254TiP - ENGOT-cx11/KEYNOTE-A18: A Phase 3, Randomized, Double-Blind Study of Pembrolizumab With Chemoradiotherapy in Patients With High-Risk Locally Advanced Cervical Cancer

Background

High-risk locally advanced cervical cancer has a poor prognosis, and most patients (pts) experience recurrence in 2 y. External beam radiotherapy (EBRT) with concurrent chemotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer. The immunostimulatory activity of the PD-1 inhibitor pembrolizumab (pembro) may be enhanced by concurrent chemoradiotherapy (CRT). After the KEYNOTE-158 study, in which pembro had durable antitumor activity, pembro monotherapy was approved for pts with PD-L1–positive recurrent or metastatic cervical cancer who progressed during or after chemotherapy. ENGOT-cx11/KEYNOTE-A18 (NCT04221945) is a phase 3, randomized, placebo (pbo)-controlled study of pembro with concurrent CRT for the treatment of locally advanced cervical cancer.

Trial design

~980 pts with high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA), locally advanced, histologically confirmed cervical cancer who have not received systemic therapy, immunotherapy, definitive surgery, or radiation will be randomized 1:1 to receive either 5 cycles of pembro 200 mg Q3W + CRT then 15 cycles of pembro 400 mg Q6W or 5 cycles of pbo Q3W + CRT then 15 cycles of pbo Q6W. The CRT regimen includes 5 cycles (with optional 6th dose) of cisplatin 40 mg/m² Q1W + EBRT then brachytherapy.

Randomization is stratified by planned EBRT type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cancer stage at screening (stage IB2-IIB vs III-IVA), and planned total radiotherapy dose. Treatment will continue until the pt has received 20 cycles of pembro (5 cycles 200 mg Q3W, 15 cycles 400 mg Q6W) vs pbo (~2 y) or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are PFS per RECIST version 1.1 by blinded independent central review and OS. Secondary endpoints are PFS at 2 y; OS at 3 y; CR at 12 wk; ORR; PFS and OS in PD-L1–positive pts; EORTC Quality of Life Questionnaire (QLQ)–Core 30 and Cervical Cancer Module (EORTC QLQ-CX24); and safety. Enrollment is ongoing in 30 countries.

Clinical trial identification

ClinicalTrials.gov identifier, NCT04221945; EudraCT number, 2019-003152-37