Efficacy and activity of PD-1 blockade in patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis with focus on the value of PD-L1 combined positive score

Leone, Alberto Giovanni; Petrelli, Fausto; Ghidini, Antonio; Raimondi, Alessandra; Smyth, Elizabeth; Pietrantonio, Filippo

doi:10.1016/j.esmoop.2021.100380

Cited by 38 publications

(29 citation statements)

References 21 publications

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“…Immunotherapy regimens targeting the PD-1 or EGFR pathways have variable response rates 52 , 53 , demonstrating the importance of identifying novel molecular pathways associated with HNSCC carcinogenesis. For instance, the efficacy of anti-PD-1 therapy is limited to patients with high PD-L1 expression, which is heterogeneously expressed in tumors 54 . Here, we report a provocative finding for GPR68 in limiting the severity of chemical-induced OED, correlating with increased frequencies of splenic Tregs in male GPR68 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

GPR68 limits the severity of chemical-induced oral epithelial dysplasia

Shore

Griggs

Graffeo

et al. 2023

Sci Rep

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Head and neck cancer is the sixth most common malignancy, and there is an urgent need to identify physiological processes contributing to tumorigenesis. Extracellular acidification caused by aerobic glycolysis within tumor microenvironments can stimulate proton-sensing receptors. GPR68, or ovarian cancer G protein-coupled receptor 1, responds to extracellular acidity and is highly expressed in head and neck squamous cell carcinoma (HNSCC) as well as normal esophageal tissue. To study the role of GPR68 in oral dysplasia, wild-type and GPR68−/− mice were treated with 4-Nitroquinoline N-oxide (4NQO) in drinking water for 11–13 weeks, followed by normal water for 11–12 weeks. 4NQO treatment resulted in 45 percent of GPR68−/− mice developing severe dysplasia or squamous cell carcinoma compared to only 10.5 percent of GPR68+/+ mice. This correlated with increased frequencies of regulatory T cells in the spleens of male GPR68−/− mice. Dysplastic regions of the tongue had increased CD31 staining compared to normal regions in both GPR68−/− and GPR68+/+ mice, suggesting that angiogenesis was GPR68-independent. RNA knockdown studies using HNSCC cell lines demonstrated no direct effect of GPR68 on survival or growth. Overall, we demonstrate that GPR68-deficiency worsens the severity of chemical-induced oral dysplasia, suggesting a protective role for this gene in tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

GPR68 limits the severity of chemical-induced oral epithelial dysplasia

Shore

Griggs

Graffeo

et al. 2023

Sci Rep

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“…Accordingly, anlotinib has the potential to be a partner for the combination of chemotherapy and immunotherapy, improving the survival of patients with ESCC, and further clinical trials (NCT05013697) are being conducted. Notably, since a relevant proportion of patients did not benefit from ICIs, biomarker-driven selection of immunotherapy responders and non-responders would minimize unnecessary exposure of patients to potentially permanent and life-threatening immune-related toxicities and optimize treatment personalization [46]. Therefore, our future studies may benefit from a validated biomarker (programmed death-ligand 1 [PD-L1]) assessed by combined positive score (CPS) and tumor proportion score (TPS), which will be helpful for direction of better achievement of optimal selection of patients and individualized treatment.…”

Section: Discussionmentioning

confidence: 99%

A multi-center, single-arm, phase II study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma

Hong

et al. 2022

BMC Med

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Background Anlotinib, a tyrosine kinase inhibitor, has shown encouraging anti-tumor activity in esophageal squamous cell carcinoma (ESCC). This study was designed to assess the efficacy and safety of anlotinib plus paclitaxel and cisplatin (TP) as first-line therapy for advanced ESCC. Methods In a multi-center, single-arm, phase II clinical trial, patients (aged > 18 years) with ESCC, which was judged to be locally advanced, recurrent, or metastatic, received 10 mg oral anlotinib once daily on days 1–14, 135 mg/m2 intravenous paclitaxel on day 1, and 60–75 mg/m2 intravenous cisplatin on days 1–3 every 3 weeks for a maximum of 4–6 cycles as the initial therapy in five centers in China. Subsequently, patients received anlotinib monotherapy (10 mg) as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Results Forty-seven patients were enrolled in this study between October 2019 and March 2021. The median follow-up was 14.04 months (IQR, 9.30–19.38). Of 46 with assessable efficacy, the median PFS and median overall survival were 8.38 months (95% CI, 6.59–10.17) and 18.53 months (95% CI, 13.11–23.95), respectively. The objective response rate was 76.1% (95% CI, 61.2–87.4%), with 4 (8.7%) complete responses and 31 (67.4%) partial responses. The disease control rate was 91.3% (95% CI, 79.2–97.6%). The median duration of response was 6.80 months (95% CI, 4.52–9.08), and 1 patient had an ongoing response for 23 months. Subgroup analysis revealed no association between clinical factors and survival or response. Of the 47 patients with assessable safety, the main grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (17.0%), bone marrow suppression (12.8%), and vomiting (10.6%). No treatment-related deaths or serious TEAEs were observed. Notably, higher c-Kit levels were an independent factor for superior PFS (HR = 0.032; 95% CI, 0.002–0.606; P = 0.022). Conclusions The study demonstrated a manageable safety profile and durable clinical response of anlotinib plus TP as first-line therapy in advanced ESCC, which suggested a potential therapeutic option for this population. Trial registration ClinicalTrials.gov NCT04063683. Registered 21 August 2019.

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“…Nevertheless, taking into account those limitations, the role of PD-L1 as predictive and/or prognostic biomarkers has been explored. In this regard, a recently published systematic review and metanalysis from Leone AG et al reported the data from 5257 patients included in 10 randomized controlled trials of immunotherapy for advanced ESCC [ 30 ]. In this analysis, immunotherapy showed to improve survival outcomes (HR: 0.71) regardless of the country (Asian versus non-Asian) and the line of treatment (first versus subsequent lines).…”

Section: Molecular Biomarkers For Immunotherapymentioning

confidence: 99%

Immunotherapy for Squamous Esophageal Cancer: A Review

Petrillo¹,

Smyth

2022

JPM

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Esophageal squamous cell carcinoma (ESCC) is a rare gastrointestinal tumour with high mortality. A multimodality treatment based on chemoradiotherapy followed by surgery is the standard of care in the case of non-metastatic disease; chemotherapy has historically been the gold standard in the metastatic setting. However, the rate of relapse after curative treatment is high and the prognosis of ESCC is poor. In this context, immunotherapy is a novel and intriguing chance to improve survival. Therefore, in this narrative review, we depict the current scenario in the field of immunotherapy for ESCC according to the stage of disease and alongside the discussion of promising biomarkers and future perspectives. The Checkmate-577 trial showed that nivolumab is the best option as adjuvant treatment in patients with non-metastatic ESCC and residual disease after a multimodality approach. In the metastatic setting, nivolumab, pembrolizumab, camrelizumab, sintilimab and toripalimab improved survival outcomes as a first-line treatment in addition to chemotherapy. In the second-line, nivolumab, pembrolizumab, camrelizumab and tislelizumab showed positive results, with differences according to the subgroups, agents and study population included in the trials. Then, the finding of valid molecular biomarkers is crucial in selecting patients for immunotherapy.

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Efficacy and activity of PD-1 blockade in patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis with focus on the value of PD-L1 combined positive score

Cited by 38 publications

References 21 publications

GPR68 limits the severity of chemical-induced oral epithelial dysplasia

GPR68 limits the severity of chemical-induced oral epithelial dysplasia

A multi-center, single-arm, phase II study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma

Immunotherapy for Squamous Esophageal Cancer: A Review

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