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.
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.
Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches ...are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.
Immunotherapy denotes an exemplar change in an oncological setting. Despite the effective application of these treatments across a broad range of tumors, only a minority of patients have beneficial ...effects. The efficacy of immunotherapy is affected by several factors, including human immunity, which is strongly correlated to genetic features, such as intra-tumor heterogeneity. Classic imaging assessment, based on computed tomography (CT) or magnetic resonance imaging (MRI), which is useful for conventional treatments, has a limited role in immunotherapy. The reason is due to different patterns of response and/or progression during this kind of treatment which differs from those seen during other treatments, such as the possibility to assess the wide spectrum of immunotherapy-correlated toxic effects (ir-AEs) as soon as possible. In addition, considering the unusual response patterns, the limits of conventional response criteria and the necessity of using related immune-response criteria are clear. Radiomics analysis is a recent field of great interest in a radiological setting and recently it has grown the idea that we could identify patients who will be fit for this treatment or who will develop ir-AEs.
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
BackgroundNivolumab is an anti-PD-1 antibody approved for treating metastatic melanoma (MM), for which still limited evidence is available on the correlation between drug exposure and patient ...outcomes.MethodsIn this observational retrospective study, we assessed whether nivolumab concentration is associated with treatment response in 88 patients with MM and if the patient’s genetic profile plays a role in this association.ResultsWe observed a statistically significant correlation between nivolumab serum concentration and clinical outcomes, measured as overall and progression-free survival. Moreover, patients who achieved a clinical or partial response tended to have higher levels of nivolumab than those who reached stable disease or had disease progression. However, the difference was not statistically significant. In particular, patients who reached a clinical response had a significantly higher concentration of nivolumab and presented a distinct genetic signature, with more marked activation of ICOS and other genes involved in effector T-cells mediated proinflammatory pathways.ConclusionsIn conclusion, these preliminary results show that in patients with MM, nivolumab concentration correlates with clinical outcomes and is associated with an increased expression of ICOS and other genes involved in the activation of T effectors cells.
The median overall survival (OS) and local control (LC) of patients with melanoma brain metastases (MBMs) are poor even with immune checkpoint inhibitors and/or radiotherapy (RT). The aims of the ...study were to evaluate the association and timing of stereotactic radiotherapy (SRT)/radiosurgery (SRS) performed with the CyberKnife
System and ipilimumab (IPI). A total of 63 MBMs patients were analyzed: 53 received RT+IPI and 10 RT alone. Therefore, the patients were divided into four groups: RT PRE-PI (>4 weeks before IPI) (18), RT CONC-IPI (4 weeks before/between first and last cycle/within 3 months of last cycle of IPI) (20), RT POST-IPI (>3 months after IPI) (15), and NO-IPI (10). A total of 127 lesions were treated: 75 with SRS (one fraction) and 24 with SRT (three to five fractions). The median follow-up was 10.6 months. The median OS was 10.6 months for all patients, 10.7 months for RT+IPI, and 3.3 months for NO-IPI (
= 0.96). One-year LC was 50% for all patients, 56% for RT+IPI, and 18% for NO-IPI (
= 0.08). The 1-year intracranial control was 45% for all patients, 44% for RT+IPI, and 51% for NO-IPI (
= 0.73). IPI with SRS/SRT in MBMs treatment could improve LC. However, the impact and timing of the two modalities on patients' outcomes are still unclear.
BackgroundAdjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) significantly improved relapse-free survival (RFS).1 In the phase 3 keynote-054 trial showed that ...pembrolizumab (anti-PD1) administration in adjuvant setting provided a longer RFS (59,8%) than the placebo group (41,4%) at a 3.5-year median follow-up.2 Moreover, 4 years RFS results from the phase 3 checkmate 238 trial, showed a superior efficacy of nivolumab versus ipilimumab in patients with resected AJCC-7 stage III or IV melanoma. RFS rate was of 58% in the nivolumab arm and 45% in the ipilimumab arm.3 Although treatment with ICIs has improved the RFS of melanoma patients in adjuvant setting, there is still a large proportion of patients who do not respond to the treatment and then relapse. The aim of this study was to investigate the molecular mechanisms underlying resistance to anti-PD1 treatment in the adjuvant setting.MethodsFrom December 2018 to July 2020, n. 121 melanoma patients in stage III or IV NED were treated with anti-PD1s as adjuvant (minimum follow up of 12 months, range 12–30 months). These patients received nivolumab (n=95) or pembrolizumab (n=26). Distant and local metastases was observed in 33 (27%) and 7 (6%) patients, respectively (patients baseline characteristics are listed in table1). Gene expression profiles, using NanoString IO 360 panel, were performed from peripheral blood mononuclear cell (PBMCs), collected retrospectively, from n.73 patients (of which n.26 had relapse). All patients have appropriately signed informed consent. Statistical analysis was performed via Bonferroni correction, P< 0.05 was considered statistically significant for median stratification.ResultsAt a minimum follow-up of 12 months, the 12-month rate of Relapse-free survival was 72%, confirming the data reported by checkmate 238 trial. In the transcriptomic analysis we observed that in patients with local-regional metastases there was a higher expression of ITGA2 (p<0.05), a gene that promotes malignant tumor aggression by up-regulating PD-L1 expression through STAT3 pathway and the downregulation of DUSP1 (p<0.05) that is linked in promotion of angiogenesis, invasion and metastasis. Moreover, in male group we found a higher expression of HLA-DQB1 and HLA-DQA1 which belonged to HLA class II beta chains.Abstract 308 Table 1ConclusionsIn this preliminary report we found that RFS 1-yr rate is similar to checkmate 238 study, and that patients with local metastasis have a higher expression of genes related to promote PDL1 levels. Further investigations are needed to get additional information.AcknowledgementsThe study was supported by the Institutional Project ”Ricerca Corrente” of Istituto Nazionale Tumori IRCCS Fondazione ”G. Pascale” of Napoli, Italy.ReferencesWeber J, Mandala M, Del Vecchio M, et al, CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017 November 9;377(19):1824–1835.Eggermont AMM, Blank CU, Mandalà M, et al. EORTC melanoma group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2021 May;22(5):643–654.Ascierto PA, Del Vecchio M, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2020 November;21(11):1465–1477.Ethics ApprovalThe study was approved by internal ethics board of the Istituto Nazionale Tumori IRCCS Fondazione ”G. Pascale” of Napoli Italy, approval number of registry 33/17 OSS.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.
