There were 7 ineligible patients in the ipilimumab plus sargramostin treatment group and 4 in the ipilimumab-only treatment group. These patients were confirmed to be ineligible based on the central review conducted at the Eastern Cooperative Oncology Group (ECOG) after randomization. All were included in the efficacy analysis.
A, Primary efficacy treatment analysis (stratified hazard ratio [HR] = 0.64; 1-sided 90% repeated CI with an upper bound of 0.90; P value was 1-sided and calculated using the stratified log-rank test). B, Intent-to-treat patient population. There was no significant difference in progression-free survival between treatment groups (stratified HR = 0.87 [95% CI, 0.64-1.18]; P value was 2-sided and calculated using the stratified log-rank test).
A, Shows subgroup analyses of overall survival among subgroups of patients as defined by baseline characteristics (age, sex, Eastern Cooperative Oncology Group [ECOG] performance status, lactate dehydrogenase [LDH]) and stratification factors (prior therapy and metastasis [M] stage classified according to the TNM categorization for melanoma of the American Joint Committee on Cancer [AJCC]). There was a differential treatment effect on overall survival by sex. Although men treated with ipilimumab plus sargramostim had better overall survival, women treated with ipilimumab alone had better overall survival. This trend needs to be interpreted with caution because the sample size and number of deaths in subgroups by sex were relatively small. Size of data markers are inversely proportional to SE of hazard ratios (HRs). Bars represent 2-sided 95% CIs. The stratified HR for overall survival was 0.64 with 1-sided 90% RCI (not applicable-0.90). HRs and the 95% CIs were calculated using univariate Cox models for each category. Overall HR was estimated from the Cox model stratified by AJCC stage and prior therapy.
eTable 1A. Summary on Patients Receiving Treatment by Cycle
eTable 1B. Reasons for Treatment Termination
eFigure 1. Kaplan-Meier Estimates of OS by Line of Therapy in ITT Patients
eFigure 2. Kaplan-Meier Estimates of OS and PFS in 234 Eligible Patients
eTable 2. Incidence of Treatment-Related Grade 3-5 Toxicities by Toxicity Type
eTable 3. Treatment-Related Lethal Toxicities
eTable 4. Survival Comparison With Lethal Adverse Events Censored
eFigure 3. Changes in Inducible T-Cell Costimulator Expression of CD4+ and CD8+ T Cells Correlated to Treatment Group
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Hodi FS, Lee S, McDermott DF, et al. Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma: A Randomized Clinical Trial. JAMA. 2014;312(17):1744–1753. doi:10.1001/jama.2014.13943
Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade.
To compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on overall survival (OS) in patients with metastatic melanoma.
Design, Setting, and Participants
The Eastern Cooperative Oncology Group (ECOG) conducted a US-based phase 2 randomized clinical trial from December 28, 2010, until July 28, 2011, of patients (N = 245) with unresectable stage III or IV melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1.
Patients were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 μg subcutaneously, on days 1 to 14 of a 21-day cycle (n = 123) vs ipilimumab alone (n = 122). Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle.
Main Outcomes and Measures
Primary end point: comparison of length of OS. Secondary end point: progression-free survival (PFS), response rate, safety, and tolerability.
Median follow-up was 13.3 months (range, 0.03-19.9). Median OS as of December 2012 for ipilimumab plus sargramostim was 17.5 months (95% CI, 14.9-not reached) vs 12.7 months (95% CI, 10.0-not reached) for ipilimumab. The 1-year survival rate for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%-85.5%) compared to 52.9% (95% CI, 43.6%-62.2%) for ipilimumab alone (stratified log-rank 1-sided P = .01; mortality hazard ratio 0.64 [1-sided 90% repeated CI, not applicable-0.90]). A planned interim analysis was conducted at 69.8% of expected events (104 observed with 149 expected deaths). Planned interim analysis using the O’Brien-Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Median PFS for ipilimumab plus sargramostim was 3.1 months (95% CI, 2.9-4.6) vs 3.1 months (95% CI, 2.9-4.0) for ipilimumab alone. Grade 3 to 5 adverse events occurred in 44.9% (95% CI; 35.8%-54.4%) of patients in the ipilimumab plus sargramostim group vs 58.3% (95% CI, 49.0%-67.2%) of patients in the ipilimumab-alone group (2-sided P = .04).
