Checkpoint Inhibitors In Melanoma Research Articles

Tumor fitness, immune exhaustion and clinical outcomes: impact of immune checkpoint inhibitors

Recently proposed tumor fitness measures, based on profiling neoepitopes for reactive viral epitope similarity, have been proposed to predict response to immune checkpoint inhibitors in melanoma and small-cell lung cancer. Here we applied these checkpoint based fitness measures to the matched checkpoint treatment naive Cancer Genome Atlas (TCGA) samples where cytolytic activity (CYT) imparts a known survival benefit. We observed no significant survival predictive power beyond that of overall patient tumor mutation burden, and furthermore, found no association between checkpoint based fitness and tumor T-cell infiltration, cytolytic activity, and abundance (tumor infiltrating lymphocyte, TIL, burden). In addition, we investigated the key assumption of viral epitope similarity driving immune response in the hepatitis B virally infected liver cancer TCGA cohort, and uncovered suggestive evidence that tumor neoepitopes actually dominate viral epitopes in putative immunogenicity and plausibly drive immune response and recruitment.

Immune checkpoint inhibitors in melanoma in the metastatic, neoadjuvant, and adjuvant setting.

Immune checkpoint inhibitors (ICI) are now standards of care in metastatic melanoma. We highlight here the dramatic improvement that these drugs brought in the history of melanoma care. The monoclonal antibody directed against cytotoxic T-lymphocyte-associated protein 4, ipilimumab, was approved in 2011. Antiprogramed death cell protein 1 antibodies, nivolumab and pembrolizumab, were developed afterward and approved in 2014, demonstrating an improved efficacy/safety ratio as compared with ipilimumab. The association of ipilimumab and nivolumab now appears as the most efficient immunotherapy but the toxicity of this regimen is a limitation. These drugs have also been evaluated in the adjuvant setting for patients with stage III or IV resected melanoma where they have shown a significant benefit in terms of relapse-free survival. ICI-based immunotherapy radically modified melanoma management and now appear as the most efficient treatment for patients with metastatic melanoma with characterized by long-lasting cancer remissions, and a distinct spectrum of immune-related adverse events. Their efficacy is now also established in the adjuvant setting and they are now actively evaluated as neoadjuvant treatment with promising early results.Intensive translational work is ongoing to identify predictive biomarkers of efficacy and toxicity to improve ICI benefit/risk ratio.

Current Treatment for Cervical Cancer: An Update.

Cervical cancer is the leading gynecologic health problem which is considered as the 4th most widespread tumour in women. The prevalence of this fatal ailment is emerging gradually across the globe as about 18.1 million new cancer cases have been reported in 2018. The predominance of cervical cancer has been significantly found in low and middle-income countries as cervical cancer ranks fourth for both incidence and mortality, conversely, there are no effective screening systems available. This mortal state is certainly influenced by exposure of human papillomavirus, dysregulation of caspase enzyme, elevated expression of Inhibitor Apoptotic Protein (IAP), overexpression of Vascular Endothelial Growth Factors (VEGF), active/passive smoking, and dysfunction of the immune system. Generally, the clinical trial on pipeline drugs leads to the development of some promising new therapies that are more effective than standard approaches and often unavailable outside of the clinical setting. Indeed, several biological interventions that can modulate the pathological cascade of cervical cancer are still under investigation. Thus, there is a need to further summarise the promising therapies for cervical cancer as we have accomplished in HER2-positive breast cancer by targeting HER2 therapies and immune checkpoint inhibitors in melanoma. The present report revealed the pharmacokinetic/ pharmacodynamics aspects of various pipeline drugs that are promising for the treatment of cervical cancer. Moreover, the study revealed the possible mechanism, adverse drug reaction, combined therapy and pleiotropic action of these under investigational drugs, which can further improve the therapeutic efficacy and restrict the imaginable harmful effects.

Prognosis of patients developing immune-related adverse events with immune checkpoint inhibitors in melanoma influenced by the ability to resume therapy.

