Ultrasensitive detection and tracking of circulating tumor DNA to predict relapse and survival in patients with locally advanced cervical cancer: phase III CALLA trial analyses

J Mayadev; J C Vázquez Limón; F J Ramírez Godinez; M Leiva; L D C Cetina-Pérez; S Varga; A Molina Alavez; A E Alarcon-Rozas; N Valdiviezo; C Acevedo; A Figueroa; A Santini; L Vera; F Rey; Z Kahán; P Galaz; G Meléndez Mier; X Wu; M Mandai; R Shapira-Frommer; M D P Estevez-Diz; S Limaye; W Xin; H Dry; M A S Broggi; D Y Yuan; R A Stewart; B J Monk

doi:10.1016/j.annonc.2025.05.533

Ultrasensitive detection and tracking of circulating tumor DNA to predict relapse and survival in patients with locally advanced cervical cancer: phase III CALLA trial analyses

Ann Oncol. 2025 Jun 2:S0923-7534(25)00738-0. doi: 10.1016/j.annonc.2025.05.533. Online ahead of print.

Authors

J Mayadev¹, J C Vázquez Limón², F J Ramírez Godinez³, M Leiva⁴, L D C Cetina-Pérez⁵, S Varga⁶, A Molina Alavez⁷, A E Alarcon-Rozas⁸, N Valdiviezo⁹, C Acevedo¹⁰, A Figueroa¹¹, A Santini¹², L Vera¹³, F Rey¹⁴, Z Kahán¹⁵, P Galaz¹⁶, G Meléndez Mier¹⁷, X Wu¹⁸, M Mandai¹⁹, R Shapira-Frommer²⁰, M D P Estevez-Diz²¹, S Limaye²², W Xin²³, H Dry²⁴, M A S Broggi²⁵, D Y Yuan²⁶, R A Stewart²⁷, B J Monk²⁸

Affiliations

¹ Radiation Medicine and Applied Sciences Department, University of California San Diego Medical Center, San Diego, USA. Electronic address: jmayadev@health.ucsd.edu.
² Department of Medical Oncology, Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde", University of Guadalajara, Guadalajara, Mexico.
³ Department of Medical Oncology, Hospital Civil de Guadalajara, Guadalajara, Mexico.
⁴ Oncology Medicine, Institute of Oncology and Radiotherapy of the Ricardo Palma Clinic, San Isidro, Peru.
⁵ Department of Clinical Research, National Cancer Institute, Mexico City, Mexico.
⁶ National Institute of Oncology, Budapest, Hungary.
⁷ Centro de atención e Investigación Clínica en Oncología, Mérida, Mexico.
⁸ Santa Beatriz Clinic, Lima, Peru.
⁹ National Institute of Neoplastic Diseases, Lima, Peru.
¹⁰ Cayetano Heredia National Hospital, San Martín de Porres, Peru.
¹¹ ALIADA, Lima Oncology Center, Lima, Peru.
¹² Antofagasta Cancer Center, Antofagasta, Chile.
¹³ International Clinic-San Borja, Lima, Peru.
¹⁴ CIDO Clinic, Temuco, Chile.
¹⁵ Department of Oncotherapy, University of Szeged, Szeged, Hungary.
¹⁶ Radio Medicine Institute, Santiago, Chile.
¹⁷ Autonomous University of Nuevo León, San Nicolás de los Garza, Monterrey, Mexico.
¹⁸ Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
¹⁹ Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
²⁰ Ella Lemelbaum Institute for Immuno Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel.
²¹ Department of Radiology and Oncology, Instituto do Cancer do Estado de Sao Paulo-Universidade de Sao Paulo, São Paulo, Brazil.
²² Department of Medical Oncology, Sir H N Reliance Foundation Hospital, Mumbai, India.
²³ Biometrics Late Respiratory Immunology, AstraZeneca, Gothenburg, Sweden.
²⁴ Late Development Oncology R&D, AstraZeneca, Waltham, USA.
²⁵ Translational Medicine, Oncology R&D, AstraZeneca, Gaithersburg, USA.
²⁶ Oncology Data Science, Oncology R&D, AstraZeneca, Gaithersburg, USA.
²⁷ Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK.
²⁸ Florida Cancer Specialists and Research Institute, West Palm Beach, USA.

PMID: 40500687
DOI: 10.1016/j.annonc.2025.05.533

Abstract

Background: After chemoradiotherapy (CRT), 30%-50% of patients with locally advanced cervical cancer (LACC) relapse, highlighting the unmet need for prognostic biomarkers. In the global randomized CALLA trial (NCT03830866), the addition of durvalumab during and after CRT did not significantly improve progression-free survival (PFS) in a biomarker-unselected intent-to-treat population. We analyzed the association of ultrasensitive circulating tumor DNA (ctDNA) and circulating human papillomavirus (cHPV) DNA detection with relapse and survival in the largest dataset in LACC to date.

Patients and methods: In CALLA, adult women with stage IB2-IIB node-positive or IIIA-IVA any node-status LACC were randomized 1 : 1 to receive durvalumab + CRT or CRT alone. The NeXT Personal® (Personalis) ultrasensitive tumor-informed assay with up to 1800 patient-specific variants was used for ctDNA and cHPV DNA analysis at baseline, cycle 3 day 1 (C3D1, post-CRT), and C6D1 (3 months post-CRT). Correlations were analyzed between ctDNA/cHPV DNA detection and outcomes [PFS, overall survival (OS)].

Results: ctDNA was detected in 98.9% (183/185) of baseline samples, with no difference between treatment arms. Detection levels of ctDNA were predictive of disease progression and survival at baseline: hazard ratios (95% confidence intervals) comparing PFS and OS, respectively, in the ctDNA less than median versus ctDNA greater than median subgroups were 0.61 (0.28-1.35) and 0.55 (0.23-1.35) with durvalumab + CRT, and 0.49 (0.26-0.95) and 0.65 (0.33-1.28) with CRT. Post-treatment trends were similar and independent of stage or lymph node status. ctDNA detection at C3D1 occurred a median of 164 days (95% confidence interval 85-250) days before clinical progression. Baseline cHPV DNA levels were similar but were only predictive following treatment.

Conclusions: This study demonstrates the potential utility of ultrasensitive detection of ctDNA as a predictive and prognostic marker of disease progression and OS in LACC independent of disease stage.

Keywords: cHPV; ctDNA; efficacy outcomes; locally advanced cervical cancer; predictive marker; ultrasensitive.