Conclusion and Relevance
Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer OS and lower toxicity, but no difference in PFS. These findings require confirmation in larger studies with longer follow-up.
clinicaltrials.gov Identifier: NCT01134614
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that enhances activation of dendritic cells for antigen presentation and potentiates T- and B-lymphocyte antitumor functions.1-3 Systemic administration of GM-CSF has activity in prostate and ovarian carcinoma and is being evaluated in phase 3 adjuvant trials for melanoma and lymphoma.4,5 A concern for clinical development is evidence that GM-CSF may induce negative regulatory immune responses.6
Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is an immune checkpoint molecule that inhibits T-lymphocyte activity. Ipilimumab, a fully human IgG1 monoclonal antibody that blocks CTLA-4, has demonstrated survival advantages in patients with pretreated metastatic melanoma when compared to a gp100 peptide vaccine,7 as well as in treatment-naive patients when combined with dacarbazine chemotherapy as compared with dacarbazine alone.8 In multiple preclinical models, the combination of CTLA-4–antibody blockade and GM-CSF–secreting tumor cell vaccines demonstrated therapeutic synergies.9 Initial clinical experience raised the possibility of important therapeutic interactions between CTLA-4 blockade and GM-CSF–secreting tumor cell vaccines10-12 with clinical benefits observed in melanoma, prostate cancer, and ovarian carcinoma. Pathologic analysis of responding metastases revealed infiltration by multiple types of immune effector cells associated with dying tumor deposits. Combining systemic GM-CSF with CTLA-4 blockade in patients with hormone-refractory prostate cancer demonstrated clinical responses in more than 50% of patients experiencing prostate-specific antigen declines.13 Together, these findings suggest that a more detailed analysis of the interplay of GM-CSF and CTLA-4 blockade should be undertaken. One key unanswered question is whether the systemic administration of GM-CSF enhances CTLA-4 blockade. As a result, the current study sought to assess the overall survival for the combination of systemic GM-CSF (sargramostim) plus ipilimumab and ipilimumab treatment alone.
The study was approved by the Eastern Cooperative Oncology Group (ECOG), the Cancer Therapeutic Evaluation Program of the National Cancer Institute (NCI), and the institutional review board responsible for each treating institution. Written informed consent was obtained from study participants or a legally authorized representative prior to enrollment.
Patients were eligible if they had a histologic diagnosis of metastatic melanoma; measureable disease; no more than 1 prior therapy; no central nervous system metastases; ECOG performance status of 0 or 1; at least 18 years of age; greater than a 4-week time lapse from prior therapy; adequate hematologic, hepatic, and renal function; no autoimmune disease or infection with HIV, hepatitis B, or hepatitis C; and prior CTLA-4 blockade or CD137 agonist.
Because this was an NCI-sponsored clinical trial, obtainment of patient sex, race, and ethnicity data was required to analyze differences in treatment effect and to assess for disparity. Race and ethnicity data were reported by enrolling institutions at the time of registration. Given the nature of the melanoma population, however, differences in treatment effect by race and ethnicity could not be fully assessed in this study.
The primary objective of the study was to evaluate the overall survival for the combination of ipilimumab plus sargramostim vs ipilimumab alone in patients with advanced melanoma. Secondary objectives were to evaluate the progression-free survival, response rate, safety, and tolerability of study treatments. Patients were stratified according to metastatic (M) stage and whether they had received a prior therapy or not. The final trial protocol is reported in Supplement 1. The planned accrual goal was 220 patients but due to rapid accrual, 245 patients were enrolled.
Patients were equally randomized to receive ipilimumab, 10 mg/kg, every 3 weeks intravenously for 4 doses then every 12 weeks plus sargramostim (yeast-derived, rhu GM-CSF), 250 μg total dose subcutaneously, on days 1 to 14 of 21-day cycles (group A; patients received no treatment days 15-21 of each cycle) or ipilimumab alone 10 mg/kg (group B). Stratified (American Joint Committee on Cancer [AJCC] stage and prior therapy) randomization based on permuted blocks within strata with dynamic institution balancing was used. Treatment assignments were obtained from the central randomization desk at the ECOG coordinating center. No maximum number of cycles was planned. Patients could continue treatment without confirmed continued progression of disease or toxicity as outlined in the protocol. Due to known inflammatory effects of treatments that may appear as disease progression,14 patients were permitted to continue with as much as a 100% increase in the sum of the product of the diameter of target lesions and the development of as many as 4 new lesions in the absence of declining performance status and at the discretion of the treating physician.
