Tremelimumab Is the Focus of Several Studies in Advanced and Metastatic Melanoma

Clinical Trial Reports from ASCO

Advances in Hematologic Malignancies

Tremelimumab (CP-675, 206) is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte— associated antigen 4 (CTLA-4, CD152). Blocking the CTLA- 4 negative costimulatory receptor with the antagonistic antibody tremelimumab results in immune activation. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumor regressions. Its IgG2 isotype minimizes the possibility of cytotoxic effects on activated T lymphocytes and cytokine release syndrome. Clinical investigations of tremelimumab in melanoma were the focus of several presentations at ASCO.

Tremelimumab Versus Standard, Single-Agent Chemotherapy in Patients with Advanced Melanoma

In an oral presentation, Antoni Ribas, MD, Department of Surgery, Division of Surgical Oncology, University of California Los Angeles (UCLA), Los Angeles, Department of Medicine, Division of Hematology/Oncology, UCLA, Los Angeles, and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, revealed the results of a phase III study comparing overall survival (OS) with tremelimumab versus standard, single-agent chemotherapy in patients with advanced melanoma.

Patients with unresectable stage IIIc- IV melanoma without brain metastasis, lactate dehydrogenase below 2x the upper limit of normal, and no prior systemic treatment for advanced melanoma were randomized 1:1 to either tremelimumab 15 mg/kg IV q90d or the investigator’s choice of temozolomide (TMZ) 200 mg/m2 PO d1-5 q28d or DTIC 1,000 mg/m2 IV q21d (chemotherapy arm).

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A total of 665 patients were enrolled, of whom 328 were randomized to receive tremelimumab and 327 were randomized to receive standard chemotherapy. Based on a protocol-specified second interim analysis noting 340 deaths, the independent Data/Safety Monitoring Committee advised stopping the study because the log-rank teststatistic ( = 0.729) had crossed the O’Brien—Fleming futility boundary. Median OS by intent-to-treat analysis was 11.8 months in the tremelimumab group, compared with 10.7 months in the chemotherapy group, with a hazard ratio (chemotherapy over tremelimumab) of 1.04 (95% CI 0.84, 1.28).

In this trial, tremelimumab as a single agent failed to demonstrate an improvement in OS as a first-line treatment in patients with metastatic melanoma when compared with standard chemotherapy. Dr. Ribas suggested that analysis of secondary endpoints may provide further information on the role of tremelimumab in the management of metastatic melanoma.

Combination of Tremelimumab and High-Dose Interferon Alfa-2b Exhibits Antitumor Efficacy that Is Promising

In a separate oral presentation, Ahmad A. Tarhini, MD, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institite, Pittsburgh, Pennsylvania, disclosed the results of a phase II trial evaluating the safety and efficacy of combination biotherapy with high-dose interferon alfa-2b (HDI) and tremelimumab for recurrent, inoperable stage III or IV melanoma.

Tremelimumab was given at 15 mg/kg IV per course (12 wk). HDI was given concurrently starting with IV induction at 20 MU/m2 IV, 5 days/week, for four weeks followed by maintenance with 10 MU/m2 SC three times a week (TIW), for eight weeks per course. From course 2 onward, HDI was given only SC at 10 MU/m2 TIW. A two-stage design was adopted. HDI dose modification guidelines as for adjuvant therapy were used. Dose delays up to 12 weeks were allowed for tremelimumab.

Dr. Tarhini presented results for 16 patients (median age, 55 yr) enrolled to date. All had stage IV melanoma and had previously received therapy for metastatic disease (range, 1—5 prior regimens). Two patients had previously treated, stable brain metastases. A total of 24 courses had been administered (median of 1 course per patient; 6 patients continue on therapy) at the time of the analysis.

The overall response rate was 19% (3 partial responses lasting ≥2 to ≥4 mo). Two of the partial responses were associated with autoimmune manifestations (autoimmune colitis and marked vitiligo). Six patients have stable disease lasting 1 to 4.5 months and three have had progression.

The frequency of grade 3/4 toxicities did not exceed experience with the FDA-approved HDI regimen alone. Grade 3/4 toxicities included neutropenia (3 patients, 19%), hepatic enzyme elevations >5x the upper limit of normal (2, 13%), fatigue (6, 38%), anxiety (2, 13%). One patient had grade-4 autoimmune colitis leading to treatment discontinuation, but the patient recovered completely following steroid therapy.

The investigators concluded that the combination of tremelimumab and HDI can be administered with acceptable toxicity and exhibits antitumor efficacy that is promising. This study has now proceeded into a second stage in which 21 more patients will be treated.

Hematologic Malignancies

Phase II Study To Assess the Antitumor Activity of Tremelimumab in Patients with Advanced Melanoma

In a poster discussion, John M. Kirkwood, MD, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, presented the results of a phase II, open-label, single-arm study conducted to assess the antitumor activity of tremelimumab in patients with advanced melanoma.

Patients with measurable, surgically incurable stage III or IV melanoma who had progressed, relapsed, or could not tolerate previous treatment received tremelimumab 15 mg/kg IV every 12 weeks for up to four cycles or until progression of disease or intolerable toxicity. Patients with clinical benefit were eligible for <4 additional doses. The primary study endpoint was proportion of confirmed objective RECIST responses per independent review.

Of 251 patients enrolled, 246 patients (241 response-evaluable) received a median of 1 dose (range, 1 to 7). The preliminary objective response rate was 8.3% (20 partial responses [PRs], of which five are pending independent confirmation). In addition, 13/15 (86.7%) confirmed PRs are ongoing (4.0 to 11.1 mo). The majority of PRs involved target lesions in lung, lymph nodes, and/or liver. The clinical benefit rate was 22.8% (PRs stable diseases >70 days since first dose). In addition, seven patients (2.9%) with mixed responses (ie, best overall response of progressive disease but PR in target lesion) remain alive on study with censored OS (9.7 to 13.5 mo). Median overall survival was 10.0 months.

The majority of drug-related adverse events (AEs) were mild to moderate, and grade 3/4 AEs were primarily diarrhea (28, 11.4%), fatigue (6, 2.4%), and colitis (5, 2.0%). There were two (0.8%) treatment-related deaths (1 sudden death and 1 diverticular perforation).

Although this study does not demonstrate a second-line response rate exceeding 10%, the duration of response suggests a role for tremelimumab in this population. A full assessment of clinical benefit will await survival data from this study and an ongoing, randomized, phase III, first-line study.

The role of tremelimumab in the management of metastatic melanoma has yet to be defined. Additional studies are ongoing.