and GI (16.3%). To provide context for the safety profile of the nivolumab plus ipilimumab combination therapy relative to nivolumab monotherapy, the Data Supplement lists the incidence and severity of treatment-related AEs and the time course of treatment-related select AEs from this pooled combination safety analysis along with those from the nivolumab monotherapy pooled safety analysis.14
In all patients who received the combination therapy, the ORR was 57.8%; for patients with one or more treatment-related select AEs or no treatment-related select AEs, the ORRs were 62.6% and 21.2%, respectively (Data Supplement). Patients who experienced a select AE after the first 12 weeks of treatment had a higher ORR than those who had a select AE at ≤ 12 weeks (73.1% v 58.9%). Baseline characteristics (Data Supplement) and median number of doses received for the patient groups (Data Supplement) show that patients with no select AEs had an increased frequency of poor prognostic factors, including elevated lactate dehydrogenase levels and M1c disease, and that patients with select AEs only after the first 12 weeks of treatment had much higher treatment exposure. Median PFS was 19.4 months for all treated patients, 6.7 months for patients with no treatment-related select AEs, and not reached for patients with treatment-related select AEs after ≤ 12 weeks of treatment or after 12 weeks of treatment (Data Supplement).
The four treatment-related deaths in this population during the study were previously reported.1,7 One death in CA209-004 was a result of a primary event of immune colitis, with a delay in treatment leading to sepsis and multiorgan failure. Three deaths in CheckMate 069 were a result of pneumonitis (n = 1), ventricular arrhythmia (n = 1), and panhypopituitarism with severe adrenal deficiency and adrenal crisis (n = 1). No treatment-related deaths occurred within 100 days of the last dose of study therapy during the phase III CheckMate 067 study, although two treatment-related deaths occurred beyond the standard 100-day reporting period. One patient with a history of cardiac disease developed cardiomyopathy that led to study drug discontinuation; this patient subsequently had disease progression and died as a result of cardiomyopathy approximately 1 year after the last study dose and 2 months after rechallenge with pembrolizumab. A second patient died 7 months after the last study dose as a result of liver necrosis from uncontrolled transaminase elevations likely exacerbated by poor patient compliance.
To our knowledge, this report is the first of pooled safety data from patients with advanced melanoma treated with the regulatory-approved dose and schedule of combination nivolumab plus ipilimumab therapy. The pooled clinical trial data were consistent with individual trial data.5-7,13 More than one-half of patients (55.4%) experienced grade 3/4 treatment-related AEs with combination therapy. Grade 3/4 select AEs occurred in 41.5% of patients, with the most common being hepatic or GI and onset occurring within 4 to 12 weeks of treatment initiation. Most grade 3/4 select AEs were manageable on the basis of established algorithms that involved IMs and resolved within 4 to 5 weeks.
The frequency and severity of treatment-related AEs with nivolumab plus ipilimumab were higher than with either agent alone. In a pooled safety analysis of patients with melanoma treated with nivolumab monotherapy, the most common treatment-related AEs were fatigue (25%), pruritus (17%), diarrhea (13%), and rash (13%), with 10% of patients experiencing grade 3/4 treatment-related AEs.14 In studies of ipilimumab 3 mg/kg monotherapy, grade 3/4 treatment-related AEs occurred in 20% to 27% of patients.5,7 The rate of treatment-related AEs that led to discontinuation with combination therapy (35.7%) was also higher than with nivolumab (3%)14 or ipilimumab (9% to 15%) alone.5,7 However, the nature of the AEs was consistent, with the most common that led to discontinuation being colitis and diarrhea in all studies.