61 Background: Immune checkpoint inhibitors (ICPis) have improved survival in melanoma patients, however their use is associated with 5-60% patients experiencing severe immune related adverse events (irAEs). Severe irAEs may affect survival benefit imparted by ICPis. Objective: We aimed to analyze disease outcomes with resumption of immunotherapy as compared to non-resumption of immunotherapy in patients with severe irAEs (Grade 3/4 in CTCAE v5.0). Methods: Patients with melanoma being treated with ICPis who developed severe irAEs were discussed in an institutional irAE tumor board (TB). We analyzed all patients discussed in TB from September 2017 to September 2019 for cancer outcome of withholding versus resuming immunotherapy in the face of severe irAEs. Results: Out of 26 total patients with melanoma discussed in TB, 23 had severe irAE. Colitis was the most common irAE 9/23 (39.1%) followed by 2/23 (8.7%) of pneumonitis and hepatitis each. ICPi was resumed in 8 patients (resume group) (median age 53, range 42-67) and withheld in 15 patients (non-resume group) (median age 57, range 42-91). In the resume group all 8 patients (100%) are alive, of which 2/8 (25%) had disease progression (median follow up 106.5wk, range 35wk-131wk); whereas, in the non-resume group 9/15 (60%) progressed, of which 6/15 (40%) died (median follow up 91wk, range 3wk-197wk). Conclusions: Our data suggest that the ability to resume ICPi after an episode of severe irAE is associated with better prognosis in terms of disease progression and survival. Immunotherapy being the mainstay of the management in metastatic melanoma, inability to resume therapy is associated with worse prognosis. Timely management of irAEs should be prioritized in order to resume treatment.

TMIC-62. FYN, AN EFFECTOR OF ONCOGENIC RECEPTOR TYROSINE KINASES SIGNALING IN GLIOBLASTOMA, INHIBITS ANTI-GLIOMA IMMUNE RESPONSES: IMPLICATIONS FOR IMMUNOTHERAPY

Abstract There is currently much excitement for the use of immunotherapies in cancer. In spite of positive results using checkpoint inhibitors in melanoma and CAR T cells in leukemias, these strategies have not yet achieved robust clinical responses in human gliomas. A powerful inhibitory microenvironment is thought to be the culprit. Mechanisms that determine the inhibitory microenvironment remain poorly understood. Herein we demonstrate that FYN, a downstream target of receptor tyrosine kinases signaling, inhibits the anti-glioma immune response. We utilized genetically engineered mouse models (GEMM) of glioma based on the Sleeping Beauty Transposon method. We examined the activities of FYN in NP (N-ras + shp53), NPA (NP + shATRX), and NPD (NP + PDGF overexpression) tumors. We also generated FYN knockdown glioma stem cells in vitro to induce gliomas in immune-competent and immune-deficient mice of varying genetic backgrounds (NSG, CD8-/-). Flow cytometry was used to characterize immune cells within the glioma microenvironment. Our results show that FYN knockdown in NP, NPA, or NPD GEMM of glioma reduced tumor progression and increased survival by 25–77%. GSEA analysis of differential expressed genes of WT vs. FYN knockdown gliomas revealed enrichments of gene ontologies related to immune functions. In NSG and CD8-/- immune-deficient mice, FYN knockdown failed to inhibits tumor growth and increase animal survival. These results suggest that FYN enhances tumor progression through changes in anti-glioma immune activation. Examination of tumor immune infiltrates by flow cytometry indicate a 50–70% reduction in powerful immune inhibitory myeloid derived cells (MDSCs) with no changes in the total level of CD8+ and CD4+ cells. Our results show for the first time that FYN reduces anti-glioma immune responses, likely through a reduction in inhibitory MDSCs. The specific inhibition of FYN exclusively within glioma cells, could improve the efficacy of anti-glioma immunotherapies.

Biomarkers Predictive of Survival and Response to Immune Checkpoint Inhibitors in Melanoma.

