The PD-L1 inhibitor pembrolizumab continued to demonstrate a survival benefit compared to chemotherapy among patients with advanced urothelial carcinoma, according to mature findings from the KEYNOTE-045 study presented during the ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Furthermore, no new safety signals for pembrolizumab were raised with long-term follow-up.
Ronald de Wit, Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands, and an international team of researchers conducted the phase III, multicentre, open label KEYNOTE-045 trial (NCT02256436) of pembrolizumab compared to investigators’ choice of chemotherapy, including paclitaxel, docetaxel, or vinflunine in patients with recurrent, advanced urothelial carcinoma.
Previously reported results from this study demonstrated that overall survival (OS) was significantly improved with pembrolizumab.
At ESMO 2017, mature results from KEYNOTE-045 were presented. The study randomly assigned 270 patients with recurrent, advanced urothelial carcinoma to pembrolizumab at 200 mg every 3 weeks and 272 were assigned to investigators’ choice of chemotherapy. The patients’ baseline characteristics were balanced between arms.
Longer overall survival with pembrolizumab than with chemotherapy
As of 19 May 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 with pembrolizumab compared to 7.4 months with chemotherapy, hazard ratio [HR] 0.70 (p = 0.0003).
Overall survival in KEYNOTE-045.
© Ronald de Wit.
The median OS was significantly longer with pembrolizumab compared to chemotherapy in the overall patient population. Median OS was 10.3 with pembrolizumab compared to 7.4 months with chemotherapy, hazard ratio [HR] 0.70 (p = 0.0003).
Overall survival as measured by combined positive score (CPS) in patient having CPS ≥10.
© Ronald de Wit.
Importantly, OS was longer with pembrolizumab versus chemotherapy regardless of age, liver metastases, haemoglobin, the presence of visceral disease, and the choice of chemotherapy.
The 18-month OS rates according to Kaplan-Meyer estimates, were 33.2% (95% CI 27.5, 38.9) compared to 19.7% (95% CI 14.7, 24.8) with pembrolizumab versus chemotherapy, respectively.
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% confidence interval [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 (range 1.6+ to 24.6+ months) versus 4.4 months (range 1.4+ to 24.0+ months).
Fewer patients experienced treatment-related adverse events (TRAEs) with pembrolizumab compared with chemotherapy. The incidence of TRAEs any grade was 62.0 % versus 90.6%, and the incidence of grade > 3 TRAEs was 16.5% versus 50.2%, respectively.
Pembrolizumab granted FDA and EMA approvals in urothelial cancer
Based on findings from the KEYNOTE-045 trial, 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. Also, 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.
On 20 July 2017, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending a change to the terms of the marketing authorisation for pembrolizumab. The CHMP adopted a new indication as follows: Pembrolizumab as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. Pembroliuzmab as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy.
Conclusions
Additional follow-up in KEYNOTE-045 study demonstrated that OS with pembrolizumab continued to improve compared to chemotherapy and the pembrolizumab responses continued to be more durable.
Pembrolizumab demonstrated a superior long-term safety profile compared with chemotherapy in patients with recurrent, advanced urothelial carcinoma.
Maria De Santis, University of Warwick, UK who discussed the study results said that pembrolizumab continues to demonstrate statistically significant and clinically meaningful OS benefit versus chemotherapy with longer follow-up. Pembrolizumab is the first immunotherapy to demonstrate superior OS over chemotherapy in patients with advanced urothelial carcinoma after failure of platinum-based therapy and should be considered a standard of care for these patients.
Disclosure
This trial was sponsored by Merck & Co, Inc., Kenilworth, NJ, USA.
Reference
LBA37_PR – de Wit R, et al. Pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer (UC): mature results from the phase 3 KEYNOTE-045 trial.