Zimberelimab Combined With Concurrent Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer

Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer

Pembrolizumab has efficacy in programmed death ligand 1 (PD-L1)-positive metastatic or unresectable cervical cancer that has progressed during chemotherapy. We assessed the relative benefit of adding pembrolizumab to chemotherapy with or without bevacizumab. In a double-blind, phase 3 trial, we randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. The dual primary end points were progression-free survival and overall survival, each tested sequentially in patients with a PD-L1 combined positive score of 1 or more, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more. The combined positive score is defined as the number of PD-L1-staining cells divided by the total number of viable tumor cells, multiplied by 100. All results are from the protocol-specified first interim analysis. In 548 patients with a PD-L1 combined positive score of 1 or more, median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.50 to 0.77; P<0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P<0.001). In 317 patients with a PD-L1 combined positive score of 10 or more, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P<0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P<0.001), 50.4% and 40.4% (hazard ratio, 0.67; 95% CI, 0.54 to 0.84; P<0.001), and 54.4% and 44.6% (hazard ratio, 0.61; 95% CI, 0.44 to 0.84; P = 0.001), respectively. The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively). Progression-free and overall survival were significantly longer with pembrolizumab than with placebo among patients with persistent, recurrent, or metastatic cervical cancer who were also receiving chemotherapy with or without bevacizumab. (Funded by Merck Sharp and Dohme; KEYNOTE-826 ClinicalTrials.gov number, NCT03635567.).

Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002)

Patients with persistent/recurrent cervical cancer following platinum-based chemotherapy have limited therapeutic options. The Gynecologic-Oncology-Group conducted a phase II trial to assess efficacy and tolerability of nivolumab, an immune checkpoint inhibitor, in persistent/recurrent cervical carcinoma. Key eligibility criteria included persistent/recurrent cervical cancer, failure of prior systemic therapy and ECOG PS 0-1. Nivolumab 3 mg/kg was given IV every 2 wk. until disease progression or intolerable toxicity. Response was assessed every 8 wk. for 6 months and every 12 wk. thereafter. The primary endpoints were objective response as assessed by RECIST 1.1. The study used a 2-stage group sequential design. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1%. Of 26 enrolled patients with persistent/recurrent cervical cancer, 25 were evaluable for response/toxicity with a median age of 45. 36% had ECOG PS of 1, and 100% had received one prior systemic chemotherapy regimen. PD-L1 expression (≥1%) was identified in 77.3% of tumor samples. As of 03/05/19, all patients were off study treatment; median follow-up for survival status was 32 months (range, 2-41.5). There were 21 (84%) patients with a treatment-related adverse event (TRAE) and most were grades 1-2. Six (24%) patients had grade 3 TRAEs with 1 discontinuing nivolumab due to hepatic toxicity. No grade 5 TRAEs occurred, and 2 patients had grade 4 TRAEs. One confirmed partial response (4%; 90% CI, 0.4%-22.9%), duration of response 3.8 months. Thirty-six percent of patients had stable disease (SD) (9/25; 90% CI, 20.2%-54.4%); the median duration of SD was 5.7 months (range, 3.5-12.7). Estimated PFS and OS at 6 months were 16% and 78.4%, respectively. Single agent nivolumab exhibited low antitumor activity and an acceptable safety profile in patients with persistent/recurrent cervical cancer previously treated with platinum-based chemotherapy.

Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis

The knowledge that persistent human papillomavirus (HPV) infection is the main cause of cervical cancer has resulted in the development of prophylactic vaccines to prevent HPV infection and HPV assays that detect nucleic acids of the virus. WHO has launched a Global Initiative to scale up preventive, screening, and treatment interventions to eliminate cervical cancer as a public health problem during the 21st century. Therefore, our study aimed to assess the existing burden of cervical cancer as a baseline from which to assess the effect of this initiative. For this worldwide analysis, we used data of cancer estimates from 185 countries from the Global Cancer Observatory 2018 database. We used a hierarchy of methods dependent on the availability and quality of the source information from population-based cancer registries to estimate incidence of cervical cancer. For estimation of cervical cancer mortality, we used the WHO mortality database. Countries were grouped in 21 subcontinents and were also categorised as high-resource or lower-resource countries, on the basis of their Human Development Index. We calculated the number of cervical cancer cases and deaths in a given country, directly age-standardised incidence and mortality rate of cervical cancer, indirectly standardised incidence ratio and mortality ratio, cumulative incidence and mortality rate, and average age at diagnosis. Approximately 570 000 cases of cervical cancer and 311 000 deaths from the disease occurred in 2018. Cervical cancer was the fourth most common cancer in women, ranking after breast cancer (2·1 million cases), colorectal cancer (0·8 million) and lung cancer (0·7 million). The estimated age-standardised incidence of cervical cancer was 13·1 per 100 000 women globally and varied widely among countries, with rates ranging from less than 2 to 75 per 100 000 women. Cervical cancer was the leading cause of cancer-related death in women in eastern, western, middle, and southern Africa. The highest incidence was estimated in Eswatini, with approximately 6·5% of women developing cervical cancer before age 75 years. China and India together contributed more than a third of the global cervical burden, with 106 000 cases in China and 97 000 cases in India, and 48 000 deaths in China and 60 000 deaths in India. Globally, the average age at diagnosis of cervical cancer was 53 years, ranging from 44 years (Vanuatu) to 68 years (Singapore). The global average age at death from cervical cancer was 59 years, ranging from 45 years (Vanuatu) to 76 years (Martinique). Cervical cancer ranked in the top three cancers affecting women younger than 45 years in 146 (79%) of 185 countries assessed. Cervical cancer continues to be a major public health problem affecting middle-aged women, particularly in less-resourced countries. The global scale-up of HPV vaccination and HPV-based screening-including self-sampling-has potential to make cervical cancer a rare disease in the decades to come. Our study could help shape and monitor the initiative to eliminate cervical cancer as a major public health problem. Belgian Foundation Against Cancer, DG Research and Innovation of the European Commission, and The Bill & Melinda Gates Foundation.

Alessandro D. Santin

Michael Frumovitz