The KEYNOTE-826 trial has produced some “keynote” findings that could change the management of metastatic cervical cancer. According to the trial, addition of pembrolizumab to standard chemotherapy with or without bevacizumab reduced progression of disease and also improved overall survival.

In this phase III, double-blind trial 617 patients with persistent, recurrent, or metastatic cervical cancer were randomized assigned to receive pembrolizumab (200 mg) or placebo x 3 weeks for up to 35 cycles +  platinum-based chemotherapy (paclitaxel with cisplatin or carboplatin) with or without bevacizumab. Patients were followed up for 22 months. The progression-free survival (PFS) and overall survival (OS) were selected as the primary endpoints and were evaluated in three patient subgroups, those with a of programmed death ligand-1 (PD-L1) combined positive score of ≥1, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of ≥10.

The beneficial impact of pembrolizumab was evident both overall as well as in patients who had higher PD-L1 levels, but not in those with PD-L1-negative tumors. Both PFS and OS were longer in the pembrolizumab treated patients regardless of PD-L1 expression and who were also receiving concomitant chemotherapy with or without bevacizumab. Patients who received bevacizumab and those who did not showed similar benefit from addition of pembrolizumab.

• The PFS increased from around 8 months in the placebo group to a little over 10 months with pembrolizumab combination therapy. In 548 patients with a PD-L1 combined positive score of ≥1, the median PFS was 10.4 months in the pembrolizumab treated patients compared to 8.2 months in the placebo-treated patients (hazard ratio for disease progression or death 0.62). In the intention-to-treat population (n=617), the PFS was 10.4 months and 8.2 months, respectively (HR 0.65). In 317 patients with a PD-L1 combined positive score of ≥10, PFS was 10.4 months and 8.1 months, respectively (HR 0.58).
• The OS rates also improved significantly with pembrolizumab combination in comparison to placebo (24.4 months versus 16.5 months, respectively; HR 0.67) in 617 patients with recurrent or metastatic cervical cancer who did not previously receive systemic chemotherapy and were no longer candidates for curative treatments such as surgery and/or radiation.

Anemia was the most common adverse event noted (30.3% in the pembrolizumab-treated group vs 26.9% in the placebo group) followed by neutropenia (12.4% in the pembrolizumab-treated group and 9.7% in the placebo group). But these could be managed, as per the authors.

PD-1 inhibitors have been effective as monotherapy in women with metastatic or unresectable cervical cancer that has progressed during chemotherapy, but have not been studied for their effects when coadministered with standard chemotherapy. Based on their findings, the study authors propose that “pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care for women with persistent, recurrent, or metastatic cervical cancer”. But, they also caution that since treatment with pembrolizumab is longer (≥2 years) than chemotherapy, patients may need to be explained the benefits of treatment.

The trial was presented Saturday at the European Society for Medical Oncology (ESMO) Congress 2021, which ends today and also simultaneously published in the New England Journal of Medicine.

Reference

1. Colombo N, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. September 18, 2021, DOI: 10.1056/NEJMoa2112435.
2. New standard of care in cervical cancer  - Medscape - Sep 19, 2021.
3. MedPage Today September 18, 2021
4. ESMO Congress 2021. Presented September 18, 2021.