Pancreatic Cancer: Beyond Brca Mutations.

Pancreatic cancer is the fourth-leading cause of cancer-related deaths worldwide. The outcomes in patients with pancreatic cancer remain unsatisfactory. In the current review, we summarize the genetic and epigenetic architecture of metastatic pancreatic cancer beyond the BRCA mutations, focusing on the genetic alterations and the molecular pathology in pancreatic cancer. This review focuses on the molecular targets for the treatment of pancreatic cancer, with a correlation to future treatments. The potential approach addressed in this review may lead to the identification of a subset of patients with specific biological behaviors and treatment responses.

Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.

The real-life application of immune checkpoint inhibitors (ICIs) may yield different outcomes compared to the benefit presented in clinical trials. For this reason, there is a need to define the group of patients that may benefit from treatment. We retrospectively investigated 578 metastatic melanoma patients treated with ICIs at the Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale" of Napoli, Italy (INT-NA). To compare patients' clinical variables (i.e., age, lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR), eosinophil, BRAF status, previous treatment) and their predictive and prognostic power in a comprehensive, non-hierarchical manner, a clinical categorization algorithm (CLICAL) was defined and validated by the application of a machine learning algorithm-survival random forest (SRF-CLICAL). The comprehensive analysis of the clinical parameters by log risk-based algorithms resulted in predictive signatures that could identify groups of patients with great benefit or not, regardless of the ICI received. From a real-life retrospective analysis of metastatic melanoma patients, we generated and validated an algorithm based on machine learning that could assist with the clinical decision of whether or not to apply ICI therapy by defining five signatures of predictability with 95% accuracy.

The Ratio of GrzB+ - FoxP3+ over CD3+ T Cells as a Potential Predictor of Response to Nivolumab in Patients with Metastatic Melanoma.

The understanding of the molecular pathways involved in the dynamic modulation of the tumor microenvironment (TME) has led to the development of innovative treatments for advanced melanoma, including immune checkpoint blockade therapies. These approaches have revolutionized the treatment of melanoma, but are not effective in all patients, resulting in responder and non-responder populations. Physical interactions among immune cells, tumor cells and all the other components of the TME (i.e., cancer-associated fibroblasts, keratinocytes, adipocytes, extracellular matrix, etc.) are essential for effective antitumor immunotherapy, suggesting the need to define an immune score model which can help to predict an efficient immunotherapeutic response. In this study, we performed a multiplex immunostaining of CD3, FOXP3 and GRZB on both primary and unmatched in-transit metastatic melanoma lesions and defined a novel ratio between different lymphocyte subpopulations, demonstrating its potential prognostic role for cancer immunotherapy. The application of the suggested ratio can be useful for the stratification of melanoma patients that may or may not benefit from anti-PD-1 treatment.

Clinical trials and drug cost savings for Italian health service.

BACKGROUND: The cost of anticancer drugs is constantly growing. The aim of this study was determine the impact in terms of cost reduction for anticancer drug in the Italian Health Service due to patient participation in clinical trials. METHODS: We evaluated the cost of drugs administered to patients treated in clinical trials at the National Cancer Institute of Naples in a four-week time period. Patients with a diagnosis of different cancers were considered, including adjuvant therapy and treatment for advanced disease, pharma sponsored and investigator initiated phase I, II and III clinical studies. We defined the expected standard treatment for each patient and we calculated the cost of the standard antineoplastic drugs that should be administered in clinical practice outside clinical trials. We used the market price of drugs to determine the cost savings value. Costs other than drugs were not included in the cost saving calculation. RESULTS: From 23.10.2017 to 17.11.2017, 126 patients were treated in 34 pharma sponsored and investigator initiated clinical trials, using experimental drugs provided free of charge by the sponsors, for an overall number of 152 cycles of therapy. If these patients were treated with conventional therapies in clinical practice the cost of antineoplastic drugs would account for 517,658 Euros, with an average of 5487 Euros saved per patients for a period of 4 weeks. CONCLUSIONS: Clinical trials with investigational antineoplastic drugs provided free of charge by Sponsors render considerable cost savings, with a tangible benefit in clinical and administrative strategies to reduce drug expenditures.

