Potential new standard of care in first-line cervical cancer could include combination of Pembrolizumab Plus chemotherapy

In the population of all arrivals, the median PFS was 10.4 months (95% CI, 9.1-12.1) in the investigation arm vs. 8.2 months (95% CI, 6, 4-8.4) in the control arm (RR: 0.65; 95% CI, 0.53-0.79; P <0.001). The median OS in this population was 24.4 months (19.2 - NR) with pembrolizumab versus 16.5 months (95% CI: 14.5-19.4) with placebo (RR: 0.67 ; 95% CI: 0.54-0.84; P <0.001).

In the group of patients who had a PD-L1 CPS of 10 or greater, the median PFS with pembrolizumab plus chemotherapy with or without bevacizumab was 10.4 months (95% CI, 8.9-15.1) vs.8 , 1 month (95% CI, 6.2-8.8) with chemotherapy with or without bevacizumab (RR: 0.58; 95% CI: 0.44-0.77; P <0.001). The median OS was also NR (95% CI, 19.1-NR) in the investigation arm versus 16.4 months (95% CI, 14.0-25.0) in the control arm (RR: 0.61; 95% CI: 0.44-0.84; P = .001).

“Adding pembrolizumab to chemotherapy with or without bevacizumab offers statistically significant and clinically significant improvements in PFS and OS in patients with persistent, recurrent or metastatic cervical cancer. The significant benefit was observed in all populations of primary analysis and was generally consistent across all subgroups specified in the protocol ”, lead study author Nicoletta Colombo, MD, PhD, director of the oncology division gynecologist at the European Institute of Oncology and associate professor of obstetrics and gynecology at the University of Milan-Bicocca in Milan, Italy, said in a presentation of the results. “Overall, data from KEYNOTE-826 suggests that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new standard of primary care for treatment. [of these patients]. “

Platinum-based chemotherapy has served as standard treatment for patients with persistent, recurrent, or metastatic cervical cancer, with the preferred regimen being platinum, paclitaxel, and bevacizumab. Although PD-1 inhibitors, such as pembrolizumab and cemiplimab (Libtayo),

have already been shown to be effective in patients with previously treated cervical cancer, no data are available to indicate whether adding a PD-L1 inhibitor to chemotherapy with or without bevacizumab would improve the results.

To this end, the researchers initiated the KEYNOTE-826 double-blind trial, which recruited patients with persistent, recurrent, or metastatic cervical cancer that was not amenable to curative treatment.

Eligible patients had to have an ECOG performance index of 0 or 1 and could not have previously received systemic chemotherapy. However, prior radiotherapy and chemoradiotherapy were permitted.

A total of 617 participants were randomized 1: 1 to receive pembrolizumab intravenously (IV) 200 mg every 3 weeks for up to 35 cycles plus paclitaxel and cisplatin or carboplatin every 3 weeks for up to 6 cycles with or without bevacizumab IV at 15 mg / kg every 3 weeks (n = 308) or placebo plus chemotherapy with or without bevacizumab at the same dose and at the same schedule (n = 309).

Stratification factors included metastatic disease at diagnosis (yes vs. no), CPS PD-L1 (<1 vs. 1 to <10 vs. ≥10), and intended use of bevacizumab (yes vs. no).

The two primary endpoints of the study were OS and PFS assessed by the investigator according to the RECIST v1.1 criteria; the main secondary endpoints included overall response rate (ORR), duration of response (DOR), PFS at 12 months, and safety. Patient Reported Outcomes (PRO) were assessed using the EuroQoL EQ-5D-5L Visual Analog Scale (VAS) score and served as an exploratory endpoint.

The benefit of PFS and OS of adding pembrolizumab was evaluated sequentially in 3 patient populations: those with a PD-L1 CPS of 1 or greater, all newcomers, and those with a PD-L1 CPS of 10. or more. The overall alpha was controlled at 2.5% one-sided for the 6 main assumptions and all planned analyzes. The statistical analysis plan allows 2 intermediate analyzes before a final analysis.

The first interim analysis was to take place when approximately 370 events of disease progression or death were reported in the patient population with a PD-L1 CPS of 1 or greater. At that time, all primary hypotheses had to be tested, Colombo noted.

As of the data cut-off date of May 3, 2021, 307 patients in the investigation arm and 309 patients in the control arm have received treatment.

“The median length of follow-up was almost 3 years, and approximately twice as many patients in the pembrolizumab arm continued or completed study treatment,” Colombo said.

The baseline characteristics in the all-rounder CPS and PD-L1 subassemblies were well balanced between the 2 treatment arms, Colombo added.

Among the all-comer population, the median age between the arms was 50.5 years (range, 22-82). In addition, 43.3% of patients had an ECOG performance index of 1, 72.3% had squamous cell disease, and 48.3% had previously received radiochemotherapy or radiotherapy.

