Melanoma Combo Improves Overall Survival - full text below
Published: June 05, 2011
* Explain that combining a biologic agent (ipilimumab) with a cytotoxic drug (dacarbazine) significantly improved overall survival among patients with previously untreated metastatic melanoma.
* Note that grade 3 or 4 adverse events occurred in 56.3% of drug combination patients which was significantly higher than the 27.5% in those treated with dacarbazine and placebo.
CHICAGO -- Combining a biologic agent with a cytotoxic drug significantly improved overall survival (OS) among patients with previously untreated metastatic melanoma, researchers reported.
In a randomized, phase III clinical trial, patients treated with ipilimumab (Yervoy) and dacarbazine (DTIC-Dome) had a median survival of 11.2 months, according to Jedd Wolchok, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York City, and colleagues.
That was in contrast to the median of 9.1 months for patients treated with dacarbazine and placebo, Wolchok and colleagues reported online in the New England Journal of Medicine and at the annual meeting of the American Society of Clinical Oncology (ASCO).
Ipilimumab is a fully human IgG1 monoclonal antibody that augments T-cell activity and growth by blocking the so-called cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), the researchers noted.
Phase II studies in previously treated patients showed that ipilimumab improved responses in a dose-dependent fashion, while the combination of the two drugs yielded durable responses.
To investigate the issue further, the researchers enrolled 502 patients with previously untreated metastatic melanoma, and assigned them to in a one-to-one fashion to the combination or dacarbazine and placebo, given at weeks one, four, seven, and 10.
That was followed by an induction phase with dacarbazine alone every three weeks through week 22. At week 24, patients with stable disease, or an objective response during the induction phase, were eligible to enter a maintenance phase in which they were given placebo or ipilimumab every 12 weeks until disease progression, toxicity, or the end of the study.
Ipilimumab was given at 10 mg/kg of body weight while dacarbazine was dosed at 850 mg/meter2 of body-surface area, the researchers reported.
The primary endpoint of OS was significantly longer in the group receiving the drug combination, the researchers reported. The hazard ratio (HR) for death was 0.72, with a 95% confidence interval from 0.59 to 0.87, which was significant at P<0.001, they reported.
The proportion of patients who remained alive was higher for the drug combination versus the placebo combination in all three years of the study:
* 47.3% versus 36.3% at one year
* 28.5% versus 17.9% at two years
* 20.8% versus 12.2% at three years
There was also a 24% reduction in the risk of progression among ipilimumab-dacarbazine patients, compared with the dacarbazine group, Wolchok and colleagues reported. The HR for progression was 0.76, with a 95% confidence interval from 0.63 to 0.93, which was significant at P=0.006.
Grade 3 or 4 adverse events occurred in 56.3% of drug combination patients, they reported, which was significantly higher (at P<0.001) than the 27.5% in those treated with dacarbazine and placebo.
Adverse events were similar to those seen in earlier studies of ipilimumab, but there were more instances of elevated liver enzymes and fewer cases of gastrointestinal events than expected, the researchers noted.
There were no drug-related deaths or gastrointestinal perforations among patients getting the drug combination.
The study was supported by Bristol-Myers Squibb. Wolchok reported financial links with the company.
Primary source: New England Journal of Medicine
Robert C, et al. "Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma." N Engl J Med 2011.
Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma - pdf attached
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Caroline Robert, M.D., Ph.D., Luc Thomas, M.D., Ph.D., Igor Bondarenko, M.D., Ph.D., Steven O'Day, M.D., Jeffrey Weber M.D., Ph.D., Claus Garbe, M.D., Celeste Lebbe, M.D., Ph.D., Jean-Franćois Baurain, M.D., Ph.D., Alessandro Testori, M.D., Jean-Jacques Grob, M.D., Neville Davidson, M.D., Jon Richards, M.D., Ph.D., Michele Maio, M.D., Ph.D., Axel Hauschild, M.D., Wilson H. Miller, Jr., M.D., Ph.D., Pere Gascon, M.D., Ph.D., Michal Lotem, M.D., Kaan Harmankaya, M.D., Ramy Ibrahim, M.D., Stephen Francis, M.Sc., Tai-Tsang Chen, Ph.D., Rachel Humphrey, M.D., Axel Hoos, M.D., Ph.D., and Jedd D. Wolchok, M.D., Ph.D.
