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Original Investigation
November 27, 2019

Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer

Author Affiliations
  • 1Department of Radiation Medicine and Applied Sciences, University of California, San Diego, Medical Center, La Jolla
  • 2NRG Oncology, Clinical Trial Development Division, Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
  • 3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles
  • 4Biopathology Center, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio
  • 5Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 6Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Augusta University Medical Center, Augusta, Georgia
  • 7Department of Obstetrics and Gynecology, Oklahoma University Health Science Center, Oklahoma City
  • 8Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Davis Comprehensive Cancer Center, Sacramento
  • 9Department of Medicine, UVA Cancer Center, University of Virginia, Charlottesville
  • 10Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
JAMA Oncol. Published online November 27, 2019. doi:https://doi.org/10.1001/jamaoncol.2019.3857
Key Points

Question  Is immunotherapy after chemoradiotherapy in node-positive cervical cancer tolerable?

Findings  In this multi-institutional phase 1 trial, 21 patients with node-positive cervical cancer received chemoradiotherapy followed by ipilimumab therapy at a maximum tolerated dose of 10 mg/kg. Two patients experienced self-limiting grade 3 toxic effects.

Meaning  This study’s findings suggest that treatment with anti–cytotoxic T-lymphocyte antigen 4 after chemoradiotherapy is tolerable for patients with node-positive cervical cancer.

Abstract

Importance  Despite standard chemoradiotherapy (CRT), most women with lymph node (LN)–positive cervical cancer experience disease recurrence. Immunotherapy is being investigated in the up-front treatment setting.

Objectives  To assess the safety of sequential immunotherapy after CRT and to investigate human papillomavirus (HPV) genotype and HLA allele status on survival and programmed cell death 1 (PD-1) expression before and after CRT and sequential immunotherapy.

Design, Setting, and Participants  This prospective phase 1 trial conducted in 29 Gynecology Oncology Cooperative Group member institutions enrolled participants from December 18, 2012, to August 31, 2016, with a 14.8-month median follow-up and translational end points. Thirty-four women with International Federation of Gynecology and Obstetrics stage IB2 to IVA cervical cancer with positive pelvic LNs, para-aortic LNs, or both were enrolled; 13 did not receive ipilimumab and were excluded from the analysis. Data were analyzed from January 21 to April 4, 2018.

Interventions  Treatment consisted of 6 weekly doses of cisplatin, 40 mg/m2, concurrent with radiotherapy. After completion of chemotherapy, sequential ipilimumab was given every 21 days for 4 doses. Two dosage levels of ipilimumab, 3 mg/kg and 10 mg/kg, were studied to identify the maximum tolerated dose.

Main Outcomes and Measures  The primary end point was safety, and the secondary end points were overall survival and progression-free survival. Exploratory end points included HPV genotype, HLA allele status, and PD-1 expression measured in peripheral blood.

Results  The median age of the 32 participants included in the intent-to-treat analysis was 50 (range, 26-61) years, and 22 patients (69%) were white. Of the 21 patients who received ipilimumab, all had positive pelvic LN, and 6 (29%) had positive para-aortic LNs. All patients completed CRT, and of the 21 patients who received at least 2 cycles of ipilimumab, 18 (86%) completed 4 cycles of ipilimumab, and 3 (14%) completed 2 cycles. The maximum tolerated dose was 10 mg/kg. Two of the 21 patients (9.5%) who received ipilimumab had self-limiting grade 3 toxic effects (lipase increase; dermatitis). The 12-month overall survival was 90%, and progression-free survival was 81%. Human papillomavirus genotype and HLA subtype were not associated with progression-free survival or overall survival. T cells expressing PD-1 increased after CRT, and levels were sustained with ipilimumab.

Conclusions and Relevance  This study’s findings suggest that the use of immunotherapy after CRT for curative-intent treatment of patients with cervical cancer is tolerable and effective. The results indicated that PD-1 was upregulated after CRT and sustained with sequential ipilimumab therapy. These immune findings may help guide future therapies to harness the activated T-cell phenotype in patients with node-positive cervical cancer.

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