Checkpoint Inhibitor Immunotherapy for Treatment of Advanced Cervical Cancer
by Dr. C.H. Weaver M.D. Medical Editor update 3/2021
The use of PD-1 "checkpoint inhibitor" immunotherapy appears promising for the treatment of advanced cervical cancer. The U.S. Food and Drug Administration (FDA) approved Keytruda (pembrolizumab) for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 in 2018. Keytruda was the first "checkpoint inhibitor" anti-PD-1 immunotherapy approved for patients with advanced cervical cancer. (1) Reports also suggest the checkpoint inhibitor Opdivo (nivolumab) produces similar responses.(2)
According to Dr. Bradley Monk, oncologist with Arizona Oncology, medical director of US Oncology Research Gynecology Program and professor of obstetrics and gynecology at University of Arizona’s College of Medicine and Creighton University School of Medicine “Even with the many advances observed across gynecologic cancers, new treatment options have been lacking for previously treated patients with advanced cervical cancer. The approval of immunotherapy for cervical cancer patients is important news – and as an oncologist, it is exciting to see a much needed option made available to these patients.”
About Cervical Cancer
Each year in the United States, more than 12,000 women are diagnosed with cervical cancer and more than 4,000 die of the disease. Traditional chemotherapy drugs have limited effectiveness against advanced cervical cancer, highlighting the importance of finding new ways to treat this disease.
About Keytruda (pembrolizumab)
Keytruda is a monoclonal antibody know as a checkpoint inhibitor that helps to restore the body’s immune system in fighting cancer. It creates its anti-cancer effects by blocking a specific protein used by cancer cells called PD-L1, to escape an attack by the immune system. Once PD-L1 is blocked, cells of the immune system are able to identify cancer cells as a threat and initiate an attack to destroy the cancer. Keytruda is approved for the treatment of several types of cancer.
The current study evaluated 98 patients with recurrent or metastatic cervical cancer in study called Keynote-158. Patients were treated with Keytruda intravenously at a dose of 200 mg every three weeks until unacceptable toxicity or documented disease progression. Among the 98 patients in treated 77 (79%) had tumors that expressed PD-L1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the an FDA approved assay.
For the 77 patients whose tumors expressed PD-L1 the overall response rate was 14.3 percent with a complete response rate of 2.6 percent and partial response rate of 11.7 percent. Among the 11 responding patients, the median duration of response has not yet been reached (range, 4.1 to 18.6+ months) and 91 percent experienced a duration of response of six months or longer. No responses were observed in patients whose tumors did not have PD-L1 expression.
Opdivo - Yervoy Immunotherapy Combination
Opdivo (nivolumab) in combination with Yervoy (ipilimumab) appears to benefit women with recurrent or metastatic cervical cancer regardless of PD-L1 status, according to results of the results of the CheckMate 358 clinical trial presented at the 2019 European Society for Medical Oncology Congress.
Opdivo blocks the activity of a molecule PD-1 found on T cells and is approved for advanced non-small cell lung cancer, melanoma, and renal cell carcinoma patients. Yervoy targets a molecule called CTLA-4 on T cells and is approved for advanced melanoma patients. Studies have shown that Opdivo combined with Yervoy results in improved anti-tumor activity when compared to either agent alone. Doctors from Dana Farber Cancer Institute in Boston MA have reported this observation in the treatment of malignant melanoma further supporting the idea that this combination precision cancer immunotherapy is promising.
Researchers treated 91 women with advanced cervical cancer with 2 different dosing strategies combining Opdivo and Yervoy for up to 24 months, of until disease progression or unacceptable side effects occurred. With an average follow up of approximately one year 46% of previously untreated and 36% of those receiving prior systemic treatment responded to therapy with Opdivo -Yervoy combination. (2,3)
Balstilimab - Zalifrelimab Active in Advanced Cervical Cancer
Checkpoint blockade with the PD-1 inhibitor balstilimab, alone or in combination with the anti-CTLA-4 drug zalifrelimab have also been demonstrated to have anti-cancer activity in women with recurrent or metastatic cervical cancer according to the results from two early phase clinical trials. (4)
Each of the studies involved women with recurrent or metastatic cervical cancer who experienced a recurrence following platinum-based chemotherapy as first-line treatment.
In patients treated with balstilimab alone, the overall response rate was 14%, including complete responses in 2%, In individuals who received both investigational agents -- balstilimab plus zalifrelimab the response rate increased to 22%, including complete responses in 6%.
When evaluated by histology, the response rate was higher in patients with squamous cell carcinoma who received the combination therapy (27% vs 18% with balstilimab alone).
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Libtayo is a fully human monoclonal antibody targeting the programmed death receptor-1 (PD-1) on T cells. Libtayo blocks the PD-1 protein that interferes with certain types of immune responses and may enhance the ability of the immune system to fight cancer.
A Phase 3 clinical trial investigating the PD-1 inhibitor Libtayo® (cemiplimab) compared to chemotherapy in patients with recurrent or metastatic cervical cancer was stopped early because Libtayo monotherapy demonstrated an improvement in overall survival. The trial included women with either squamous cell carcinoma or adenocarcinoma. Libtayo monotherapy was directly compared to the investigator’s choice of commonly used chemotherapy (pemetrexed, vinorelbine, topotecan, irinotecan or gemcitabine). Libtayo treated patients experienced delayed recurrence and prolonged survival compared to women treated with chemotherapy. (5)
- FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Previously Treated Patients with Recurrent or Metastatic Cervical Cancer Whose Tumors Express PD-L1 (CPS Greater Than or Equal to 1)
- J Clin Oncol. 2019;37:2825-2834
- Naumann W, et al. Abstract LBA62. Presented at: European Society for Medical Oncology; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
- [O'Malley DM, et al "Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): Preliminary results of two independent phase II trials" ESMO 2020; Abstract LBA34.](https://www.annalsofoncology.org/article/S0923-7534(20%2942346-4/pdf)