NEJM June 5, 2011
Background: Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma.
Methods: We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival.
Results: Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group.
Conclusions: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.)
In this phase 3 study, ipilimumab (at a dose of 10 mg per kilogram), in combination with dacarbazine (at a dose of 850 mg per square meter), as compared with dacarbazine plus placebo, was associated with a significant improvement in overall survival among patients with previously untreated metastatic melanoma. More than 50% of the patients had M1c disease (indicating the presence of visceral metastases, elevated lactate dehydrogenase levels, or both), and more than 35% had baseline elevations in lactate dehydrogenase levels - both of which are associated with poor survival.20,21 Durable objective responses were observed (median duration of best overall response, 19.3 months in the ipilimumab-dacarbazine group, vs. 8.1 months in the dacarbazine group). Prolonged survival was noted among some patients who were followed for up to 4 years. In the ipilimumab-dacarbazine group, an estimated 28.5% of the patients were alive at 2 years, and an estimated 20.8% at 3 years, as compared with an estimated 17.9% and 12.2%, respectively, in the dacarbazine group.
The rates of some high-grade adverse events in the current study differ from those in previous phase 2 studies of ipilimumab monotherapy (at a dose of 10 mg per kilogram).13,22-24 The absence of gastrointestinal perforations and the low rates of other grade 3 or 4 gastrointestinal events are in contrast to the results of phase 2 studies involving 325 patients (rate of diarrhea, 4% in this study vs. 11% in the previous studies; rate of colitis, 2% vs. 5%). No cases of hypophysitis were observed during the course of this study, whereas 2% of the patients in the previous studies had high-grade endocrinopathy. The rate of grade 3 or 4 rash was similar (1% in the current study and 2% in the previous studies). However, the rates of high-grade hepatic adverse events in the current study were higher than those in the previous studies (elevated alanine aminotransferase level, 21% vs. 8%; elevated aspartate aminotransferase level, 17% vs. 7%). The apparent shift in the rates of adverse events associated with ipilimumab may be due to its combination with dacarbazine, which is known to cause hepatotoxic effects when it is used as monotherapy.25-27 The role of systemic glucocorticoids (which were administered to manage hepatic events) in the apparent reduction in gastrointestinal and endocrine events is undefined.
In summary, this trial showed that there was a significant improvement in overall survival among patients with previously untreated metastatic melanoma who received ipilimumab plus dacarbazine as compared with dacarbazine plus placebo. Adverse events other than those typically seen with dacarbazine or ipilimumab therapy were not identified. An increase in liver-function values is an important side effect that was observed more frequently than expected with the combination therapy. Other ipilimumab-associated adverse events (enterocolitis and endocrinopathy) were observed, albeit at a rate that was lower than expected. The key side effects of ipilimumab were managed through adherence to treatment according to well-established guidelines, including the administration of systemic glucocorticoids or other immunosuppressant agents.
Supported by Bristol-Myers Squibb.
Patients and Treatment
Between August 8, 2006, and January 22, 2008, a total of 250 patients were randomly assigned to receive ipilimumab plus dacarbazine (ipilimumab-dacarbazine group) and 252 were randomly assigned to receive dacarbazine plus placebo (dacarbazine group). The baseline characteristics of the patients were balanced between the two groups (Table 1Table 1Demographic and Baseline Clinical Characteristics of the Patients.). A total of 92 patients in the ipilimumab-dacarbazine group (36.8%) and 165 patients in the dacarbazine group (65.5%) received all four doses of ipilimumab or placebo. At least one maintenance dose was administered in 43 patients in the ipilimumab-dacarbazine group (17.2%) and 53 in the dacarbazine group (21.0%). The follow-up time between the start of the study (the first visit of the first enrolled patient) and the end of the study (the last visit of the last enrolled patient) was 54 months, and the follow-up time between the time the last patient underwent randomization (the first visit of the last patient) and the end of the study was 36.6 months.
