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Clinical Trial
. 2020 Jan 1;6(1):92-99.
doi: 10.1001/jamaoncol.2019.3857.

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

Jyoti S Mayadev  1 , Danielle Enserro  2 , Yvonne G Lin  3 , Diane M Da Silva  3 , Heather A Lankes  4 , Carol Aghajanian  5 , Sharad Ghamande  6 , Kathleen N Moore  7 , Vanessa A Kennedy  8 , Paula M Fracasso  9 , Russell J Schilder  10
Affiliations
Clinical Trial

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

Jyoti S Mayadev et al. JAMA Oncol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mayadev reported receiving grant U10 27469 from the National Cancer Institute (NCI) during the conduct of the study, personal fees from AstraZeneca, grants from NRG Oncology, and personal fees and nonfinancial support from the GOG Foundation outside the submitted work; receiving compensation for serving on the advisory board of Varian Medical Systems in 2018; and for being a speaker for Samsung Medical Systems in 2017. Dr Enserro reported receiving grants from NCI during the conduct of the study. Dr Lin reported receiving grants from the National Institutes of Health–NCI and funding from University of Southern California Norris Women’s Auxiliary Group during the conduct of the study, and other from Genentech-Roche outside the submitted work. Dr Da Silva reported receiving grants from the Cancer Research Institute during the conduct of the study. Dr Aghajanian reported receiving grants from NCI during the conduct of the study; personal fees from Cerulean, Clovis, Eisai, ImmunoGen, Mateon Therapeutics, and Tesaro; and grants from AbbVie, AstraZeneca, Clovis, and Genentech outside the submitted work. Dr Ghamande reported receiving consulting fees from Tesaro outside the submitted work. Dr Moore reported receiving personal fees from Aravive, AstraZeneca, Clovis, Genentech-Roche, Janssen, Merck, OncoMed, Pfizer, Samumed, Tesaro, and VBL Therapeutics outside the submitted work. Dr Kennedy reported receiving grants from NRG Oncology/Gynecology Oncology Group during the conduct of the study. Dr Fracasso reported receiving grants from NCI Gynecologic Oncology Group (now NRG Oncology) during the conduct of the study and being an employee of Bristol-Myers Squibb from May 2014 to December 2018. Before her employment with Bristol-Myers Squibb and Adaptimmune, Dr Fracasso was a professor of medicine and obstetrics and gynecology at the University of Virginia, where she is now a visiting professor. Her work on this clinical study was done while she was a professor at University of Virginia, and no activities in this article have any relationship to her earlier work at Bristol-Myers Squibb or her ongoing work at Adaptimmune. Dr Schilder reported receiving grants from NCI/NRG during the conduct of the study and personal fees from Celsion, Flatiron, Immunogen, and Incyte outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Schema
After the maximum tolerated dose was estimated, the expansion cohort started treatment. GOG indicates Gynecology Oncology Group; HDR, high dose rate brachytherapy; and LDR, low dose rate brachytherapy.
Figure 2.
Figure 2.. Gynecology Oncology Group 9929 Study CONSORT Diagram
DLT indicates dose-limiting toxic effects; CRT, chemoradiotherapy.
Figure 3.
Figure 3.. Progression-Free and Overall Survival in Patients Receiving 2 or More Cycles of Ipilimumab
Figure 4.
Figure 4.. Expression of Programmed Cell Death 1 (PD-1) After Chemoradiotherapy (CRT) and Ipilimumab Administration
Peripheral blood lymphocytes were phenotyped by multicolor flow cytometry for T-cell activation markers. Both CD4+ and CD8+ T cells were associated with significantly increased expression of PD-1 compared with baseline, and the percentage of PD-1–positive cells was sustained throughout the 12 weeks of ipilimumab treatment. Boxplots show 25th to 75th percentiles, with median (horizontal line in the box) PD-1 expression in all patients (solid circles) with evaluable data. Whiskers indicate minimum and maximum values.
See this image and copyright information in PMC

Comment in

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