Mature results from the phase III KEYNOTE-045 study presented at the 2017 ESMO Congress demonstrated that overall survival with pembrolizumab (Keytruda) continued to improve compared to chemotherapy in patients with recurrent, advanced urothelial carcinoma.
Ronald de Wit MD, PhD
Mature results from the phase III KEYNOTE-045 study presented at the 2017 ESMO Congress demonstrated that overall survival (OS) with pembrolizumab (Keytruda) continued to improve compared to chemotherapy in patients with recurrent, advanced urothelial carcinoma.
As of the cutoff point on May 19, 2017, median follow-up was 22.5 months in both arms. The median OS was significantly longer with pembrolizumab compared to chemotherapy in the overall patient population; median OS was 10.3 versus 7.4 months, respectively (hazard ratio [HR], 0.70; P = 0.0003).
Significantly improved OS was observed regardless of the level of PD-L1 expression, as measured by combined positive score (CPS), with patients having CPS ≥10% demonstrating a median OS of 8.9 with pembrolizumab versus 5.2 months with chemotherapy (HR, 0.58 P = 0.003).
The 18-month OS rates were 33.2% (95% CI, 27.5-38.9) compared to 19.7% (95% CI, 14.7-24.8) with pembrolizumab versus chemotherapy, respectively.
Ronald de Wit MD, PhD, group leader of the experimental systematic therapy of urogenital cancers program at Erasmus MC Cancer Institute, Rotterdam, Netherlands, presented mature results from the phase III, multicenter, open label KEYNOTE-045 trial (NCT02256436), which randomly assigned 270 patients with recurrent, advanced urothelial carcinoma to pembrolizumab at 200 mg every 3 weeks and 272 patients to investigators’ choice of chemotherapy (paclitaxel [Abraxane], docetaxel [Taxotere], or vinflunine [Javlor]).
Importantly, OS was longer with pembrolizumab versus chemotherapy regardless of age, liver metastases, hemoglobin levels, the presence of visceral disease, and the choice of chemotherapy.
“Pembrolizumab is the first agent to improve survival over chemotherapy in the second-line setting. Not all patients benefit from checkpoint inhibition, but a sizeable proportion of patients who respond have very durable responses, even well over one year,” noted de Wit. “These resulting are striking in the setting of urothelial cancer, which is highly lethal in the metastatic state.”
Similar progression-free survival (PFS) was observed between the treatments; median PFS was 2.1 versus 3.3 months with pembrolizumab versus chemotherapy, respectively (HR, 0.96 P = 0.32).
The objective response rate (ORR) was nearly doubled with pembrolizumab; ORR was 21.1% (95% CI, 16.4-26.5) with pembrolizumab versus 11.0% (95% CI, 7.6-15.4) with chemotherapy. The responses with pembrolizumab were more durable than with chemotherapy; the median response duration of response was not reached in the pembrolizumab arm (range, 1.6+ to 24.6+ months) versus 4.4 months (range 1.4+ to 24.0+ months).
Furthermore, no new safety signals for pembrolizumab were raised, which had a superior long-term safety profile versus chemotherapy.
“Treatment-related adverse events [TRAEs] of any grade occurred in 62.0% of pembrolizumab-treated patients compared to 90.6% of those treated with chemotherapy,” noted de Wit. The incidence of grade >3 TRAEs was 16.5% versus 50.2%, respectively. Immune-related AEs occurred in 19.5% of patients on pembrolizumab compared to 7.5% of patients on chemotherapy. Discontinuation due to an AE occurred in 7.1% versus 12.5% of pembrolizumab versus chemotherapy patients, respectively.
“The US Food and Drug Administration [FDA] approved pembrolizumab in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy,” noted de Wit. “Also, in July 2017, the FDA granted an accelerated approval to frontline pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.”
The KEYNOTE-45 trial was sponsored by Merck & Co, based in Kenilworth, New Jersey.
De Wit R, Vaughn DJ, Fradet Y, et al. Pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer (UC): mature results from the phase 3 KEYNOTE-045 trial. Abstract presented at: 2017 ESMO Congress; September 8-12; Madrid, Spain. Abstract LBA37.