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.
Serum levels of IL-6 were correlated with clinical outcomes in a retrospective study.
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.
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.
Following 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
-mutated and wild-type melanoma.
The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable,
-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)
-mutated patients will receive over 6 weeks (1) + (3); B)
-mutated patients will receive over 6 weeks (2) + (3) + (4); C)
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).
Neoadjuvant 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.
eudract.ema.europa.eu/protocol.htm, identifier 2018-004841-17.
BackgroundThe immune checkpoint inhibitors (ICIs) revolutionized cancer therapeutic landscape and substantially improved the survival of patients (pts) with advanced malignancies, especially in skin ...cancer pts.1–5 IL-6 is a key inflammatory molecule secreted by M2 macrophages after polarization, mediating the progression of pancreatic and colorectal cancer.6 7 The purpose of this study is to retrospectively investigate the relationships between IL-6 and outcome in skin cancer patients treated with immunotherapy.MethodsIL-6 levels were analyzed in two independent cohorts, in cohort 1 serum IL-6 were evaluated from 386 consecutive skin cancer pts before start ICIs. We included pts with unresectable/metastatic cutaneous squamous cell carcinoma (cSCC) treated with cemiplimab (n=47); pts with resected stage III/IV melanoma (n=98) treated with anti-PD1; pts with metastatic melanoma treated with anti-PD1 (n=139), combo ipi+nivo (n=65) and ipilimumab alone (n=37). IL-6 was measured by Electrochemiluminescence immunoassays (ECLIA) from Cobas C6000 (Roche). In cohort 2 we conducted a gene profile analysis with Nanostring from PBMCs of 121 metastatic melanoma pts. All pts signed informed consent. Patient’s characteristics are listed in table 1. ROC curves were used to determine the best cut off. Survival rates were analyzed using the Kaplan-Meier method. Hazard Ratios (HR) and their 95% confidence intervals (CI) were estimated using a Cox regression model.ResultsAmong 507 pts, in cohort 1 lower serum IL-6 was associated with a better Progression Free Survival (PFS) 18.67 months (95% CI 16.6–20.7) versus 10.31 months (95% CI 8.5–12.0), HR = 0.45 (CI 0,3–0,5, p<0.0001); Overall Survival (OS) (27.59 months (95% CI 25.9–29.2) versus 20.12 months (95% CI 17.7–22.4), HR = 0.32 (CI 0,23–0,47, p<0.0001) and Overall Response Rate (ORR) (p<0.001). Similarly, IL-6 and previous therapy are associated with OS and PFS in multivariate analysis (p <0.01). We also confirmed the association between IL-6 and outcomes in all subgroups. In cohort 2 we observed a similar trend in pts with lower IL-6 expression. Moreover, higher IL-6 was associated to MAP3K12, EGFR, SELL,FPR1 genes.ConclusionsWe found that lower levels of both serum and gene expression of IL-6 are associated with better OS, PFS and ORR. Furthermore, IL-6 is associated to higher expression of genes relate to cell cycle, proliferation and metastasis. Further investigations are needed to get additional information.AcknowledgementsThis work was supported by the Italian Ministry of Health Ricerca Corrente fundsReferencesJames Larkin, Vanna Chiarion-Sileni, Rene Gonzalez, Jean Jacques Grob, C Lance Cowey et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23–34.Robert C, Long GV, Brady B, Dutriaux C, Maio M, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320–30.Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375–84.Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, et al. CheckMate 238 Collaborators. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017 Nov 9;377(19):1824–1835.Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23–34.He Z, Wang J, Zhu C, Xu J, Chen P, Jiang X, et al. Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis. Cancer Lett 2022;548:215751. doi: 10.1016/j.canlet.2022.215751.Li W, Wu Z, Meng W, Zhang C, Cheng M, Chen Y, et al. Blockade of IL-6 inhibits tumor immune evasion and improves anti-PD-1 immunotherapy. Cytokine. 2022;158:155976. doi: 10.1016/j.cyto.2022.155976.Ethics ApprovalThis study was approved by the Ethics Committee of National Cancer Institute—IRCCS—Fondazione ‘‘G. Pascale’’, Naples, Italy, protocol number 32/22 oss. All patients provided their written informed consent to participate in this study.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 42 Table 1
BackgroundCutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer in white-skinned populations. Advanced or metastatic disease is rare, less than 5% of patients (pts), but when ...it occurs, is difficult to treat and often has a poor prognosis. Immune checkpoint blockade with cemiplimab, a PD-1 inhibitor, has been approved for advanced/metastatic CSCC1 were is getting excellent results.2 However, unlike what is already standard pratice for melanoma skin cancer,3 4 we do not know yet which is the optimal treatment duration. The aim of this study is to evaluate the minimum treatment period with cemiplimab in order to guarantee a durable clinical benefit.MethodsIn this retrospective study was evaluated the duration standard treatment with cemiplimab 350 mg every 3 weeks (Q3W) in 95 pts with CSCC, on which 22 were discontinued not by clinical decision (figure 1). Demographic and clinical data were tabulated using descriptive statistics. PFS was calculated as the time from randomization until objective tumor progression or death, whichever occurs first; OS was calculated from randomization until death by any cause.ResultsOverall, 95 pts were enrolled. Demographic and clinical characteristics are reported in table 1. The median age was 75 years (range, 32–96 years), and 68 (72%) pts were males. Cemiplimab was administered as first-line therapy in 45 (47%) pts and as second-line in 50 (53%) subjects; The most frequent comorbidities were blood hypertension (51%) and angina/coronary artery disease (23%). At the first follow-up visit, 10 (11%) pts achieved CR, 25 (26%) PR, 35 (37%) reached SD, and 25 (35%) were in progression. Twenty-two stopped cemiplimab treatment due to comorbidity (n=7), toxicity (n=3), no compliant (n=9) and complete response (n=3). No significant difference was observed in this cohort compared to general population (figure 2) in terms of OS (p=0.47; HR 0.80 (95% CI 0.42 to 1.48)) and PFS (p=0.29; HR 0.72 (95% CI 0.39 to 0.32). In the swimmer plot cartoon (figure 3), we observed 10 death events in pts treated for less than a year (n=12), only 1 death in pts treated at least 1 year (n=10) and 0 death in pts treated at least 2 years (n=5) (figure 4).ConclusionsFrom a patients, healthcare, and economic perspective, shorter treatment duration is preferred, and overtreatment should be prevented. In these preliminary result we showed that at least one year of treatment with cemiplimab appears to be a valid option. Further investigations are needed to get additional information.ReferencesGoodman DT. Cemiplimab and Cutaneous Squamous Cell Carcinoma: From Bench to Bedside. JPRAS Open. 2022 Jun 23;33:155−160. doi: 10.1016/j.jpra.2022.06.003.Baggi A, Quaglino P, Rubatto M, Depenni R, Guida M, et al. Real world data of cemiplimab in locally advanced and metastatic cutaneous squamous cell carcinoma. Eur J Cancer. 2021 Nov;157:250−258. doi: 10.1016/j.ejca.2021.08.018.Mulder EEAP, de Joode K, Litière S, Ten Tije AJ, Suijkerbuijk KPM, et al. Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial. BMC Cancer. 2021 Mar 25;21(1):323. doi: 10.1186/s12885-021-08018-w.Coen O, Corrie P, Marshall H, Plummer R, Ottensmeier C,et al. The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma. BMC Cancer. 2021 Jul 1;21(1):761. doi: 10.1186/s12885-021-08509-w.Ethics ApprovalThis study was approved by the Ethics Committee of National Cancer Institute—IRCCS—Fondazione ‘‘G. Pascale’’, Naples, Italy, protocol number 32/22 oss. All patients provided their written informed consent to participate in this study.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journalAbstract 579 Figure 1Abstract 579 Figure 2Abstract 579 Figure 3Abstract 579 Figure 4Abstract 579 Table 1
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.
Treatment duration with checkpoint inhibitors must be optimized to prevent unjustified toxicity, but evidence for the management of cutaneous squamous cell carcinoma is lacking. A retrospective study ...was performed to evaluate the survival of patients with cutaneous squamous cell carcinoma (CSCC) who discontinued cemiplimab due to different causes and without progression. Among 95 patients with CSCC who received cemiplimab, 22 (23%) patients discontinued immunotherapy due to causes other than progression, such as comorbidities, toxicity, complete response or lack of compliance (group that discontinued before censoring DBC), then 73 patients had standard treatment scheduled (STS). The overall survival was 25.2 months (95% CI: 8.9–29.4) in STS group and 28.3 months (95% CI: 12.7–28.3) in the DBC group; deaths for all causes were 11/22 (50%) in the DBC group and 34/73 (46.6%) in the STS group (
p
= 0.32). 10/22 (45.4%) subjects died due to CSCC in the DBC after discontinuation and 34/73 (46.6%) in the STS group, and the difference between groups was not significant (
p
= 0.230). Duration of treatment was significantly lower in subjects with stable disease versus those with complete or partial response (16.9, 30.6 and 34.9 months, respectively;
p
= 0.004). Among the 22 STS patients, 12 received cemiplimab for less than 12 months (10 83% died) and 10 for at least 12 months (1 10% died). Our observation, finding no outcome difference between DBC and STS groups, suggests that ICI treatment after one year might expose patients to further treatment related events without efficacy advantages.
Graphical abstract
