PRO Data Support the Use of Pembrolizumab Combo in Persistent, Recurrent, or Metastatic Cervical Cancer

Bradley Monk, MD, FACOG, FACS

Updated findings from the phase 3 KEYNOTE-826 trial (NCT03635567) showed that patient-reported outcome (PRO) findings support a favorable benefit/risk profile for the combination of pembrolizumab (Keytruda) plus chemotherapy, with or without bevacizumab (Avastin), in patients with persistent, recurrent, or metastatic cervical cancer.

The data, which were presented during the 2022 SGO Annual Meeting on Women’s Cancer, showed that the global geometric least square mean change from baseline to 30 weeks per the European Organisation for Research and Treatment of Cancer (EORTC): Quality of Life Questionnaire-Core 30 (QLQ-C30) for global health status (GHS)/quality of life (QOL) was –0.3 (95% CI, -3.1 to 2.6) in the pembrolizumab arm vs –1.3 (95% CI, -4.2 to 1.7) in the placebo arm (difference in least squares mean, 1.01; 95% CI, –2.7 to 4.7). Although the difference was not determined to be statistically significant, pembrolizumab was noted to have a numeric improvement over placebo in terms of QOL.

“Overall findings from KEYNOTE-826 support pembrolizumab plus chemotherapy with or without bevacizumab as the new standard of care for women with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 [combined positive score] of 1 or more,” Bradley Monk, MD, FACOG, FACS, professor in the department of obstetrics and gynecology, University of Arizona College of Medicine, said in his presentation of the data.

Eligible patients were randomized 1:1 to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for 35 cycles plus intravenous paclitaxel, cisplatin, or carboplatin for up to 6 cycles with or without 15 mg/kg of intravenous bevacizumab every 3 weeks.

Co-primary end points of the KEYNOTE-826 trial were progression-free survival (PFS) and overall survival (OS). Key secondary end points included overall response rate, duration of response, 12-month PFS rate, safety, and changes from baseline in QOL questionnaire scores. Changes in PROs was an exploratory end point of the research.

Key eligibility criteria required patients to have persistent, recurrent, or metastatic cervical cancer not amenable to curative treatment, no prior systemic chemotherapy, and an ECOG performance score of 0 or 1.

The KEYNOTE-826 trial’s co-primary end points were previously reported, showing that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab significantly improved PFS and OS over placebo while maintaining a tolerable safety profile.

“KEYNOTE-826 improved progression-free survival and overall survival, but it’s all about the patient experience,” Monk explained in his presentation of the data. “We have to contextual this clinical benefit to see if it satisfies the risk-benefit ratio in the clinic.”

To measure PROs, the investigative team used the EORTC: QLQ-C30, EuroQol 5-Dimension 5-Level visual analog scale questionnaire (EQ-5D-5L VAS), and the EORTC QLQ-CX24 Cervical Cancer questionnaire which were administered before every cycle of treatment through cycle 14, and then after every subsequent cycle, end of treatment, and at safety follow up visit.

All PRO end points were prespecified, with the change in EORTC QLQ-C30 global health status labeled as a key secondary end point. To ensure the data were reliable, 60% and 80% compliance rates were required in the pembrolizumab and placebo groups, respectively.

At 30 weeks, completion and compliance rates were sufficient among the pembrolizumab and placebo groups to create the study’s focal end point.

When looking at the EORTC QLQ-C30 scale, physical, role, cognitive, and social functioning were slightly worse in the pembrolizumab group compared with the placebo group. By the QLQ-CX24 scale, peripheral neuropathy was worse in the placebo group than the pembrolizumab group.

In the time to true deterioration (TTD) analysis, with deterioration defined as a 10-point decrease in PRO scores, the pembrolizumab arm performed numerically better than the placebo arm across most measures. For the GHS/QOL by EORTC QLQ-C30, median TTD in the pembrolizumab arm was not reached (NR; 95% CI, 13.4-NR) compared with 12.9 months (95% CI, 6.6-NR) in the placebo arm (HR, 0.84; 95% CI, 0.65-1.09; P = .1851). For EQ-5D-5L VAS, median TTD in the pembrolizumab arm was NR (95% CI, 17.2-NR) vs 7.7 months (95% CI, 6.0-NR) in the placebo arm (HR, 0.75; 95% CI, 0.58-0.97; P = .0273).

For physical functioning by EORTC QLQ-C30, the proportion of patients with improved PROs was 42.1% compared with 26.8% in the placebo arm. For the EQ-5D-5L VAS, the proportion of patients with improved PROs was 42.8% and 36.4% in the pembrolizumab and placebo groups, respectively.

Reference

1. Monk BJ, Tewari KS, Hasegawa CK, et al. Patient-reported outcomes from the phase 3 randomized, double-blind, KEYNOTE-826 trial of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for the first-line treatment of persistent, recurrent, or metastatic cervical cancer. Presented at: 2022 SGO Annual Meeting on Women’s Cancer; March 18-21, 2022; Phoenix, AZ.