BackgroundThe availability of immune checkpoint inhibitors (ICI) has radically changed the prognosis of patients (pts) with metastatic melanoma. More recently, PD-1 inhibitors have also become the ...standard of care as adjuvant therapy in high-risk and resected melanoma.1–7 However, 65–80% of patients treated with ICI experience immune-related adverse events (irAEs)8 causing morbidity and a potential decrease in clinical benefit. Currently, there are no biomarkers that can predict which patients are at risk of developing irAEs. Aim of this study is to recognize patients who will develop toxicity to anti-PD1 treatment.MethodsGene profiling analysis was performed using NanoString IO360 panel from basal PBMCs of patients treated with anti-PD1 in both setting (adjuvant and first line therapy). Patient’s characteristics are reported in (table 1). To identify the best genes signature the Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) was applied. Differences in characteristics of patients with and without toxicity were tested by t-test or Wilcoxon test (according to their distribution) and Pearson chi-squared test for continuous and categorical variables, respectively. ROC curves were used to determine the best cut off which defines the border line between absence and presence of toxicity (table 2).ResultsAmong 161 pts included, 75 received anti-PD1 as adjuvant therapy (AT) and 86 as first line therapy (FLT). Arthralgia and fever were observed in the 27% and 14% of total population (12% and 9% respectively in AT; 15% and 4% respectively in FLT). A specific gene signature for predicting the onset of arthralgia has been identified and characterized by the most representative genes such as: ZEB2, TNFS13, RPTOR, NFKBIE, GNLY, CCNB1. In particular, we observed that genes involved in the mTORC/NF-κB pathway correlate with arthralgia. Differently, the gene signature for predicting the onset of fever is mainly characterized by humoral immunity genes such as: HLA-F, CD8B, CD45RA, CD27. In both cases, the increase of signature value is associated with a greater probability of toxicity onset.ConclusionsIn this retrospective study, we found a gene signature model able to predict the onset of toxicities (arthralgia and fever) related to anti-PD1 treatment. Further investigations are needed to get additional information.ReferencesCarlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet. 2021;398(10304):1002–14. https://doi.org/10.1016/S0140–6736(21)01206-X.Jiang YZ, Liu YR, Xu XE, Jin X, Hu X, Yu KD, Shao ZM. Transcriptome analysis of triple-negative breast cancer reveals an integrated mRNA-lncRNA signature with predictive and prognostic value. Cancer Res. 2016;76(8):2105–14. https://doi.org/10.1158/0008–5472.CAN-15–3284.Gandhi S, Pandey MR, Attwood K, Ji W, Witkiewicz AK, Knudsen ES, Allen C, Tario JD, Wallace PK, Cedeno CD, Levis M, Stack S, Funchain P, Drabick JJ, Bucsek MJ, Puzanov I, 2021John SP, Sun J, Carlson RJ, Cao B, Bradfield CJ, Song J, Smelkinson M, Fraser IDC. IFIT1 exerts opposing regulatory effects on the inflammatory and interferon gene programs in LPS-activated human macrophages. Cell Rep. 2018;25(1):95–106.e6. https://doi.org/10.1016/j.celrep.2018.09.002.Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(13):1270–1. https://doi.org/10.1056/NEJMc1509660.Li JW, Zhou J, Shi ZT, Li N, Zhou SC, Chang C. Sonographic features of triple-negative breast carcinomas are correlated with mRNA-lncRNA signatures and risk of tumor recurrence. Front Oncol. 2021;10: 587422. https://doi.org/10.3389/fonc.2020.587422.Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000 Prime Rep. 2014;6:13. https://doi.org/10.12703/P6–13.Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015 Sep 4;13:211. doi: 10.1186/s12916–015-0455–8.Ethics ApprovalThis study was approved by the Ethics Committee of Istituto Nazionale Tumori - IRCCS - Fondazione ‘G. Pascale’, Naples, Italy, protocol number 33/17 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 1247 Table 1Abstract 1247 Table 2
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