Assunta Esposito

Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy.

Cancer radiotherapy (RT) may induce what is referred to as the “abscopal effect,” a regression of non-irradiated metastatic lesions distant from the primary tumor site directly subject to irradiation. This clinical response is rare, but has been surmised to be an immune-mediated phenomenon, suggesting that immunotherapy and RT could potentially synergize. Here, we report the outcome of patients with advanced melanoma treated with the immune checkpoint blockade monoclonal antibody antagonist, ipilimumab followed by RT. Patients were selected for enrollment at the National Cancer Institute “Fondazione G.Pascale” through the expanded access program in Italy. Those who experienced disease progression after ipilimumab thus received subsequent RT and were selected for analysis. Among 21 patients, 13 patients (62%) received RT to treat metastases in the brain and 8 received RT directed at extracranial sites. An abscopal response was observed in 11 patients (52%), 9 of whom had partial responses (43%) and 2 had stable disease (10%). The median time from RT to an abscopal response was 1 month (range 1–4). Median overall survival (OS) for all 21 patients was 13 months (range 6–26). Median OS for patients with abscopal responses was extended to 22.4 months (range 2.5–50.3) vs. 8.3 months (range 7.6–9.0) without. A local response to RT was detected in 13 patients (62%) and, of these, 11 patients (85%) had an abscopal response and abscopal effects were only observed among patients exhibiting a local response. These results suggest RT after ipilimumab may lead to abscopal responses in some patients with advanced melanoma correlating with prolonged OS. Our data also suggest that local responses to RT may be predictive of abscopal responses. Further research in larger randomized trials is needed to validate these results.

Serious haematological toxicity during and after ipilimumab treatment: a case series

IntroductionImmunotherapy with the anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody ipilimumab has been shown to improve overall survival in previously treated and treatment-naïve patients with unresectable stage III or IV melanoma. Consistent with its proposed immunomodulating mechanism of action, the most common toxicities associated with ipilimumab therapy are immune-related in nature and include those related to the skin and gastrointestinal tract, with endocrine and hepatic events also frequent. Other rare adverse events, including haematological aberrations, may also occur and can have serious consequences if unrecognised. Here we describe three patients who developed serious haematological adverse events during or after treatment with ipilimumab.Case presentationThree Caucasian patients (two women aged 68 and 49 years and one man aged 70 years) with metastatic melanoma experienced anaemia and/or leukopenia (neutropenia) with toxicity of various grades during or after treatment with ipilimumab, without significant changes to other haematological values. Two of the patients stopped treatment after the third ipilimumab dose, one because of severe anaemia that required blood transfusion and the other due to febrile neutropenia that was treated with antibiotics and granulocyte-macrophage colony-stimulating factor stimulation. The third patient developed anaemia and leukopenia after treatment during the follow-up period. The results of autoimmunity tests performed were positive and corticosteroids were used to treat these events as per side-effects treatment algorithms specifically developed for the management of immune-related adverse events associated with ipilimumab, an approach that was safe and effective.ConclusionsHaematological toxicity is a rare but potentially serious immune-related side effect of ipilimumab therapy. However, if promptly recognised and treated, haematological toxicity is manageable and can be reversed with standard corticosteroid treatment as recommended for other ipilimumab immune-related side effects.

Do BRAF inhibitors select for populations with different disease progression kinetics

Ipilimumab, an anti-CTLA-4 monoclonal antibody, has been shown to improve overall survival in patients with metastatic melanoma. Preliminary data suggest that patients who fail BRAF inhibitor treatment experience a very rapid progression of disease. Such selectivity for more rapid disease progression may mean these patients do not receive the same benefit from subsequent treatment with ipilimumab as patients without prior BRAF inhibitor treatment. The current challenge is focused on how to identify and approach the two populations of fast and slow progressors and recent hypothesis suggest that treatment choice could be guided by baseline risk factors. However, no data have yet defined which the best sequence is and more research is needed to identify predictors of response in patients with metastatic melanoma to help guide whether a BRAF inhibitor or ipilimumab should be used first in sequential therapy.

Systems biology analysis of immune signaling in peripheral blood mononuclear cells (PBMC) of melanoma patients receiving ipilimumab; basis for response biomarker identification.