During the clinical development of nivolumab, a separate category of select AEs with a presumed immune-related etiology was identified for characterization of events that occurred in the skin, GI, endocrine, hepatic, pulmonary, or renal organ systems. Grade 3/4 select AEs occurred in 41.5% of patients with the combination regimen compared with 4% with nivolumab monotherapy14 and in 15% to 19% of patients with ipilimumab monotherapy.5,7 Median time to onset of select AEs was shorter with the combination therapy than with nivolumab alone14 and ipilimumab 10 mg/kg.15 Except for select endocrine AEs that necessitated permanent hormone replacement therapy, at least 79% of select AEs in other organ systems resolved with or without the use of corticosteroids and, when necessary, secondary IMs. Resolution times of select AEs with the combination therapy generally were similar compared with single-agent ipilimumab and nivolumab.5,7,14
With increased clinical experience, rare AEs have been reported in the predefined select organ systems as well as in multiple other organ systems, which were also immune related. Our pooled analyses of the combination regimen has provided an opportunity to detect relatively rare AEs and rare severe manifestations of more common toxicities with important clinical consequences. These included sarcoidosis (0.2%); insulin-dependent diabetes mellitus (0.4%), which in some patients presented as diabetic ketoacidosis (0.2%); Guillain-Barré syndrome (0.4%) or other polyneuropathies (0.4%) or neuritis (0.2%); intestinal perforation (0.2%) or large bowel perforation (0.2%); clinical signs and symptoms of pancreatitis (0.9%) beyond common asymptomatic lipase and amylase elevations; arthropathies (0.4%), spondyloarthropathies (0.2%), and myositis (0.4%), which in some patients were associated with debilitating symptoms; eye-related events, including uveitis (1.6%), dry eye syndrome (1.1%), and episcleritis (0.9%); and cytopenias that affected one or more lineages, including anemia (3.8%), thrombocytopenia (1.6%), and neutropenia (1.1%). The rate of infections was low (any grade, 6.9%; grade 3/4, 0.7%), even with the common use of immunosuppressive drugs to treat AEs.
Rare cardiac toxicities also were observed. One death was related to cardiac arrhythmia, and a second poststudy fatal cardiomyopathy was reported, although the relationship to study drug was confounded by pembrolizumab rechallenge. Unrelated to our study, two cases of fatal myocarditis/cardiomyopathy or rhabdomyolysis with nivolumab and ipilimumab combination treatment were recently reported.16 Although myocarditis appears to be rare with the combination regimen (0.27%)16 and is not unique to this drug class, heightened vigilance with regard to this toxicity is imperative with the use of checkpoint inhibitors because of the potential fulminant and fatal course of myocarditis.
The deaths observed in this analysis, although rare, illustrate the importance of prompt diagnosis and use of the established management algorithms,6,10-12 which have led to high resolution rates in most organ classes of AEs. Broad familiarization with the management algorithms likely contributed to the low mortality rate in these trials. Clinical experience to date also suggests that treatment-related morbidity is likely to be reduced by concerted efforts to educate patients on potential AEs and by emphasis on patient communication of AEs to the appropriate nursing and medical staff to allow for early intervention.
Although this pooled analysis demonstrates that the majority of patients can be treated safely with the approved dose and schedule of ipilimumab and nivolumab by using established algorithms, the rate of grade 3/4 AEs is high, and a rare patient may develop prolonged severe toxicity or die as a result of treatment-related AEs. In view of the high regimen activity rate observed in metastatic melanoma and emerging activity data in other diseases, approaches to reduce AEs or improve AE management without affecting efficacy are desirable. Studies continue to assess the safety and activity of modified doses and schedules of ipilimumab and nivolumab. With the introduction of additional immuno-oncology therapies and schedules, the necessity and safety of reinitiating treatment after resolution of severe toxicity should be carefully investigated. Current data from these studies, where rechallenge of patients with select severe AEs was largely prohibited, have suggested that patients who discontinue therapy as a result of toxicity receive benefit similar to those who continue therapy.7,17
Although factors that predict specific immune-related AEs remain unknown, studies continue to assess the relationship of the microbiome or genome-wide polymorphisms with development of treatment-related toxicity. Predictive biomarker development might improve patient selection or heighten the monitoring for specific toxicities and could lead to earlier interventions. Although established algorithms for management of toxicity with corticosteroids and secondary IMs are broadly effective, even more effective approaches could be explored from the vast array of novel agents approved or in development for autoimmunity. The latter agents, which include anticytokines or specific inhibitors, such as cytotoxic T-lymphocyte–associated protein 4 immunoglobulin, may be necessary for patients with rapidly evolving life-threatening toxicity that is not immediately responsive to the standard algorithm or for patients with chronic toxicities that do not resolve with standard approaches.