Impact of COVID-19 outbreak on cancer immunotherapy in Italy: a survey of young oncologists.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients.

In the era of personalized medicine, BRAF mutational assessment is mandatory in advanced-stage melanoma and non-small cell lung cancer (NSCLC) patients. The identification of actionable mutations is crucial for the adequate management of these patients. To date various drugs have been implemented in clinical practice. Similarly, various methods may be adopted for the identification of BRAF mutations. Here, we briefly review the current literature on BRAF in melanoma and NSCLC, focusing attention in particular on the different methods and drugs adopted in these patients. In addition, an overview of the real-world practice in different Italian laboratories with high expertise in molecular predictive pathology testing is provided.

Outcomes and biomarker analyses among patients with COVID-19 treated with interleukin 6 (IL-6) receptor antagonist sarilumab at a single institution in Italy.

BACKGROUND: The inflammatory pathology observed in severe COVID-19 disease caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by elevated serum levels of C reactive protein (CRP) and cytokines, including interferon gamma, interleukin 8 (IL-8), and interleukin 6 (IL-6). Initial reports from the outbreak in Italy, China and the USA have provided anecdotal evidence of improved outcomes with the administration of anti-IL-6 agents, and large-scale trials evaluating these therapies are ongoing. STUDY DESCRIPTION: In this retrospective case series, clinical outcomes and correlates of response to treatment with the IL-6 receptor antagonist sarilumab are described for 15 patients with COVID-19 from a single institution in Southern Italy. Among 10 patients whose symptoms improved after sarilumab treatment, rapid decreases in CRP levels corresponded with clinical improvement. Lower levels of IL-6 at baseline as well as lower neutrophil to lymphocyte ratio as compared with patients whose COVID-19 did not improve with treatment were associated with sarilumab-responsive disease. CONCLUSIONS: This observation may reflect a possible clinical benefit regarding early intervention with IL-6-modulatory therapies for COVID-19 and that CRP could be a potential biomarker of response to treatment.

Nivolumab for the treatment of small cell lung cancer.

Introduction: Treatment of extensive-stage SCLC is still a challenge but immunotherapy with checkpoint inhibitors is showing promising results. Nivolumab alone or in combination with ipilimumab has demonstrated a benefit in terms of response and survival in patients with pre-treated extensive-stage disease and has been approved as third-line therapy after failure of chemotherapy. However, data from two phase III trials with nivolumab are negative. In the first trial, nivolumab was administered as a single agent compared to second-line chemotherapy, while in the second it was given alone or in combination with ipilimumab as maintenance treatment after platinum-based chemotherapy.Areas covered: Our review focuses on the role of immunotherapy, and in particular nivolumab, in the treatment of SCLC, describing the results of the main trials and its future perspectives, with reference to clinical trials with other checkpoint inhibitors.Expert opinion: The future of nivolumab in the treatment of SCLC needs to be clarified with further clinical trials, in which improved patient selection and a more specific setting and/or timepoint of the disease may be identified.

Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab.

BACKGROUND: Previous studies have suggested that elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors. METHODS: This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. The best cutoff values for NLR and dNLR were derived using Cutoff Finder software based on an R routine which optimized the significance of the split between Kaplan-Meier survival curves. RESULTS: In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR (hazard ratio [HR] = 2.85; 95% CI 1.60-5.08; p < 0.0001) and LDH (HR = 2.51; 95% CI 1.36-4.64; p < 0.0001) maintained a significant association with OS in multivariate analysis. Patients with baseline NLR ≥5 had significantly worse OS and PFS than patients with NLR < 5, as did patients with baseline dNLR ≥3 versus < 3. Optimal cut-off values were ≥ 4.7 for NLR and ≥ 3.8 for dNLR. Using this ≥4.7 cut-off for NLR, the values for OS and PFS were overlapping to the canonical cut-off for values, and dNLR< 3.8 was also associated with better OS and PFS. CONCLUSION: Both Neutrophil-to-lymphocyte ratio (NLR) and derived (d) NLR were associated with improved survival when baseline levels were lower than cut-off values. NLR and dNLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with advanced melanoma.

Combined vemurafenib and fotemustine in patients with BRAF V600 melanoma progressing on vemurafenib.

