Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study

Katsuya, Yuki; Horinouchi, Hidehito; Seto, Takashi; Umemura, Shigeki; Hosomi, Yukio; Satouchi, Miyako; Nishio, Makoto; Kozuki, Toshiyuki; Hida, Toyoaki; Sukigara, Tamie; Nakamura, Kenichi; Kuchiba, Aya; Ohe, Yuichiro

doi:10.1016/j.ejca.2019.03.012

Cited by 108 publications

(125 citation statements)

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“…In addition to the prognostic role, the CD8 + cells in local tumor sites have been reported to be associated with tumor mutation burden and treatment outcome of immune‐checkpoint inhibitors 17 . Considering the conflicting efficacy of PD‐1 blockade in thymic carcinoma, pembrolizumab (overall response rate 22.5%) and nivolumab (overall response rate 0.0%), further evaluation of CD8 + cell density as a prognostic or predictive biomarker for ICI is warranted, particularly in pre–treatment and post–treatment analysis 10,11 …”

Section: Discussionmentioning

confidence: 99%

“…The recent development of immune‐checkpoint inhibitors (ICI), to block program death‐1 (PD‐1) or program death‐ligand 1 (PD‐L1), has succeeded in many types of solid tumors 8,9 . Among thymic carcinoma patients, conflicting results of the efficacy of anti–PD‐1 antibody, pembrolizumab and nivolumab have been reported in phase 2 clinical trials 10,11 …”

Section: Introductionmentioning

confidence: 99%

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CD20⁺ tumor‐infiltrating immune cells and CD204⁺ M2 macrophages are associated with prognosis in thymic carcinoma

et al. 2020

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Thymic carcinoma is a rare malignant disease with no standard systemic chemotherapy. The purpose of the present study was to investigate tumor‐infiltrating immune cells (TIIC) in the tumor microenvironment (TME), focusing on the impact of TIIC and program death‐ligand 1 (PD‐L1) expression on clinical outcomes in thymic cancer. Patients with thymic carcinoma resected between 1973 and 2017 were investigated. The tissue specimens were analyzed through immunohistochemical staining to elucidate the prognostic effects of TIIC, their ratios and PD‐L1 in a preliminary cohort (n = 10). The density of TIIC as well as PD‐L1 expression was evaluated in intraepithelial and tumor‐stromal areas on the representative whole section of tumors. The immune factors showing significant association with disease‐free survival (DFS) were evaluated in the total cohort (n = 42). TIIC in the preliminary population showed no significant difference between the two groups. However, CD8, CD20, CD204, FOXP3 and CD20/CD204 ratio demonstrated a tendency to act as predictive markers for recurrence. In the total cohort, significant differences were observed for CD8+, CD20+ and CD204+ cells in tumor islets, and for CD8+, CD20+ and FOXP3+ cells as well as the CD8/CD204 and CD20/CD204 ratios in the stroma, indicating their prognostic effect. The prognostic effect of the PD‐L1 expression in tumor cells could not be established, possibly because of intratumoral heterogeneity. CD8, CD20 and CD204 positive TIIC in stroma were identified as possible better prognostic biomarkers, considering the heterogeneity of other biomarkers. The present study paves the way for exploring strategies of combination immunotherapy targeting B cell immunity in thymic carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD20⁺ tumor‐infiltrating immune cells and CD204⁺ M2 macrophages are associated with prognosis in thymic carcinoma

et al. 2020

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“…Based on results obtained in other solid, refractory tumors in adults, especially of squamous cell differentiation, and possibly considering PD-L1 expression observed in thymic epithelial tumor cellsdespite its intrinsic and constitutive relationship with the thymic origin of cancer cellsimmune checkpoint inhibitors of the PD-1/PD-L1 axis have been assessed in advanced and metastatic thymic epithelial tumors, mainly thymic carcinomas. Several case reports have been published, and four trials have assessed the efficacy and safety of PD-1/PD-L1 inhibitors in patients with advanced thymic epithelial tumors (Table 3) [48][49][50][51][52][53][54][55][56][57][58].…”

Section: Immunotherapy In Thymic Malignanciesmentioning

confidence: 99%

“…A phase II trial with nivolumab, an IgG4 antibody that targets the PD-1 receptor, was conducted in Japan for patients with thymic carcinomas [53]; 15 patients were accrued in the first stage, which aimed to identify at least one patient with a response. No response was actually observed.…”

Section: Clinical Trialsmentioning

confidence: 99%

Immune checkpoints in thymic epithelial tumors: challenges and opportunities

Girard

2019

Immuno-Oncology Technology

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“…3 4 However, there are conflicting results with other ICIs. 5 Before starting, it is important to rule out autoimmune disorders to evade serious, even life-threatening immune-complications. The high likelihood of irAEs in TC also underpin the importance of predictive biomarkers.…”

