A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study

Abstract

BackgroundMost patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients.MethodsWe conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population.ResultsThirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56–84%) with median RFS of 21 months (95% CI, 14–40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05–0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15–0.93, p = 0.0351, respectively).ConclusionsAdjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.

Optimising Multimodality Treatment of Resectable Oesophago-Gastric Adenocarcinoma

“…All of the 7 patients (18%) with tumours expressing PD-L1 CPS ≥ 10 were alive at 1 year. Of the 19 patients (51%) with PD-L1 CPS ≥ 1, median OS was significantly superior compared to patients with PD-L1 CPS < 1 (40.4 vs. 25.0 months, p = 0.0132) [75]. Though this study was underpowered due to small study size, it highlights the potential for PD-L1 to be used as a predictive biomarker to immunotherapy in the adjuvant setting for resected OG adenocarcinoma.…”

“…Patients who received adjuvant chemotherapy had improved DFS (HR 0.58, 95% CI 0.44-0.72; p < 0.0001) and OS (HR 0.66, 95% CI 0.51-0.85; p= 0.0015) compared to surgery and observation alone. The estimated 5-year OS rate was 78% (95% CI [74][75][76][77][78][79][80][81][82] in the adjuvant capecitabine and oxaliplatin group versus 69% (95% CI [64][65][66][67][68][69][70][71][72][73] in the observation group [26,27].…”

Efficacy and safety of radiotherapy/chemoradiotherapy combined with immune checkpoint inhibitors for locally advanced stages of esophageal cancer: A systematic review and meta-analysis

“…The six trials consisted of five non-randomized trials ( 10 – 13 , 15 ) and one randomized controlled trial ( 14 ). Two trials were conducted in the United States of America ( 14 , 15 ), three in China ( 10 , 12 , 13 ), and one in the Netherlands ( 11 ). Of the six studies included, two were phase I/Ib trials ( 12 , 13 ), three were phase II trials ( 10 , 11 , 15 ), one was a phase III trial ( 14 ).…”

“…Numerous ICI clinical trials have reported promising anti-tumor activity of for the treatment of EC ( 7 – 9 ). Some attention has been given to the clinical efficacy and safety of combination RT/CRT and ICIs for EC, but further investigation is still needed ( 10 – 15 ).…”

Transcriptomic datasets of cancer patients treated with immune-checkpoint inhibitors: a systematic review

“…In NCT02639065, FFPE samples were used in the Illumina NovaSeq 6000 platform, the primary endpoint was 1 year relapse-free survival (RFS), and 37 patients’ normalized expression data (fragments per kilo base of transcript per million mapped fragments (FPKM)) has been uploaded to NCBI GEO (GSE183924), along with RFS time. Adjuvant durvalumab therapy caused improvement in one-year RFS and was associated with the presence of M2 tumor-associated macrophages (TAMs), along with memory T cells [ 82 ].…”