Clinical Outcomes of Metastatic Melanoma Treated With Checkpoint Inhibitors and Multisite Radiotherapy

138 Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains challenging and lacks a standard of care. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients. In this study, we compared the clinical outcomes of CIT with immunotherapy or chemotherapy alone after PD-1 blockade failure. Methods: We reviewed MM patients seen at Mayo Clinic between Jan, 2012 and Jun, 2018 who failed anti-PD1 therapy and received subsequent CIT, or immune checkpoint inhibitors (ICI) or chemotherapy alone. A total of 60 patients were analyzed, the CIT cohort [n=33 (55%)] treatment consisted of carboplatin/paclitaxel (n=29), nab-paclitaxel (n=2), paclitaxel (n=1), and temozolomide (n=1). In the ICI (n=9) or chemotherapy alone cohort (n=18) [n=27 (45%)], treatment consisted of carboplatin/paclitaxel (n=11), temozolomide (n=4), nab-paclitaxel (n=3), ipilimumab/nivolumab (n=4), pembrolizumab (n=4), or nivolumab (n=1). Results: Patients in the CIT cohort had a median OS of 3.5 years (95% CI: 1.7-NR) compared to 1.8 years (95% CI: 0.9-2) in the ICI or chemotherapy alone cohort, p=0.02. The median EFS following CIT was 7.6 months (95% CI: 6-10) compared to 3.4 months (95% CI: 2.8-4.1) following either ICI or chemotherapy alone, p=0.0005. A trend towards longer median EFS with use of CIT was seen in patients with BRAF wild-type [median 9 months (95% CI: 6-12)] compared to those harboring a BRAF mutation [median 6.5 months (95% CI: 1.8-9.1), p=0.29]. Side effects were similar among both groups. Conclusions: In MM patients who have failed anti-PD-1 therapy, the CIT combination showed favorable clinical outcomes and acceptable safety profile. This regimen should be considered for MM pts in this setting who have limited treatment options. [Table: see text]

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uPAR+ extracellular vesicles: a robust biomarker of resistance to checkpoint inhibitor immunotherapy in metastatic melanoma patients

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002372 ◽

2021 ◽

Vol 9 (5) ◽

pp. e002372

Author(s):

Letizia Porcelli ◽

Michele Guida ◽

Simona De Summa ◽

Roberta Di Fonte ◽

Ivana De Risi ◽

...

Keyword(s):

T Cell ◽

Metastatic Melanoma ◽

Clinical Outcomes ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Extracellular Vesicle ◽

Lower Percentage ◽

Kaplan Meier ◽

Metastatic Sites

BackgroundEmerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes.MethodsBlood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR+ EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed.ResultsResponders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8+ T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR+EV quartiles indicated that higher levels of melanoma-derived uPAR+ EVs were strongly correlated with poorer progression-free survival (p<0.0001) and overall survival (p<0.0001). We also found a statistically significant correlation between lower levels of uPAR+ EVs from both CD8+ T cells and DCs and better survival.ConclusionsOur results indicate that higher levels of tumor-derived, DC-derived and CD8+ T cell-derived uPAR+ EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR+ EVs represent a new potential target for future therapeutic approaches.

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50P Update of systematic reviews and meta-analyses studying the association between antibiotic use and clinical outcomes of cancer patients treated with immune checkpoint inhibitors

Annals of Oncology ◽

10.1016/j.annonc.2020.10.537 ◽

2020 ◽

Vol 31 ◽

pp. S1436

Author(s):

G. Zalcman ◽

A. Crespin ◽

J. Cervesi ◽

C. Le Bescop ◽

R. Buffet ◽

...

Keyword(s):

Cancer Patients ◽

Clinical Outcomes ◽

Systematic Reviews ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Antibiotic Use ◽

Meta Analyses

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231 A novel discovery pipeline identifies melanoma-specific antibodies in patients responding to immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0231 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A249-A249

Author(s):

Daniel Delitto ◽

Evan Lipson ◽

Laura Cappelli ◽

Klaus Busam ◽

Antony Rosen ◽

...