At initial diagnosis, 30.8% of patients had stage IVB disease and 19.8% had metastatic disease at the time of entry into the study. Regarding PD-L1 status, 51.4% of patients had a CPS of 10 or more, 37.4% had a CPS between 1 and 10 and 11.2% had a CPS less than 1. Bevacizumab has been used in 63.1% of patients during the study. .

Additional data reported during the meeting showed that the 12-month PFS rates in the investigation and control arms in the subset of patients with a PD-L1 CPS of 1 or greater were 45, 5% (95% CI, 39.2% to 51.5%) and 34.1% (95% CI, 28.3% to 40.0%), respectively. In the population of all arrivals, these rates were 44.7% (95% CI, 38.8% to 50.4%) and 33.5% (95% CI, 28.0% to 39 , 1%), respectively. Finally, in the subset of patients with a PD-L1 CPS of 10 or greater, these rates were 44.6% (95% CI, 36.3% to 52.5%) and 33.5%, respectively. % (95% CI, 25.9% to 41.2%).

“The benefit of adding pembrolizumab was generally consistent across all subgroups specified in the protocol, with all HR favoring the pembrolizumab arm and all overlapping 95% CIs,” Colombo said.

SG benefit from adding pembrolizumab was generally consistent across all subgroups specified by the protocol. Notably, the HR favored the addition of pembrolizumab to the two bevacizumab subgroups, suggesting that adding immunotherapy to chemotherapy is beneficial whether or not patients can receive bevacizumab, Colombo said. .

“The relative OS benefit observed in the pembrolizumab arm appeared to increase with increasing PD-L1 expression and the HR for the PD-L1 negative population was 1.00,” Colombo added. “But, given the relatively small sample size of this subgroup and the overall study design, strong conclusions regarding the efficacy of pembrolizumab plus chemotherapy with or without bevacizumab in patients with PD tumors -L1 negative cannot be drawn. “

Addition of pembrolizumab to chemotherapy with or without bevacizumab also improved ORRs compared to placebo plus chemotherapy with or without bevacizumab in the 3 primary analysis populations.

In the subset of patients with a PD-L1 CPS of 1 or greater, the ORR in the investigative arm was 68.1% (95% CI, 62.2% to 73.6%) versus 50.2% (95% CI, 44.1 to 56.2%) in the control arm, with a median duration of response (DOR) of 18.0 months (range, 1.3+ to 24.2+ ) vs. 10.4 months (range, 1.5+ to 22.0+), respectively.

In the population of all arrivals, the ORRs were 65.9% (95% CI, 60.3% -71.2%) versus 50.8% (95% CI, 45.1% to 56, 5%), respectively, with the same median DORs as reported in PD-L1 CPS of 1 or more subset. Finally, in the group of patients with a PD-L1 CPS of 10 or greater, the ORRs were 69.6% (95% CI, 61.8% to 76.7%) vs 49.1% (CI to 95%, 41.1% to 57.1%), respectively, with median ORDs of 21.1 months (range, 1.3+ to 24.2+) versus 9.4 months (range, 2.1+ at 21.5+), respectively.

Investigators collected information about OWPs throughout the treatment of the trial. The time to deterioration of the EQ-5D-5L VAS score was improved in the pembrolizumab arm, with an HR of 0.75 (95% CI, 0.58-0.97). According to Colombo, the median time to deterioration was not reached in the investigation arm compared to 7.7 months in the control arm.

The safety profile of the pembrolizumab regimen was manageable. The incidence of all-cause, treatment-related or Grade 3 or more serious adverse reactions (AEs) was numerically higher in the immunotherapy arm, but patients receiving pembrolizumab were generally on treatment longer than those receiving the placebo, according to Colombo.

“About a third of patients in the pembrolizumab arm discontinued any component of treatment due to an AE,” Colombo said. “The incidence of AEs leading to death was similar in the treatment arms. As expected, the incidence of immune-related AEs was higher in the pembrolizumab arm.

The most common all-cause AEs reported in the investigation and control arms included anemia (61.2% vs. 53.4%, respectively), alopecia (56.4% vs. 57.9%) , nausea (39.7% vs. 43.7%), diarrhea (35.5% vs. 29.8%) and fatigue (28.7% vs. 27.2%), among others. The most common immune-mediated AEs were hypothyroidism (18.2% vs. 9.1%) and hyperthyroidism (7.5% vs. 2.9%).

Reference

Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent or metastatic cervical cancer: randomized, double-blind phase 3 study, KEYNOTE-826. Presented at: ESMO 2021 Congress; September 16-21, 2021; virtual. Abstract LBA2_PR.