Pembrolizumab Plus Chemo With or Without Bevacizumab Approaches EU Approval for Select Cervical Cancer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of pembrolizumab (Keytruda) for use in combination with chemotherapy with or without bevacizumab (Avastin) in patients with persistent, recurrent, or metastatic cervical cancer who have a PD-L1 combined positive score (CPS) of 1 or higher.¹

The positive opinion is based on findings from the phase 3 KEYNOTE-826 trial (NCT03635567), in which the immunotherapy regimen was found to significantly prolong overall survival (OS) vs placebo in this subset of patients.² The 24-month estimates of patients alive in the investigative and control arms were 53.0% (95% CI, 46.0%-59.4%) and 41.7% (95% CI, 34.9%-48.2%), respectively (HR, 0.64; 95% CI, 0.50-0.81; P < .001).

The pembrolizumab combination also significantly improved progression-free survival (PFS) vs placebo in this subset, with a median of 10.4 months (95% CI, 9.7-12.3) and 8.2 months (95% CI, 6.3-8.5), respectively (HR, 0.62; 95% CI, 0.50-0.77; P < .001).

“The CHMP’s positive recommendation brings us closer to providing patients with an immunotherapy regimen that has the potential to extend the lives of certain people living with persistent, recurrent, or metastatic cervical cancer compared with current standard-of-care treatment,” Gursel Aktan, MD, vice president of global clinical development at Merck Research Laboratories, stated in a press release. “We look forward to the European Commission’s decision, which could mark the first time an anti–PD-1/PD-L1 regimen is approved in the European Union for these patients.”

KEYNOTE-826 enrolled patients with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment.

To be eligible for enrollment, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria. They were allowed to have received prior radiotherapy, including chemoradiation, if it was completed at least 2 weeks prior to randomization and all associated toxicities had resolved.

A total of 617 participants were randomized 1:1 to receive pembrolizumab at 200 mg (n = 308) or placebo (n = 309) every 3 weeks for up to 35 cycles. All patients received paclitaxel at 175 mg/m² and investigator’s choice of cisplatin at 50 mg/m² or carboplatin at area under the curve 5 mg/mL/min every 3 weeks.

Chemotherapy was limited to 6 cycles per the second protocol amendment, although those with ongoing benefit who were receiving that treatment without unacceptable toxicity could continue beyond the 6 cycles following consultation with the sponsor. Patients could receive bevacizumab at 15 mg/kg every 3 weeks per investigator discretion.

Key stratification factors included metastatic disease at diagnosis (yes vs no), planned bevacizumab use (yes vs no), and PD-L1 CPS (less than 1 vs 1 to less than 10 vs 10 or higher).

Spanning the treatment arms, the median age was 50.5 years (range, 22-82), with 16.2% of patients aged 65 years or older; 58.35% of patients were White, 56.4% had an ECOG performance status of 0, 30.8% had stage IVB disease at the time of diagnosis, and most patients had squamous cell carcinoma.

Moreover, 18.8% of those in the pembrolizumab arm and 20.7% of those in the placebo arm had metastatic disease at trial entry. In the investigative arm, 11.4% of patients had a PD-L1 CPS of less than 1, 37.3% had a score of 1 to less than 10, and 51.3% had a score of 10 or higher; in the control arm, these rates were 11.0%, 37.5%, and 51.5%, respectively.

The most common prior treatment received on both arms was chemoradiation only, with 40.6% of patients on the investigative arm having received it vs 38.2% of those on the control arm. The majority of patients on the pembrolizumab and control arms also received bevacizumab during the trial, at 63.6% and 62.5%, respectively.

Additional data from the trial published in The New England Journal of Medicine showed that in the intention-to-treat (ITT) population, the median PFS with the pembrolizumab regimen was 10.4 months (95% CI, 9.1-12.1) vs 8.2 months (95% CI, 6.4-8.4) with placebo (HR, 0.65; 95% CI, 0.53-0.79; P < .001). The estimated 24-month OS rates in the investigative and control arms were 50.4% (95% CI, 43.8%-56.6%) and 40.4% (95% CI, 34.0%-46.6%), respectively (HR, 0.67; 95% CI, 0.54-0.84; P < .001).

In the subset of patients with a PD-L1 CPS of 10 or higher, the median PFS in the immunotherapy arm was 10.4 months (95% CI, 8.9-15.1) vs 8.1 months (95% CI, 6.2-8.8) in the placebo arm (HR, 0.58; 95% CI, 0.44-0.77; P < .001). The estimated 24-month OS rates in the investigative and control arms were 54.4% (95% CI, 45.5%-62.4%) and 44.6% (95% CI, 36.3%-52.5%), respectively (HR, 0.61; 95% CI, 0.44-0.84; P = .001).

In patients with a PD-L1 CPS or 1 or higher, the confirmed response in the pembrolizumab arm was higher than that of the placebo arm, at 68.1% and 50.2%, respectively. In the ITT population, these rates were 65.9% and 50.8%, respectively, and in the subset of patients with a PD-L1 CPS of 10 or higher, these rates were 69.6% and 49.1%, respectively.

In these 3 populations, more complete responses were observed with the immunotherapy than with placebo. In the subset with a PD-L1 CPS of 1 or higher, these rates were 22.7% and 13.1%, respectively; in the ITT population, these rates were 21.4% and 12.9%, respectively; and in the subset with a PD-L1 CPS of 10 or higher, these rates were 22.2% and 11.3%, respectively. The duration of response also proved to be longer in the immunotherapy arm vs the placebo arm.

Regarding safety, toxicities that were grade 3 to 5 in severity were experienced by 81.8% of those in the pembrolizumab arm vs 75.1% of those in the control arm. Serious adverse effects (AEs) were observed in 49.8% and 42.4% of those in the investigative and control arms, respectively, and included febrile neutropenia (6.8% and 4.2%, respectively) and urinary tract infection (5.2% and 5.8%).

Toxicities resulting in treatment discontinuation of any trial agent occurred in 37.5% of those on the investigative arm and 26.5% of those on the control arm. Toxicities resulting in the discontinuation of all trial agents occurred in 5.9% and 4.9% of patients, respectively. Fourteen patients in each arm died.

The most common any-grade toxicities reported in both treatment arms included anemia, alopecia, and nausea. The most frequent grade 3 to 5 AEs comprised anemia, neutropenia, decreased neutrophil count, and hypertension.

At the 2022 SGO Annual Meeting on Women’s Cancer, patient-reported outcome data supported a favorable risk/benefit profile for the combination in this population.³ The data 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.

In October 2021, the FDA approved pembrolizumab for use in combination with chemotherapy, with or without bevacizumab, in patients with persistent, recurrent, or metastatic cervical cancer whose tumors have a PD-L1 CPS of 1 or higher.⁴

References

1. Merck receives positive EU CHMP opinion for KEYTRUDA (pembrolizumab) plus chemotherapy, with or without bevacizumab, as treatment of patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS≥1). News release. Merck; March 25, 2022. Accessed March 28, 2022. https://bit.ly/3uCmZ8v
2. Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385(20):1856-1867. doi:10.1056/NEJMoa2112435
3. 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.
4. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. News release. FDA; October 13, 2021. Accessed March 28, 2022. https://bit.ly/3lE3vNS