Background: Immunotherapy became the new treatment paradigm in a wide spectrum of cancers including MSI-H tumors. However, therapeutic options are limited with development of resistance to an anti-PD-1 inhibitor. Therefore, overcoming acquired resistance to immunotherapy remains an important high unmet need in the field of immuo-oncology. Herein, we present the first case of advanced cervical cancer with MSI-H trait that showed notable response to dual-immunotherapy with nivolumab and ipilimumab after acquired resistance to an anti PD-1 inhibitor.

Case presentation: A 58-year-old woman with stage Ib1 invasive poorly differentiated squamous cell carcinoma of cervix was treated with chemoradiation therapy with cisplatin for 10 months. Then she developed progression of disease with lung metastasis. Systemic therapy regimen was changed to paclitaxel/bevacizumab, and mixed response was observed during six months of treatment. However, it was prematurely discontinued due to worsening peripheral neuropathy. Next regimen with topotecan was also discontinued after one month because of cytopenia. Subsequently, she was started on pembrolizumab 200 mg once every three weeks based on the MSI-H trait. She initially had partial response followed by stable disease throughout the 16 months of pembrolizumab treatment. However, she was found to have disease progression with increase in size of the lung mass. At this point, decision was made for a trial of dual-immunotherapy with nivolumab 3 mg/kg once every two weeks and ipilimumab 1 mg/kg once every six weeks to possibly overcome immunotherapy resistance given her tolerability of immunotherapy. After six weeks, the follow-up CT scan demonstrated deep partial response (RECIST 1.1). The 72 mm main lung mass was significantly decreased to the 10 mm cystic lesion. Other small nodules were stable. The follow-up CT after three months from dual therapy revealed durable response. She has not had any immune-related toxicity except mild pruritic rash to date for four months.

Discussion: There has been no report of response to combination immunotherapy in patients who acquired anti-PD-1 inhibitor resistance in advanced cervical cancer. We for the first time report the case of advanced cervical cancer with MSI-H trait that showed notable response to dual combination immunotherapy with nivolumab and ipilimumab after acquired resistance to an anti PD-1 inhibitor. Our case highlights the potential benefit of sequential administration of combined immunotherapy to advanced cervical cancer patients with MSI-H trait exhibiting acquired resistance to anti-PD-1 inhibitors. To date, there is no ongoing prospective study on the use of combined anti-PD-1 and anti-CTLA-4 therapy at the time of progression on anti-PD-1 inhibitors in patients with MSI-H tumors or advanced cervical cancer. Such further investigations are warranted.

Citation Format: Gahyun Gim, Sukjoo Cho, Dongyup Lee, Jonghanne Park, Leeseul Kim, Horyun Choi, Cyra Y. Kang, Elena Vagia, Pedro Viveiros, Young Kwang Chae. Response to nivolumab and ipilimumab in microsatellite instability-high (MSI-H) cervical carcinoma with acquired resistance to pembrolizumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6659.