Systems biology analysis of immune signaling in peripheral blood mononuclear cells (PBMC) of melanoma patients receiving ipilimumab; basis for response biomarker identification Drew Hotson, Ryan Alvarado, Andy Conroy, Santosh Putta, Ester Simeone, Assunta Esposito, Mariaelena Capone, Gabriele Madonna, Antonio M Grimaldi, David B Rosen, Spencer Liang, Alessandra Cesano, Carmela Cacciapuoti, Paolo A Ascierto, Rachael E Hawtin

Correlation between previous treatment with BRAF inhibitors and clinical response to pembrolizumab in patients with advanced melanoma

ABSTRACT The optimal sequencing of targeted treatment and immunotherapy in the treatment of advanced melanoma is a key question and prospective studies to address this are ongoing. Previous observations suggest that treating first with targeted therapy may select for more aggressive disease, meaning that patients may not gain full benefit from subsequent immunotherapy. In a single-center retrospective analysis, we investigated whether response to pembrolizumab was affected by previous BRAF inhibitor therapy. A total of 42 patients with metastatic cutaneous or mucosal melanoma who had received previous treatment with ipilimumab were treated with pembrolizumab as part of the Italian expanded access program. Sixteen of these patients had BRAF-mutated melanoma and had also been previously treated with a BRAF inhibitor (vemurafenib or dabrafenib), while 26 had BRAF wild-type melanoma (no previous BRAF inhibitor). Patients with BRAF-mutant melanoma who were previously treated with BRAF inhibitors had a significantly lower median progression-free survival (3 [2.3–3.7] versus not reached [2–8+] mo; p = 0.001) and disease control rate (18.6% versus 65.4%; p = 0.005) than patients with BRAF wild-type, while there was also a trend toward a lower response rate (assessed using immune-related response criteria) although this was not significantly different between groups (12.5% versus 36.4%; p = 0.16). These data are consistent with previous reports that BRAF inhibitor therapy may affect subsequent response to immunotherapy.

Efficacy of radiotherapy in patients on progression after treatment with ipilimumab 3 mg/kg

Background Ipilimumab, a fully human monoclonal antibody (IgG1) that promote antitumor immunity by blocking CTLA4, was the first agent which showed a long-term survival benefit, about the 20% of patients, for the treatment of metastatic melanoma. The combination of ipilimumab with other therapies might improve its efficacy. The term “abscopal effect” refers to a regression of metastatic lesions distant from the primary site of radiotherapy (RT). This new phenomenon represent the systemic response observed in patients who received ipilimumab. Here we reported the outcomes from patients treated in the ipilimumab Italian expanded access program (EAP) who received RT after ipilimumab progression. Patients and methods Patients with advanced melanoma after ipilimumab progression were selected for analysis. Patients, who failed ipilimumab therapy and for whom no other therapeutic options were available, were elegible for radiotherapy. Results

The abscopal effect: efficacy of radiotherapy in patients on progression after treatment with ipilimumab 3 mg/kg

Meeting abstracts After more than 30 years, Ipilimumab was the first agent which showed a survival benefit for the treatment of metastatic melanoma. However, only about the 20% of patients have a long-term survival benefit. The combination of ipilimumab with other therapies might improve its

Correlation between immune-related adverse events and response to pembrolizumab in advanced melanoma patients

Meeting abstracts Immunomodulation with pembrolizumab (anti-PD-1) has been shown to reach significant objective response (RR) and extend overall survival (OS) both in ipilimumab pre-treated and naive patients with metastatic melanoma. While this immunotherapy gives OS and OR benefits, it can also

High expression of a spliced variant of FKBP51 in peripheral blood mononuclear cells of melanoma patients may be related to PDL-1 on tumour and predictive of response to Ipilimumab

Meeting abstracts Identifying molecular biomarkers in melanoma may provide useful diagnostic and therapeutic tools. Melanoma delivers immune suppressive stimuli through the pathway PDL-1/PD-1. Recent data suggest tumour-cell expression of PD-L1 in melanoma may be driven by constitutive oncogenic

Correlation between BRAF mutational status and clinical response to pembrolizumab in advanced melanoma patients

Meeting abstracts About 50% of melanoma (MM) have BRAF V600 mutation and BRAF inhibitors, such as vemurafenib and dabrafenib, have shown an high response rate (RR) and overall survival (OS) improvement in BRAF-mutated MM patients (pts). Pembrolizumab, a monoclonal antibody anti-PD-1, has shown a