SUMMARY: The American Cancer Society estimates that for cervical cancer in the US for 2021, about 14,480 new cases of invasive cervical cancer will be diagnosed and about 4,290 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to develop cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.
Patients with persistent, recurrent, or metastatic cervical cancer often receive Platinum-based chemotherapy, (Cisplatin or Carboplatin along with Paclitaxel) plus Bevacizumab. The addition of Bevacizumab to chemotherapy improved the median Overall Survival from 13.3 months to 17 months in a randomized study.
KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. In the KEYNOTE-158 trial, the Objective Response Rate (ORR) with single agent KEYTRUDA® in previously treated recurrent or metastatic cervical cancer patients with PD-L1 positive tumors was 14.3%. KEYNOTE-826 trial was conducted to assess whether adding KEYTRUDA® to Platinum-based chemotherapy with or without Bevacizumab would improve efficacy, as compared with chemotherapy with or without Bevacizumab, as first line therapy for persistent, recurrent, or metastatic cervical cancer.
KEYNOTE-826 is a global, multicenter, double-blind, randomized Phase III trial, in which 617 women with recurrent, persistent, or metastatic cervical cancer were randomly assigned in a 1:1 ratio to receive KEYTRUDA® 200 mg IV or placebo, every 3 weeks for up to 35 cycles. Patients in both treatment groups received Paclitaxel 175 mg/m2 IV and the investigator’s choice of Cisplatin 50 mg/m2 or Carboplatin AUC 5 IV every 3 weeks. Chemotherapy was limited to 6 cycles, although patients with ongoing clinical benefit without unacceptable side effects could continue beyond 6 cycles. Bevacizumab at a dose of 15 mg/kg IV every 3 weeks was allowed at the investigator’s discretion. Enrolled patients were not previously treated for advanced disease and were not considered curable. The median patient age was 50 years, and close to two thirds of the patients had persistent or recurrent disease with distant metastases. Patients were stratified according to metastatic disease at diagnosis, planned Bevacizumab use and PD-L1 Combined Positive Score (CPS) less than 1, 1-9 and 10 or more. All the treatment groups were well balanced and about 63% of patients in each treatment group received Bevacizumab. Eighty eight percent (88%) of patients had PD-L1 CPS 1 or more at baseline, and 51% had CPS 10 or more. Approximately 72% of the patients had Squamous Cell Carcinoma, 56% received previous chemoradiotherapy with or without surgery, and 20% had previously untreated metastatic disease at trial entry. The dual Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS). The median follow up for the first interim analysis was 22.0 months.
The median PFS in those patients with a PD-L1 CPS of 1 or more (N=548) was 10.4 months in the KEYTRUDA® group and 8.2 months in the placebo group (HR for disease progression or death=0.62; P<0.001). This represented a 38% reduction in the risk of disease progression or death in the KEYTRUDA® group. The PFS in all enrolled patients (N=617) was 10.4 months and 8.2 months, respectively (HR=0.65; P<0.001). The PFS in patients with a PD-L1 CPS of 10 or more (N=317) was 10.4 months and 8.1 months, respectively (HR=0.58; P<0.001).
The OS at 24 months was significantly longer in the KEYTRUDA® group, compared to the placebo group, among patients with a PD-L1 CPS of 1 or more, and was 53% in the KEYTRUDA® group and 41.7% in the placebo group (HR for death= 0.64; P<0.001), 50.4% and 40.4% among all enrolled patients (HR=0.67; P<0.001), and 54.4% and 44.6% among patients with a PD-L1 CPS of 10 or more (HR=0.61; P=0.001), respectively. The confirmed Response Rates were also higher and Duration of Response longer in all patient groups receiving KEYTRUDA®, compared to placebo. Side effects with the combination therapy were manageable and were as expected, based on known adverse events with the individual drugs.
It was concluded that the addition of KEYTRUDA® to chemotherapy, with or without Bevacizumab, significantly prolonged Progression Free and Overall Survival, among patients with persistent, recurrent, or metastatic cervical cancer.
Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. Colombo N, Dubot C, Lorusso D, et al. for the KEYNOTE-826 Investigators. September 18, 2021. DOI: 10.1056/NEJMoa2112435.