Serum alanine aminotransferase as an early marker of outcomes in patients receiving anti-PD-1 or anti-CTLA-4 antibody

AbstractImmune-oncology (IO) drug therapy is effective against various types of cancer. Although several, potential, clinical predictive markers have been identified, none so far have proven reliable. Herein we evaluated changes in serum alanine aminotransferase (ALT), which is upregulated by the accumulation of activated CD8+T cells in the liver, as a potentially reliable predictive marker. We retrospectively analyzed 265 patients with advanced malignancies at three institutions between 2016 and 2019. The patients received IO drug therapy. We defined the ALT ratio (ALR) as the serum ALT value at baseline / the highest serum ALT during IO drug therapy, then determined whether the ALR correlated with the objective response rate or progression-free survival. The median follow-up was 3.1 months. We observed objective responses in 65 patients. The ALR ranged from 0.19 to 32.2 (median 1.5), and a significant ALR increase was observed in responders (p < 0.001). In receiver operating characteristic analysis, ALR = 1.55 had the highest sensitivity and specificity. The patients with ALR < 1.55 had a significantly poorer PFS than those with ALR ≥ 1.55. A high ALR was associated with a tumor response and good PFS in patients with advanced malignancies. The ALR based on activated cytotoxic T lymphocyte dynamics is therefore a reliable predictive marker.

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Serum Alanine Aminotransferase As An Early Marker of Outcomes in Patients Receiving Immuno-Oncology Drugs

10.21203/rs.3.rs-155568/v1 ◽

2021 ◽

Author(s):

Takeshi Azuma ◽

Takumi Takeuchi ◽

Yukihide Matayoshi ◽

Shin Namiki ◽

Tetsuya Obara ◽

...

Keyword(s):

Drug Therapy ◽

Alanine Aminotransferase ◽

Cytotoxic T Lymphocyte ◽

Objective Response ◽

Progression Free Survival ◽

Predictive Marker ◽

Characteristic Analysis ◽

Serum Alanine Aminotransferase ◽

Advanced Malignancies ◽

Immune Oncology

Abstract Immune-oncology (IO) drug therapy is effective against various types of cancer. Although several, potential, clinical, predictive markers have been identified, none so far have proven reliable. Herein we evaluated changes in serum alanine aminotransferase (ALT), which is upregulated by the accumulation of activated CD8 + T cells in the liver, as a potentially reliable predictive marker. We retrospectively analyzed 265 patients with advanced malignancies at three institutions between 2016 and 2019. The patients received IO drug therapy. We defined the ALT ratio (ALR) as the serum ALT value at baseline / the highest serum ALT during IO drug therapy, then determined whether the ALR correlated with the objective response rate or progression-free survival. The median follow-up was 3.1 months. We observed objective responses in 65 patients. The ALR ranged from 0.19 to 32.2 (median 1.5), and a significant ALR increase was observed in responders (p < 0.001). In receiver operating characteristic analysis, ALR = 1.55 had the highest sensitivity and specificity. The patients with ALR < 1.55 had a significantly poorer PFS than those with ALR ≥ 1.55. A high ALR was associated with a tumor response and good PFS in patients with advanced malignancies. The ALR is a reliable predictive marker based on activated cytotoxic T lymphocyte dynamics.

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Efficacy and Safety of Nivolumab and Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study

Current Oncology ◽

10.3390/curroncol28020133 ◽

2021 ◽

Vol 28 (2) ◽

pp. 1402-1411

Author(s):

Koji Iinuma ◽

Koji Kameyama ◽

Kei Kawada ◽

Shota Fujimoto ◽

Kimiaki Takagi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Predictive Marker ◽

