Background Prognostic factors for initial response of advanced cutaneous squamous cell carcinoma to cemiplimab treatment are lacking. Il-6 has been found to affect immune cell populations which impact tumor development. The aim was to investigate the prognostic significance of IL-6 serum levels before and during treatment. Methods Serum levels of IL-6 were correlated with clinical outcomes in a retrospective study. Results Overall, 39 patients were enrolled. High serum levels of IL-6 (> 5.6 pg/ml) were associated with poorer survival (45.1% vs 0 deaths; OS: 16.1 ± 1.5 vs 20.8 ± 0 months, 95% CI 13,046 to 19,184) and shorter PFS (10.3 ± 1.9 vs 18.9 ± 1.5 months; 95% CI 3433 to 10,133) in patients with advanced CSCC treated with cemiplimab. In addition, patients whose IL-6 level increased after treatment with cemiplimab, independently of the basal level, had a poorer response to treatment than patients whose level was reduced or stable after immunotherapy. Conclusions Serum levels of IL-6 at baseline and changes after cemiplimab immunotherapy may have a prognostic significance in patients with advanced cutaneous squamous cell carcinoma.
Purpose of Review The treatment strategy for BRAF-mutated melanoma remains unsatisfactory, although the advent of immune checkpoint inhibition has improved the prognosis of advanced melanoma. This article reports current evidence on the efficacy and safety of sequential immunotherapy with targeted therapy in patients with BRAF-mutated melanoma. It discusses criteria for the use of available options in clinical practice. Recent Findings Targeted therapy provides rapid disease control in a relatively high proportion of patients, although the development of secondary resistance limits the duration of responses; in contrast, immunotherapy may induce slow but more durable responses in a subset of patients. Summary Therefore, the identification of a combination strategy for the use of these therapies seems a promising perspective. Currently, inconsistent data have been obtained, but most studies indicate that the administration of BRAFi/MEKi prior to immune checkpoint inhibitors appears to reduce the efficacy of immunotherapy. On the contrary, several clinical and real-life studies suggest that frontline immunotherapy with subsequent targeted therapy may be associated with better tumor control than immunotherapy alone. Larger clinical studies are ongoing to confirm the efficacy and safety of this sequencing strategy for treating BRAF-mutated melanoma with immunotherapy followed by targeted therapy.
BackgroundFollowing the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma.MethodsThe study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43).Patients will be randomized to three different arms: A) BRAF-mutated patients will receive over 6 weeks (1) + (3); B) BRAF-mutated patients will receive over 6 weeks (2) + (3) + (4); C) BRAF wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks).DiscussionNeoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival.Clinical trial registrationeudract.ema.europa.eu/protocol.htm, identifier 2018-004841-17.
Background The immune checkpoint inhibitors revolutioned cancer therapeutic landscape and substantially improved the survival of patients with advanced malignancies, especially in skin cancer patients. [1][2][3][4][5] Several predictive biomarkers are under evaluation, in order to identify patients who can derive benefit from ICI while also limiting exposure and toxicity. IL-6 is a pleiotropic cytokine involved not only in immune responses but it is also a major player in chronic inflammatory diseases. [6][7] Additionally, elevated levels of IL-6 are observed in a large number of patients (pts) with solid tumours. 8 The purpose of this study is to retrospectively investigate the relationships between IL-6 serum concentration and outcome in skin cancer patients treated with immunotherapy. Methods From June 2020 to October 2021 at INT IRCCS Pascale, Naples, we analyzed interleukin -6 from 265 consecutive serum samples in different skin cancer pts before and during immunotherapy treatment. We included pts with cutaneous squamous cell carcinoma (SCC) treated with cemiplimab (n=32), melanoma in adjuvant setting (n=61), metastatic melanoma treated with: anti-PD1 (n=103), combo ipi+nivo (n=36) and ipilimumab alone (n=32). All patients signed informed consent. Patients baseline characteristics are listed in table 1. IL6 ere measured by Electrochemiluminescence immunoassays (ECLIA) from Roche Cobas. ROC curves were used to determine the best cut off. Survival rates were analyzed using the Kaplan-Meier method and differences among curves were assessed by the log-rank test. Hazard Ratios (HR) and their 95% confidence intervals (CI) were estimated using a Cox regression model. Results Among 265 pts, lower serum concentration of interleukin-6 was associated with a better PFS (15.07 months (95% CI 9,76 to 18,86) versus 8.01 months (95% CI 2,80 to 4,03), HR = 0.34 (CI 0,23-0,50, p<0.0001), OS (19.83 months (95% CI 18.57 to 21.03) versus 14.53 months (95% CI 12.38 to 16.68), HR = 0.41 (CI 0,26-0,64, p=0.0001) and ORR (95% CI 6.86 to 13.30, p<0.001). Similarly, IL6 (p <0.01) and ORR (p <0.01) are significantly associated with OS and PFS in the multivariate analysis. We also confirmed the association between IL6 with PFS and OS in adjuvant setting. Moreover, pts with an IL-6 ratio (on treatment/baseline) £1 have a better PFS and OS. Conclusions In this retrospective study, we found that lower IL-6 level are associated with better OS, PFS and ORR. In addition, minimum variation of IL-6 during immunotherapy are strongly associated to outcome. Further investigations are needed to get additional information.Ethics Approval This study was approved by the Ethics Committee of Istituto Nazionale Tumori -IRCCS -Fondazione 'G. Pascale', Naples, Italy, protocol number 17/17 oss.
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