Safety and tolerability were evaluated according to the NCI Common Terminology Criteria for Adverse Events, version 4.0. Protocol guidelines were used for management of immune-related adverse events. Ipilimumab delay was permitted for any related adverse event (≥ grade 2) except laboratory abnormalities, any skin-related adverse events (≥ grade 3 but resolution to ≤ grade 1 was required before continuing treatment), and any treatment-related laboratory abnormality (≥ grade 3). Patients who developed hypophysitis could continue treatment once receiving stable hormone replacement. Patients who experienced elevated liver function tests could continue once laboratory values returned to pretreatment grade. When adverse events resolved to grade 1 or less or returned to baseline within 2 weeks of ipilimumab administration, continued treatment was permitted at the next scheduled time point. If the adverse event did not resolve in this time frame, that dose was omitted. GM-CSF was reduced by 50% for documented white blood cell count greater than 60 000/mm3 and discontinued for any significant toxicity believed by the investigator to be caused by GM-CSF.
This study was powered to compare an improvement in median survival from 0.87 to 1.23 years, including 1 interim analysis at 50% information time. This design provided an overall 1-sided type I error rate of .10 and 80% power. Information time refers to a percentage of deaths observed at the time of an interim analysis in comparison to the total number of expected deaths in the study (ie, 50% information time = 75 deaths of 149 expected deaths). To preserve the overall type I error rate, critical values in these analyses were determined using the O’Brien and Fleming boundary.15 The repeated confidence interval (RCI) of Jennison-Turnbull16 was constructed using the nominal type I error rate corresponding to the O’Brien and Fleming boundary. The RCI is an interval that provides a measure of accuracy for the estimated hazard ratio (HR) while adjusting for the fact that the HR was evaluated at the interim analysis during the course of study. Since the primary comparison is based on overall survival using the 1-sided type I error rate of .10, a 1-sided 90% RCI of the HR for overall survival accurately describes the HR with an adjusted coverage probability for this design.
Patients were required to complete eligibility assessments within 28 days of randomization. Computed tomography scans of the chest, abdomen, and pelvis and magnetic resonance imaging of the brain were performed prior to treatment and subsequently every 12 weeks following the initiation of treatment. If restaging scans indicated partial or complete response, a repeat confirmatory scan was performed 4 weeks later. Tumor responses were determined by the investigators using RECIST (Response Evaluation Criteria in Solid Tumors) criteria and were audited as a part of ECOG-ACRIN (American College of Radiology Imaging Network) standard procedures.
Overall survival was defined as time from randomization to death from any cause, censoring patients who had not died at the date last known alive. Progression-free survival was defined as time from randomization to disease progression or death (whichever occurred first), censoring patients without progression or death at the date of last disease assessment documenting the patient was free of progression. Patients without any postbaseline tumor assessments were censored at random assignment. Overall survival and progression-free survival were assessed per the standard ECOG-ACRIN follow-up schedule, ie, every 3 months if the patient was less than 2 years from study entry, and every 6 months if the patient was 2 to 5 years from study entry. Tumor assessments were made using RECIST v1.1 criteria. Complete and partial responses were accepted as responses. Response rate refers to the percentage of patients who achieved a response. The highest grade for adverse events recorded was assessed at the completion of each cycle and 30 days after the last dose of protocol therapy.
Peripheral blood was collected before and during treatment. Of the patients with both pretreatment and posttreatment samples (40 patients in each of the 2 groups), 20 patients with good survival outcome and 20 patients with poor survival outcome were selected by the study biostatistician. Due to limited resources, only 80 patients could be included in this initial analysis. This method of sampling was used to balance patient groups representing a broad range of outcomes. Posthoc analyses were performed blinded to clinical outcomes or assigned treatment group. Inducible T-cell costimulator (ICOS) T-cell expression is necessary for optimal therapeutic effects of CTLA-4 blockade and is associated with improved survival with ipilimumab.17,18 Changes of ICOS expression in CD4+ and CD8+ T cells were assayed by multicolor flow cytometry.
Efficacy analyses on overall survival, progression-free survival, and response data were performed in 245 randomized patients. Two treatment groups were compared using the intent-to-treat (defining groups by assigned treatment) method. Distributions of overall survival and progression-free survival were estimated using the Kaplan-Meier method.19 One-year overall survival and 6-month progression-free survival rates were assessed from Kaplan-Meier estimates. Treatment effect was assessed using the stratified log-rank test for overall survival and progression-free survival. The HR was estimated based on the Cox proportional hazard model while adjusting for the stratification factors.20 The stratification factors used in the randomization (AJCC stage and prior therapy) were used for the stratified log-rank test and estimation of the HRs. The distributions of categorical data (clinical response and toxicity) were compared using the χ2 test or Fisher exact test21 (for small samples).