BACKGROUND: BRAF inhibitor vemurafenib achieves high response rate and an improvement in survival in patients with BRAF-mutated metastatic melanoma. However, median progression-free survival is only 6.9 months in the phase 3 study. Retrospective analyses suggest that treatment with BRAF inhibitors beyond initial progression might be associated with improved overall survival. We aimed to prospectively investigate the activity of prolonged treatment with vemurafenib and the addition of fotemustine in patients with systemic progression on prior single-agent BRAF inhibitor. PATIENTS AND METHODS: In this two-centres, single-arm Phase 2 trial, we enrolled patients with systemic progressive disease during single-agent vemurafenib treatment. Participants received vemurafenib 960 mg twice daily or dose administered at time of disease progression with vemurafenib previous treatment and fotemustine 100 mg/m2 intravenously every three weeks. The primary endpoint was PFS. RESULTS: Thirty-one patients were enrolled in the study; 16 patients had brain metastases at baseline. Median PFS was 3.9 months and 19 patients (61.3%) achieved disease control (1 CR, 4 PR, 14 SD). For patients achieving disease control, median duration of treatment was 6 months. Median OS was 5.8 months from enrolment and 15.4 months from start of previous vemurafenib. Five patients (16.1%) had a G3-4 AE, the most common being thrombocytopenia, which occurred in 3 patients.This trial is registered with ClinicalTrials.gov number NCT01983124. CONCLUSION: The combination of vemurafenib plus fotemustine has clinical activity and an acceptable safety profile in BRAF-refractory patients.

Electrochemotherapy efficacy evaluation for treatment of locally advanced stage III cutaneous squamous cell carcinoma: a 22-cases retrospective analysis.

BACKGROUND: Extensive squamous cell carcinoma has few therapeutic options. In such cases, electrochemotherapy involving electroporation combined with antineoplastic drug appears to be a new potential option and may be considered as an alternative treatment. The aim of this retrospective single-center study was to evaluate electrochemotherapy efficacy in treatment of locally advanced stage III squamous cell carcinoma, in which surgical procedures would have entailed wide tissue sacrifice. METHODS: Clinical features, treatment response, and adverse effects were evaluated in 22 patients treated with electrochemotherapy with intravenous injection of bleomycin for extensive stage III cutaneous squamous cell carcinoma. Treatment of cutaneous lesions were performed according to the European Standard Operating Procedures of Electrochemotherapy. RESULTS: Overall response to electrochemotherapy treatment was observed in 18 (81.8%) patients. Clinical response with necrosis of tumor mass was observed from the first session and lasted for all follow up period that ranged between 5 and 48 months with a median of 34 months. Overall the treatment was well tolerated with a very low complication rate. CONCLUSIONS: Electrochemotherapy represents a safe and effective therapeutic approach, associated with a good tolerability.

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

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.

Complete response to nivolumab monotherapy in a treatment-naive, BRAF wild-type patient with advanced mucosal melanoma and elevated lactate dehydrogenase: a case report from a phase III trial.

The anti-PD-1 agent, nivolumab, has been approved both as monotherapy and in combination with ipilimumab for the treatment of unresectable or metastatic melanoma in the USA and European Union. Here we present the case of a patient with treatment-naive, metastatic mucosal melanoma and baseline LDH approximately seven times the upper limit of normal. The patient was enrolled in a clinical trial (CheckMate 066) and achieved a partial response, followed by a durable complete response with nivolumab treatment. The patient's LDH levels were documented in each cycle and dropped markedly within 2 months, when partial response to treatment was already evident. LDH levels remained low for the rest of follow-up, consistent with the ongoing complete response to treatment. The patient experienced only mild immune-related adverse events (grade 1-2), which included vitiligo and rash. This exceptional response suggests that patients with high LDH levels at baseline should be considered for nivolumab treatment. LDH levels, however, should not serve as a predictive marker of response to nivolumab. Moreover, this case suggests the need to identify patients who will achieve the greatest benefit from nivolumab monotherapy.

Single versus combination immunotherapy drug treatment in melanoma.