Immunotherapy has revolutionized the treatment of melanoma. Targeting of the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 has led to improved survival in a subset of patients. Unfortunately, the use of immune checkpoint inhibitors is associated with significant side effects and many patients do not respond to treatment. Thus, there is an urgent need both for prognostic biomarkers to estimate risk and for predictive biomarkers to determine which patients are likely to respond to therapy. In this review, prognostic and predictive biomarkers that are an active area of research are outlined. Of note, certain transcriptomic signatures are already used in the clinic, albeit not routinely, to prognosticate patients. In the predictive setting, programmed cell death protein ligand 1 expression has been shown to correlate with benefit but is not precise enough to be used as an exclusionary biomarker. Future investigation will need to focus on biomarkers that are easily reproducible, cost effective, and accurate. The use of readily available clinical material, such as serum or hematoxylin and eosin-stained images, may offer one such path forward.

Immune Checkpoint Inhibitors in Melanoma: A Review of Pharmacokinetics and Exposure–Response Relationships

Immune checkpoint inhibitors are a new class of monoclonal antibodies that amplify T-cell-mediated immune responses against cancer cells. The introduction of these new drugs, first anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and then anti-programmed death-1 (anti-PD1), was a major improvement in the treatment of advanced or metastatic melanoma, a highly immunogenic tumour. The development strategy for immune checkpoint immunotherapies differed from that traditionally used for cytotoxic therapies in oncology. The choices of doses at which to conduct clinical trials, and subsequently the choice of doses at which to use these new therapies, were not based on the identification of a maximum tolerated dose from dose-escalation studies; thus, pharmacokinetic and pharmacokinetic-pharmacodynamic modelling was essential. The studies conducted have shown that the pharmacokinetics of ipilimumab were linear and not time-dependent. In addition, there was a correlation between the trough concentrations of ipilimumab and its therapeutic efficacy. On the contrary, the anti-PD1 immunotherapies nivolumab and pembrolizumab had time-dependent pharmacokinetics. Their therapeutic efficacy was not related to their trough concentration, but there was a correlation between the clearance of anti-PD1 and the survival of melanoma patients. This review highlights the complexity of interpreting the exposure-response relationships of these agents. Further studies are needed to assess the value of therapeutic drug monitoring of immune checkpoint inhibitors in the treatment of melanoma.

Abstract PD3-10: Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial

Abstract Background: In the CCTG (Canadian Clinical Trials Group) MA.31 randomized phase 3 trial, the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2-positive metastatic breast cancer (MBC). We previously reported the prognostic utility of pretreatment serum PD-L1 in the trastuzumab arm of MA.31 (ASCO 2018, #1031), and here we evaluate serum PD-L1 in the lapatinib arm, and in the whole trial. Higher serum PD-L1 has been reported to be associated with reduced response to treatment with the immune checkpoint inhibitors in melanoma and lung cancer. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positivepatients; 186 in the trastuzumab arm, and 202 in the lapatinib armhad pretreatment serum available. TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1. Step-wise forward Cox multivariate analysis was used for PFS and OS, and testing for treatment-biomarker interaction was based on the local partial-likelihood method (Liu Y, Jiang W, and Chen BE, Statistics in Medicine 34, 3516-3530, 2015). Results: In the total study population, pretreatment serum PD-L1 concentration had a median of 86.2 pg/ml, and 25% and 75% interquartiles of 64.1 and 134.3 pg/ml, respectively. In univariate analysis in the whole trial, and within both treatment arms, serum PD-L1 was not a significant biomarker for PFS. For OS, higher serum PD-L1 (as a continuous variable) was significant for shorter OS within the trastuzumab arm (HR=3.84, p=0.04), but was not associated with OS in the lapatinib arm (p=0.37). In the whole trial, in multivariate analysis for OS [15 covariates included: age, race, ECOG status, anthracyclines, other chemo, endocrine, radio, other prior adjuvant therapy, disease status, ER status, PR status, Ki67 (log transformed), CK5, EGFR, treatment arm, and serum PD-L1 (with median cut point)], serum PD-L1 remained a significant independent covariate (HR= 2.27, p= 0.001 (Table).There was significant interaction between treatment arm and continuous serum PD-L1 (Bootstrap method, p=0.0025); above 214.2 pg/ml serum PD-L1 (89% percentile), higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Conclusions: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in the advanced breast cancer setting is warranted to identify HER2-positive MBC patients who may benefit from novel immune-targeted therapies in addition to trastuzumab. Multivariate Analysis (whole trial): Significant Independent CovariatesCovariateP-ValueHRLower 95% CIHigher 95% CISerum PD-L1 (pretreatment) (>median vs <median)0.0012.271.403.68EGFR Status (continuous IHC score)0.0031.0121.0041.019Other Chemotherapy (yes vs no)0.0081.911.193.07Treatment Arm (trastuzumab vs. lapatinib)0.0100.530.330.86ECOG Performance Status (0 vs 1 or 2)0.0250.590.370.94Ki67 (log)0.0461.451.0062.081 Citation Format: Moku PR, Shepherd LE, Ali SM, Leitzel K, Parulekar WE, Zhu L, Virk S, Nomikos D, Aparicio S, Gelmon KA, Drabick JJ, Cream L, Halstead SE, Umstead T, Mckeone D, Maddukuri A, Polimera HV, Ali A, Poulose J, Pancholy N, Spiegel H, Nagabhairu V, Chen BE, Lipton A. Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-10.