There was 1 planned interim analysis on overall survival around 50% information time (75 deaths observed of 149 expected deaths) using the O’Brien-Fleming boundary. Due to rapid accrual, information time on death accumulated slowly at the beginning but then rapidly reached 69.8% (104 deaths observed of 149 expected deaths) in December 2012. The planned analysis was conducted using the O’Brien-Fleming boundary corresponding to 69.8% information time. The corresponding nominal significance level was 0.05. Using the corresponding significance level at this information time, RCI16 was estimated. Per study design, this represents a 1-sided CI for the HR of overall survival at this information time. Per study design, a 1-sided P value was presented for the primary end point (overall survival) comparison. All other P values were based on 2-sided tests (P < .05 considered significant). Analyses were conducted using SAS software version 9.2.
A total of 245 patients were randomized between December 28, 2010, and July 28, 2011 (123 patients to the ipilimumab plus sargramostim group and 122 patients to the ipilimumab-only group). The baseline patient characteristics are shown in Table 1. Treatment groups were demographically well-balanced. The median time of follow up was 13.3 months (range, 0.03-19.9). Treatment summary by cycle and reasons for treatment termination are presented in eTable 1 in Supplement 2. Populations of patients screened, treated, and followed up are represented in the enrollment and outcomes diagram (Figure 1). Overall survival data as of December 2012 and other data as of March 2013 were used. Efficacy analyses were performed on the 245 intent-to-treat (ITT) patients. Safety data analysis was performed on the 238 patients who received protocol therapy and submitted data by March 2013.
Efficacy data are summarized in Table 2. The median overall survival was 17.5 months (95% CI, 14.9-not reached) for the ipilimumab plus sargramostim group and 12.7 months (95% CI, 10.0-not reached) for the ipilimumab-only group. The 1-year overall survival was 68.9% (95% CI, 60.6%-85.5%) for the ipilimumab plus sargramostim group and 52.9% (95% CI, 43.6%-62.2%) for the ipilimumab-only group. The overall survival was significantly improved with the addition of sargramostim to ipilimumab with a stratified log-rank 1-sided P value of .01. The Kaplan-Meier curves for overall survival are shown in Figure 2. The stratified HR for overall survival on sargramostim plus ipilimumab compared to ipilimumab alone was 0.64 (1-sided 90% RCI, not applicable-0.90). The O’Brien-Fleming boundary for overall survival was crossed at 69.8% (104 deaths observed of 149 expected deaths) information time. The progression-free survival for the ipilimumab plus sargramostim group was 3.1 months (95% CI, 2.9-4.6) and for the ipilimumab-only group was 3.1 months (95% CI, 2.9-4.0). The differences between the treatment groups for progression-free survival were not statistically significant (P = .37). The Kaplan-Meier curves for progression-free survival are presented in Figure 2. The difference in response rate for the ipilimumab plus sargramostim group (15.5%; 95% CI, 9.6%-23.1%) and for the ipilimumab-only group (14.8%; 95% CI, 9.0%-22.3%) was not statistically significant (P = .88). The subgroup analyses of overall survival and progression-free survival HRs are presented for line of therapy (the number of treatment regimens a patient has received) in eFigure 1 (in Supplement 2) and eligible patients (those whose eligibility status was centrally reviewed and confirmed) in eFigure 2 (in Supplement 2). Forest plots for treatment effects in the ITT patients are presented in Figure 3 for overall survival and for progression-free survival. ECOG performance status of zero (HR = 0.45; 95% CI, 0.25-0.80) and men (HR = 0.44; 95% CI, 0.25-0.76) subgroups had significant benefit for overall survival favoring ipilimumab plus sargramostim. Otherwise there were no significant differences for overall survival and progression-free survival in each category.
Toxicity and treatment data were compared for all patients who received treatment and had data submitted by March 11, 2013. Of the 123 patients randomized to the ipilimumab plus sargramostim group, 4 patients did not start therapy (1 due to early death and 3 due to refusal) and 1 patient had no data submitted. Of the 122 patients randomized to the ipilimumab-only group, 1 patient did not start therapy due to early death and 1 patient had no data submitted. Thus 118 vs 120 patients in ipilimumab plus sargaramostim and ipilimumab-only groups were included in toxicity and treatment analyses.