Efficacy And Safety ◽

Lymphocyte Ratio

We conducted a multicenter, retrospective study to evaluate the efficacy and safety of combination nivolumab plus ipilimumab (NIVO+IPI) in 35 patients with advanced or metastatic renal cell carcinoma (mRCC). In this study, we focused on patients who received NIVO+IPI and were stratified into intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium model at five institutions in Japan. The primary endpoint was overall survival (OS). Secondary endpoints were disease control rate (DCR), best overall response (BOR), objective response rate (ORR), and progression-free survival (PFS). In addition, we evaluated the role of inflammatory cell ratios, namely neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as predictive biomarkers in patients with mRCC. The median follow-up period was 1 year, and the 1-year OS rate was 95.8%. The ORR and DCR were 34.3% and 80.0%, respectively. According to BOR, four patients (11.4%) achieved complete response. According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively (p = 0.04). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively (p = 0.033). Although 71.4% of the patients experienced treatment-related adverse events (TRAEs) with NIVO+IPI, only four patients discontinued NIVO+IPI due to grade 3/4 TRAEs. Patients treated with NIVO+IPI as a first-line therapy for advanced or mRCC achieved relatively better oncological outcomes. Therefore, NIVO+IPI may have potential advantages and may lead to a treatment effect compared to those receiving targeted therapies. In addition, PLR >188.1 may be a useful predictive marker for mRCC patients who received NIVO+IPI.

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Tumor metabolic volume by 18F-FDG-PET as a prognostic predictor of first-line pembrolizumab for NSCLC patients with PD-L1 ≥ 50%

Scientific Reports ◽

10.1038/s41598-020-71735-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ou Yamaguchi ◽

Kyoichi Kaira ◽

Kosuke Hashimoto ◽

Atsuto Mouri ◽

Ayako Shiono ◽

...

Keyword(s):

Objective Response ◽

Prognostic Significance ◽

Standardized Uptake Value ◽

Progression Free Survival ◽

Predictive Marker ◽

Distant Metastases ◽

Metabolic Tumor Volume ◽

First Line ◽

Prognostic Predictor ◽

Fdg Uptake

Abstract There is a lack of markers for predicting favorable outcomes after pembrolizumab therapy in patients with non-small cell lung cancer (NSCLC) with programmed death ligand-1 (PD-L1) expression ≥ 50%. This retrospective study examined the prognostic significance of 2-deoxy-2-[18F] fluoro-d-glucose (18F-FDG) uptake as a predictive marker of first-line pembrolizumab. Forty-eight patients with previously untreated NSCLC and PD-L1 expression levels ≥ 50% who underwent 18F-FDG-positron emission tomography (PET) just before administration of pembrolizumab monotherapy were eligible and underwent assessment of metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum of standardized uptake value (SUVmax) on 18F-FDG uptake. The objective response rate, median progression-free survival, and median overall survival were 51.1%, 7.1 months, and 18.6 months, respectively. In univariate survival analyses, high MTV was barely a significant prognostic predictor and was confirmed as an independent factor linked to worse outcomes in multivariate analysis, predominantly in patients with a histological diagnosis of adenocarcinoma. A high MTV was significantly associated with distant metastases (especially bone metastasis), C-reactive protein (CRP) level, and PD-L1 expression ≥ 75%. Metabolic tumor activity assessed as MTV from 18F-FDG uptake predicted the prognosis after first-line pembrolizumab treatment in patients with NSCLC and PD-L1 expression ≥ 50%, especially for adenocarcinoma.

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Association of matrix metalloproteinase 2 (MMP2) baseline plasma level to objective response (OR), progression free survival (PFS), and overall survival (OS) and changes under treatment in patients treated with bevacizumab (Bev) for recurrent high-grade glioma (HGG).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2024 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2024-2024 ◽

Cited By ~ 1

Author(s):

Emeline Tabouret ◽

Francoise Boudouresque ◽

Jaime Callego Perez-Larraya ◽

Maryline Barrie ◽

Giuseppe Lombardi ◽

...

Keyword(s):