The most frequent reason for discontinuation of the study drug across the entire study was disease progression (in 46.2% of patients in the ipilimumab-dacarbazine group and 77.3% in the dacarbazine group). Discontinuation due to a drug-related adverse event was reported in 89 of the 247 patients in the ipilimumab-dacarbazine group who received at least one dose of the study drug (36.0%) and 10 of the 251 patients in the dacarbazine group who received at least one dose of the study drug (4.0%): 85 of the 247 patients (34.4%) and 10 of the 251 patients (4.0%) in the two groups, respectively, discontinued the study drug because of a drug-related adverse event after receiving treatment in the induction phase; 4 of the 43 patients in the ipilimumab-dacarbazine group who received at least one maintenance dose (9.3%) and none of the 53 patients in the dacarbazine group who received at least one maintenance dose discontinued the therapy after receiving treatment in the maintenance phase.
Therapy after disease progression was balanced between the two groups; 54.7% of the patients in the ipilimumab-dacarbazine group and 59.0% in the dacarbazine group received subsequent therapy. In the ipilimumab-dacarbazine group, 37.7% of the patients received chemotherapy, and 2% immunotherapy; in the dacarbazine group, 34.7% received chemotherapy, and 2% immunotherapy. One patient in the dacarbazine group received the BRAF inhibitor, vemurafenib, at the time of disease progression, but tumors were not routinely assessed for the presence of the BRAF V600E mutation.
Efficacy analyses were performed on the intention-to-treat population. A survival analysis was performed after 414 deaths occurred, 37 months after the last patient was enrolled. The median overall survival in the ipilimumab-dacarbazine group was 11.2 months (95% confidence interval [CI], 9.4 to 13.6), as compared with 9.1 months (95% CI, 7.8 to 10.5) in the dacarbazine group, with estimated survival rates in the two groups, respectively, of 47.3% and 36.3% at 1 year, 28.5% and 17.9% at 2 years, and 20.8% and 12.2% at 3 years (hazard ratio for death with ipilimumab-dacarbazine, 0.72; P<0.001) (Figure 1AFigure 1Kaplan-Meier Curves for Overall Survival, Progression-free Survival, and Duration of Response.). Ipilimumab was associated with improved overall survival across patient subgroups, including those defined according to age, sex, ECOG performance status, baseline serum lactate dehydrogenase level, and substage of metastatic disease (Figure 2Figure 2Overall Survival According to Subgroup.).
There was a 24% reduction in the risk of progression in the ipilimumab-dacarbazine group as compared with the dacarbazine group (hazard ratio for progression, 0.76; P=0.006). The median values for progression-free survival were similar in the two groups at the time of the first assessment (week 12), after which the Kaplan-Meier curves separated (Figure 1B).
The rate of disease control (i.e., a complete or partial response or stable disease) did not differ significantly between the two groups: 33.2% in the ipilimumab-dacarbazine group and 30.2% in the dacarbazine group (P=0.41). The rate of best overall response (i.e., a complete or partial response) was 15.2% in the ipilimumab-dacarbazine group and 10.3% in the dacarbazine group (P=0.09) (Table 2Table 2Efficacy Results.). The median duration of response among all randomly assigned patients with a complete or partial response was 19.3 months (95% CI, 12.1 to 26.1) in the ipilimumab-dacarbazine group and 8.1 months (95% CI, 5.19 to 19.8) in the dacarbazine group (P=0.03) (Figure 1C). Some patients in the study who were receiving ipilimumab had an improvement from partial response to complete response after 6 months (data not shown). Responses in the presence of new lesions were also observed, although these were not captured as part of the best overall response.