The treatment-related adverse events reported in the safety evaluation are listed in Table 3; based on the worst degree, grade 3 to 5 adverse events occurred in 44.9% (95% CI, 35.8%-54.4%) of patients treated with ipilimumab plus sargramostim and in 58.3% (95% CI, 49.0%-67.2%) of patients treated with ipilimumab alone. Toxicity was significantly lower in the ipilimumab plus sargramostim group than in the ipilimumab-only group (P = .04). Grade 3 to 5 adverse events are summarized in 2 ways in Table 3: by incidence rate of more than 3% in at least in 1 group; and by toxicity categories. Most notable among those listed by toxicity category were differences in gastrointestinal toxicities (16.1% [95% CI, 9.9%-24.0%] vs 26.7% [95% CI, 19.0%-35.5%]; P = .05) and pulmonary toxicities (0% [95% CI, 0%-3.1%] vs 7.5% [95% CI, 3.5%-13.8%]; P = .003) in patients treated with ipilimumab plus sargramostim vs ipilimumab alone, respectively. All grade 3 to 5 adverse events by grade are reported in eTable 2 (in Supplement 2). Treatment-related lethal adverse events occurred in 2 patients (1 cardiac arrest, 1 colonic perforation) in the ipilimumab plus sargramostim group and in 7 patients (2 colonic failure, 2 multiorgan failure, 2 respiratory failure, 1 hepatic failure) in the ipilimumab-only group (eTable 3 in Supplement 2). To investigate whether the improved survival benefit with sargramostim was due to less toxicity, cases were censored with lethal adverse events that included treatment relations of possibly, probably, or definitely, and all lethal adverse events regardless of attributions. Overall survival improvement was maintained with sargramostim when cases with lethal adverse events were censored (eTable 4 in Supplement 2). Among patients who terminated treatment due to adverse events, those in the ipilimumab plus sargromostim group (n = 25) had better overall survival than those in the ipilimumab-alone group (n = 39) (1-sided P = .04).
Posthoc analyses for changes in CD4+ and CD8+ ICOS T cells and correlation to treatment group are summarized in eFigure 3 (in Supplement 2). ICOS (CD278) increases as a function of treatment were greater in the ipilimumab plus sargramostimgroup. The median change in CD4+ cells was 2.55 vs 1.85 (P = .11) and the median change in CD8+ cells was 0.5 vs 0.4 (P = .01).
This randomized phase 2 study supports the evidence that the addition of sargramostim to ipilimumab therapy improved overall survival in patients with metastatic melanoma. It is the first study, to our knowledge, to suggest a survival advantage for sargramostim. These results are consistent with the preclinical animal models and preliminary clinical experience of combining CTLA-4 blockade with GM-CSF-secreting whole-cell vaccines. The 1-year overall survival rates in both groups of this study are higher than the estimated 1-year overall survival rates of 36% for the ipilimumab plus sargramostim group and 33% for the ipilimumab-only group in the context of previous outcomes from multicenter cooperative group trials adjusting for sex, visceral disease, and performance status.22
The progression-free survival, however, was not affected by the addition of sargramostim to ipilimumab. The lack of correlation between overall survival and progression-free survival in this study presents challenges to clinical management and drug development because conventional radiographic criteria have not proven reliable for determining patient benefit. This introduces important considerations for the evaluation of treatment efficacy with particular immune therapies such as ipilimumab.14 Both sargramostim and ipilimumab can provoke inflammation at tumor sites resulting in misinterpretation of inflammatory responses as disease progression. Prior studies demonstrated that this inflammatory tumor microenvironment frequently involves multiple immune effector cells, fibrosis, and edema.10 Inflammatory responses may be difficult to discern radiographically from tumor cells and may contribute to a disconnection between overall survival and progression-free survival. Such uncoupling of overall survival and progression-free survival benefit has previously been described with sipuleucel-T for the treatment of advanced prostate cancer.23 Sipuleucel-T comprises antigen-presenting cells activated with antigenic proteins that include GM-CSF. This supports the biologic and clinical behaviors for GM-CSF witnessed in the current study and emphasizes the importance of end point selection when evaluating efficacy as well as the continued need for reliable predictive biomarkers.
Possible mechanisms for the improved efficacy observed in this trial may relate to improved antigen presentation with GM-CSF via recruitment of dendritic cells and macrophages, or to counteracting immune regulatory cells with ipilimumab. Preclinical and early clinical studies of GM-CSF–secreting tumor cell vaccines plus CTLA-4 blockade demonstrated that the combination treatment stimulated an increase in the ratio of tumor-infiltrating CD8+ cytotoxic T cells to FoxP3+ regulatory T cells.11,24 Because GM-CSF alone may stimulate myeloid and monocytic-derived suppressor-cell populations, as well as FoxP3+ regulatory T cells that limit antitumor immunity,25-27 the addition of CTLA-4 blockade may overcome the potential tolerizing effects of the cytokine6,28 and favor instead the development of protective T-cell responses. Whether GM-CSF also promotes anti-CTLA-4 monoclonal antibody–mediated depletion of intratumoral regulatory T cells,29 is an interesting possibility that will require further study. Moreover, the GM-CSF receptor organization allows graded cellular responses that are dependent on cytokine concentrations, resulting in a multitude of GM-CSF effects on suppressor cells, growth, and function.30 As a result, GM-CSF activity may depend on additional factors present in the tumor microenvironment such as CTLA-4 expression and degree of inflammation to determine whether GM-CSF promotes antitumor immune responses or tumor propagation. Interestingly, sargramostim-improved expression of ICOS on CD4+ and CD8+ T cells validates the dependent mechanism of ICOS for ipilimumab function 17,18 and supports one mechanism for ipilimumab synergy with GM-CSF.
