3 - A Phase 3 Study of Pembrolizumab (Pembro) + Concurrent Chemoradiotherapy (CCRT) for High-Risk Locally Advanced Cervical Cancer (LACC): Safety Findings

G. Macchia¹, A. Cerrotta², M. Christiaens³, S. Lalondrelle⁴, W. D. Zhao⁵, S. Suzuki⁶, K. Reginacova⁷, L. Helpman⁸, A. Ayhan⁹, F. Zagouri¹⁰, B. Aktas¹¹, L. Bjorge¹², K. Romano¹³, M. Aguilar Vasquez¹⁴, F. Cruz¹⁵, P. Rodríguez Monarca¹⁶, K. Yamada¹⁷, K. Li¹⁷, E. C. Fields¹⁸, and D. Lorusso¹⁹; ¹Radiation Oncology Unit, Responsible Research Hospital, Campobasso, Italy, ²Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, ³Department of Radiation-Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium, ⁴Department of Clinical Oncology, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research London, London, United Kingdom, ⁵Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China, ⁶Department of Gynecologic Oncology, Aichi Cancer Center Hospital, Aichi, Japan, ⁷Department of Oncology, University Hospital Kralovske Vinohrady, Prague, Czech Republic and Charles University, Third Faculty of Medicine, Department of Oncology, Prague, Czech Republic, ⁸Tel Aviv University and Sheba Medical Center, Ramat Gan, Israel, ⁹Turkish Society of Gynecologic Oncology (TRSGO), Baskent University, Ankara, Turkey, ¹⁰Alexandra Hospital, Athens, Athens, Greece, ¹¹Department of Gynaecology, University Hospital Leipzig, Leipzig, Germany, ¹²Haukeland University Hospital, Department of Obstetrics and Gynecology and University of Bergen, Department of Clinical Science, Center for Cancer Biomarkers CCBIO, Bergen, Norway, ¹³Department of Radiation Oncology, University of Virginia School of Medicine, Charlottesville, VA, ¹⁴Medi-K Cayala, Guatemala City, Guatemala, ¹⁵Instituto Brasileiro de Controle do Câncer, São Paulo, SP, Brazil and Centro Universitário São Camilo, São Paulo, SP, Brazil, ¹⁶Iram Cancer Research, Santiago, Chile, ¹⁷Merck & Co., Inc., Rahway, NJ, ¹⁸Department of Radiation Oncology, Virginia Commonwealth University Health System, Massey Cancer Center, Richmond, VA, ¹⁹Gynaecology Oncology Unit, Fondazione Policlinico Universitario A Gemelli IRCCS and Catholic University of Sacred Heart, Rome, Italy

Purpose/Objective(s): In ENGOT-cx11/GOG-3047/KEYNOTE-A18 (NCT04221945), pembro + CCRT improved PFS (HR, 0.70 [95% CI, 0.55?0.89]; P = 0.0020) and showed a favorable trend in OS (HR, 0.73 [95% CI, 0.49?1.07]) vs placebo (pbo) + CCRT in high-risk LACC at interim analysis 1 (IA1). Here we report IA1 safety data. Materials/

Methods: Patients (pts) with previously untreated, high-risk LACC (FIGO 2014 stage IB2?IIB node-positive or stage III?IVA) were randomized 1:1 to 5 cycles of pembro 200 mg or pbo Q3W + CCRT, then 15 cycles of pembro 400 mg or pbo Q6W. CCRT included 5 cycles (optional 6th dose) of cisplatin 40 mg/m² QW + EBRT followed by brachytherapy. Safety was evaluated in all randomized and treated pts.

Results: Of 1060 randomized pts, 1058 were included in the safety analysis. At data cutoff (Jan 9, 2023), median follow-up was 17.9 mo. AE rates were similar between the treatment arms (table). AEs were more common during the pembro + CCRT combination therapy phase vs pembro monotherapy phase. Exposure-adjusted AE rates generally decreased after 3 mo; hypothyroidism was most common between 3-6 mo with pembro + CCRT. Event rates for genitourinary AEs were <10.0 events per 100 person-months of exposure during any period.

Conclusion: Pembro + CCRT had manageable safety that was consistent with the known profiles of pembro monotherapy and chemoradiotherapy. Most AEs occurred during the combination therapy phase.

Abstract 3 – Table 1: Safety results

	Pembro + Chemo n = 528				Pbo + Chemo n = 530
	Combination therapy		Monotherapy		Combination therapy		Monotherapy
Any AE, n (%)	520 (98.5)		455 (86.2)		522 (98.5)		435 (82.1)
Any TRAE, n (%)	499 (94.5)		384 (72.7)		507 (95.7)		318 (60.0)
Grade 3-5 TRAE, n (%)	331 (62.7)		88 (16.7)		307 (57.9)		51 (9.6)
Discontinuation due to TRAE, n (%)
Pembro/pbo	8 (1.5)		24 (4.5)		5 (0.9)		5 (0.9)
Cisplatin	55 (10.4)		0		57 (10.8)		1 (0.2)
EBRT	0		0		0		1 (0.2)
Brachytherapy	0		1 (0.2)		1 (0.2)		1 (0.2)
	Pembro + Chemo				Pbo + Chemo
	0-3 mo	3-6 mo	6-12 mo	>12 mo	0-3 mo	3-6 mo	6-12 mo	>12 mo
Most common exposure-adjusted AEsa
Anemia	439 (28.65)	13 (1.00)	42 (2.13)	35 (1.76)	398 (25.90)	18 (1.39)	38 (1.97)	18 (0.95)
Nausea	409 (26.69)	9 (0.69)	12 (0.61)	4 (0.20)	426 (27.72)	6 (0.46)	12 (0.62)	3 (0.16)
Decreased WBC count	402 (26.24)	30 (2.31)	32 (1.62)	15 (0.75)	423 (27.53)	47 (3.63)	44 (2.28)	12 (0.63)
Diarrhea	375 (24.48)	35 (2.69)	36 (1.82)	14 (0.70)	364 (23.69)	11 (0.85)	21 (1.09)	7 (0.37)
Decreased neutrophil count	315 (20.56)	13 (1.00)	15 (0.76)	13 (0.65)	303 (19.72)	21 (1.62)	11 (0.57)	3 (0.16)
Vomiting	199 (12.99)	15 (1.15)	9 (0.46)	6 (0.30)	249 (16.21)	4 (0.31)	3 (0.16)	2 (0.11)
Immune-mediated AEsa
Hyperthyroidism	36 (2.35)	11 (0.85)	10 (0.51)	9 (0.45)	4 (0.26)	0 (0)	4 (0.21)	3 (0.16)
Hypothyroidism	28 (1.83)	41 (3.15)	42 (2.13)	11 (0.55)	11 (0.72)	7 (0.54)	7 (0.36)	3 (0.16)
aEvent rate =10.0 for AEs and =1.0 for immune-mediated AEs during any period. Data are event counts with rates in parentheses (events/100 person-months of exposure).