PERFECT trial results: Combining neoadjuvant chemoradiotherapy with atezolizumab is feasible in resectable esophageal adenocarcinoma

Abstract

Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth leading cause of cancer mortality in the world. It is a heterogeneous disease with high regional variations. The incidence and disability adjusted life years (DLAYs) of esophageal adenocarcinoma (EAC) is rising in western countries, while China contributes the largest number of esophageal squamous-cell carcinomas (ESCC) cases and burden worldwide. Surgery is the most common treatment for early-stage esophageal cancer. Previous studies have shown that CROSS (carboplatin, paclitaxel and concurrent radiotherapy)-based neoadjuvant chemoradiotherapy can extend the median survival of EAC patients with surgery alone from 27.1 months to 43.2 months. However, approximately 50% of all patients with resectable EAC experience disease progression resulting in death after <5 years of clinical stability. Esophageal cancer has a unique immune microenvironment, suggesting that immune checkpoint inhibitors (ICIs) may improve the prognosis of patients with resectable EAC. Indeed, ICIs have been demonstrated to improve the response rate and survival of patients with metastatic gastroesophageal carcinoma, but the clinical efficacy of ICI in these patients varies greatly. Expression level of programmed deathligand 1 (PD-L1), composition of tumor immune microenvironment and microbiome, and tumor mutational burden are known factors that affect the clinical efficacy of ICI. Both preclinical and clinical evidence indicate that traditional tumor therapies can change the tumor immune microenvironment of EAC. For example, taxane-based chemotherapy can evoke T cell response and radiotherapy can elevate PD-L1 expression in EAC. However, the feasibility and efficacy of neoadjuvant chemoradiotherapy plus ICI for resectable EAC remains to be determined. In the PERFECT trial recently published in Clinical Cancer Research, entitled “Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: A single arm phase II feasibility trial (PERFECT)”, Ende et al. investigated the feasibility and efficacy of neoadjuvant chemoradiotherapy combined with PD-L1 inhibitor (atezolizumab) for resectable EAC. A total of 40 patients were enrolled in this study. Among them, 34 (85%) patients received all cycles of atezolizumab and 33 (83%) underwent surgery. Immune-related adverse events (IRAEs) were observed in six (15%) patients. Reasons for not undergoing surgery were disease progression (n = 4; 10%), patient choice (n = 2; 5%), and death (n = 1; 3%). A total of 10 (25%) patients had achieved complete pathological remission. There was no statistically significant difference in response or survival between the PERFECT and neoadjuvant chemoradiation cohort. The baseline IFNγsignature (a six-gene IFNy-signature previously established by Ayers et al.) expression of responders was higher than that of nonresponders (p = 0.043). The common characteristic of nonresponders receiving treatment is the presence of a large number of cytotoxic lymphocytes with transcriptional signature consistent with the expression of immune checkpoints, or a small number of cytotoxic lymphocytes. This is the first trial combining CROSS (carboplatin, paclitaxel, and concurrent radiotherapy)-based neoadjuvant chemoradiotherapy with PD-L1 inhibitor (atezolizumab) for resectable EAC. Most of the participants (85%) in this study received all planned cycles of atezolizumab suggesting that the treatment regimen is feasible. The neoadjuvant chemotherapy-related advanced events and postoperative complications reported in the PERFECT trial were basically the same as those reported in the CROSS trial, apart from the immune-related adverse events associated with PD-L1 inhibition. Fortunately, all immune-related adverse events reported in the PERFECT trial were manageable and did not affect the surgical treatment. Compared with the CROSS trial, the PERFECT trial had a higher pathological complete response rate. In addition, there were more patients who progressed before or during the operation in the PERFECT trial. As the positron emission tomography-computed tomography (PET-CT)-based response evaluation in the CROSS trial was not mandatory, it was very likely that it would to lead to insufficient assessment of disease progression. The pathological response rate, overall survival, and progression-free survival in the matched cohort of patients treated with carboplatin, paclitaxel, and concurrent Received: 5 April 2021 Accepted: 9 April 2021