Phase II study of pembrolizumab after chemoradiotherapy (CRT) as adjuvant therapy for locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients at high risk of recurrence following preoperative CRT plus surgery.

TPS259 Background: LA-ESCC is a potentially curable disease, for which preoperative CRT followed by esophagectomy is a standard-of-care. Previous studies have identified that close/involved margin and lymph node metastasis with extranodal invasion (ENI) in post-CRT surgical specimens are associated with increased risk of recurrence. In CheckMate-577 trial, adjuvant nivolumab significantly improved disease-free survival (DFS) in patients with esophageal cancer treated with preoperative CRT and surgery; in another trial (the “PACIFIC” trial), adjuvant durvalumab has significantly improved overall survival (OS) in stage III non-small cell lung cancer treated with definitive CRT. We hypothesize that adding pembrolizumab to CRT as an adjuvant therapy would improve the outcomes of LA-ESCC patients who are treated with preoperative CRT plus esophagectomy and with high-risk of recurrence. Methods: This single institution single-arm phase II study include patients with histologically confirmed LA-ESCC (AJCC 7th staging system:cT3-4aN0M0 or T1-4aN1-3M0) harboring at least one risk factor (closed/involved margin, ENI, or ypN2-3) in post-CRT surgical specimens. Patients with adenocarcinoma of esophagus or gastroesophageal junction or synchronously diagnosed with a squamous cell carcinoma of aero-digestive way other than ESCC are excluded. Patients enrolled will receive adjuvant weekly cisplatin–CRT (cisplatin, 30mg/m2 for 2 cycles every week; radiotherapy, 180-200 cGy/fraction for 10-13 times) followed by pembrolizumab (200 mg, every 3 weeks, for 18 cycles). The primary endpoint of this study is 1-year relapse-free survival (RFS) rate; and the key secondary endpoints include RFS, 3-year RFS rate, OS, 3-yr OS rate, toxicity and safety. The study, registered with clinical trial ID of NCT03322267, started patient enrollment in Aug 2018. As of Aug of 2020, 11 of 46 planned patients have been enrolled. Clinical trial information: NCT03322267.

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Serum microRNAs to predict the response to nivolumab in patients with esophageal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14511 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14511-e14511 ◽

Cited By ~ 1

Author(s):

Kazuki Sudo ◽

Ken Kato ◽

Juntaro Matsuzaki ◽

Junpei Kawauchi ◽

Satoko Takizawa ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Squamous Cell ◽

Phase Ii Study ◽

Progression Free Survival ◽

Free Survival ◽

Linear Discriminant ◽

Expression Levels

e14511 Background: A phase II study demonstrated that nivolumab (Nivo), a PD-1 inhibitor, had a meaningful activity for patients with esophageal squamous cell carcinoma. Although several biomarkers, including PD-L1 expression levels in tumor tissue, are explored to predict the efficacy of Nivo, further investigation is needed. Here we evaluated whether serum levels of microRNA (miRNA) could be a candidate of predictive markers. Methods: Among 65 patients who participated in the phase II study (JapicCTINo.142422) and received Nivo 3 mg/kg IV Q2W, 19 patients were treated at our institution. Patients were classified into responder and non-responder by investigators based on modified ir-RECIST. Serum samples were stored before and during treatment in the National Cancer Center Biobank. Comprehensive miRNA microarray analyses were performed using a 3D-Gene Human miRNA Oligo Chip (Toray Industries, Inc.), which was designed to detect 2565 miRNA expression levels. miRNA were compared between responders and non-responders using Fisher’s linear discriminant analysis, and then we calculated the area under curve (AUC) values of receiver operating characteristic curve. We explored the miRNA that showed AUC values of more than 0.8 and difference by 0.5 in the average log2 value of miRNA levels (log2miRNA) between responders and non-responders, and investigated their relation to progression-free survival using Kaplan-Meier curves and log-rank tests. Results: Among 19 patients, 5 responded (CR/PR, 1/4) to Nivo. We identified 3 miRNAs in the serum before treatment that were related to response to Nivo with AUC of 0.84 (log2miRNA of non-responder/responder: 13.16/12.47), 0.90 (8.65/10.20) and 0.81 (7.18/6.57), respectively. In the serum after the first treatment, 5 miRNAs were related to response to Nivo with AUC of 0.93 (11.93/11.09), 0.93 (11.87/11.13), 0.85 (7.92/8.53), 0.92 (6.61/5.82) and 0.93 (7.77/ 7.09), respectively. Among these 8 miRNAs, 4 miRNAs were significantly associated with progression-free survival. Conclusions: We identified miRNA candidates that could predict the response to Nivo. Further validation is warranted to confirm the results of our explorative research.

