Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial

Abstract

Importance: 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.

Objective: 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.

Interventions: 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.

Results: 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.

Trial registration: clinicaltrials.gov Identifier: NCT01134614.

Figures

Figure 1

Enrollment and Outcomes Diagram. There were 7 and 4 ineligible patients in Ipilimumab+Sargramostin and Ipilimumab treatment groups, respectively. These cases were confirmed to be ineligible based on the central review conducted at ECOG after randomization. All of them were included in the efficacy analysis.

Figure 2

Kaplan-Meier Estimates for overall survival and progression-free survival. Panel A shows the primary efficacy treatment analysis of sargramostim plus ipilimumab as compared to ipilimumab alone (stratified hazard ratio = 0.64; One-sided 90% Repeated Confidence Interval (RCI), with an upper bound 0.90; stratified log rank test one-sided P=.01). Panel B shows the Kaplan-Meier estimates for progression-free survival by treatment group in the intent-to-treat patient population. There was no significant difference in progression-free survival between treatment groups (stratified hazard ratio =.87, 95% confidence interval (CI), 0.64 , 1.18; stratified log rank test two-sided P=.37).

Figure 2

Kaplan-Meier Estimates for overall survival and progression-free survival. Panel A shows the primary efficacy treatment analysis of sargramostim plus ipilimumab as compared to ipilimumab alone (stratified hazard ratio = 0.64; One-sided 90% Repeated Confidence Interval (RCI), with an upper bound 0.90; stratified log rank test one-sided P=.01). Panel B shows the Kaplan-Meier estimates for progression-free survival by treatment group in the intent-to-treat patient population. There was no significant difference in progression-free survival between treatment groups (stratified hazard ratio =.87, 95% confidence interval (CI), 0.64 , 1.18; stratified log rank test two-sided P=.37).

Figure 3

Subgroup analyses for overall survival and progression-free survival in intent-to treat patient population. Panel A shows subgroup analyses of overall survival among subgroups of patients as defined by baseline characteristics (age, sex, ECOG PS, LDH) and stratification factors (prior therapy and metastasis (M) stage classified according to the tumor-none-metastasis (TNM) categorization for melanoma of the American Joint Committee on Cancer). The hazard ratios were lower than one indicating a lower risk of death in each subgroup in favor of the sargramostim plus ipilimumab group except for gender. There was a differential treatment effect on OS by gender. While male patients treated with Ipilimumab+Sargramostim had better overall survival, female patients treated with Ipilimumab alone had better overall survival. This trend needs to be interpreted with caution as the sample size and number of deaths in subgroups by gender were relatively small. Boxes represent hazard ratios, size of box inversely proportional to SE of HR. Bars represent two-sided 95% confidence intervals. The stratified HR for overall survival was .64 with one-sided 90% RCI (not applicable, .90). ECOG PS: Eastern Cooperative Oncology Group performance status, LDH: Lactate dehydrogenase. AJCC: American Joint Committee on Cancer. HRs and the 95%CI were calculated using univariate Cox models for each category. Overall HR was estimated from the Cox model stratified by AJCC stage and prior therapy. Panel B: Subgroup analyses of progression-free survival. There were no significant differences for progression-free survival by treatment in any of the sub-groups.

Figure 3

Subgroup analyses for overall survival and progression-free survival in intent-to treat patient population. Panel A shows subgroup analyses of overall survival among subgroups of patients as defined by baseline characteristics (age, sex, ECOG PS, LDH) and stratification factors (prior therapy and metastasis (M) stage classified according to the tumor-none-metastasis (TNM) categorization for melanoma of the American Joint Committee on Cancer). The hazard ratios were lower than one indicating a lower risk of death in each subgroup in favor of the sargramostim plus ipilimumab group except for gender. There was a differential treatment effect on OS by gender. While male patients treated with Ipilimumab+Sargramostim had better overall survival, female patients treated with Ipilimumab alone had better overall survival. This trend needs to be interpreted with caution as the sample size and number of deaths in subgroups by gender were relatively small. Boxes represent hazard ratios, size of box inversely proportional to SE of HR. Bars represent two-sided 95% confidence intervals. The stratified HR for overall survival was .64 with one-sided 90% RCI (not applicable, .90). ECOG PS: Eastern Cooperative Oncology Group performance status, LDH: Lactate dehydrogenase. AJCC: American Joint Committee on Cancer. HRs and the 95%CI were calculated using univariate Cox models for each category. Overall HR was estimated from the Cox model stratified by AJCC stage and prior therapy. Panel B: Subgroup analyses of progression-free survival. There were no significant differences for progression-free survival by treatment in any of the sub-groups.