Keyword(s):

Metastatic Melanoma ◽

Treatment Response ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Specific Antibodies ◽

Cancer Testis Antigens ◽

Circulating Antibodies ◽

Cancer Testis

BackgroundTumor-specific antibodies have been reported in patients with cancers responding to immune checkpoint inhibitors (ICI), and there is an increasing appreciation for the potential role of B cells in mediating ICI responses. However, the humoral immune response to melanoma remains incompletely defined. We hypothesized that screening sera for antibodies by immunoprecipitation with lysates of cultured melanoma cells would increase the likelihood of detecting circulating antibodies in melanoma patients receiving ICI, and potentially identify novel antibody targets associated with treatment response and/or immune-related adverse events (IRAEs).MethodsPre-and on/post-treatment sera or plasma from 12 clinically-annotated patients with advanced metastatic melanoma receiving ICI were assayed for tumor-specific antibodies with an established immunoprecipitation platform. 35S-methionine-labeled lysates from cultured 624Mel cells were used for immunoprecipitation. 624Mel expresses several shared non-mutated melanoma antigens (e.g., MAGEA3, tyrosinase, MART-1/Melan-A, gp75, and gp100). Antigen identity was determined using on-bead digests followed by mass spectrometry, and was confirmed by immunoprecipitation with in vitro transcription/translation (IVTT) products.ResultsAntibodies reactive against 624Mel proteins were detected in 4 of 12 (33%) patients (table 1). Mass spectrometric sequencing performed on proteins captured with sera from 3 of 4 patients identified several putative antigens. Immunoprecipitation with IVTT candidate proteins confirmed antibodies against melanoma-associated and cancer testis antigens NY-ESO-1, SSX2 and MAGEA10. Antibodies were observed in 1 of 1 (100%) patient with a complete response, 2 of 4 (50%) with a partial response, 1 of 1 (100%) with stable disease, and 0 of 6 (0%) with progressive disease. Antibody levels varied over the course of therapy, with previously undetectable specificities arising during treatment response in patients #1–3. Patient #1 with a complete tumor regression developed antibodies to SSX2 and MAGEA10 that were absent before treatment. Further, detection of these antibodies coincided with diagnosis of IRAEs (anti-SSX2 with pancreatitis and anti-MAGEA10 with dermatitis). In contrast, patient #3, initially with a partial tumor regression, demonstrated a loss of detectable anti-NY-ESO-1 antibodies upon disease progression, and subsequent metastasectomy demonstrated loss of NY-ESO-1 protein expression in the progressing tumor. Testing sera from all 12 patients with IVTT products for NY-ESO-1, SSX2 and MAGEA10 did not reveal additional humoral responses.Abstract 231 Table 1Antibodies detected in the serum or plasma of patients with metastatic melanoma treated with ICI therapy. Treatment response indicates best overall response according to RECIST v1.1. Post-treatment blood collections were drawn during or after ICI therapy.ConclusionsOur comprehensive screening platform detected circulating antibodies specific to multiple melanoma-associated and cancer testis antigens in patients deriving clinical benefit from ICI. Expanded investigations of the evolution of antibody production over the course of ICI therapy, associated with tumor response to treatment and development of IRAEs, are warranted.AcknowledgementsThis study was supported by the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, and NIH P30-AR070254.Ethics ApprovalThis study was approved by the Johns Hopkins Institutional Review Board, approval #NA_00090257.

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671 Update of a systematic review and meta-analysis studying the association between antibiotic use and clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0671 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A708-A708

Author(s):

Pierre-Alain Bandinelli ◽

Julie Cervesi ◽

Clément Le Bescop ◽

Renaud Buffet ◽

Jean De Gunzburg ◽

...

Keyword(s):

Systematic Review ◽

Clinical Outcomes ◽

Time Window ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Antibiotic Use ◽