The safety analysis included all patients who underwent randomization and received at least one dose of the assigned study drug (498 patients). The adverse events reported in the safety population are listed in Table 3Table 3Adverse Events and Immune-Related Adverse Events.. Adverse events (all grades) for which there was a higher incidence in the ipilimumab-dacarbazine group than in the dacarbazine group included elevation of alanine aminotransferase levels (in 33.2% of patients vs. 5.6%), elevation of aspartate aminotransferase levels (29.1% vs. 5.6%), diarrhea (36.4% vs. 24.7%), pruritus (29.6% vs. 8.8%), and rash (24.7% vs. 6.8%). Grade 3 or 4 adverse events occurred in 56.3% of patients receiving ipilimumab plus dacarbazine and in 27.5% of patients receiving placebo plus dacarbazine (P<0.001).
No gastrointestinal perforations were reported. No cases of hypophysitis were noted in the ipilimumab-dacarbazine group except for a single case that was reported on day 364 (which was outside the protocol-specified reporting window of <70 days after the last dose - a period representing 5 times the half-life of ipilimumab - and was therefore not categorized as an “on-study” event). No drug-related deaths were reported in the ipilimumab-dacarbazine group; one fatal gastrointestinal hemorrhage was reported in the dacarbazine group. Nausea and vomiting (Table 3) as well as myelosuppression (data not shown), which are common side effects of dacarbazine, were not increased in the ipilimumab-dacarbazine group as compared with the dacarbazine group.
The most common study-drug-related adverse events were those classified as immune-related adverse events, which were seen in 77.7% of the patients treated with ipilimumab plus dacarbazine and 38.2% of the patients treated with dacarbazine and placebo (Table 3). The most common immune-related adverse events in the ipilimumab-dacarbazine group were elevated liver-function values, with grade 3 or 4 elevations in liver-function values noted in 17.4 to 20.7% of the patients.
An alternative characterization of inflammatory events was performed in which noninflammatory causes of the event (e.g., tumor progression or infection) were ruled out (immune-mediated adverse reactions). Severe (grade 3 or higher) immune-mediated adverse reactions were seen in 38.1% of the patients in the ipilimumab-dacarbazine group and 4.4% of the patients in the dacarbazine group. The most common grade 3 or 4 immune-mediated adverse reaction was immune-mediated hepatitis, which was seen in 78 patients in the ipilimumab-dacarbazine group (31.6%) and in 6 patients in the dacarbazine group (2.4%). Grade 3 or 4 immune-mediated enterocolitis was seen in 12 patients in the ipilimumab-dacarbazine group (4.9%) and no patients in the dacarbazine group. Hepatic immune-mediated adverse reactions were generally reversible with treatment according to established guidelines specified in the research protocol. The proportion of patients who received glucocorticoids or other immunosuppressant agents after the emergence of high-grade immune-mediated hepatitis was 80.8% (63 of 78 patients, including 5 patients who received mycophenolate mofetil) in the ipilimumab-dacarbazine group and 33.3% (2 of 6 patients) in the dacarbazine group. High-grade elevations in liver-function values were normalized in 67.9% of patients in the ipilimumab-dacarbazine group, with a median time to normalization of 9.9 weeks (range, 1.0 to 56.1; interquartile range, 7.0 to 15.0). No patient died as a result of complications of immune-mediated hepatitis or enterocolitis during the course of the study.
Among the 43 patients who received ipilimumab and the 53 patients who received placebo during the maintenance phase, the most common adverse events (all grades, occurring in >5% of patients in the ipilimumab group) were rash (25.6% vs. 5.7%), pruritus (16.3% vs. 3.8%), diarrhea (14.0% vs. 5.7%), nausea (7.0% vs. 5.7%), and fatigue (9.3% vs. 3.8%). Low-grade increases in liver-function values were noted in 2 patients receiving ipilimumab during the maintenance phase. No high-grade elevations in liver-function values were noted among the patients receiving ipilimumab during the maintenance phase. High-grade adverse events during the maintenance phase were infrequent; among the grade 3 or 4 adverse events noted were colitis and diarrhea (in 1 patient) and rash or pruritus (in 3 patients). No grade 3 or 4 adverse events occurred in patients receiving placebo during the maintenance phase.