Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab

PurposeThe purpose of this study was to set up a prognostic model for the identification of survival predictors specific for melanoma patients treated with ipilimumab.Experimental designThe following prospectively collected data were utilised: patient and primary tumour characteristics, relapse-free-interval, site and number of metastases, previous therapies and level of serum biomarkers (lactic dehydrogenase (LDH), C-reactive protein, β2-microglobulin, vascular endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP), transaminases, leucocyte count, lymphocytes subpopulations). A multivariate prognostic model was developed using the Cox regression model fitted to the data of 113 consecutive metastatic patients treated with ipilimumab (3 mg/kg, q3w) at Veneto Institute of Oncology (IOV). External validation was obtained using the data of 69 and 34 patients treated at European Oncology Institute (IEO) and University of Torino (UT), respectively.ResultsMedian survival was 8.3, 4.9 and 7.1 months from first ipilimumab administration at IOV, IEO and UT, respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v = 1.36, 95% Confidence Interval [CI] 1.16–1.58, P < .001) and neutrophils (HR = 1.76, 95% CI 1.41–2.10, P < .001) were associated with worse prognosis. Model performance was satisfactory both upon internal validation (Dxy = 0.42) and external validation (Dxy = 0.40). Serum LDH and neutrophil count discriminated patients who lived more (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24 months.ConclusionSerum LDH and neutrophil count were significant independent prognostic factors. This externally validated prognostic nomogram, could help clinicians to identify the patients who would benefit most from ipilimumab and consequently to improve resource allocation. These easily available biomarkers deserve further validation.     

Prognostic score for patients with advanced melanoma treated with ipilimumab

BackgroundImmunotherapies like the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab show durable clinical benefit in patients with advanced melanoma. Reliable prognostic markers and risk scores in the era of immunotherapy are still lacking.Patients and methodsWe collected characteristics and outcomes on 134 patients with metastatic melanoma treated with ipilimumab between 2011 and 2014 at a single centre. Cox regression including multivariable fractional polynomials was used to identify independent markers for overall survival (OS). Internal model validation was done using bootstrap procedures.ResultsAfter a median follow-up of 16.1 months the median OS was 7.1 months (95% confidence interval [CI], 6.5–9.8). Nineteen of 134 patients (14.2%) had tumour remissions, 16 partial and 3 complete; 75% had progressive disease. We identified three independent adverse factors for OS: elevated lactate dehydrogenase (LDH) (hazard ratio [HR] 1.03, 95% CI 1.02–1.04), Eastern Cooperative Oncology Group performance status >0 (HR 1.91, 95% CI 1.10–3.30), and number of organs involved (NOI) (HR 1.51, 95% CI 1.22–1.86). To build an easy-to-apply risk score, we dichotomized LDH (>upper limit of normal) and NOI (>2) to built 3 prognostic groups: favourable (no adverse factors, N = 17), intermediate (1 adverse factor, N = 38), and poor prognosis (≥2 adverse factors, N = 73). Respective 12 and 18-month OS for the risk groups were: 85% and 73% (favourable), 41% and 29% (intermediate), and 12% and 6% (poor) (p < 0.001).ConclusionWe propose a simple prognostic score for survival in patients with advanced melanoma treated with ipilimumab using readily available clinical parameters.     

Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: Analysis of 60 Japanese patients

Background

Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching.

Nivolumab in melanoma

Introduction: The treatment of melanoma is evolving rapidly over the past few years.

Areas covered: We conducted a comprehensive review of the literature on the role of nivolumab in melanoma

Expert commentary: Nivolumab is approved by FDA and EMA for the treatment of patients with metastatic melanoma. Nivolumab is superior to chemotherapy and to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of an increase in grade 3–4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients most likely to benefit from this combination and its pharmacoeconomics are to be elucidated. Prospectively validated predictive markers are lacking. Of particular interest are immune-related adverse events which should be managed according to published guidelines.     

Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors

Background

The use of immune checkpoint inhibitors (ICI) has grown incessantly since they were first approved in 2014. These monoclonal antibodies inhibit T cell activation, yielding a dramatic tumor response with improved survival. However, immunotherapy is frequently hampered by immune adverse events (iAE) such as hypophysitis, colitis, hepatitis, pneumonitis and rash. Until recently, rheumatic side effects were only infrequently reported.

Updated European Association of Urology Guidelines: Recommendations for the Treatment of First-line Metastatic Clear Cell Renal Cancer

The randomised phase III clinical trial Checkmate-214 showed a survival superiority for the combination of ipilimumab and nivolumab when compared with the previous standard of care in first-line metastatic/advanced clear cell renal cell carcinoma (RCC) (Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. LBA5, ESMO 2017, 2017). These results change the frontline standard of care for this disease and have implications for the selection of subsequent therapies. For this reason the European Association of Urology RCC guidelines have been updated.

Pharmacotherapy of metastatic melanoma: Emerging trends and opportunities for a cure

Metastatic melanoma is one of the most deadly forms of cancer and is poorly responsive to standard chemotherapeutics, such as Dacarbazine and Paclitaxel. Recently, the advent of Vemurafenib and Ipilimumab has broadened the spectrum of therapeutic options for advanced melanoma patients but the occurrence of resistance and of high-grade toxicities call for better and more effective treatments. This review focuses on approved and experimental therapies for metastatic melanoma. The mechanism of action and the reported efficacy data for small molecule drugs and biologics are discussed, outlining directions for future pharmaceutical research in this field.     

New Treatments of Metastatic Melanoma in 21th Century: 2011 and future

Introduction Melanoma is the fifth most common cancer in the United States.The estimated number of new cases of melanoma in 2012 is 76,250,with 9,180melanoma-related death[1,2].     

The use of systemic therapies for the treatment of brain metastases in metastatic melanoma: Opportunities and unanswered questions

The development of brain metastases is common in patients with metastatic melanoma and heralds a particularly poor prognosis. The development of the immunological agent ipilimumab and targeted treatments such as the selective BRAF inhibitor vemurafenib have revolutionised the treatment of metastatic disease. Evidence from clinical trials suggest these drugs may be effective in the treatment of brain metastases from melanoma. However efficacy may be limited by a lack of penetration of the blood brain barrier (BBB) and by multi substrate efflux pumps expressed on the BBB. The role and sequencing of radiotherapy, both whole brain and stereotactic radiotherapy, is yet to be determined but combinations of radiotherapy and systemic therapies may further increase the effects of these drugs on brain metastases. Considering the impact of brain metastases on morbidity and mortality in metastatic melanoma, future research into systemic drug therapy for the treatment of brain metastases and improvements in BBB penetrance should be a priority.