Plasma Levels ◽

Baseline Level ◽

Randomized Clinical Trials ◽

Objective Response ◽

Progression Free Survival ◽

Predictive Marker ◽

Cytotoxic Agents ◽

Matrix Metalloproteinase 2 ◽

Tumor Control ◽

Multiple Time

2024 Background: Predictive marker of Bev activity is an unmet medical need. We evaluated predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent HGG treated with Bev. Methods: A set of eleven prebiomakers of interest (VEGF, VEGF-R2, bFGF, SDF1, PlGF, uPA, PAI1, MMP2, MMP7, MMP9, and adrenomedulline) were analyzed in plasma, using ELISA, at baseline from Bev initiation in a prospective cohort of 26 patients (Cohort1). Correlations were validated in a separate retrospective Bev treated cohort (Cohort2; n = 50) and then tested in a cohort of patients treated with cytotoxic agents without Bev (Cohort3; n = 34). Dosages were correlated to OR, PFS, and OS. MMP2 and MMP9 were then analyzed at multiple time points up to progression. Results: In cohort1, high MMP2 baseline level was associated with an OR rate of 83.3% for high levels versus 15.4% for low MMP2 levels (p = 0.001). In multivariate analysis, MMP2 baseline level was correlated with PFS (hazard-ratio (HR), 3.92; 95% confidence-interval (CI):1.46-10.52; p = 0.007) and OS (HR, 4.62; 95%CI 1.58-13.53; p = 0.005), as MMP9 (p = 0.016 for PFS and p = 0.025 for OS). Similar results were found in cohort2 for MMP2, (MMP2: p<0.001 for OR; p = 0.009 for PFS; p = 0.009 for OS) but not for MMP9. In cohort3, no association was found between MMP2, MMP9 and outcome. Significant changes in MMP2 and MMP9 plasma levels were observed during treatment. MMP2 increased after Bev initiation (p = 0.002), and decreased at progression (p = 0.002) while MMP9 initially decreased (p = 0.007) then increased at progression (p = 0.031). Conclusions: In patients with recurrent HGG treated with bevacizumab, but not with cytotoxic agents, high MMP2 plasma levels are associated with prolonged tumor control and survival while changes over time may reflect tumor control. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role should be reassessed.

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A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies

Scientific Reports ◽

10.1038/s41598-021-01707-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Siqing Fu ◽

David E. Piccioni ◽

Hongtao Liu ◽

Rimas V. Lukas ◽

Santosh Kesari ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Cytotoxic T Lymphocyte ◽

Wilms Tumor ◽

Biological Marker ◽

Human Leukocyte ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Open Label ◽

Advanced Malignancies

AbstractWT2725 is a Wilms’ tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56–81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309–648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6–19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.

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Initial therapy with FOLFOXIRI plus bevacizumab (bev) for RAS mutant metastatic colorectal cancer (mCRC) and gene mutations in circulating tumor DNA (ctDNA) as a predictive marker for the efficacy: JACCRO CC-11.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.635 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 635-635

Author(s):

Yu Sunakawa ◽

Hironaga Satake ◽

Joshua L. Usher ◽

Yolanda S Jaimes ◽

Yuji Miyamoto ◽

...

Keyword(s):

Clinical Outcomes ◽

Objective Response ◽

Gene Mutations ◽

Progression Free Survival ◽

Predictive Marker ◽

Japanese Patients ◽

Initial Therapy ◽

Circulating Tumor Dna ◽

Depth Of Response ◽

Pre Treatment

635 Background: We have reported that modified (m)-FOLFOXIRI plus bev was feasible and had a good objective response rate (ORR) for Japanese patients (pts) in a phase II trial of the JACCRO CC-11 (ESMO 2017 #543P). In addition, a pre-planned research was performed to investigate if the change of gene mutations in ctDNA during therapy can serve as a predictor for clinical outcomes in RAS mutant mCRC. Methods: The efficacy of m-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², levofolinate 200 mg/m², and fluorouracil 2400 mg/m² repeated biweekly) plus bev was evaluated prospectively in 62 pts (median age 63, 55% male, 92% PS0, and 27% right-sided tumors) with mCRC harboring RAS mutation (mt). The primary endpoint was ORR. Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Plasma samples for extraction of ctDNA were collected at 3 points (pre-, 8w, and progression) and analyzed for specific KRAS, NRAS, BRAF, and PIK3CA variants with real-time PCR assays. Results: Updated median follow-up time was 10.2 months. ORR and disease control rate were 75.8% and 96.8%, respectively. ETS was 73.8%, and median DpR was 49.6%. Median PFS was 11.5 months (95%CI 9.5-14.0). KRAS/ NRAS mt from pre-treatment plasma was confirmed in 79% of pts. In 41 pts with RAS mt at pre-treatment, mt status at 8 weeks predicted clinical outcomes (Table). Moreover, combined assessment of mt in ctDNA and ETS served as a refined predictor for efficacy. Pts with PIK3CA mt at pre-treatment had a poor outcome (ORR, 43%; median PFS, 8.8 months). Conclusions: FOLFOXIRI plus bev regimen is active for RAS mutant mCRC. RAS mt in ctDNA and ETS evaluation might potentially be a useful on-treatment biomarker in mCRC pts with RAS mt. Clinical trial information: UMIN000015152. [Table: see text]

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Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2016.67.1529 ◽

2016 ◽

Vol 34 (22) ◽

pp. 2619-2626 ◽

Cited By ~ 262

Author(s):

Igor Puzanov ◽

Mohammed M. Milhem ◽

David Minor ◽

Omid Hamid ◽

Ai Li ◽

...