Abstract IA20: Targeting the immune microenvironment in breast cancer

Abstract Immunotherapy has revolutionized cancer treatment, but the benefits are not ubiquitous or absolute. In breast cancer, higher levels of lymphocytic infiltrate confer significant prognostic advantage, predict response to chemotherapy in early stage disease and are associated with benefit from PD-1 inhibition. To enhance the modest benefits of immunotherapy seen in breast cancer thus far, it is expected that a greater understanding of the immune subpopulations in the tumor microenvironment will be necessary, emphasizing that the quality and quantity of tumor infiltrating lymphocytes are important. We have profiled the T cell infiltrate in primary and metastatic breast cancers, using flow cytometry, single cell mRNASeq, multiplex immunohistochemistry and bulk RNASeq on flow sorted CD8 populations. In this work, we found that CD8 T cells display tissue resident specialization. In particular, we confirmed the presence of a CD8 T cell population with tissue resident memory features. This population was notable for high expression of T cell checkpoint receptors and cytotoxic markers, active proliferation, and a distinct T cell receptor repertoire in contrast to CD8 effector memory T cells. A gene signature derived from this population was found to be prognostic in early stage breast cancer and associated with benefit from PD-1 checkpoint inhibition in melanoma. We find that single cell profiling in human samples is a powerful technique which unveils tissue resident aspects of the anti-cancer immune response. This approach may lead to better immunotherapy biomarkers and optimization of immunotherapeutic strategies. Citation Format: Sherene Loi, Peter Savas. Targeting the immune microenvironment in breast cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA20.

The mechanisms of acute interstitial nephritis in the era of immune checkpoint inhibitors in melanoma.

Treatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of patients with a number of types of cancer, but the frequent development of immune-related adverse effects (irAEs) can worsen the outcome. The most common irAEs involve the gastrointestinal, cutaneous, and endocrine systems, but nephrotoxicity, resulting from damage to the tubule-interstitial compartment, may occur in some patients. The early phases of acute interstitial nephritis (AIN) are characterized by systemic symptoms that indicate a poor clinical state as well as a mild deterioration of renal function. Tubular injury is due to a direct effect mediated by cytotoxic CD8+ T cells, which sustain the local production of pro-inflammatory cytokines that progressively impair renal function. The treatment of AIN is mainly based on high-dose steroids, which in most instances leads to the recovery of renal function. However, the premature discontinuation of ICI therapy may prevent the impact of treatment on the clinical progression of the malignancy. Adequately addressing irAEs requires a standardized therapy that is based on the results of large clinical trials.

Resistance mechanisms in melanoma to immuneoncologic therapy with checkpoint inhibitors.

