The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion in favor of recommending that the label for pembrolizumab (Keytruda) in Europe be updated to include findings from the phase 3 KEYNOTE-361 trial (NCT02853305).1
Results from the trial indicated that the PD-1 inhibitor plus chemotherapy failed to result in a statistically significant improvement in progression-free survival (PFS) or overall survival (OS) over chemotherapy in patients with treatment-naïve advanced urothelial carcinoma.2
Specifically, the PFS by blinded independent central review (BICR) was 8.3 months (95% CI, 7.5-8.5) with pembrolizumab plus chemotherapy in the intent-to-treat (ITT) population vs 7.1 months (95% CI, 6.4-7.9) with chemotherapy alone (HR, 0.78; 95% CI, 0.65-0.93; P = .0033). The 12-month PFS rates were 33.7% and 20.9% in the investigative and control arms, respectively.
Additionally, the median OS with pembrolizumab and chemotherapy in the ITT population was 17.0 months (95% CI, 14.5-19.5) vs 14.3 months (95% CI, 12.3-16.7) with chemotherapy alone (HR, 0.86; 95% CI, 0.72-1.02; P = .0407). The 12-month OS rate in the investigative arm was 61.8% vs 56.0% in the control arm.
Although the trial failed to meet its primary end points of PFS and OS for the pembrolizumab/chemotherapy combination, the CHMP concluded that the benefit–risk profile continues to be positive and including the data from the trial permits providers to weigh the potential risks vs benefits of pembrolizumab on an individualized basis.
“[Pembrolizumab] has become an important treatment options for certain patients with locally advanced or metastatic bladder cancer in the European Union and other countries around the world,” Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “We are pleased with today’s positive opinion by the CHMP, which fulfills our post-marketing requirement for [pembrolizumab] in these patients win the European Union and will enable continued access for patients win need of another treatment option.”
The phase 3 trial enrolled patients with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra. To be eligible for enrollment, patients had to have locally advanced, unresectable or metastatic disease, an ECOG performance status of 0 to 2, and a tissue sample available for PD-L1 assessment. Patients could not have under previous systemic treatment for advanced disease.
A total of 1010 patients were randomized 1:1:1 to receive pembrolizumab at 200 mg every 3 weeks plus gemcitabine at 1000 mg/m2 and cisplatin at 70 mg/m2 or carboplatin at area under the curve (AUC) of 5 for 6 cycles or less, followed by pembrolizumab at 200 mg every 3 weeks for 29 cycles or less (n = 351); pembrolizumab at 200 mg every 3 weeks for 35 cycles or less (n = 307); or gemcitabine at 1000 mg/m2 on days 1 and 8 every 3 weeks plus cisplatin at 70 mg/m2 or carboplatin at AUC 5 on day 1 every 3 weeks for 6 cycles or less (n = 352).
The co-primary end points of the trial were PFS per RECIST v1.1 criteria by BICR and OS, while key secondary end points included objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) per BICR and RECIST v1.1 criteria, as well as safety.
The median age of participants across the arms was 68.6 years, the majority were male, and 48.3% had an ECOG performance status of 1. Moreover, 74.4% had visceral metastasis, 23.5% had lymph node–only metastasis, and 21.5% had liver metastasis. Across the arms, 43.4% had cisplatin chemotherapy, while 54.6% had carboplatin.
Additional results revealed that the PFS per investigator assessment in the ITT population, which was an exploratory end point of the trial, in the investigative arm was 8.3 months (95% CI, 7.4-8.5) vs 6.5 months (95% CI, 6.2-7.4) in the control arm (HR, 0.69; 95% CI, 0.59-0.82). The 12-month PFS rates were 32.3% with pembrolizumab plus chemotherapy vs 18.5% with chemotherapy alone.
Less early censoring and more events per investigator were observed compared with BICR assessment, particularly in the chemotherapy arm. Discordance in the control arm was predominantly driven by patients who had disease progression per investigator assessment, but not by BICR assessment. All subgroups analyzed for PFS and OS by BICR favored pembrolizumab plus chemotherapy.
Moreover, 35.3% of those in the pembrolizumab/chemotherapy arm received any subsequent treatment vs 41.0% of those in the pembrolizumab monotherapy arm and 61.1% in the chemotherapy arm. Also, 48.0% of those in the chemotherapy arm received subsequent PD-(L)1 therapy vs 6.6% of those in the pembrolizumab plus chemotherapy arm and 4.6% of those in the single-agent pembrolizumab arm.
In patients with a combined positive score of 10 or greater, the median OS in the investigative and control arms was 16.1 months (95% CI, 13.6-19.9) and 15.2 months (95% CI, 11.6-23.3), respectively (HR, 1.01; 95% CI, 0.77-1.32). Here, the 12-month OS rates were 58.7% and 57.6%, respectively.
Additionally, the ORRs in the pembrolizumab/chemotherapy arm, the pembrolizumab monotherapy arm, and the chemotherapy arm were 54.7%, 30.3%, and 44.9%, respectively; the DCRs in these arms were 80.3%, 47.2%, and 75.9%, respectively. The median DOR in the pembrolizumab/chemotherapy arm was 8.5 months vs 28.2 months in the pembrolizumab monotherapy arm and 6.2 months in the chemotherapy arm.
Regarding safety, any-grade toxicities were reported in 99.7% of those in the pembrolizumab/chemotherapy arm as well as the chemotherapy-alone arm; 87.4% and 81.9% of these effects, respectively, were grades 3 to 5 in severity. Moreover, 9.2% led to death in the pembrolizumab with chemotherapy arm vs 2.6% in the chemotherapy arm. Approximately 30% of these toxicities resulted in treatment discontinuation in the pembrolizumab/chemotherapy arm vs 18.1% in the chemotherapy arm. In the single-agent pembrolizumab arm, 95.7% of patients experienced any-grade adverse effects, 62.9% were grade 3 to 5 in severity, 8.6% led to death, and 15.9% resulted in discontinuation.