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confidence: 99%

775 Rare case reports on thymic carcinoma patients treated with pembrolizumab

Paszkan

Ganofszky

Ghimessy

et al. 2020

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BackgroundThymomas and thymic carcinomas (TC) are intrathoracic malignancies that, although rare, represent the most common anterior mediastinal tumors in adults (comprising approximately 0.2-1.5% of all malignancies).1 Recent accumulating evidence on immune checkpoint pathways suggests that immunotherapy might be a promising therapeutic option for refractory TCs.2 We herein report two cases of a pembrolizumab-treated TC patient.MethodsImmunotherapy is accessible through individual permission for the treatment of TC in Hungary. We retrospectively collected data of two TC patients treated with pembrolizumab in one institute.ResultsThe first patient was a 66-year-old woman. Squamous cell TC was diagnosed in her left parasternal region. She was a former smoker, had no history of autoimmune disorders, and had no associated symptoms at the time of diagnosis. She underwent open thymectomy. The histology proved type C (WHO classification) TC with a pathological TNM of T1aN0 and microscopic-positive margins. Consequently, the patient received 60 Gy of postoperative radiotherapy. Nine months after the surgery local recurrence and multiple hepatic metastases appeared. Six cycles of chemotherapy (ADOC regimen) were introduced as first-line systemic therapy which resulted in stable disease (SD) for 8 months. Pembrolizumab was administered as second-line treatment (200 mg every 3 weeks) for 6 cycles. The best result was SD. Due to progression, third-line docetaxel treatment was initiated. Shortly after, ptosis and diplopia developed. Myasthenia gravis was diagnosed, and third-line chemotherapy was judged ineffective. The second patient was a 63-year-old man. He was diagnosed with unresectable TC and treated with chemotherapy (ADOC regimen) up-front. After six cycles the tumor regressed, and surgery was performed with R2 result. Postoperatively, the patient was given six cycles of chemotherapy (cisplatin/etoposide) and radiotherapy. Six months later local progression was detected and pembrolizumab was commenced. Eight cycles of pembrolizumab produced SD as best response. No immune-related adverse effects (irAEs) were detected. After progression Sunitinib therapy was started. In both cases, additional immunohistochemistry investigations were performed.ConclusionsIn the literature, there is no phase 3 trial on immune-checkpoint inhibitor (ICI) therapy of TC. Phase 2 trials reported promising results with pembrolizumab.3 4 However, there are conflicting results with other ICIs.5 Before starting, it is important to rule out autoimmune disorders to evade serious, even life-threatening immune-complications. The high likelihood of irAEs in TC also underpin the importance of predictive biomarkers. Further studies are required to evaluate the efficacy and safety of immunotherapy in TC.AcknowledgementsThe authors thank the multidisciplinary clinical teams involved in the treatment and management of the patient.ReferencesBushan K, Sharma S, Verma H. A review of thymic tumors. Indian Journal of Surgical Oncology 2013;4(2):112–116. https://doi.org/10.1007/s13193-013-0214-2Isshiki T, Isobe K, Tochigi N, et al. Successful use of pembrolizumab to treat refractory thymic carcinoma with high PD-L1 expression. Case Rep Oncol2018;11(3):688–692. Published 2018 Oct 31. doi:10.1159/000493187Giaccone G, Kim C, Thompson J, McGuire C, Kallakury B, Chahine JJ, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 2018;19:247–255.Cho J, Kim HS, Ku BM, Choi YL, Cristescu R, Han J, et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial. J Clin Oncol 2019;37(JCO2017773184):2162–2170.Katsuya Y, Horinouchi H, Seto T, Umemura S, Hosomi Y, Satouchi M, et al. Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study. Eur J Cancer 2019;113:78e86.

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Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study

Cited by 108 publications

References 23 publications

CD20⁺ tumor‐infiltrating immune cells and CD204⁺ M2 macrophages are associated with prognosis in thymic carcinoma

CD20⁺ tumor‐infiltrating immune cells and CD204⁺ M2 macrophages are associated with prognosis in thymic carcinoma

Immune checkpoints in thymic epithelial tumors: challenges and opportunities

775 Rare case reports on thymic carcinoma patients treated with pembrolizumab

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Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study

Cited by 108 publications

References 23 publications

CD20+ tumor‐infiltrating immune cells and CD204+ M2 macrophages are associated with prognosis in thymic carcinoma

CD20+ tumor‐infiltrating immune cells and CD204+ M2 macrophages are associated with prognosis in thymic carcinoma

Immune checkpoints in thymic epithelial tumors: challenges and opportunities

775 Rare case reports on thymic carcinoma patients treated with pembrolizumab

Contact Info

Product

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CD20⁺ tumor‐infiltrating immune cells and CD204⁺ M2 macrophages are associated with prognosis in thymic carcinoma

CD20⁺ tumor‐infiltrating immune cells and CD204⁺ M2 macrophages are associated with prognosis in thymic carcinoma