INTRODUCTION: The advent of new immunotherapies for the treatment of metastatic melanoma has resulted in various novel combination strategies. Because of their distinct modes of action, different immunotherapies have been investigated in combination with one another, as well as combined with targeted therapies and other treatment modalities. AREAS COVERED: Anti-CTLA-4 and anti-PD-1 treatments enhance antitumor immunity through complementary and non-redundant mechanisms. The combination of the anti-CTLA-4 agent ipilimumab and the anti-PD-1 agent nivolumab has been shown to improve progression-free survival and objective response rate compared with either agent alone as monotherapy in patients with advanced melanoma. However, the combination was associated with significant toxicity, with around one-third of patients discontinuing treatment as a result. The sequential use of nivolumab and ipilimumab was associated with similar outcomes and comparable toxicity to concurrent therapy. Clinical trials assessing various combinations of immunomodulating antibodies are ongoing or planned. Ipilimumab and pembrolizumab have also been investigated in combination with the oncolytic virus, talimogene laherparepvec (T-VEC), with promising results. In addition, immunotherapies have also been combined with chemotherapy, radiotherapy and electrochemotherapy. EXPERT OPINION: Investigation of combination approaches represents the start of a new story that begins with melanoma treatment and expands to embrace other solid and hematological cancers.

Novel mechanisms and therapeutic approaches in melanoma: targeting the MAPK pathway.

The development of novel treatments that selectively inhibit the RAS-RAF-MAPK pathway represents a milestone in the history of melanoma treatment. BRAF mutations occur in approximately 45% of cutaneous melanomas, while mutations in NRAS occur in 15-25%. Vemurafenib was the first BRAF inhibitor to be approved in 2011, based on the results of a phase III trial (BRIM-3) that showed higher progression-free survival and overall survival compared with dacarbazine chemotherapy in metastatic BRAF-mutated melanoma. Dabrafenib, another BRAF inhibitor, has shown similar results and was approved in 2013. Preclinical studies suggested that another novel group of agents, the MEK inhibitors, showed stronger inhibition of both mutated BRAF and NRAS cell cultures than vemurafenib. Trametinib was the first MEK inhibitor approved in 2014, both as a single agent and in combination with dabrafenib for the treatment of advanced BRAF-mutated melanoma. Other MEK inhibitors are also in development. Concomitant inhibition of both MEK and BRAF has shown more durable and greater tumor response than BRAF monotherapy, by overcoming the multiple genetic mechanisms of escape. Combined therapy prevents the development of acquired resistance as well as decreasing cutaneous toxicity secondary to paradoxical activation of the MAPK pathway induced by BRAF inhibitors. Various combinations of BRAF and MEK inhibitors have shown promising results. Moreover, triple combination therapies involved other agents with novel mechanisms of action are also being evaluated. These and other combination strategies involving immunotherapies and targeted therapies offer the hope of improving outcomes beyond those already achieved with anti-BRAF treatments.

Clinicopathologic features and surgical management of primary umbilical melanoma: a case series.

BACKGROUND: Primary umbilical melanoma is an uncommon tumor that is poorly described in the medical literature. The umbilical region is a particular anatomic site owing to the presence of embryonal remnants, which can be a potential metastatic pathway, as well as the braided lymphatic network drainage. Hence, primary malignant neoplasms affecting the umbilicus require a different and more radical surgical approach compared with other melanomas. CASE PRESENTATION: In this report, we describe a series of three patients of Caucasian ethnicity who presented with primary umbilical melanoma at the National Cancer Institute of Naples, Italy. All patients underwent wide excision of the tumor including the underlying peritoneum. No surgical complications, either immediate or delayed, were observed in any of the patients. Sentinel lymph node biopsy was negative in two cases. Two of the patients developed metastatic disease and died after systemic medical therapy. The other patient is currently in follow-up, and remains disease-free after 21 months. CONCLUSIONS: The umbilicus has vascular and embryological connections with the underlying peritoneum, so that early visceral involvement is more likely to occur with primary umbilical melanomas. As such, tumor resection including the underlying peritoneum is required to avoid local relapse, whilst sentinel lymph node biopsy appears to be of poor diagnostic value.

Electrochemotherapy in melanoma patients: a single institution experience.

