Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response.

PURPOSE: Therapy targeting CTLA-4 immune checkpoint provides increased survival in patients with advanced melanoma. However, immunotherapy is frequently associated with delayed and heterogeneous clinical responses and it is important to identify prognostic immunological correlates of clinical endpoints. EXPERIMENTAL DESIGN: 77 patients with stage III/IV melanoma were treated with ipilimumab alone every 3 weeks, during 9 weeks. Blood samples were collected at the baseline and before each dose for in depth immune monitoring. RESULTS: The median follow-up was 28 mo with a median survival of 7 mo. Survival and clinical benefit were significantly improved when absolute lymphocyte count at the baseline was above 1 × 10(9)/L. Notably, ipilimumab had a global effect on memory T cells, with an early increase of central and effector subsets in patients with disease control. By contrast, percentages of stem cell memory T cells (TSCM) gradually decreased despite stable absolute counts and sustained proliferation, suggesting a process of differentiation. Higher proportions of eomes(+) and Ki-67(+) T cells were observed, with enhanced skin homing potential and induction of cytotoxic markers. CONCLUSION: These results suggest that CTLA-4 blockade is able to reshape the memory subset with the potential involvement of Eomes and memory subsets including TSCM.

Single-center study under a French Temporary Authorization for Use (TAU) protocol for ipilimumab in metastatic melanoma: negative impact of baseline corticosteroids.

UNLABELLED: Ipilimumab is an anti-CTLA-4 antibody which has recently been approved in Europe as a monotherapy in the treatment of metastatic melanoma. We report a single-center study among patients treated within a Temporary Authorization for Use (TAU) protocol. We also performed a review of the literature involving expanded access program studies with a focus on factors associated with overall survival (OS). PATIENTS AND METHODS: This retrospective, observational study included patients between June 2010 and July 2011 with a diagnosis of non-resectable stage III or IV melanoma with at least one previous line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose of 3mg/kg every three weeks. RESULTS: 45 patients were included, among whom 23 (51%) had brain metastases. 33 (71%) of the patients completed the induction phase. The best overall response rate (BORR) was 13% and median overall survival (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with brain metastases at baseline and those without (p = 0.10), regardless of BRAF V600E status (p = 0.61). OS was poorer in patients who were being treated with corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008). CONCLUSION: A subset of patients most likely to benefit from ipilimumab should be defined. In our series we found a negative association of baseline corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain metastases should not be barriers to the initiation of treatment.

Vemurafenib in the French temporary authorization for use metastatic melanoma cohort: a single-centre trial.

Vemurafenib, a selective BRAF inhibitor, has recently shown an improved overall survival (OS) in metastatic melanoma with V600E mutation in phase 2 and 3 trials. Patients with BRAF V600E metastatic melanoma received vemurafenib orally, in the French temporary authorization for use program from April 2011 to April 2012. We analysed the clinical benefit and safety of vemurafenib. Secondary analyses included the impact of brain metastases on median OS and progression-free survival (PFS). Fifty patients were enrolled, of whom 20% had stage IIIC and 80% stage IV disease. The majority were men (58%), with a median age of 58 years (51-69). Forty-three patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 (86%). Twenty patients had brain metastases (40%). Overall response rate was 53%. Complete response was achieved in five patients (10%), partial response in 21 patients (43%) and stable disease in seven patients (14%). Median OS was 7.5 months (95% confidence interval 5.6-12.7) and PFS was 3.6 months (95% confidence interval 2.9-5.9). Patients with brain metastasis had a response rate of 50% (nine partial response, one complete response), and median OS and PFS were, respectively, 4.3 and 3.1 months. Common adverse events were fatigue, arthralgia and cutaneous side effects. Sixteen per cent developed squamous cell carcinoma. Grade 3/4 was observed in 11 patients (22%). Six per cent required temporary discontinuation and/or dose reduction because of toxic effects. This study confirms the considerable clinical benefit of vemurafenib for patients with brain metastasis, with manageable toxicity.