Forest Plot ◽

Antibiotic Exposure ◽

Hazard Ratios

BackgroundImmune checkpoint inhibitors (ICIs) have been shown to improve patients‘ clinical outcomes in a variety of cancers, but with variable efficacy. Prior research has also suggested that systemic antibiotic (ABX) exposure may impact the intestinal microbiota and result in suboptimal ICI treatment outcomes. Our team published a systematic review and meta-analysis showing that ABX use could indeed decrease the survival of patients diagnosed with non-small-cell lung cancer (NSCLC) and treated with ICIs.1 The present abstract aims at updating this meta-analysis by incorporating new studies that have been published in the period ranging from September 2019 to August 2020.MethodsMedline (through PubMed), the Cochrane Library and major oncology conferences proceedings were systematically searched to identify studies assessing the impact of ABX use on the clinical outcomes of NSCLC patients treated with ICIs. Studies were found eligible for inclusion when they mentioned a hazard ratio (HR) or Kaplan–Meier curves for overall survival (OS) or progression-free survival (PFS) based on antibiotic exposure. Pooled HRs for OS and PFS and HRs for OS and PFS according to different time windows for ABX exposure were calculated.Results6 eligible new studies were identified between September 2019 and August 2020 while 3 other studies were updated with new information. Altogether, 27 studies reported data for OS (6,436 patients, 826 of whom coming from new studies) and 24 for PFS (3,751 patients, 786 of whom coming from new studies). The pooled HR was 1.75 (95% confidence interval [CI]: 1.38–2.23) for OS and 1.57 (95% CI: 1.28–1.92) for PFS, confirming a significantly reduced survival in patients with NSCLC exposed to ABX. The detailed analysis in subgroups based on the time window of exposure (figure 1, figure 2) suggests that the deleterious effect of ABX is stronger when the exposition happens shortly before and after the initiation of the ICI treatment.Abstract 671 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 671 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureConclusionsThe update of the meta-analysis confirms the previously reported deleterious effect of ABX on ICI treatment outcomes, taking into account the latest publications in the field. The topic deserves further research to uncover if the effect will stand with 1st line use of ICI together with chemotherapies and/or other approved combinations, elucidate the mechanisms at stake and improve care of patients.ReferencesLurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol 2020;15:1147–1159.

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Combining checkpoint inhibitors and BRAF-targeted agents against metastatic melanoma

OncoImmunology ◽

10.4161/onci.24320 ◽

2013 ◽

Vol 2 (5) ◽

pp. e24320 ◽

Cited By ~ 33

Author(s):

Zachary A. Cooper ◽

Dennie T. Frederick ◽

Zain Ahmed ◽

Jennifer A. Wargo

Keyword(s):

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Targeted Agents

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637 Immune-related adverse events (irAEs) may indicate a favorable prognosis in metastatic renal cell carcinoma (mRCC) patients treated with immune checkpoint inhibitors (ICI)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0637 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A672-A673

Author(s):

Dylan Martini ◽

Sean Evans ◽

Subir Goyal ◽

Yuan Liu ◽

T Anders Olsen ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Adverse Events ◽

Clinical Outcomes ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Free Survival ◽

Kaplan Meier ◽

Emory University

BackgroundImmune checkpoint inhibitors (ICI) have become an increasingly utilized treatment in metastatic renal cell carcinoma (mRCC). Although they have a favorable toxicity profile, immune-related adverse events (irAEs) can have a significant impact on patients‘ quality of life. It is not well understood whether irAEs are associated with improved clinical outcomes. We investigated the relationship between irAEs and clinical outcomes in mRCC patients treated with ICI.MethodsWe performed a retrospective study of 200 patients with mRCC who received ICI at Winship Cancer Institute of Emory University from 2015–2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from ICI-initiation to date of death and radiographic or clinical progression, respectively. CB was defined as a best radiographic response of complete response (CR), partial response (PR), or stable disease (SD) for >6 months per response evaluation criteria in solid tumors (RECIST) version 1.1. Toxicity data was collected from clinic notes and laboratory values. The association with OS and PFS was modeled by Cox proportional hazards model. Kaplan-Meier curves were created for survival estimates.ResultsMost patients were males (71%), and 78% had clear-cell RCC (ccRCC). Most patients (58%) received anti-PD-1 monotherapy. The majority were international mRCC database consortium (IMDC) intermediate (57%) or poor-risk (26%). Anti-PD-1 monotherapy was the most common (58%) treatment regimen and most patients received ICI as first (38%) or second-line (42%) treatment. One-third of patients (33%) experienced an irAE, with the most common being endocrine (13%), gastrointestinal (11%), and dermatologic (10%). Patients who experienced irAEs had significantly longer OS (HR: 0.52, 95% CI: 0.32–0.87, p=0.013), higher chance of CB (OR: 2.10, 95% CI: 1.11–4.00, p=0.023) and showed a trend towards longer PFS (HR: 0.71, 95% CI: 0.49–1.02, p=0.065) in MVA (table 1). Patients who had thyroid irAEs had significantly longer OS, PFS, and higher chance of CB in MVA (table 1). The objective response rate was higher for patients who experienced irAEs (34% vs. 18%). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p=0.005) and PFS (7.5 vs 3.6 months, p=0.0028) compared to patients who did not (figure 1).Abstract 637 Table 1MVA* of association between irAEs and clinical outcomesAbstract 637 Figure 1Kaplan-Meier curves of association between immune-related adverse events (irAEs) and overall survival (OS, top panel) and progression-free survival (PFS, bottom panel)ConclusionsWe showed that mRCC patients who experienced irAEs, particularly thyroid irAEs, had improved clinical outcomes. This suggests that irAEs may be prognostic of favorable outcomes in mRCC patients treated with ICI. Larger, prospective studies are needed to validate these findings.AcknowledgementsResearch reported in this publication was supported in part by the Breen Foundation and the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNot applicableEthics ApprovalThis retrospective study was approved by the Emory University Institutional Review Board.ConsentNot applicableReferencesNot applicable

