Merck, known as MSD outside the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved two new indications for Keytruda (pembrolizumab), the company’s anti-PD-1 therapy, for certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer. In the first-line setting, Keytruda is now approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In the second-line setting, Keytruda is now approved 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. Keytruda is approved for use in these indications at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Immune-mediated adverse reactions occurred with Keytruda including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, Keytruda should be withheld or discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions.

Monitor patients for signs and symptoms of infusion-related reactions; for Grade 3 or 4 reactions, stop infusion and permanently discontinue Keytruda (pembrolizumab). Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see “Selected Important Safety Information” below.

“Keytruda is now available for use as a first-line treatment option for patients with advanced urothelial bladder cancer who are not eligible for the standard of care, cisplatin-based chemotherapy,” said Dean F. Bajorin, M.D., study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. “With the second-line indication, Keytruda also provides a new option for patients with advanced urothelial bladder cancer – and is the only anti-PD-1 therapy to show an overall survival benefit versus chemotherapy in a phase 3 study.”

“These two indications mark important additions to the growing list of tumors and treatment settings for which Keytruda is now approved. This FDA approval further demonstrates Merck’s commitment to help improve the lives of patients with many types of advanced cancer,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.

The Keytruda clinical development program includes more than 30 tumor types in nearly 500 clinical trials, including more than 250 trials that combine Keytruda with other cancer treatments. Currently, Merck has the largest immuno-oncology clinical development program in bladder cancer, with 29 trials underway involving Keytruda as monotherapy and in combination, including four registration-enabling studies.

The first-line approval is based on data from a multicenter, open-label, single-arm trial, KEYNOTE-052, investigating Keytruda in 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medication were excluded from the trial. Patients received Keytruda at a dose of 200 mg every three weeks until unacceptable toxicity or disease progression; patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were objective response rate (ORR), according to the Response Evaluation Criteria In Solid Tumors (RECIST) as assessed by independent radiology review, and duration of response.

The efficacy analysis showed an ORR of 29 percent (95% CI: 24, 34), with 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 17.8+ months). The median follow-up time was 7.8 months.

In KEYNOTE-052, Keytruda (pembrolizumab) was discontinued due to adverse reactions in 11 percent of patients. The most common adverse reactions (in = 20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%) and diarrhea (20%). Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with Keytruda experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of Keytruda occurred in 22 percent of patients; the most common (=1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42 percent of patients, the most frequent (=2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

The second-line approval is based on data from a multicenter, randomized, active-controlled trial, KEYNOTE-045, investigating Keytruda in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded from the trial. Patients were randomized 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 (n=84), docetaxel 75 mg/m2 (n=84), or vinflunine 320 mg/m2 (n=87). Treatment continued until unacceptable toxicity or disease progression; patients without disease progression could be treated for up to 24 months. The major efficacy outcomes were overall survival (OS) and progression-free survival (PFS), as assessed by a blinded independent central review (BICR) per RECIST additional efficacy outcome measures were ORR, as assessed by BICR per RECIST and duration of response.

Keytruda demonstrated superior 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=0.004); the median OS was 10.3 months (95% CI: 8.0, 11.8) in the Keytruda arm, compared to 7.4 months (95% CI: 6.1, 8.3) in the chemotherapy arm. In October 2016, the study was stopped early at the recommendation of an independent Data Monitoring Committee following an interim analysis that showed Keytruda met the superiority thresholds for OS in the overall study population.

There was no statistically significant difference between Keytruda (pembrolizumab) 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=0.833). 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.

Analysis of the ORR endpoint showed a statistically significant improvement with Keytruda, as compared to chemotherapy. The ORR was 21 per cent (95% CI: 16, 27) in the Keytruda arm (with a complete response rate of 7 percent and a partial response rate of 14 percent), compared to 11 percent (95% CI: 8, 16) in the chemotherapy arm (with a complete response rate of 3 percent and a partial response rate of 8 percent) (p=0.002). 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 median follow-up time for this trial was 9.0 months.

In KEYNOTE-045, Keytruda was discontinued due to adverse reactions in eight percent of patients. The most common adverse reaction resulting in permanent discontinuation of Keytruda was pneumonitis (1.9%). Adverse reactions leading to interruption of Keytruda occurred in 20 percent of patients; the most common (=1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (=20%) in patients who received Keytruda versus those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%) and rash (20% vs 13%). Serious adverse reactions occurred in 39 percent of Keytruda-treated patients, the most frequent (=2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.