Checkpoint inhibitors act by blocking physiologic mechanisms coopted by tumor cells to evade immune surveillance, restoring the immune system’s ability to identify and kill malignant cells. These therapies have dramatically improved outcomes in multiple tumor types with durable responses in many patients, leading to FDA approval first in advanced melanoma, then in many other malignancies. However, as experience with checkpoint inhibitors has grown, populations of patients who are primary nonresponders or develop secondary resistance have been the majority of cases, even in melanoma. Mechanisms of resistance include those inherent to the tumor microenvironment, the tumor cells themselves, and the function of the patient’s native immune cells. This review will discuss resistance to checkpoint inhibitors in melanoma as well as possible methods to restore sensitivity.

Immune Checkpoint Inhibitors in Melanoma: Review and Update

The overall increasing incidence of melanoma will very probably be the trend over the next two decades. This data stresses the need for new therapeutic resources, other than classic chemotherapy. Nevertheless, the treatment of advanced melanoma has been changed in the last decade due to novel therapeutic strategies, including immunotherapy with immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Inhibition of these targets enhances immune host response against cancer and results in durable objective responses, establishing immunotherapy as standard treatment for BRAF wild-type melanoma patients in advanced stages (III – unresectable and IV – metastases at distant sites). Anti-CTLA-4, ipilimumab, was the first–in-class immune checkpoint inhibitor to show improvement in overall survival in advanced melanoma. Latter, anti-PD-1 agents, nivolumab and pembrolizumab, have improved tumour response and tolerability in comparison with ipilimumab. Differences in outcome are expected considering the distinct target of checkpoint inhibition pathways. In this setting, it is of utmost importance the assessment of efficacy by combined therapy and the identification of biomarkers capable of predicting response to anti-CTLA-4 and anti-PD-1. After a previous review on cancer biology and mechanisms of action of immune checkpoint inhibitors we will focus on the main data on the immune checkpoint inhibitors for melanoma currently available in daily practice.

Circulating T Cell Subpopulations Correlate With Immune Responses at the Tumor Site and Clinical Response to PD1 Inhibition in Non-Small Cell Lung Cancer.

Agents targeting the PD1–PDL1 axis have transformed cancer therapy. Factors that influence clinical response to PD1–PDL1 inhibitors include tumor mutational burden, immune infiltration of the tumor, and local PDL1 expression. To identify peripheral correlates of the anti-tumor immune response in the absence of checkpoint blockade, we performed a retrospective study of circulating T cell subpopulations and matched tumor gene expression in melanoma and non-small cell lung cancer (NSCLC) patients. Notably, both melanoma and NSCLC patients whose tumors exhibited increased inflammatory gene transcripts presented high CD4+ and CD8+ central memory T cell (CM) to effector T cell (Eff) ratios in blood. Consequently, we evaluated CM/Eff T cell ratios in a second cohort of NSCLC. The data showed that high CM/Eff T cell ratios correlated with increased tumor PDL1 expression. Furthermore, of the 22 patients within this NSCLC cohort who received nivolumab, those with high CM/Eff T cell ratios, had longer progression-free survival (PFS) (median survival: 91 vs. 215 days). These findings show that by providing a window into the state of the immune system, peripheral T cell subpopulations inform about the state of the anti-tumor immune response and identify potential blood biomarkers of clinical response to checkpoint inhibitors in melanoma and NSCLC.

Biomarkers for Immune Checkpoint Inhibitors in Melanoma.

Immune checkpoint inhibitors have now become a standard therapy for malignant melanoma. However, as immunotherapies are effective in only a limited number of patients, biomarker development remains one of the most important clinical challenges. Biomarkers predicting clinical benefit facilitate appropriate selection of individualized treatments for patients and maximize clinical benefits. Many biomarkers derived from tumors and peripheral blood components have recently been reported, mainly in retrospective settings. This review summarizes the recent findings of biomarker studies for predicting the clinical benefits of immunotherapies in melanoma patients. Taking into account the complex interactions between the immune system and various cancers, it would be difficult for only one biomarker to predict clinical benefits in all patients. Many efforts to discover candidate biomarkers are currently ongoing. In the future, verification, by means of a prospective study, may allow some of these candidates to be combined into a scoring system based on bioinformatics technology.

