Merck, known as MSD outside the United States and Canada, announced that the European Commission has approved Keytruda (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer. Specifically, Keytruda is approved for use as monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy, as well as adults who are not eligible for cisplatin-containing chemotherapy.
The approval in patients previously treated with platinum-containing chemotherapy was based on superior overall survival (OS) for Keytruda versus investigator-choice chemotherapy (paclitaxel, docetaxel, vinflunine) (HR, 0.73 [95% CI: 0.59, 0.91], p=0.002), as demonstrated in the randomized, phase 3 KEYNOTE-045 trial. The approval in patients ineligible for cisplatin-containing chemotherapy was based on phase 2 data from the KEYNOTE-052 trial, which demonstrated an overall response rate (ORR) of 29 percent (95% CI, 25-34). The approval allows for the marketing of Keytruda in these two new indications in all 28 EU member states plus Iceland, Lichtenstein and Norway at a dose of 200 mg every three weeks until disease progression or unacceptable toxicity.
"This approval of Keytruda is important for patients with advanced urothelial carcinoma,” said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. “Our focus is now on working with health authorities in Europe to ensure access for these patients as quickly as possible.”
“Despite advances, there remain limited treatment options available to patients with locally advanced or metastatic urothelial carcinoma who are either not eligible to receive cisplatin-containing chemotherapy – which is platinum-based and currently the standard of care – or for those patients whose cancer returns after receiving prior platinum-containing chemotherapy,” said professor Ronald de Wit, M.D., Ph.D., group leader experimental systemic therapy of urogenital cancers, Erasmus MC Cancer Institute. “It is exciting that with this approval of Keytruda, we now also have a new treatment option for patients previously treated with platinum-containing chemotherapy that has shown a clinically meaningful and improved overall survival benefit versus chemotherapy in this difficult-to-treat population.”
The approval in patients previously treated with platinum-containing chemotherapy is based on data from a multicenter, randomized, controlled trial, KEYNOTE-045, investigating Keytruda (pembrolizumab) in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. Patients must have received a first-line platinum-containing regimen for locally advanced/metastatic disease or as neoadjuvant/adjuvant treatment, with recurrence/progression =12 months following completion of therapy. Patients were randomized (1:1) to receive either Keytruda 200 mg every three weeks (n=270) or investigator’s choice of any of the following chemotherapy regimens, all given intravenously every three weeks (n=272): paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2. Patients were treated with Keytruda until unacceptable toxicity or disease progression, or for up to 24 months in patients without disease progression. The study excluded patients with autoimmune disease, a medical condition that required immunosuppression and patients with more than two prior lines of systemic chemotherapy for metastatic urothelial cancer. The primary efficacy outcomes were OS and progression-free survival (PFS) (as assessed by BICR using RECIST v1.1); secondary outcome measures were ORR (as assessed by BICR using RECIST v1.1) and duration of response.
In the study, Keytruda demonstrated a statistically significant improvement in OS compared to chemotherapy. Findings demonstrated that Keytruda resulted in a 27 percent reduction in the risk of death compared to chemotherapy – with 155 events (57%) observed in the Keytruda arm, compared to 179 events (66%) in the chemotherapy arm (HR, 0.73 [95% CI: 0.59, 0.91], p=0.002); the median OS was 10.3 months (95% CI: 8.0, 11.8) in the Keytruda (pembrolizumab) arm, compared to 7.4 months (95% CI: 6.1, 8.3) in the chemotherapy arm.
There was no statistically significant difference between Keytruda and chemotherapy with respect to PFS. There were 218 events (81%) observed in the Keytruda arm, compared to 219 events (81%) in the chemotherapy arm (HR, 0.98 [95% CI: 0.81, 1.19], p=0.416). The median PFS was 2.1 months (95% CI: 2.0, 2.2) in the Keytruda arm, compared to 3.3 months (95% CI: 2.3, 3.5) in the chemotherapy arm.
The ORR was 21 percent (95% CI: 16, 27) for patients receiving Keytruda, with a complete response rate of 7 percent and a partial response rate of 14 percent. In the chemotherapy arm, the ORR was 11 percent (95% CI: 8, 16), with a complete response rate of 3 percent and a partial response rate of 8 percent (p=0.001). The median duration of response for patients treated with Keytruda had not yet been reached (range: 1.6+ to 15.6+ months), compared to 4.3 months (range: 1.4+ to 15.4+ months) in the chemotherapy arm.
The approval in patients ineligible for cisplatin-containing chemotherapy is based on data from a multicenter, open-label study, KEYNOTE-052, investigating Keytruda in 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients received Keytruda at a dose of 200 mg every three weeks until unacceptable toxicity or disease progression, or for up to 24 months in patients without disease progression. The study excluded patients with autoimmune disease or a medical condition that required immunosuppression. The primary efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1; secondary efficacy outcome measures were duration of response, PFS, and OS.
The efficacy analysis, with a median follow-up time of 9.5 months, showed an ORR of 29 percent (95% CI: 25, 34), a complete response rate of 7 percent, and a partial response rate of 22 percent. The median duration of response had not been reached (range: 1.4+ to 19.6+ months).
Keytruda is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Studies of Keytruda – from the largest immuno-oncology program in the industry with more than 550 trials – include a wide variety of cancers and treatment settings. The Keytruda clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with Keytruda, including the exploration of several different biomarkers across a broad range of tumors.
Merck\'s keytruda, european approval, treat certain patients with bladder cancer
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