Keyword(s):

Objective Response Rate ◽

Response Rate ◽

Cytotoxic T Lymphocyte ◽

Objective Response ◽

Progression Free Survival ◽

Talimogene Laherparepvec ◽

Duration Of Treatment ◽

Open Label ◽

Durable Response ◽

Grade 3

Purpose Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte–associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma. Methods In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (106 plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (108 plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety. Results Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%. Conclusion T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy.

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The neutrophil-lymphocyte ratio has a role in predicting the effectiveness of nivolumab in Japanese patients with metastatic renal cell carcinoma: A multi-institutional retrospective study

10.21203/rs.2.12455/v1 ◽

2019 ◽

Author(s):

Naotaka Nishiyama ◽

Megumi Hirobe ◽

Takuya Kikushima ◽

Masahiro Matsuki ◽

Atsushi Takahashi ◽

...

Keyword(s):

Objective Response ◽

Progression Free Survival ◽

Predictive Marker ◽

Japanese Patients ◽

Free Survival ◽

Neutrophil Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Initiation Of Therapy ◽

Better Than

Abstract Background: The neutrophil-lymphocyte ratio (NLR) is a well-known prognostic marker in various cancers. However, its role as a predictive marker for the effectiveness of nivolumab in patients with metastatic RCC (mRCC) remains unclear. We evaluated the relationships between the NLR and progression-free survival (PFS) or overall survival (OS) in mRCC patients treated with nivolumab. Methods: The data of 46 mRCC patients who received nivolumab therapy were collected from six institutes and evaluated. The median follow-up period from treatment with nivolumab was 12.5 months (IQR 10.0-16.7). Results: The median duration of nivolumab therapy was 6.5 months (IQR 3.3-13.7). The objective response rate was 22% and the 1- and 2-year PFS rates were 49.4% and 34.8%, respectively. The median NLR values at baseline and 4 weeks were 3.7 (IQR 2.7-5.2) and 3.7 (IQR 2.5-5.9), respectively. In the multivariate analysis, an NLR of ≥ 3 at 4 weeks was an independent predictor of PFS (P = 0.005) and OS (P = 0.031). The 1-year PFS of patients with an NLR of < 3 at 4 weeks was better than that of those with an NLR of ≥ 3 (83% versus 27%, P = 0.001). The 1-year OS of patients with an NLR of < 3 at 4 weeks was also better than that of those with an NLR of ≥ 3 (94% versus 71%, P = 0.002). Conclusions: Although the baseline NLR was not associated with PFS or OS, an NLR of ≥3 at 4 weeks after the initiation of therapy might be a robust predictor of poor PFS and OS in mRCC patients undergoing sequential treatment with nivolumab.

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Phase II multicenter trial of ipilimumab combined with fotemustine in patients with metastatic melanoma: The Italian Network for Tumor Biotherapy (NIBIT)-M1 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8513 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8513-8513 ◽

Cited By ~ 5

Author(s):

Anna Maria Di Giacomo ◽

Paolo Antonio Ascierto ◽

Lorenzo Pilla ◽

Ruggero Ridolfi ◽

Mario Santinami ◽

...

Keyword(s):