Abstract 558: Prognostic gene signature use in checkpoint inhibitor monotherapy for melanoma

Abstract Introduction: The successful deployment of checkpoint inhibitors in cancer immunotherapy relies on the responsiveness of an individual's immune system for relief of that particular blockade in the cancer immunity cycle. As most patients fail to respond to immunotherapy, there is a need for biomarkers that can predict clinical benefit of the therapeutic by identifying the patient population most likely to respond. Gene expression signatures characterizing basal immune state within tumor have shown utility in retrospective analysis of clinical trials. This study utilizes tumor and PBMCs from patients with metastatic melanoma receiving either anti-CTLA-4 or anti-PD-1/PD-L1 to characterize local and peripheral patterns of gene expression associated with clinical benefit of therapy. The goal of this study is to evaluate existing gene signatures and develop novel signatures that predict response to checkpoint inhibitors in melanoma. Methods: Pretreatment biopsies from metastatic lesions of melanoma stage IV patients treated with ipilimumab (anti-CTLA4) or pembrolizumab (anti-PD-L1) were retrieved from the Department of Pathology archives. Cohorts were assembled of 30 patients receiving each drug, equally stratified between responders and nonresponders. RNA expression in tumor biopsies will be profiled with a pilot version of the NanoString® IO360 gene expression panel. In parallel, pre- and post-treatment PBMC from independent cohorts receiving either ipilimumab (anti-CTLA4) or pembrolizumab (anti-PD-1) were collected and profiled with the NanoString PanCancer Immune Panel (gene expression) and Immune Profiling Panel (protein expression). Results: Patterns of gene expression in the tumor biopsies and gene and protein expression in the PBMCs will be assessed for correlation to clinical outcome (PFS, OS, ORR). Specifically, the Tumor Inflammation Signature described by Ayers et al. (1), an investigational 18-gene signature of suppressed adaptive immune response that enriches for clinical response to pembrolizumab, will be assessed in these cohorts. Other patterns of gene and protein expression that correlate with response to immunotherapy or lack thereof will also be evaluated. Conclusion: Correlating patterns of gene expression from tumor with clinical response can lead to the development of biomarkers to better select patients who will respond to immunotherapy. It can also lead to identifying immune evasion. Gene and protein profiling from a readily accessed sample such as PBMC may give insights into early on-treatment signatures of efficacy. Utilization of a clinical grade platform such as the NanoString nCounter® may speed the development of diagnostic assays that can be used to predict and monitor patient response to immunotherapy. Reference: 1. Ayers et al., J Clin Invest 2017;127:2930. Citation Format: Mariaelena Capone, Gabriele Madonna, Paolo Ascierto, Patrick Danaher, SuFey Ong, Sarah Warren, Joseph M. Beechem, Alessandra Cesano. Prognostic gene signature use in checkpoint inhibitor monotherapy for melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 558.

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

BackgroundImmune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.MethodsCutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.ResultsPD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.ConclusionsIn this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

BrUOG 324: Adjuvant nivolumab and low-dose ipilimumab for stage IIC, III, and resected stage IV melanoma: A phase II Brown University Oncology Research Group trial.

