New Standard of Care in Cervical Cancer 

Neil Osterweil

September 19, 2021

The new standard of care for women with persistent, recurrent, or perhaps primary metastatic cervical cancer should be pembrolizumab added to chemotherapy with bevacizumab in [the] biomarker-positive population.

That declaration was made by Raza Mirza, MD, chief oncologist at Copenhagen University Hospital in Denmark, who was invited to discuss the pros and cons of the KEYNOTE-826 trial at the European Society for Medical Oncology (ESMO) Congress 2021.

The trial showed that adding the checkpoint inhibitor pembrolizumab (Keytruda) to standard chemotherapy — with or without bevacizumab — resulted in about a one third reduction in the risk for both disease progression and death compared with chemotherapy alone.

The benefit of adding pembrolizumab was seen both in the overall study population and in patients with higher levels of programmed death ligand-1 (PD-L1), but not in those with biomarker-negative tumors, reported investigator Nicoletta Colombo, MD, PhD, from the University of Milan-Bicocca, Italy.

"Overall, data from KEYNOTE-826 suggest that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care," she said in a late-breaking oral abstract presentation. The study was also simultaneously published online in The New England Journal of Medicine.

Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, plus bevacizumab, based on the results of the GOG 240 study.

Immunotherapy with PD-1 inhibitors have shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but until now no data about the addition of these agents to chemotherapy were available, Colombo noted.

Mirza noted that there is sound rationale for using checkpoint inhibitors targeted against PD-1 in patients with cervical cancer, because PD-L1 has been shown to be a consistent biomarker for infection of the cervix with human papillomavirus (HPV), which is responsible for more than 90% of cervical cancers.

"PD-L1 is significantly upregulated in cervical cancer and detectable by immunohistochemistry," he said. "PD-L1 expression reduces the immune response since it is able to bind to PD-1 on T-cell lymphocytes, thereby inhibiting their function. These findings suggest that targeting the PD-1/PD-L1 pathway may be therapeutically effective and should be considered in the treatment of cervical cancer."

KEYNOTE-826 Details

This was a double-blind trial conducted in 617 patients stratified by metastatic disease status at diagnosis; PD-L1 combined positive score (CPS) either < 1, 1 to < 10, or ≥ 10. They were randomized in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator's discretion.

The dual primary endpoints of progression-free survival (PFS) and overall survival (OS) were each tested sequentially in patients with a PD-L1 CPS ≥ 1 in both the intention-to-treat (ITT) or "all-comers" population, and in patients with a PD-L1 CPS ≥ 10.

Patient characteristics were generally well balanced between the treatment groups, except for a slightly higher proportion of patients with squamous cell histology in the pembrolizumab versus the placebo group (76.3% vs 68.3%).

PFS and OS Results

The addition of pembrolizumab was associated with improved PFS across most protocol-specified subgroups, Colombo and colleagues noted.

After a median follow-up of 22 months, the 12-month PFS rate in the biomarker-selected population (all patients with a PD-L1 CPS ≥ 1) was 45.5% for patients in the pembrolizumab group versus 34.1% in the placebo group. This translated into a hazard ratio (HR) for progression on pembrolizumab of 0.62 (P < .001).

The respective PFS rates in the ITT population were 44.7% and 33.5%, with an HR for progression of 0.65 (P < .001) with the checkpoint inhibitor.

In patients with PD-L1 CPS ≥ 10, the respective rates of PFS and the HR were 44.6%, 33.5%, and 0.58 (P < .001).

OS rates were also significantly improved, he noted.

The 12-month and 24-month OS rates in all patients with PD-L1 CPS ≥ 1 were 75.3% and 53%, respectively, for patients assigned to pembrolizumab versus 63.1% and 41.7% in patients assigned to placebo, translating to an HR for death with pembrolizumab in this group of 0.64 (P < .001).

In the all-comers (ITT) population, respective 12- and 24-month OS rates were 74.8% and 50.4% with pembrolizumab versus 63.6% and 40.4% with placebo. This difference translated into an HR for death with anti-PD-1 of 0.67 (P < .001).

Among patients with the higher PD-L1 levels (≥ CPS 10), the respective OS rates were 75.7% and 54.4% with pembrolizumab versus 61.5% and 44.6% with placebo (HR 0.61, P < .001).

Mirza emphasized that "we did not see any efficacy of pembrolizumab in the biomarker-negative population," with an HR for PFS of 0.94 and HR for OS of 1.0 in this subgroup.

The most common grade ≥ 3 adverse events were anemia, which occurred in 30.3% of patients assigned to pembrolizumab compared with 26.9% in the placebo group, and neutropenias, which occurred in 12.4% and 9.7% of patients, respectively. One patient in the pembrolizumab group died from an immune-related event, encephalitis.

Despite his enthusiasm for the regimen, Mirza tempered it by pointing out that there was imbalance in the sample sizes regarding histology, and a potential bias introduced by the failure to stratify by tumor histology.

He noted that in other studies checkpoint inhibitors have had only modest activity against adenocarcinomas, which were more frequent in the placebo group in KEYNOTE-826, resulting in a potential positive bias in favor of pembrolizumab.

KEYNOTE-826 is funded by MSD. Colombo has disclosed consultant, research, and promotional speaking activities for multiple companies. Mirza has disclosed personal financial interests with Merck and other companies.

N Engl J Med. Published online September 18, 2021. Abstract

ESMO Congress 2021. Abstract LBA2. Presented September 18, 2021.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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