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FDA Approves Keytruda for Certain Bladder Cancer Cases

Approval marks the fifth type of cancer for which the drug is indicated

The FDA has approved two new indications for pembrolizumab (Keytruda, Merck) for certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer.

In the first-line setting, pembrolizumab is now approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. This indication was granted 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 confirmatory trials. In the second-line setting, pembrolizumab 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.

Pembrolizumab 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.

The Keytruda clinical development program includes more than 30 tumor types in nearly 500 clinical trials, including more than 250 trials that combine pembrolizumab with other cancer treatments.

The first-line approval is based on data from a multicenter, open-label, single-arm trial, KEYNOTE-052, investigating pembrolizumab 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. The major efficacy outcome measures were objective response rate (ORR) and duration of response.

The efficacy analysis showed an ORR of 29% (95% confidence interval [CI], 24–34), with a complete response rate of 7% and a partial response rate of 22%. The median duration of response had not been reached (range, 1.4+ months to 17.8+ months). The median follow-up time was 7.8 months.

In this trial, pembrolizumab was discontinued due to adverse reactions in 11% of patients. The most common adverse reactions (in 20% of patients or greater) 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 pembrolizumab experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia that led to death. Adverse reactions leading to interruption of pembrolizumab occurred in 22% of patients; the most common (1% or greater) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients, the most frequent (2% or greater) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

The second-line approval of pembrolizumab is based on data from a multicenter, randomized, active-controlled trial investigating the treatment 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 pembrolizumab 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); additional efficacy outcome measures were ORR and duration of response.

Pembrolizumab demonstrated superior OS compared to chemotherapy. Findings demonstrated that pembrolizumab resulted in a 27% reduction in the risk of death compared to chemotherapy—with 155 events (57%) observed in the pembrolizumab arm, compared to 179 events (66%) in the chemotherapy arm (hazard ratio [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 pembrolizumab 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 pembrolizumab met the superiority thresholds for OS in the overall study population.

There was no statistically significant difference between pembrolizumab and chemotherapy with respect to PFS. There were 218 events (81%) observed in the pembrolizumab arm, compared with 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 pembrolizumab arm, compared with 3.3 months (95% CI, 2.3–3.5) in the chemotherapy arm.

Analysis of the ORR endpoint showed a statistically significant improvement with pembrolizumab, as compared with chemotherapy. The ORR was 21% (95% CI, 16–27) in the pembrolizumab arm (with a complete response rate of 7% and a partial response rate of 14%), compared with 11% (95% CI, 8–16) in the chemotherapy arm (with a complete response rate of 3% and a partial response rate of 8%) (P = 0.002). The median duration of response for patients treated with pembrolizumab had not yet been reached (range, 1.6+ months to 15.6+ months), compared with 4.3 months (range: 1.4+ months to 15.4+ months) in the chemotherapy arm. The median follow-up time for this trial was 9.0 months.

In this trial, pembrolizumab was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of pembrolizumab was pneumonitis (1.9%). Adverse reactions leading to interruption of pembrolizumab occurred in 20% of patients; the most common (1% or greater) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (20% or greater) in patients who received pembrolizumab versus those who received chemotherapy were fatigue (38% versus 56%), musculoskeletal pain (32% versus 27%), pruritus (23% versus 6%), decreased appetite (21% versus 21%), nausea (21% versus 29%), and rash (20% versus 13%). Serious adverse reactions occurred in 39% of pembrolizumab-treated patients, the most frequent (2% or greater) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

Source: Merck; May 18, 2017.

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