TPS202 Background: Adjuvant ipilimumab improves survival in stage III melanoma. Adjuvant nivolumab improves progression-free survival as compared to ipilimumab with reduced toxicity. Checkpoint 067 showed that the combination of ipilimumab and nivolumab is more active in advanced melanoma than either agent alone. The Brown University Oncology Research Group sought to evaluate dual checkpoint inhibition in the adjuvant setting. This may be particularly beneficial to patients with melanoma with low PD-L1 expression. To balance safety and efficacy, the combination of low dose ipilimumab and standard dose nivolumab was investigated. Methods: Patients with stage IIc, III and resected stage IV disease are eligible. No prior treatment for melanoma other than surgery or radiation was allowed. All patients received nivolumab 3mg/kg (maximum 240 mg) every 2 weeks and ipilimumab 1mg/kg every 6 weeks for 6 months. The primary goal is to determine the toxicity of adjuvant ipilimumab and nivolumab in patients with melanoma. Unacceptable toxicity has been defined as the development of grade 4 hematologic toxicity (neutropenia or thrombocytopenia), any transient grade ≥3 or persistent grade 2 treatment-related non-hematologic toxicity that prevents completion of the planned 6 month course of treatment in more than 35% of the enrolled patients; thus, if such events occur in 10 or more patients out of 25 evaluable patients, the study will have exceeded the limit for unacceptable adverse events. Secondary objectives are to determine the recurrence-free and overall survival. Results: Between August 2016 and August 2017, 17 patients have been enrolled, 11 male and 6 female. Median age is 59 (range 25-84). Twelve patients were Stage III disease, 2 patients were stage IIC and 3 were stage IV. Conclusions: BrUOG 324 represents one of the first trials investigating adjuvant dual checkpoint inhibition in melanoma. Preliminary safety and efficacy are being assessed. Acknowledgements: This study was supported in part by the Washington Trust Company and LIFEcycle Clinical trial information: NCT02656.

Immune Checkpoint Inhibitors in Melanoma and HIV Infection.

Introduction:Immunotherapy with immune checkpoint inhibitors increases the overall survival of patients with metastatic melanoma regardless of their oncogene addicted mutations. However, no data is available from clinical trials of effective therapies in subgroups of melanoma patients that carry chronic infective diseases such as HIV. Evidences suggest a key role of the immune checkpoint molecules as a mechanism of immune escape not only from melanoma but also from HIV host immune response.Conclusion:In this article, firstly, we will describe the role of the immune checkpoint molecules in HIV chronic infection. Secondly, we will summarize the most relevant clinical evidences utilizing immune checkpoint inhibitors for the treatment of melanoma patients. Lastly, we will discuss the potential implications as well as the potential applications of immune checkpoint molecule-based immunotherapy in patients with melanoma and HIV infection.

The scope of possible combination therapy with immunotherapy and targeted therapy.

3056 Background: Combination treatment of two recent trends in cancer therapy, namely immunotherapy with checkpoint inhibitors and drugs that target specific gene mutations, could improve cancer survivorship overall. Targeted drugs usually induce rapid tumor death leading to the release of neoantigens, and can affect immune development pathways, which could increase the efficacy of checkpoint inhibitor treatment. Assessment of somatic mutation profiles from large public databases provides an estimate of the prevalence of targetable somatic mutations and the burden of somatic nonsynonymous mutations (NsM), used as a surrogate for overall neoantigen load, which, in turn, correlates with clinical utility of checkpoint inhibitors for melanoma and lung adenocarcinoma. The rational design of these combinations based on somatic genomic profiles offers a prioritization scheme for new clinical trials. Methods: We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents and/or a burden of exome-wide non-synonymous mutations (NsM) that exceeds a recently suggested threshold for response to checkpoint inhibitors. Results: Overall, 8.9% of cases have profiles that could benefit from combination therapy, which corresponds to approximately 11.2% of US annual incident cancer cases; the most commonly targetable mutations were observed in PIK3CA, BRAF, NF1, NRAS, and PTEN genes . Interestingly, cases with mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and/or MET appear to be enriched in those with high burdens of NsM, who have a higher likelihood of responding to immunotherapy. Of the 13,349 cases that could benefit from combination therapy, 50.9% had BRAF, NF1, GNAQ and/or GNA11 mutations which can be targeted by Trametinib ; 26.1% by Taselisib (targets PIK3CA mutations); and 19.8% by Afatinib ( EGFR and ERBB2 mutations). Conclusions: Our results indicate a significant proportion of solid tumor patients are eligible for combination therapy and suggest prioritizing specific cancers for combination trials using target drugs and checkpoint inhibitor therapy.