An exploratory subgroup analysis of the efficacy and safety outcomes from the final analysis of the phase III KEYNOTE-826 study based on the use of bevacizumab indicate that the addition of pembrolizumab to chemotherapy resulted in clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) compared with placebo plus chemotherapy regardless of concomitant bevacizumab use in patients with persistent, recurrent, or metastatic cervical cancer. Additionally, objective response rate (ORR) was higher and duration of response (DoR) was longer with the addition of pembrolizumab. The findings were consistent in patients whose tumours expressed PD-L1 combined positive score (CPS) ≥1 and all comers.
The safety profile of pembrolizumab plus chemotherapy with or without bevacizumab was manageable, and no new safety signals were identified. The findings are reported by Prof. Domenica Lorusso of the Humanitas San Pio X and Humanitas University in Milan, Italy and colleagues on 9 October 2024 in the Annals of Oncology.
The authors wrote in the background that approval of chemotherapy plus bevacizumab in that setting was based on the results from the phase III GOG 240 study in which the combination therapy significantly improved OS and PFS versus chemotherapy alone. Although the addition of bevacizumab to chemotherapy did not result in significant deterioration of health-related quality-of-life (HR QoL) in the GOG 240 study, combination therapy was associated with greater toxicity. Bevacizumab is considered a preferred first-line regimen for patients with advanced cervical cancer, but its use is determined according to local practice, physician discretion, and the presumed benefit/risk profile accounting for clinical contraindications for bevacizumab use.
Approval of the pembrolizumab-containing regimen was based on the phase III KEYNOTE-826 study, which evaluated first-line pembrolizumab plus chemotherapy with or without bevacizumab compared with placebo plus chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. At the first interim analysis, patients in the pembrolizumab arm had significant improvements in PFS and OS in the all-comer population (intention-to-treat) and in patients whose tumours expressed PD-L1 CPS ≥1 or PD-L1 CPS ≥10.
The improvements in PFS and OS were maintained at the protocol-specified final analysis of KEYNOTE-826. The addition of pembrolizumab to chemotherapy with or without bevacizumab did not negatively affect HR QoL, but was associated with a higher rate of immune-mediated adverse events (34.5% versus 16.5% at final analysis). This exploratory analysis examined outcomes in patient subgroups defined by bevacizumab use.
Eligible adult patients had persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix not previously treated with chemotherapy and not amenable to curative treatment; they had measurable disease per RECIST v1.1 and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomised 1:1 to pembrolizumab 200 mg every 3 weeks or placebo for up to 35 cycles plus chemotherapy with or without bevacizumab 15 mg/kg. Dual primary endpoints were OS and PFS per RECIST v1.1 by investigator assessment. Outcomes were assessed in subgroups defined by bevacizumab use. Hazard ratios (HRs) and 95% confidence intervals (Cis) were based on a stratified Cox regression model.
A total of 617 patients were randomised, of whom 306 to the pembrolizumab arm (63.6% with bevacizumab) and 309 to the placebo arm (62.5% with bevacizumab). The most common reason for bevacizumab exclusion was medical contraindication (75.9%). Among patients who received bevacizumab, HR for PFS favoured the pembrolizumab arm in the PD-L1 CPS ≥1 (HR 0.56, 95% CI 0.43−0.73) and all-comer (HR 0.57, 95% CI 0.45−0.73) populations; HRs for OS were 0.60 (95% CI 0.45−0.79) and 0.61 (95% CI 0.47−0.80).
Among patients who did not receive bevacizumab, HR for PFS also favoured the pembrolizumab arm in the PD-L1 CPS≥1 (HR 0.61, 95% CI 0.44−0.85) and all-comer (HR 0.69, 95% CIs 0.50−0.94) populations; HRs for OS were 0.61 (95% CI 0.44−0.85) and 0.67 (95% CI 0.49−0.91).
Among patients who received bevacizumab, grade ≥3 treatment-related adverse events occurred in 74.0% of patients in the pembrolizumab arm and 66.8% in the placebo arm.
The authors commented that the results suggest that first-line quadruplet therapy with pembrolizumab, doublet chemotherapy, and bevacizumab may be the optimal initial treatment approach for those patients who do not have contraindications for receiving bevacizumab. The addition of pembrolizumab to doublet chemotherapy in the KEYNOTE-826 provided clinical benefits irrespective of bevacizumab use and therefore, for patients ineligible to receive bevacizumab, the combination of pembrolizumab plus doublet chemotherapy is a treatment option that provides clinical benefit.
Although the sample size was small and the results must be interpreted with caution, exploratory analysis suggested that, among patients who initiated quadruplet therapy but discontinued bevacizumab because of an adverse event, clinical benefit may have been achieved in those who continued pembrolizumab therapy.
This preplanned subgroup analysis was exploratory and not controlled for multiplicity, and therefore was not powered to assess statistical significance. Planned bevacizumab use was a prespecified stratification factor to help mitigate imbalance between the treatment arms.
The percentage of patients who were treated with bevacizumab in the first-line setting in the KEYNOTE-826 (63.0%) was within the range reported in real-world studies of patients with persistent, recurrent, or metastatic cervical cancer in Europe and the United States (42−72%). Demographic (e.g. age, race) and clinical characteristics (e.g. ECOG performance status, histology) were also similar; thus, the study patients were largely representative of the general population with cervical cancer.
The authors concluded that the results provide further support for pembrolizumab plus chemotherapy with or without bevacizumab as a standard-of-care for patients with persistent, recurrent, or metastatic cervical cancer.
This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
A portion of the data were presented at the European Congress on Gynaecological Oncology 2023 (28 September-1 October 2023, Istanbul, Turkey).
Reference
Lorusso D, Colombo N, Dubot C, et al. Pembrolizumab Plus Chemotherapy for Advanced and Recurrent Cervical Cancer: Final Analysis According to Bevacizumab Use in the Randomized KEYNOTE-826 Study. Annals of Oncology; Published online 9 October 2024. DOI: https://doi.org/10.1016/j.annonc.2024.10.002