In KEYNOTE-826 study conducted in 617 patients with cervical cancer, subgroup analyses indicate the benefit of adding pembrolizumab to chemotherapy with or without bevacizumab was generally sustained across a broad selection of patient subgroups defined by bevacizumab use, platinum use, prior chemoradiotherapy (CRT) exposure, and histologic type.
The findings from the subgroup analyses provide further support for pembrolizumab plus chemotherapy with or without bevacizumab as a new standard of care for patients with persistent, recurrent, or metastatic cervical cancer according to Dr. Krishnansu S. Tewari of the University of California Irvine in Orange, CA, US, and study colleagues who published the findings on 14 December 2023 in the JAMA Oncology.
The authors wrote that the observation in the Cervical Cancer Genome Atlas that viral DNA integration into the host genome, a prerequisite for malignant transformation, leads to amplification of the immune checkpoints provided the rationale to add pembrolizumab to combination chemotherapy with or without bevacizumab in KEYNOTE-826 study. It is a phase III randomised study to assess the efficacy and safety of adding pembrolizumab versus placebo to platinum-based chemotherapy with or without bevacizumab as first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer.
The primary results showed statistically significant and clinically meaningful survival benefits with addition of pembrolizumab. In the population of patients with a PD-L1 combined positive score (CPS) ≥1, median overall survival (OS) was not reached (NR) in the pembrolizumab arm versus 16.3 months in the chemotherapy arm, and the hazard ratio (HR) was 0.64 (p < 0.001). In the intention-to-treat (ITT) population, median OS was 24.4 months in the pembrolizumab arm versus 16.5 months in the chemotherapy arm, and the HR for death was 0.67 (p < 0.001). Significant improvements in progression-free survival (PFS) with the addition of pembrolizumab were also observed in both populations.
In the exploratory analysis, the study team assessed the efficacy of chemotherapy plus pembrolizumab with and without bevacizumab in several prognostic patient subgroups in KEYNOTE-826 study. Main outcomes and measures were OS and PFS by investigator assessment per RECIST v1.1 in subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior CRT exposure only (yes or no), and histologic type (squamous or non-squamous) in patients with PD-L1–positive tumours defined as a CPS ≥1 and in the ITT population.
A total of 617 patients were enrolled in the study. Median age was 51 years (range, 22-82 years). In the CPS ≥1 population, HRs for OS favoured the pembrolizumab group in all subgroups: with bevacizumab (HR 0.62; 95% confidence interval [CI] 0.45-0.87) and without bevacizumab (HR 0.67; 95% CI 0.47-0.96), use of carboplatin (HR 0.65; 95% CI 0.50-0.85) and cisplatin (HR 0.53; 95% CI 0.27-1.04), with prior CRT only (HR 0.56; 95% CI 0.39-0.81) and without prior CRT only (HR 0.72; 95% CI 0.52-1.00), and squamous (HR 0.60; 95% CI 0.46-0.79) and non-squamous (HR 0.70; 95% CI 0.41-1.20) histologic type.
In the ITT population, HRs for OS also favoured the pembrolizumab group in all subgroups: with bevacizumab (HR 0.63; 95% CI 0.47-0.87) and without bevacizumab (HR 0.74; 95% CI 0.53-1.04), use of carboplatin (HR 0.69; 95% CI 0.54-0.89) or cisplatin (HR 0.59; 95% CI 0.32-1.09), with prior CRT only (HR 0.64; 95% CI 0.45-0.91) and without prior CRT only (HR 0.71; 95% CI 0.53-0.97), and squamous (HR 0.61; 95% CI 0.47-0.80) and non-squamous (HR 0.76; 95% CI 0.47-1.23) histologic type. The addition of pembrolizumab prolonged PFS across all subgroups in the CPS ≥1 and ITT populations.
The authors commented that an important consideration is whether bevacizumab should be included for the treatment of recurrent or metastatic disease. Based on the survival benefit with bevacizumab seen in GOG 240 study, its inclusion should be considered if available except when contraindicated, in which case pembrolizumab plus chemotherapy alone provides a clinically meaningful benefit.
KEYNOTE-826 is 1 of only 2 completed studies to prospectively test PD-L1 expression among patients with cervical cancer. Expression of PD-L1 in cervical cancer may be influenced by histologic type. Approximately 70% of cervical cancers are squamous, and 20% are adenocarcinoma, including adenosquamous. Non-squamous tumours are more likely to be PD-L1–negative. The present analysis suggests that pembrolizumab provides benefit for squamous and non-squamous histologic types of persistent, recurrent, or metastatic cervical cancer.
The authors concluded that the present subgroup analyses confirm the activity of pembrolizumab in combination with chemotherapy for recurrent or metastatic disease, irrespective of tumour histologic type, platinum analogue, bevacizumab use, and in the setting of prior pelvic irradiation. These results provide further support for pembrolizumab plus chemotherapy with or without bevacizumab as a new standard of care for patients with recurrent or metastatic cervical cancer. Results from ongoing studies are expected to further define the role of immunotherapy for recurrent or metastatic cervical cancer in different subgroups of patients.
A portion of these results were presented at the ASCO 2022 Annual Meeting.
Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co Inc.
Reference
Tewari KS, Colombo N, Monk BJ, et al. Pembrolizumab or Placebo Plus Chemotherapy With or Without Bevacizumab for Persistent, Recurrent, or Metastatic Cervical Cancer Subgroup Analyses from the KEYNOTE-826 Randomized Clinical Trial. JAMA Oncology; Published online 14 December 2023. doi: 10.1001/jamaoncol.2023.5410