AIM: This study was undertaken to update the outcome of the treated lesions with electrochemotherapy (ECT) plus intravenous injection of bleomycin in patients with in-transit disease or distant cutaneous metastases in melanoma patients. PATIENTS & METHODS: 89 patients with relapsed and refractory cutaneous melanoma metastases or in-transit disease were submitted to 126 treatments of ECT. RESULTS: 34 patients (38.2%) had a partial response and 43 had a complete response (48.3%). 12 patients (13.5%) had no change or progressive disease. The objective response rate was 67.5%. CONCLUSION: The favorable outcome obtained in the present study demonstrates that ECT is a reliable, easy, fast and effective procedure showing benefits in terms of curative and palliative treatment for unresectable cutaneous lesions respecting the quality of life.

Tomotherapy concomitant with cetuximab, followed by cetuximab as single-agent therapy for unresectable squamous cell carcinoma of the skin: a case report.

BACKGROUND: Cutaneous squamous cell carcinoma (SCC) is the second most frequency of all skin tumors. Incidence of SCC has risen significantly due to an increased sun exposure and the number of immunodeficient patients. Cutaneous SCC is characterized by high Epidermal growth factor receptor (EGFR) expression with low frequency of RAS mutations. Generally, locoregional surgery is curative and systemic therapy is not indicated. We evaluated the activity and toxicity profile of tomotherapy concomitant with Cetuximab, followed by Cetuximab as single agent therapy in a patient affected by unresectable, locally advanced cutaneous SCC. CASE PRESENTATION: At our institution, on March 2012 we treated a 45 years-old patient affected by locally advanced, unresectable G1 SCC of the lumbar region. At our first observation, the patient was asthenic, with severe pain and functional limitations. There was also a superinfection due to Pseudomonas Aeruginosa resistant to antibiotics, and a G3 anemia secondary to the bleeding lesion. ECOG Performance Status was 2. Tomotherapy has been performed concomitant with the Cetuximab (400 mg/m2, followed by weekly doses of 250 mg/m2) at the total dose of 60 Gy (2 Gy/fx), followed by Cetuximab monotherapy.The lesion reduced progressively until disappear even after the suspension of the treatment and the patient achieved complete response. Toxicity resulted in G1 cutaneous rash and G2 toxicity to the nails, appeared after 5 months of treatment, typical toxicity profile of the anti-EGFR therapies. After one month of therapy the Pseudomonas Aeruginosa superinfection totally disappeared. Quality of life resulted significantly improved with reduction until discontinuation of the anti-pain drugs, and progressive increase of the hemoglobin levels. At follow up of 15 months there was no evidence of active disease and the ECOG Performance Status was 0 (zero). CONCLUSION: The treatment was effective and feasible. Considering these excellent results, further studies about concomitant tomotherapy with Cetuximab for advanced/inoperable SCC of the skin are needed.

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

INTRODUCTION: Immunotherapy 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 PRESENTATION: Three 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. CONCLUSIONS: Haematological 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.

Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme.

BACKGROUND: Elderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients. Data from clinical trials and expanded access programmes (EAPs) suggest ipilimumab confers a consistent survival benefit and has a similar safety profile across different age groups of patients with metastatic melanoma. Here we report the efficacy and safety of ipilimumab 3 mg/kg in elderly patients enrolled in an EAP in Italy. METHODS: Patients aged > 70 years with pretreated melanoma received ipilimumab 3 mg/kg every 3 weeks for four doses through an EAP. Tumour response was evaluated at baseline and after completion of induction therapy using immune-related response criteria and patients were monitored throughout the treatment period for adverse events (AEs), including immune-related AEs. RESULTS: The immune-related disease control rate among 188 evaluable patients was 38%, including four patients with an immune-related complete response, 24 with an immune-related partial response and 44 with immune-related stable disease. Median progression-free survival (PFS) was 4.0 months and the 1- and 2-year PFS rates were 21% and 12%, respectively. Median overall survival (OS) was 8.9 months; 1- and 2-year OS rates were 38% and 22%, respectively. The safety profile of ipilimumab was consistent with that observed in the general population of the Italian EAP and treatment-related AEs generally resolved within a median of 2 weeks with treatment as per protocol-specific guidelines. CONCLUSIONS: These results suggest ipilimumab is a feasible treatment option in elderly patients with metastatic melanoma. Ipilimumab treatment was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated at centres in Italy.