Sequential Ipilimumab after Chemoradiotherapy in Curative-Intent Treatment of Patients with Node-Positive Cervical Cancer

Jyoti S. Mayadev, Danielle Enserro, Yvonne G. Lin, Diane M. Da Silva, Heather A. Lankes, Carol Aghajanian, Sharad Ghamande, Kathleen N. Moore, Vanessa A. Kennedy, Paula M. Fracasso, Russell J. Schilder

Research output: Contribution to journalArticle

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..

Original languageEnglish (US)
JournalJAMA Oncology
DOIs
StateAccepted/In press - Jan 1 2019

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Chemoradiotherapy
Uterine Cervical Neoplasms
Immunotherapy
Cell Death
Disease-Free Survival
Therapeutics
Survival
Maximum Tolerated Dose
Genotype
Gynecology
Lymph Nodes
Alleles
T-Lymphocytes
Safety
ipilimumab
Poisons
Dermatitis
Lipase
Cisplatin
Obstetrics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mayadev, J. S., Enserro, D., Lin, Y. G., Da Silva, D. M., Lankes, H. A., Aghajanian, C., ... Schilder, R. J. (Accepted/In press). Sequential Ipilimumab after Chemoradiotherapy in Curative-Intent Treatment of Patients with Node-Positive Cervical Cancer. JAMA Oncology. https://doi.org/10.1001/jamaoncol.2019.3857

Sequential Ipilimumab after Chemoradiotherapy in Curative-Intent Treatment of Patients with Node-Positive Cervical Cancer. / Mayadev, Jyoti S.; Enserro, Danielle; Lin, Yvonne G.; Da Silva, Diane M.; Lankes, Heather A.; Aghajanian, Carol; Ghamande, Sharad; Moore, Kathleen N.; Kennedy, Vanessa A.; Fracasso, Paula M.; Schilder, Russell J.

In: JAMA Oncology, 01.01.2019.

Research output: Contribution to journalArticle

Mayadev, JS, Enserro, D, Lin, YG, Da Silva, DM, Lankes, HA, Aghajanian, C, Ghamande, S, Moore, KN, Kennedy, VA, Fracasso, PM & Schilder, RJ 2019, 'Sequential Ipilimumab after Chemoradiotherapy in Curative-Intent Treatment of Patients with Node-Positive Cervical Cancer', JAMA Oncology. https://doi.org/10.1001/jamaoncol.2019.3857
Mayadev, Jyoti S. ; Enserro, Danielle ; Lin, Yvonne G. ; Da Silva, Diane M. ; Lankes, Heather A. ; Aghajanian, Carol ; Ghamande, Sharad ; Moore, Kathleen N. ; Kennedy, Vanessa A. ; Fracasso, Paula M. ; Schilder, Russell J. / Sequential Ipilimumab after Chemoradiotherapy in Curative-Intent Treatment of Patients with Node-Positive Cervical Cancer. In: JAMA Oncology. 2019.
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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..",
author = "Mayadev, {Jyoti S.} and Danielle Enserro and Lin, {Yvonne G.} and {Da Silva}, {Diane M.} and Lankes, {Heather A.} and Carol Aghajanian and Sharad Ghamande and Moore, {Kathleen N.} and Kennedy, {Vanessa A.} and Fracasso, {Paula M.} and Schilder, {Russell J.}",
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T1 - Sequential Ipilimumab after Chemoradiotherapy in Curative-Intent Treatment of Patients with Node-Positive Cervical Cancer

AU - Mayadev, Jyoti S.

AU - Enserro, Danielle

AU - Lin, Yvonne G.

AU - Da Silva, Diane M.

AU - Lankes, Heather A.

AU - Aghajanian, Carol

AU - Ghamande, Sharad

AU - Moore, Kathleen N.

AU - Kennedy, Vanessa A.

AU - Fracasso, Paula M.

AU - Schilder, Russell J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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..

AB - 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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