The recent nivolumab pooled safety analysis reported an association between toxicity and response rate after adjusting for drug exposure and showed a significantly higher ORR in patients who experienced treatment-related AEs than in those who did not.14 However, no similar trend was observed for PFS after censoring for patients who progressed or died within the first 12 weeks on study. Prior ipilimumab studies posited that development of immune-related AEs are associated with response to checkpoint inhibitors for patients with melanoma.18-22 However, not all evidence supports this hypothesis, including a real-world expanded access program that found no association between immune-related AEs and response to ipilimumab23 and a retrospective study that found that neither immune-related AEs nor systemic corticosteroid use affected overall survival or time to treatment failure with ipilimumab monotherapy.24 For nivolumab monotherapy, a landmark analysis showed longer overall survival in patients who developed a select AE than in those who did not.25 In the current pooled analysis of patients treated with nivolumab plus ipilimumab combination therapy, patients without treatment-related select AEs had a lower ORR and shorter PFS, but a higher proportion of these patients had poor prognostic features and less overall drug exposure. In addition, patients who developed treatment-related select AEs after the first 12 weeks of combination therapy had an increased ORR and an expected longer duration of treatment. Therefore, our pooled analysis does not support an association between treatment-related toxicity and response to nivolumab plus ipilimumab.
In conclusion, this pooled safety analysis of nivolumab plus ipilimumab combination therapy shows that combination therapy increases the frequency and accelerates the tempo of treatment-related AEs, including treatment-related select AEs and AEs that lead to discontinuation, relative to either monotherapy. However, the nature of the observed AEs remain consistent. All-grade treatment-related select AEs occur earlier than with either agent administered alone. In addition, grade 3/4 treatment-related select AEs are similar in time to resolution to that observed with single-agent ipilimumab and are manageable by previously established treatment algorithms.
Supported by Bristol-Myers Squibb.
Presented at the European Society for Medical Oncology 41st Congress, Copenhagen, Denmark, October 7-11, 2016; Clinical Oncology Society of Australia 43rd Annual Scientific Meeting, Gold Coast, Queensland, Australia, November 15-17, 2016; 21st Annual Scientific Symposium of the Hong Kong Cancer Institute; Hong Kong, Special Administrative Region, People’s Republic of China, November 19-20, 2016; and Melanoma and Immunotherapy Bridge 2016, Naples, Italy, November 30-December 3, 2016.
Clinical trial information: NCT01024231, NCT01927419, and NCT01844505.
Conception and design: Mario Sznol, David Hogg, Dana Walker, Rafia Bhore, F. Stephen Hodi, Jedd D. Wolchok
Provision of study materials or patients: Mario Sznol, Pier Francesco Ferrucci, David Hogg, Michael B. Atkins, Pascal Wolter, Massimo Guidoboni, Celeste Lebbé, John M. Kirkwood, Jacob Schachter, Gregory A. Daniels, Jessica Hassel, Jonathan Cebon, Winald Gerritsen, Victoria Atkinson, Luc Thomas, John McCaffrey, Derek Power, F. Stephen Hodi, Jedd D. Wolchok
Collection and assembly of data: Jessica Hassel, Luc Thomas
Data analysis and interpretation: Mario Sznol, Pier Francesco Ferrucci, David Hogg, Michael B. Atkins, Pascal Wolter, Massimo Guidoboni, Celeste Lebbé, John M. Kirkwood, Jacob Schachter, Gregory A. Daniels, Jonathan Cebon, Winald Gerritsen, Victoria Atkinson, Luc Thomas, John McCaffrey, Derek Power, Dana Walker, Rafia Bhore, Joel Jiang, F. Stephen Hodi, Jedd D. Wolchok
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Stock or Other Ownership: Amphivena Therapeutics, Intensity Therapeutics, Adaptive Biotechnologies
Consulting or Advisory Role: Bristol-Myers Squibb, Genentech-Roche, Amgen, AstraZeneca, Symphogen, Kyowa Hakko Kirin, Lion Biotechnologies, Nektar, Novartis, Eli Lilly, Pfizer, Janssen Pharmaceuticals, Vaccinex, Merck Sharp & Dohme, Biodesix, Alexion Pharmaceuticals, Adaptimmune, Lycera, Theravance, Modulate, Omniox, Seattle Genetics, Inovio Pharmaceuticals, AgonOx, Pierre-Fabre, Ignyta, Baxalta-Shire