In addition to the improvement in overall survival, sargramostim afforded an advantage in toxicity over ipilimumab alone. The improved toxicity profile must be considered as contributing to the improved survival even in light of the survival advantage remaining when patients who discontinued therapy due to toxicity are excluded. Although the overall adverse effect profile was consistent with that reported previously for ipilimumab, there were significantly fewer high-grade treatment-related events, including deaths, that occurred in patients receiving sargramostim. Most notably the combination showed a difference in serious gastrointestinal toxicities, particularly colonic perforation. Prior clinical studies suggest that systemic GM-CSF provides benefit for some patients with Crohn disease. Interestingly, a subset of patients with Crohn disease harbors high titers of antibodies that neutralize GM-CSF function,31 and a proportion of patients with inflammatory bowel disease shows decreased levels of GM-CSF receptors.32,33 In preclinical models, GM-CSF knockout mice developed severe colitis that was prevented with the administration of GM-CSF, responsible for accelerated mucosal repair.34,35 GM-CSF is necessary for the generation of dendritic cells in the gut lamina propria to induce intestinal regulatory cells.36 As a result, GM-CSF may contribute to gastrointestinal homeostasis by protecting and promoting healing of the mucosa.37 The contrasting roles for GM-CSF in the tumor microenvironment and intestine may therefore provide reason for its improved antitumor activity and favorable toxicity profile when combined with ipilimumab.
Significant improvement in pulmonary toxicity with the addition of sargramostim was also observed. In GM-CSF knockout mice, animals developed accumulation of surfactant proteins and lipids in the alveolar space, similar to pulmonary alveolar proteinosis seen in humans.38 In addition, these mice developed significant lymphoid hyperplasia surrounding the airways and lung vasculature, further suggesting the role of GM-CSF in lung homeostasis. Analogous to the gastrointestinal mucosa, models reveal that lung macrophages induce immune regulatory cells thereby generating airway tolerance.39 As a result, independent validations of GM-CSF in gastrointestinal and pulmonary homeostasis influencing the clinical toxicity profile with CTLA-4 blockade exist. This may have additional implications in overall development and future combinations involving other checkpoint blockade therapies, such as PD-1 blockade with its risk for pneumonitis.40
Study limitations include lack of blinding so that investigator assessment of responses could have been influenced. In addition, patients may have sought additional immune therapies following participation in this trial that influenced outcomes. Long-term reporting for this study is planned. It is also important to note that the dose and schedule of ipilimumab used in this study differs from the current standard dosing (3 mg/kg for 4 doses), raising some safety concerns for the toxicity witnessed in the ipilimumab-only group. Given that the assessment of the peripheral blood for ICOS expression was a posthoc analysis in a subset of patients, further study in the entire patient population and prospective confirmation in subsequent studies is required.
Among patients with unresectable stage III or stage IV melanoma, treatment with a combination of sargramostim plus ipilimumab, compared with ipilimumab alone, resulted in longer overall survival and lower toxicity, but no difference in progression-free survival. These findings require confirmation in larger sample sizes and with longer follow-up.
Corresponding Author: F. Stephen Hodi, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 (email@example.com.
Author Contributions: Dr Hodi (principal investigator) had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Hodi, Lee, Kirkwood.
Acquisition, analysis, or interpretation of data: Hodi, Lee, McDermott, Rao, Butterfield, Tarhini, Leming, Puzanov, Shin.
Drafting of the manuscript: Hodi, Lee, Puzanov, Shin.
Critical revision of the manuscript for important intellectual content: Hodi, Lee, McDermott, Rao, Butterfield, Tarhini, Leming, Puzanov, Shin, Kirkwood.
Statistical analysis: Lee, Shin.
Administrative, technical, or material support: Hodi, McDermott, Butterfield, Tarhini, Leming, Kirkwood.
