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Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma
J Clin Oncol. 2013 Jan 7;[Epub Ahead of Print], A Ribas, R Kefford, MA Marshall, et al
Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma
J Clin Oncol. 2013 Jan 7;[Epub Ahead of Print], A Ribas, R Kefford, MA Marshall, et al
TAKE-HOME MESSAGE
Tremelimumab failed to offer an overall survival advantage as first-line treatment of metastatic melanoma, but its longer duration of response may prove beneficial in a subgroup of patients.
EXPERT COMMENTARY
Lee S. Schwartzberg, MD, FACP
Ipilumumab (IPI), a monoclonal antibody that blocks the immunoinhibitory function of CTLA-4, causes a reaction akin to taking the foot off the brake of a car and allowing the immune system to move forward in immune recognition and attack of melanoma cells. Randomized phase III trials of IPI demonstrated a survival advantage and the agent is approved in advanced, metastatic melanoma. A similar antibody, tremelimumab (TREME) was investigated in a phase Iii trial against standard of care chemotherapy, and is reported by Ribas in the Journal of Clinical Oncology online. This study failed to achieve a statistically significant survival endpoint for the antibody although there was a trend favoring the biological.
What are we to make of this seemingly disparate results? In the TREME trial, some patients in the control arm crossed over to receive IPI when that became commercially available in the US, likely improving the outcome for the control group. TREME was fairly toxic, and it is possible that better toxicity management would have allowed more patients to stay on study, receive more therapy, and result in fewer toxic deaths and withdrawals for toxicity. Schedule difference and patient entry criteria could certainly have also played a role. This negative trial should not dampen the enthusiasm for immunotherapy of melanoma but reminds us how careful we must be in designing, enrolling and managing patients in a study evaluating an agent with novel mechanisms of action and toxicity.
SUMMARY
OncologySTAT Editorial Team
Tremelimumab, a cytotoxic T-lymphocyte–associated antigen 4–blocking monoclonal antibody, has induced durable objective tumor responses in a subgroup of patients with advanced melanoma in early phase I/II trials. Ribas and colleagues conducted a phase III study to compare this novel agent with standard-of-care chemotherapy.
At 114 sites in 24 countries, 655 patients with treatment-naïve, unresectable, stage IIIc or IV melanoma participated in this study; 95% had stage IV disease. They were randomly assigned to receive treatment with tremelimumab or standard-of-care chemotherapy (dacarbazine or temozolomide). Of the 328 patients assigned to treatment with tremelimumab, 40 completed treatment; of the 327 patients assigned to treatment with chemotherapy, 33 completed treatment (22 with dacarbazine and 11 with temozolomide).
Based on an intent-to-treat analysis, the median overall survival for patients treated with tremelimumab was 12.6 months (95% CI, 10.8–14.3), compared with 10.7 months for those treated with chemotherapy (95% CI, 9.4–12.0; HR, 0.88; P = .127). Survival rates at 2 and 3 years were 26.4% (95% CI, 22.0%–31.7%) and 20.7% (95% CI, 16.7%–25.6%), respectively, for patients on tremelimumab, vs 22.7% (95% CI, 18.5%–27.8%) and 17.0% (95% CI, 13.3%–21.7%), respectively, for patients on chemotherapy.
Based on investigator assessment, the objective response rates were similar in both study groups: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. In addition, there were no major differences between the treatments in terms of the rate of complete or partial response. Defined as the time from random assignment to disease progression or death for objective responders, the median response duration was significantly longer among tremelimumab responders than chemotherapy responders (35.8 months vs 13.7 months; P = .0011). The probability of progression-free survival at 6 months was similar in the two treatment arms as well.
The most common adverse events related to the use of tremelimumab were gastrointestinal events (eg, diarrhea), dermatologic events (eg, pruritus and rash), and fatigue. The only grade ≥ 3 events reported in at least 10% of patients were diarrhea (14%) in the tremelimumab arm and neutropenia (10%) in the chemotherapy arm. Patients treated with tremelimumab experienced more cases of rash than did those treated with chemotherapy. Although most patients who discontinued treatment in either group did so because of disease progression, 43 patients stopped taking tremelimumab and 10 patients stopped taking chemotherapy because of adverse events. Finally, 7 deaths in the tremelimumab group and 1 death in the chemotherapy group were considered to be related to treatment.
Based on their study results, Ribas and colleagues concluded that tremelimumab failed to demonstrate a statistically significant overall survival advantage over standard chemotherapy in the first-line treatment of patients with metastatic melanoma. The duration of response was significantly longer after tremelimumab treatment than chemotherapy, although the rate of objective tumor response was similar with both treatments. The investigators believe that the durable responses seen in this trial confirm that tremelimumab may ultimately be of benefit to a subgroup of these patients.
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