Other Relationship: Haymarket Media, Research to Practice, TRM Oncology, Physician Education Resource, Imedex, AcademicCME, DAVA Oncology, Clinical Care Options, Vindico Medical Education, prIME Oncology
Consulting or Advisory Role: Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Pierre Fabre
Travel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme
Consulting or Advisory Role: Roche, Novartis, EMD Serono, Merck, Bristol-Myers Squibb
Expert Testimony: EMD Serono
Travel, Accommodations, Expenses: Novartis, EMD Serono
Honoraria: Bristol-Myers Squibb
Consulting or Advisory Role: Genentech, Pfizer, Novartis, GlaxoSmithKline, C-Cam, X4 Pharmaceuticals, Amgen, Eli Lilly, Alkermes, Infinity Pharmaceuticals, Genoptix, Bristol-Myers Squibb, Nektar, Merck
Research Funding: Bristol-Myers Squibb
No relationship to disclose
Honoraria: Bristol-Myers Squibb
Consulting or Advisory Role: Bristol-Myers Squibb, Novartis, Amgen, Roche
Honoraria: Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen
Consulting or Advisory Role: Roche, Bristol-Myers Squibb, Novartis, Amgen, MSD
Speakers’ Bureau: Bristol-Myers Squibb, Amgen, Roche, Novartis
Research Funding: Roche (Inst), Bristol-Myers Squibb (Inst)
Travel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, Novartis, Amgen
Consulting or Advisory Role: Bristol-Myers Squibb, Novartis, Genentech, Roche, EMD Serono, Array BioPharma, Merck
Research Funding: Paometheus (Inst), Merck (Inst)
Travel, Accommodations, Expenses: Novartis, Roche, Genentech
Honoraria: Bristol-Myers Squibb, MSD, Novartis
Consulting or Advisory Role: Merck Sharp & Dohme
Patents, Royalties, Other Intellectual Property: Merck Sharp & Dohme
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis
Research Funding: Bristol-Myers Squibb (Inst), Paometheus (Inst), Amgen (Inst), Viralytics (Inst)
Honoraria: Bristol-Myers Squibb, MSD, Roche, GlaxoSmithKline, Novartis, Amgen
Consulting or Advisory Role: MSD, Amgen
Research Funding: Bristol-Myers Squibb (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, MSD, Amgen, GlaxoSmithKline
Honoraria: GlaxoSmithKline, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Amgen, Merck
Consulting or Advisory Role: Amgen, Bionomics, Bristol-Myers Squibb, Merck Sharp & Dohme, Bionomics, Novartis, Novartis
Research Funding: GlaxoSmithKline (Inst), CSL (Inst)
Patents, Royalties, Other Intellectual Property: GlaxoSmithKline
Expert Testimony: Bristol-Myers Squibb
Consulting or Advisory Role: Amgen, Astellas Pharma, Bristol-Myers Squibb, Janssen-Cilag, Merck Sharp & Dohme, Sanofi, CureVac, Bayer AG
Research Funding: Astellas Pharma (Inst), Janssen-Cilag (Inst), Bayer AG (Inst)
Honoraria: Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Genentech
Consulting or Advisory Role: Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Merck Serono
Speakers’ Bureau: Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Genentech
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Merck Sharp & Dohme
No relationship to disclose
No relationship to disclose
No relationship to disclose
Employment: Bristol-Myers Squibb
Stock or Other Ownership: Antares Pharma (I)
Employment: Bristol-Myers Squibb
Stock or Other Ownership: Bristol-Myers Squibb
Employment: Bristol-Myers Squibb
Stock or Other Ownership: Bristol-Myers Squibb
Consulting or Advisory Role: Merck Sharp & Dohme, Novartis, Genentech, Roche, Amgen, Merck Serono, Celldex, Bristol-Myers Squibb
Research Funding: Bristol-Myers Squibb (Inst), Merck Sharp & Dohme (Inst), Genentech (Inst), Roche (Inst), Novartis (Inst)
Patents, Royalties, Other Intellectual Property: Patent pending as per institutional policy, patent pending royalties received on MICA-related disorders application to institution per institutional intellectual property policy
Travel, Accommodations, Expenses: Novartis, Bristol-Myers Squibb
Other Relationship: Bristol-Myers Squibb, Genentech, Roche
Stock or Other Ownership: Potenza Therapeutics, Tizona Therapeutics, Trieza Therapeutics
Consulting or Advisory Role: Bristol-Myers Squibb, Merck, MedImmune, ZIOPHARM Oncology, Polynoma, Polaris Pharmaceuticals, BeiGene, Advaxis, Sellas Life Sciences, Eli Lilly, Potenza Therapeutics, Tizona Therapeutics, Amgen, AstraZeneca, Chugai Pharmaceutical
Research Funding: Bristol-Myers Squibb (Inst)
Patents, Royalties, Other Intellectual Property: Co-inventor on an issued patent for DNA vaccines for treatment of cancer in companion animals, co-inventor on a patent for use of oncolytic Newcastle disease virus.