Study supervision: Hodi, Lee, Puzanov.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hodi reports receipt of support from the Cancer Therapy Evaluation Program/National Cancer Institute (CTEP/NCI) and the Eastern Cooperative Oncology Group (ECOG) during the conduct of the study; nonfinancial support from Bristol-Myers Squibb and Sanofi/Genzyme outside the submitted work; and personal fees from Sanofi. In addition, Dr Hodi reports having a patent of unrelated work licensed to Bristol-Myers Squibb as per institutional policy, a patent 20140004112 therapeutic peptides issued, and a patent 7250291 tumor antigens and uses thereof issued. Dr Lee reports receipt of support from the National Institutes of Health (NIH; NCI). Dr McDermott reports receipt of personal fees from Bristol-Myers Squibb, Pfizer, Genentech, and Merck. Dr Butterfield reports receipt of support from ECOG. Dr Tarhini reports receipt of personal fees and grant support from Bristol-Myers Squibb, Genentech, and Merck; and grant support from Prometheus and Novarti. Dr Kirkwood reports receipt of personal fees from Bristol-Myers Squibb, Merck, Glaxo-Smith-Kline, Celgene, and Vical outside the submited work. Drs Rao, Leming, Puzanov, and Mr Shin report no disclosures.
Funding/Support: This study was coordinated by ECOG (Robert L. Comis, MD, Chair); supported in part by Public Health Service grants CA23318, CA66636, CA21115, CA80775, CA39229, CA49957, CA32291; and the NCI; NIH; the US Department of Health and Human Services; Bristol-Myers Squibb; and Genzyme.
Role of the Funders/Sponsors: The NCI participated in the design and conduct of the study, but not in the data collection, management, analysis and interpretation of the data, or in the preparation, and approval of the manuscript or decision to submit the manuscript for publication. Bristol-Myers Squibb and Genzyme had no role in the design and conduct of the trial, in the collection, management, analysis, and interpretation of the data, or in the preparation and approval of the manuscript, or decision to submit the manuscript for publication. The NCI, Bristol-Myers Squibb, and Genzyme participated in the review of the manuscript.
Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NCI.
Additional Contributions: In addition to the authors, the following investigators participated in this study by contributing participants, but received no compensation: Sanjiv S. Agarwala, MD, St Luke's University Hospital-Bethlehem; Mark R. Albertini, MD, University of Wisconsin; Mitchell B. Alden, DO, Doylestown Hospital; Thomas T. Amatruda, MD, Unity Hospital; Daniel M. Anderson, MD, Regions Hospital; Jade G. Anderson, MD, Unity Hospital; Michael B. Atkins, MD, Beth Israel Deaconess Medical Center; Miklos L. Auber, MD, West Virginia University; Myron E. Bednar, MD, Hunterdon Medical Center; Michael K. Bergen, MD, Exempla Lutheran Medical Center; Kenneth B. Blankstein, MD, Hunterdon Medical Center; Sigurdur Bodvarsson, MD, Gundersen Lutheran Health System; Ernest C. Borden, MD, Cleveland Clinic Foundation; Warren S. Brenner, MD, Boca Raton Regional Hospital; Gary I. Cohen, MD, Greater Baltimore Medical Center; Justin D. Cohen, MD, Charleston Area Medical Center; Suzanne M. Cole, MD, Charleston Area Medical Center; Robert M. Conry, MD, University of Alabama at Birmingham; Edward D. Crum, MD, MetroHealth Medical Center; Shaker R. Dakhil, MD, Cancer Center of Kansas-Wichita; Morris S. Dees, MD, Orange Park Cancer Center; William T. Derosa, MD, Morristown Memorial Hospital; Lorraine S. Dougherty, MD, Doylestown Hospital; Luke P. Dreisbach, MD, Eisenhower Medical Center; Philip A. Dy, MD, Decatur Memorial Hospital; Mohammad H. Fekrazad, MD, University of New Mexico Cancer Center; Michael S. Frontiera, MD, Dean Hematology and Oncology Clinic; Vijaya K. Gadiyaram, MD, Nevada Cancer Institute; Teresa Gagliano-DeCesare, MD, Boca Raton Regional Hospital; Francois J. Geoffroy, MD, Illinois CancerCare-Peoria; Henry Gerad, MD, St