KEYNOTE-975 Study Design: a Phase III Study of Definitive Chemoradiotherapy Plus Pembrolizumab in Patients with Esophageal Carcinoma

Abstract

Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points. Clinical trial registration: NCT04210115 (ClinicalTrials.gov)

Narrative review of pembrolizumab for the treatment of esophageal cancer: evidence and outlook

“…Additionally, an ongoing phase Ib-2 trial (CP-MGAH22-05) also revealed that margatuximab in combination with pembrolizumab had good tolerability and efficacy in the treatment of human epidermal growth factor receptor 2 (HER2) positive gastroesophageal adenocarcinoma (33). KEYNOTE-975, a randomized, multicenter, double-blind, phase III study investigating the possibility of using pembrolizumab in the definitive chemoradiation setting, is currently in the patient recruitment stage (34). Patients with inoperable locally advanced, but non-metastatic ESCC or adenocarcinoma or Siewert type 1 adenocarcinoma of the EGJ will be randomly assigned (1:1) to receive pembrolizumab plus definitive chemoradiotherapy (dCRT) or a placebo plus dCRT.…”

“…The trial will attempt to determine whether pembrolizumab combined with dCRT can prolong OS and improve tolerability in patients with advanced EC compared to dCRT alone. The trial has not distinguished between different PD-L1 expression status during patient enrolment, and again, PD-L1 positivity has been defined as a CPS of ≥10 (34). Other ongoing clinical trials including NCT02844075, NCT02998268, NCT03322267, NCT04389177, and NCT04435197 are expected to yield further clinical evidence to illustrate the efficacy and tolerability of pembrolizumab.…”

“…The initial presentation at the 2020 ESMO Congress and recent publication for the CheckMate 577 trial supports the use of adjuvant nivolumab for 1 year in patients with EC specifically with lack of a complete pathologic response after neoadjuvant chemoradiotherapy and surgery [34] . As this treatment approach received category 1 recommendation in NCCN guidelines, this has emerged as a standard of care at our center and received FDA approval as of May 20, 2021.…”

Immunotherapy for Esophageal Cancers: What Is Practice Changing in 2021?

“…Thus, to further improve the survival of these patients, several trials addressing this issue are currently ongoing. The KEYNOTE-975 trial aims to investigate the benefit of the combination of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma [ 25 ]. Furthermore, the SKYSCRAPER-07 trial evaluates the efficacy and safety of tiragolumab, a monoclonal antibody designed to bind with TIGIT (a protein receptor on immune cells), plus atezolizumab, a humanized monoclonal antibody immune checkpoint inhibitor that selectively binds to PD-L1, compared with the placebo in participants with localized but unresectable esophageal SCC following definitive concurrent chemoradiotherapy.…”

Targeted Photodynamic Diagnosis and Therapy for Esophageal Cancer: Potential Role of Functionalized Nanomedicine

“…These drugs are usually given in combinations to improve their efficacies. Furthermore, to limit off-target, increase optimal therapeutic effects, and improve survival outcomes, chemotherapeutic agents are now administrated with some molecular target drugs such as trastuzumab, nivolumab, pembrolizumab, ramucirumab, fam-trastuzumab deruxtecan-nxki, and cetuximab [12,14,15]. Early-stage cancer treated with chemotherapy has shown improved survival rates, particularly in combination with radiation, while a poor prognosis is observed in advanced-stage esophageal cancer [15,16].…”