Brain Metastases ◽

Disease Control ◽

Metastatic Melanoma ◽

Cytotoxic T Lymphocyte ◽

Objective Response ◽

Stage Iv ◽

Progression Free Survival ◽

Complete Response ◽

Multicenter Trial ◽

Primary Objective

8513 Background: Ipilimumab (ipi), an antibody against cytotoxic T-lymphocyte-associated antigen-4, improves survival in patients (pts) with metastatic melanoma (MM); however, objective tumor responses are limited. NIBIT-M1 aims to investigate the efficacy and safety of ipi plus fotemustine (FTM), a cytotoxic alkylating drug, in pts with MM. Methods: Eligible pts, with or without brain metastases, received induction therapy with ipi 10 mg/kg every 3 weeks (Q3W) for four doses and FTM 100 mg/m2 weekly for 3 weeks. Ipi and FTM maintenance therapy was provided Q12W from Week 24 and Q3W from Week 9, respectively. The primary objective was the immune-related (ir) disease control rate (irDCR: pts with complete response [CR], partial response [PR] or stable disease [SD] as determined using the ir response criteria). Secondary objectives included ir objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS); overall survival (OS), and safety. Tumor assessments were performed Q8W from Week 12 to Week 36 and Q12W thereafter. Results: Among 86 pts with unresectable stage III (n=3) or stage IV (n=83) MM treated at 7 NIBIT centers, 42 were previously untreated, 44 had progressed following first-line treatment and 20 had asymptomatic brain metastases. As of December 2011, the irDCR was 46.5% (40/86; 95% CI, 35.7–57.6%); the irORR was 29.1% (95% CI, 19.8–39.8%; 5 CRs and 20 PRs) and with a median 8.3 months follow-up, median irPFS was 5.3 months (95% CI, 3.5–7.1). The 1-year OS rate was 51.8% (95% CI, 37.5–66.1%); median OS was not yet reached. Among all pts, 58.1% and 87% completed ipi or FTM induction, respectively. The most common grade 3/4 drug-related adverse events (AEs) (reported in 54.6% pts overall) were myelotoxicity (43.5%), increased ALT/AST (14.1/10.6%), gastrointestinal (4.7%) and skin-related (2.3%). AEs were generally manageable and reversible per protocol guidance. Conclusions: The study reached its primary objective with 46.5% of pts achieving disease control. The combination of ipi plus FTM is safe; the irDCR, 1-year OS rate and median irPFS warrant its further investigation in MM pts.

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Association of frequent amplification of chromosome 11q13 in esophageal squamous cell cancer with clinical benefit to immune check point blockade.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4036 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4036-4036 ◽

Cited By ~ 2

Author(s):

Feng Wang ◽

Chao Ren ◽

Qi Zhao ◽

Nong Xu ◽

Lin Shen ◽

...

Keyword(s):

Squamous Cell ◽

Messenger Rna ◽

Cell Cancer ◽

Objective Response ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Predictive Marker ◽

Genomic Amplification ◽

Chromosome 11Q13 ◽

Tumor Mutational Burden

4036 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer in South America and East Asian countries and remains an unmet medical need worldwide. Previous studies have shown the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic ESCC. However, robust predictive biomarkers to PD-1 antibody-based immunotherapy remain undefined. Methods: Patients included in this analysis were part of multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in solid tumors. To identify molecular determinants of response, we performed whole exome sequencing (WES), messenger RNA sequencing and immunohistochemistry on patients’ samples and evaluated genomic and transcriptional biomarkers, PD-L1 expression and tumor mutational burden (TMB) for correlation with clinical efficacy. Results: Sixty advanced chemo-refractory ESCC patients were enrolled and 59 were treated with toripalimab. 94.9% (56/59) patients experienced at least one treatment related adverse event after 16 months; mostly grade 1 or grade 2. Treatment-related grade 3 or higher AEs occurred in 30.5% (18/59) of subjects. By the data cutoff date, 11 (18.6%; 95%CI 9.7 to 30.9) patients achieved an objective response, while the disease control rate was 47.5% (95%CI 34.3 to 60.9). Copy number analysis identified 24 out of 50 (48%) patients with amplifications of chromosome 11q13 region, which was consistent with elevated mRNA expression of amplified genes, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Patients without 11q13 amplification, had significantly better objective response rate (ORR 30.8% versus 4.2%, p= 0.024) and progression free survival (3.7 versus 2.0 months, HR = 0.47 [95%CI 0.24 to 0.91], p= 0.025) when compared with 11q13 amplified individuals. In contrast, patients with high TMB (≥12 Mutations/Mb; 11/47, 23.4%) or positive PD-L1 expression (TC or IC 1%; 19/57, 33.3%) showed no significant advantage in ORR or survival. Conclusions: Toripalimab has demonstrated a manageablesafety profile and promising anti-tumor activity in chemo-refractory ESSC patients. Genomic amplification of 11q13 region may serve as a negative predictive marker for advanced ESSC patients receiving anti-PD-1 based immunotherapy. Further interrogation of putative resistance genes that lie within this region is under study. Clinical trial information: NCT02915432.

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