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Chugai Pharmaceutical, Roche
ACKNOWLEDGMENT
Professional medical writing and editorial assistance were provided by Melissa Kirk and Cara Hunsberger at StemScientific, an Ashfield Company, funded by Bristol-Myers Squibb.
| 1. | Wolchok JD, Hodi FS, Weber JS, et al: Development of ipilimumab: A novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 1291:1-13, 2013 Crossref, Medline, Google Scholar |
| 2. | Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010 Crossref, Medline, Google Scholar |
| 3. | Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-2526, 2011 Crossref, Medline, Google Scholar |
| 4. | Wang C, Thudium KB, Han M, et al: In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2:846-856, 2014 Crossref, Medline, Google Scholar |
| 5. | Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23-34, 2015 Crossref, Medline, Google Scholar |
| 6. | Postow MA, Chesney J, Pavlick AC, et al: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006-2017, 2015 Crossref, Medline, Google Scholar |
| 7. | Hodi FS, Chesney J, Pavlick AC, et al: Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 17:1558-1568, 2016 Crossref, Medline, Google Scholar |
| 8. | Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al: Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol 34, 2016 (suppl; abstr 9505) Google Scholar |
| 9. | Schadendorf D, Larkin J, Postow M, et al: Efficacy and safety outcomes in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity. Presented at the 12th Congress of the European Association of Dermato Oncology, Vienna, Austria, August 31-September 3, 2016 Google Scholar |
| 10. | Boutros C, Tarhini A, Routier E, et al: Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 13:473-486, 2016 Crossref, Medline, Google Scholar |
| 11. | Bristol-Myers Squibb: Opdivo: Immune-mediated adverse reactions management guide, 2015. http://www.opdivohcp.com/servlet/servlet.FileDownload?file=00Pi000000ijs1vEAA Google Scholar |
| 12. | Berman D, Korman A, Peck R, et al: The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: The Bristol-Myers Squibb experience. Pharmacol Ther 148:132-153, 2015 Crossref, Medline, Google Scholar |
| 13. | Snzol M, Callahan MK, Kluger H, et al: Updated survival, response and safety data in a phase 1 dose-finding study (CA209-004) of concurrent nivolumab (NIVO) and ipilimumab (IPI) in advanced melanoma. Presented at the Society for Melanoma Research (SMR) 2015 International Congress, San Francisco, CA, November 18-21, 2015 Google Scholar |
| 14. | Weber JS, Hodi FS, Wolchok JD, et al: Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785-792, 2017 Link, Google Scholar |
| 15. | Weber JS, Kähler KC, Hauschild A: Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30:2691-2697, 2012 Link, Google Scholar |
| 16. | Johnson DB, Balko JM, Compton ML, et al: Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 375:1749-1755, 2016 Crossref, Medline, Google Scholar |
| 17. | Hodi FS, Postow MA, Chesney JA, et al: Overall survival in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity in a phase II trial (CheckMate 069). J Clin Oncol 34, 2016 (suppl; abstr 9518) Google Scholar |
| 18. | Downey SG, Klapper JA, Smith FO, et al: Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13:6681-6688, 2007 Crossref, Medline, Google Scholar |
| 19. | Bronstein Y, Ng CS, Hwu P, et al: Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. AJR Am J Roentgenol 197:W992-W1000, 2011 Crossref, Medline, Google Scholar |
| 20. | Sarnaik AA, Yu B, Yu D, et al: Extended dose ipilimumab with a peptide vaccine: Immune correlates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res 17:896-906, 2011 Crossref, Medline, Google Scholar |
| 21. | Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, 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 15:5591-5598, 2009 Crossref, Medline, Google Scholar |
| 22. | Phan GQ, Yang JC, Sherry RM, et al: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100:8372-8377, 2003 Crossref, Medline, Google Scholar |
| 23. | Ascierto PA, Simeone E, Sileni VC, et al: Clinical experience with ipilimumab 3 mg/kg: Real-world efficacy and safety data from an expanded access programme cohort. J Transl Med 12:116, 2014 Crossref, Medline, Google Scholar |
| 24. | Horvat TZ, Adel NG, Dang TO, et al: Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 33:3193-3198, 2015 Link, Google Scholar |
| 25. | Freeman-Keller M, Kim Y, Cronin H, et al: Nivolumab in resected and unresectable metastatic melanoma: Characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 22:886-894, 2016 Crossref, Medline, Google Scholar |