Rita's Medical Center; Oscar B. Goodman, MD, Nevada Cancer Institute; Ni Gorsuch, MD, Charleston Area Medical Center; Stephen A. Grabelsky, MD, Boca Raton Regional Hospital; Sara J. Grethlein, MD, Mary Imogene Bassett Hospital; William W. Grosh, MD, University of Virginia; Randolph Hurley, MD, Regions Hospital; Nageatte Ibrahim, MD, Dana-Farber Cancer Institute; Clark S. Jean, MD, Nevada Cancer Research Foundation; Steven J. Jubelirer, MD, Charleston Area Medical Center; Howard L. Kaufman, MD, Rush University Medical Center; Ahmed A. Khalid, MD, Charleston Area Medical Center; Joseph M. Koenig, MD, Akron City Hospital; Henry B. Koon, MD, Case Western Reserve University; Andrzej P. Kudelka, MD, Stony Brook University Medical; John W. Kugler, MD, Illinois CancerCare-Peoria; Pankaj Kumar, MD, Illinois Oncology Research Associates; Timothy M. Kuzel, MD, Northwestern University; Brenda R. Larson, MD, Park Nicollet Health Services; Noel Laudi, MD, Mercy Hospital; Amy Law, MD, Eisenhower Medical Center; Donald P. Lawrence, MD, Massachusetts General Hospital; David H. Lawson, MD, Emory University; James M. Leonardo, MD, PhD, Mary Imogene Bassett Hospital; Marcia K. Liepman, MD, West Michigan Cancer Center; Theodore F. Logan, MD, Indiana University Hospital; Sameer A. Mahesh, MD, Akron City Hospital; Bassam I. Mattar, MD, Cancer Center of Kansas-Wichita; Amanda D. May, MD, Georgia Regents University; Janice M. Mehnert, MD, Rutgers Cancer Institute of New Jersey; Avanti Mehrotra, MD, North Memorial Medical Center; Sanjiv S. Modi, MD, Joliet Hematology/Oncology Associates; Manish A. Monga, MD, Wheeling Hospital; Dennis F. Moore, MD, Cancer Center of Kansas-Wichita; Stergios J. Moschos, MD, University of Pittsburgh Cancer Institute; Sujana Movva, MD, Emory University; Timothy J. Murphy, MD, Penrose-St Francis HealthCare; Suresh G. Nair, MD, Lehigh Valley Hospital; Sujatha Nallapareddy, MD, Medical Center of Aurora; Ubaid Nawaz, MD, Aurora BayCare Medical Center; James A. Neidhart, MD, San Juan Oncology Associates; Erin V. Newton, MD, Indiana University Hospital; Grzegorz S. Obara, MD, Nevada Cancer Research Foundation; Adedayo Onitilo, MD, Marshfield Clinic; Nutan K. Parikh, MD, Nevada Cancer Research Foundation; Anna C. Pavlick, MD, New York University Langone Medical Center; Andrew L. Pecora, MD, Hackensack Medical Center; Christopher G. Peterson, MD, Langlade Hospital and Cancer Center; Harlan A. Pinto, MD, VA Medical Center-Palo Alto; Maria Emelina B. Quisumbing, MD, Nevada Cancer Research Foundation; Pavan S. Reddy, MD, Cancer Center of Kansas-El Dorado; Sunil A. Reddy, MD, Stanford University; Adam I. Riker, MD, Ochsner Clinic; Wolfram E. Samlowski, MD, Nevada Cancer Research Foundation; James D. Sanchez, MD, Nevada Cancer Research Foundation; Amit Sanyal, MD, Dean Hematology and Oncology Clinic; Larry L. Schlabach, MD, Erlanger Medical Center; William H. Sharfman, MD, Johns Hopkins University; Jeffrey A. Sosman, MD, Vanderbilt University; Jonathan R. Sporn, MD, St Francis Hospital and Medical Center; Ronald L. Stephens, MD, Cancer Center of Kansas-Lawrence Memorial Hospital; Mario Sznol, MD, Yale University; Hussein A. Tawbi, MD, University of Pittsburgh Cancer Institute; Ralph D. Trochelman, MD, Akron City Hospital; Henry T. Tsai, MD, Eisenhower Medical Center; Dean G. Tsarwhas, MD, North Shore Oncology Hematology; Brian Vicuna, MD, Nevada Cancer Research Foundation; Geoffrey R. Weiss, MD, University of Virginia; Charles H. Weissman, MD, New York Oncology Hematology; Donald B. Wender, MD, Siouxland Hematology Oncology Associates; Eric D. Whitman, MD, Morristown Memorial Hospital; Diana S. Willadsen, MD, Memorial Medical Center; Michael J. Williamson, DO, IU Health Ball Memorial Hospital; Jerome D. Winegarden, MD, St Joseph Mercy Hospital - Ann Arbor; Jerry M. Winkler, MD, St Vincent Hospital Region Cancer Center; Andrew W. Yetter, MD, Vince Lombardi Cancer Clinic.
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