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Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy

Nature Communications ◽

10.1038/s41467-021-21928-4 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 3

Author(s):

Sara De Biasi ◽

Lara Gibellini ◽

Domenico Lo Tartaro ◽

Simone Puccio ◽

Claudio Rabacchi ◽

...

Keyword(s):

T Cells ◽

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Granzyme B ◽

In Silico Analysis ◽

Response To Treatment ◽

Multiparameter Flow Cytometry ◽

Mait Cells ◽

Single Cell Rna Sequencing ◽

Silico Analysis

AbstractImmune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.

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Genetic ancestry and clinical outcomes to immune checkpoint inhibitors among seven common cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10536 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10536-10536

Author(s):

Amin Nassar ◽

Elio Adib ◽

Sarah Abou Alaiwi ◽

Elie Akl ◽

Talal El Zarif ◽

...

Keyword(s):

Cell Carcinoma ◽

Clinical Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

East Asian ◽

Genetic Ancestry ◽

Sequencing Data ◽

Histologic Subtype ◽

Cancer Types

10536 Background: Prior studies and clinical trials report associations between self-reported race and clinical outcomes to Immune Checkpoint Inhibitors (ICIs). However, comprehensive studies of ancestry-associated differences in clinical outcomes have not been performed. We derived genetic ancestry scores and assessed clinical outcomes in 1341 patients with cancer treated with ICIs. Methods: Patients at the Dana-Farber Cancer Institute treated with ICIs only and with relevant cancer types and targeted exome sequencing data (Oncopanel) were included. Relevant cancer types included colorectal adenocarcinoma (CRC), esophagogastric adenocarcinoma (EGC), head and neck squamous cell carcinoma (HNSCC), melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma (UC). We developed a bioinformatics pipeline to infer fine-scale genetic ancestry for each patient (n=1341) directly from tumor sequencing data by leveraging off and on-target sequenced reads and external ancestry reference panels. Three ancestry scores were determined (African, East Asian, European). Overall survival (OS) and time-to-treatment failure (TTF) were compared by Cox logistic regression between ancestral populations. Hazard ratio (HR) was derived using multivariable analysis, adjusted for single versus combination therapy, prior lines of therapy, and tumor mutational burden (TMB, as percentiles). Results: Median follow-up was 37.8 months (m; interquartile range: 35.7-39.5m). Common cancer types included CRC (n=52), EGC (n=114), HNSCC (n=88), melanoma (n=274), NSCLC (n=571), RCC (n=99), and UC (n=143). A higher East Asian ancestry (EAS) was significantly associated with worse OS ( p=0.03) and TTF ( p=0.002) in patients with RCC, independent of the histologic subtype (Table). There was no significant association between any of the three ancestral populations and clinical outcomes in the other 6 cancer types. Conclusions: We described clinical outcomes to ICIs across three global populations in 7 cancers. As the medical field re-evaluates the use of self-reported race in clinical decision-making, we utilize a novel ancestry pipeline that can be readily applied to tumor-only sequencing panels and better characterize non-white populations. We find no ancestry differences in clinical outcomes except in patients with RCC treated with ICIs which will require future validation. We plan to analyze genomic correlates of response by ancestry in each of the cancer types to better understand these diverge clinical behaviors.[Table: see text]

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