Phase II Trial of Tremelimumab (CP-675,206) in Patients with Advanced Refractory or Relapsed Melanoma

Abstract

Purpose: This phase II study assessed the antitumor activity of tremelimumab, a fully human, anti-CTL-associated antigen 4 monoclonal antibody, in patients with melanoma.Experimental Design: Patients with refractory/relapsed melanoma received 15 mg/kg tremelimumab every 90 days. After 4 doses, patients with tumor response or stable disease were eligible to receive ≤4 additional doses. Primary endpoint was best overall tumor response assessed by an independent endpoint review committee, and secondary endpoints included duration of response, overall survival, progression-free survival, and safety.Results: Of 251 patients enrolled, 246 (241 response-evaluable) received tremelimumab. Objective response rate was 6.6% (16 partial responses); duration of response was 8.9 to 29.8 months. Eight (50%) objective responses occurred in patients with stage IV M 1c disease, and 11 (69%) were ongoing at last tumor assessment. Eight (3.3%) patients achieved responses in target lesions (Response Evaluation Criteria in Solid Tumors) despite progressive disease within the first cycle. All 8 survived for >20 months; 5 (63%) remained alive. Clinical benefit rate (overall response + stable disease) was 21% (16 partial responses and 35 stable disease), and median overall survival was 10.0 months. Progression-free survival at 6 months was 15%, and survival was 40.3% at 12 months and 22% at 24 months. Common treatmentrelated adverse events were generally mild to moderate, and grade 3/4 adverse events included diarrhea (n = 28, 11%), fatigue (n = 6, 2%), and colitis (n = 9, 4%). There were 2 (0.8%) treatment-related deaths.Conclusions: Tremelimumab showed an objective response rate of 6.6%, with all responses being durable ≥170 days since enrollment, suggesting a potential role for tremelimumab in melanoma.

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials

“…Similarly 8 patients treated on a recently reported clinical trial of tremelimumab, an IgG2 CTLA-4 blocking antibody, ultimately achieved a partial response by response criteria in solid tumors (RECIST) despite meeting criteria for progression after the first cycle of therapy. Of note, median survival of these 8 patients (20 months) compared favorably to that of the full study population (10 months) [39]. Several clinical trials evaluating CTLA-4, PD-1 and PD-L1 inhibitory antibodies that have recently initiated will contribute to elucidating the frequency and impact of worsened early imaging findings among neuro-oncology patients treated with inhibitory immune checkpoint therapeutics.…”

Anticorps anti-CTLA-4

“…Hépatites D'allure auto-immune, elles ont été observées chez 3 % à 9 % des patients [10,17,21,26,27]. Il faut bien sûr éliminer une atteinte métastatique, une infection virale ou une atteinte médicamenteuse autre.…”

“…(17 % à 68 % des patients), rarement de grade 3 [10,16,17,21,[24][25][26][27], et cédant à un traitement symptomatique par dermocorticoï-des topiques et antihistaminiques oraux. Des biopsies cutanées ont montré un oedème dermique et des infiltrats cellulaires périvasculaires contenant des lymphocytes CD4 + et CD8 + et/ou des polynucléaires éosinophiles [16,33].…”

A Screening Assay to Identify Agents That Enhance T-Cell Recognition of Human Melanomas

“…1,2 Due to the refractory responses to conventional cancer therapies, considerable energy has been devoted toward developing effective melanoma immunotherapeutic strategies. There is ample evidence that many melanoma tumor structures are immunogenic, and a growing number of melanoma-associated antigens are known targets for T-cell-mediated cytotoxicity.…”