The addition of pembrolizumab to chemotherapy prolonged survival in recurrent, persistent, or metastatic cervical cancer, according to the results of the first interim analysis of the ­KEYNOTE-826 trial, presented at a Presidential Symposium during the European Society for Medical Oncology (ESMO) Congress 2021.¹ Adding pembrolizumab to chemotherapy (paclitaxel plus cisplatin or carboplatin) with or without bevacizumab led to a 33% reduction in the risk of death and a 35% reduction in the risk of disease progression and death, according to these late-breaking results.

The progression-free survival and overall survival benefits of immunotherapy were observed regardless of bevacizumab use. The study was published in The New England Journal of Medicine to coincide with the presentation at the ESMO Congress.²

“Previous studies showed that adding antiangiogenesis therapy with bevacizumab to platinum-based chemotherapy prolonged survival by 3.7 months over chemotherapy alone. KEYNOTE-826 was the first study to explore the addition of PD-1 inhibition to chemotherapy with or without bevacizumab, and benefits in survival and disease progression were observed not only in the PD-L1–positive population, but also in the overall intention-to-treat population,” said study author Nicoletta Colombo, MD, Director of the Gynaecology Programme, European Institute of Oncology, Milan, Italy. 

Pembrolizumab plus chemotherapy with or without bevacizumab may be a new standard of care for women with persistent, recurrent, or metastatic cervical cancer.

— Nicoletta Colombo, MD

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“Our study showed that adding pembrolizumab to chemotherapy plus or minus bevacizumab provides statistically significant and clinically meaningful overall survival and progression-free survival improvement. A significant benefit was observed in all primary analysis populations and was generally consistent across all protocol-specified subgroups. Overall response rate was higher and duration of response was longer with pembrolizumab. The safety was reported to be manageable. Pembrolizumab plus chemotherapy with or without bevacizumab may be a new standard of care for women with persistent, recurrent, or metastatic cervical cancer,” Dr. Colombo stated. 

Study Details

KEYNOTE-826 was conducted at 151 sites in 19 countries and randomly assigned 617 women with recurrent, persistent, or metastatic cervical cancer to receive first-line treatment with pembrolizumab immunotherapy vs placebo. Patients also received chemotherapy with paclitaxel plus investigator’s choice of cisplatin or carboplatin and bevacizumab at the investigator’s discretion. These women were not previously treated for advanced disease and were not considered curable.

Stratification factors at enrollment were metastatic status, planned bevacizumab use, and PD-L1 Combined Positive Score (CPS). Dual primary endpoints were progression-free survival and overall survival in patients with a CPS ≥ 1, in the intention-to-treat population, and in those with a CPS ≥ 10. 

Baseline demographic and disease characteristics were similar and well balanced in both randomized groups at baseline and in all three analysis populations. About 63% of patients in each arm received bevacizumab. About 88% of patients had a PD-L1 CPS ≥ 1 at baseline, and 51.4% had a CPS ≥ 10. Overall, 72.3% had squamous cell carcinoma; 56.4% had received previous chemoradiotherapy with or without surgery, and 19.8% had previously untreated metastatic disease at study entry. At data cutoff, 33.9% of the pembrolizumab group and 17.5% of the placebo group were continuing to receive at least one trial agent.

The hazard ratio favored bevacizumab across all subgroups, which suggests there is a benefit of pembrolizumab whether or not bevacizumab was received.

— Nicoletta Colombo, MD

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Patient Outcomes

At the first interim analysis, median follow-up was 22 months. Median progression-free survival in patients with a PD-L1 CPS ≥ 1 was 10.4 months with pembrolizumab vs 8.2 months with placebo; in patients with a PD-L1 CPS ≥ 10, the rates were almost identical—10.4 months and 8.1 months, respectively. Similarly, the rates of median progression-free survival were 10.4 months and 8.2 months, respectively, in all enrolled patients regardless of PD-L1 status. The between-group differences were all statistically significant at P < .001.

Median overall survival was not reached in patients in the pembrolizumab group with a PD-L1 CPS ≥ 1  and in those with a CPS ≥ 10. In all patients, median overall survival was 24.4 months with pembrolizumab vs 16.5 months with placebo. The between-group differences were all statistically significant at P < . 001. A prespecified subgroup analysis showed progression-free survival and overall survival benefits across all subgroups.

According to investigator review, the percentage of patients with a confirmed response was higher with pembrolizumab than placebo among those with a PD-L1 CPS ≥ 1 (68.1% vs 50.2%, respectively), among those in the intention-to-treat population (65.9% vs 50.8%, respectively), and among those with a CPS ≥ 10 (69.6% vs 49.1%, respectively). Duration of response was about twice as long in the pembrolizumab-treated groups.

“The hazard ratio favored bevacizumab across all subgroups, which suggests there is a benefit of pembrolizumab whether or not bevacizumab was received,” she noted. “Overall survival appeared to increase as PD-L1 expression increased, but this is a relatively small sample size. Robust conclusions regarding PD-L1–negative tumors cannot be drawn.”

Toxicity Profile

The incidence of grade 3 or higher adverse events was 81.8% in the pembrolizumab-plus-chemotherapy arm and 75.1% in the placebo-plus-chemotherapy arm. Serious adverse events occurred in 49.8% of the pembrolizumab arm and 42.4% of the placebo group. The most common adverse events of grade 3 or higher were anemia (30.6% with pembrolizumab vs 26.9% with placebo) and neutropenia (12.4% vs 9.7%, respectively). In both groups, the most common adverse events of any grade were anemia, alopecia, and nausea; the most common grade 3 to 5 adverse events were anemia, neutropenia, decreased neutrophil count, and hypertension.

Side effects with the combination therapy were manageable, and the observed adverse events were as expected based on previous data on the individual drugs.

— Nicoletta Colombo, MD

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As expected, the incidence of immune-related adverse events was higher in the pembrolizumab group (33.9% vs 15.2%, respectively). The most common adverse events were hyperthyroidism and hypothyroidism, and they were mostly grade 1 or 2. 

“Side effects with the combination therapy were manageable, and the observed adverse events were as expected based on previous data on the individual drugs,” Dr. Colombo said.

Patient-reported outcomes suggest that quality of life was not impaired in the pembrolizumab arm compared with placebo. The time to deterioration improved by 25% in the pembrolizumab arm. The median time to deterioration on the European quality-of-life five-level questionnaire (EQ-5D-5L) visual analog scale was not reached in the pembrolizumab arm and was 7.7 months in the placebo arm. 

DISCLOSURE: The study was funded by Merck Sharp & Dohme Corp. Dr. ­Colombo has served on the speakers bureau for AstraZeneca, Merck, Novartis, Clovis, and GSK and the advisory board for Roche, PharmaMar, AstraZeneca, MSD/Merck, Clovis Oncology, Tesaro, GSK, Pfizer, Takeda, IoCAD, Immunogen, Mersana, Eisai, and ­OncXerna; and has received research funding from Roche and AstraZeneca. 

REFERENCES

1. Colombo N, Dubot C, Lorusso D, et al: Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: Randomized, double-blind, phase 3 KEYNOTE-826 study. ESMO Congress 2021. Abstract LBA2. Presented September 18, 2021.

2. Colombo N, Dubot C, Lorusso D, et al: Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. September 18, 2021 (early release online).