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Postoperative adjuvant therapy for patients with loco-regionally advanced oral squamous cell carcinoma who are at high risk of recurrence

International Journal of Oral and Maxillofacial Surgery ◽

10.1016/j.ijom.2019.12.007 ◽

2020 ◽

Vol 49 (7) ◽

pp. 848-853

Author(s):

S. Yanamoto ◽

Y. Denda ◽

Y. Ota ◽

T. Hasegawa ◽

M. Akashi ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Oral Squamous Cell Carcinoma ◽

Adjuvant Therapy ◽

Cell Carcinoma ◽

Squamous Cell ◽

Postoperative Adjuvant Therapy ◽

Risk Of Recurrence

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Anti-PD-L1 durvalumab combined with cetuximab and radiotherapy in locally advanced squamous cell carcinoma of the head and neck: A phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps6094 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS6094-TPS6094

Author(s):

Pierluigi Bonomo ◽

Isacco Desideri ◽

Mauro Loi ◽

Monica Mangoni ◽

Mariangela Sottili ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Head And Neck ◽

Phase Ii ◽

Squamous Cell ◽

Phase Ii Study ◽

Locally Advanced ◽

Disease Spread ◽

Absolute Increase

TPS6094 Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by prominent immune escape mechanisms. Potentially, the blockade of immune check points such as the PD-1/PD-L1 axis may stimulate the host T-cell activation against tumor cells and favor the FcγRIIIa-mediated, Cetuximab (CTX) induced antibody dependent cellular cytoxicity (ADCC). Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody with promising activity in recurrent/metastatic HNSCC (NCT01693562). The aim of our study is to test the hypothesis that a restored ability of the host immune system via blockade of the PD1/PD-L1 axis through DUR may enhance the antitumor activity of both CTX and radiotherapy (RT) in locally advanced HNSCC, a setting with unmet needs for effective treatment options. Methods: In this open-label, multi-center, single-arm, phase II study, enrolled patients will receive RT (69.9 Gy/2.12 Gy fx in 33 fractions over 7 weeks) with concurrent CTX (400 mg/m2 1 week before RT start followed by 250 mg/m2 q1w) and DUR (1500 mg q4w starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6 months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). Assuming a 2-year PFS of 66% based on historical data from RTOG study 0129, the experimental regimen is hypothesized to yield a 12% absolute increase at 2 years, corresponding to a hazard ratio of 0.6 (α = 0.1, power is 0.80 when the 2-year PFS is 78%). The required sample size with this design is 69 patients. A safety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk ( > N2a or > T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx ( > N2b, > 10 pack/years) will be eligible. To avoid potential RT-induced chronic loco-regional immunosuppression, protocol-indications will be undertaken to restrict target volumes to sites of gross disease and subclinical high risk lymph node basins excluding areas deemed at very low risk of disease spread. For this purpose, dose-painting intensity modulated radiotherapy (IMRT) is mandatory for this study. Clinical trial information: 2016-004668-20.

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Mature results of the LCCC1413 phase II trial of de-intensified chemoradiotherapy for HPV-associated oropharyngeal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.6022 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 6022-6022 ◽

Cited By ~ 1

Author(s):

Bhishamjit S. Chera ◽

Robert Amdur ◽

Colette J. Shen ◽

Gaorav P. Gupta ◽

Xianming Tan ◽

...

Keyword(s):

Clinical Trial ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Neck Dissection ◽

Phase Ii ◽

Squamous Cell ◽

Smoking Status ◽

Post Treatment ◽

Free Survival ◽

Pet Ct

6022 Background: To report the mature results from a prospective phase II clinical trial of highly de-intensified chemoradiotherapy (CRT) for patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: 1) T0-T3, N0-N2, M0, 2) p16 positive, and 3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin 30 mg/m2(second choice was cetuximab). Patients with T0-T2 N0-1 disease did not receive chemotherapy. All patients had a 10 to 12-week post-treatment PET/CT to determine need for planned neck dissection. The primary study endpoint was 2 year progression free survival (PFS). Secondary endpoint measures include 2 year local control (LC), regional control (RC), distant metastasis free survival (DMFS), cause specific survival (CSS) and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Results: 114 patients were enrolled (median f/u of 28.8 months, range 2.6 to 51.4) with 84 having a minimum follow-up of 2 years. Smoking status was as follows: 47% never, 33% ≤ 10 pack years, and 19% > 10 pack years. Post-treatment PET/CT complete response rate was 93% at the primary site and 80% in the neck. Eleven patients had planned neck dissection with 4 having pathological residual disease. Two year LC, RC, DMFS, PFS, CSS, and OS were the following: 96%, 99%, 91%, 88%, 97%, and 95%. Neither smoking status nor receipt of cetuximab correlated with recurrence. Four patients with recurrent disease had PIK3CA mutations. Thirty four percent of patients required a feeding tube (none permanent) for a median of 10.5 weeks. Mean pre- and 2-year post-treatment EORTC QOL scores were: Global 79/83 (lower worse), Swallowing 8/9 (higher worse), Dry Mouth 14/45 (higher worse), and Sticky Saliva 9/28 (higher worse). Mean pre- and 2 year post-treatment PRO-CTCAE (0 to 4 scale, higher worse) scores were: Swallowing 0.5/0.7 and Dry mouth 0.4/1.4. There were no ≥ Grade 3 late adverse events. Conclusions: Clinical outcomes with a highly de-intensified CRT regimen of 60 Gy IMRT with concurrent low-dose cisplatin are excellent in patients with HPV-associated OPSCC. Clinical trial information: NCT02281955.

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