Tremelimumab monotherapy ineffective for advanced colorectal cancer

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NEW YORK (Reuters Health) - Monotherapy with tremelimumab, an anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody (anti-CTLA4), had no clinically meaningful impact on refractory metastatic colorectal cancer in a phase II trial.

But we're "just (at) the beginning in the development of immune-based approaches" such as anti-CTLA4 agents, said lead author Dr. Ki Y. Chung from Memorial Sloan-Kettering Cancer Center, New York, in e-mail to Reuters Health.

"I do see tremelimumab having clinical activity as a single agent in the future," Dr. Chung said. "The key will be patient selection as always, as well as identifying surrogates for response."

The phase II study was the first clinical trial to test a CTLA4 monoclonal antibody as a treatment for colorectal cancer. The researchers enrolled 49 patients with refractory metastatic disease and treated 47. Of 45 evaluable patients, 43 (95.6%) had disease progression, one had an indeterminate response because of early discontinuation, and one had a stable cystic left pelvic mass and substantial regression in an adrenal mass on first follow-up scan at 3 months.

The lone patient with a partial response eventually had disease progression at 15 months after enrollment and died 4 months later, according to the report published online May 24th in the Journal of Clinical Oncology.

But the median progression-free survival was 2.3 months, and the probability of 6-month progression-free survival was 2.1%. Forty-six of the 47 treated patients received only a single dose of the study medication.

The median overall survival was 4.8 months (range, 0.7 months to 23.7 months). Twenty-one patients (43%) survived at least 6 months after enrollment. The probability of survival at 12 months was 10.7%.

Thirty patients had treatment-related adverse events, with diarrhea, fatigue, nausea, pyrexia, and vomiting occurring most commonly.

Serious treatment-related adverse events during the first cycle included diarrhea (5 patients), one case of autoimmune thrombocytopenia, and one case of ulcerative colitis.

All but one of the 44 patients who died during follow-up died more than 30 days after their last dose of tremelimumab, and none of the deaths was attributed to tremelimumab treatment.

"The data from this trial do not support further investigation of tremelimumab as a single agent for the treatment of advanced, treatment-refractory colorectal cancer," the investigators conclude.

Dr. Chung said the main message from this and several other large trials of anti-CTLA4 agents is that "many solid tumors may be responsive to immunologic based therapies, suggesting that further clarification of the process of immune tolerance by solid tumors will lead to effective therapies."

Several phase I trials are testing tremelimumab in combination with other agents in patients with other solid tumors, including breast cancer (with exemestane) and renal cell carcinoma (with sunitinib), according to Dr. Chung.

Five of the paper's 11 authors were employed by Pfizer Inc., which provided funding for the trial, and all of the remaining authors had received honoraria or research funding from Pfizer.

http://jco.ascopubs.org/cgi/content/abstract/JCO.2010.28.3994v1

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