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FDA grants full approval to pembrolizumab in frontline bladder cancer


The FDA has converted the accelerated approval of frontline pembrolizumab (Keytruda) in advanced bladder cancer to a full approval and revised the indication to cover the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for any platinum-containing chemotherapy.1

In May 2017, the FDA initially approved the pembrolizumab for the first-line treatment of patients with locally advanced or mUC who are ineligible for cisplatin-containing chemotherapy.

In 2018, the FDA updated the label for frontline pembrolizumab in this setting, with the approval now being specifically for the treatment of patients with locally advanced or mUC who are not eligible for cisplatin-containing therapy and whose tumors express PD-L1 (combined positive score ≥10), or the treatment of patients who are not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status.

The label update today was based on analyses from the phase 3 KEYNOTE-361 trial, which was intended to be the confirmatory trial for the frontline accelerated approval of pembrolizumab in bladder cancer. The trial randomized patients with advanced or mUC to frontline treatment with single-agent pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone.

The results showed that adding pembrolizumab to chemotherapy did not lead to a statistically significant improvement in OS or PFS. Although there was a numerical improvement in OS and PFS with the combination versus standard chemotherapy, the difference did not achieve the threshold for statistical significance established in the trial design. Since the primary OS or PFS end points were not met with the combination, the study design did not allow for formal testing of the monotherapy arm.

Despite the KEYNOTE-361 setback, a nearly split FDA ODAC panel voted 5 to 3 in May 2021 in support of maintaining the accelerated approval of pembrolizumab in this setting, concluding that the treatment still meets an unmet medical need for certain patients with bladder cancer.2 The FDA decision today upheld the ODAC recommendation.

The open-label, phase 3 KEYNOTE-361 trial (NCT02853305) randomized 1010 patients with advanced or mUC to frontline treatment with single-agent pembrolizumab (P), pembrolizumab plus chemotherapy (P + C), or chemotherapy (C) alone. Chemotherapy consisted of cisplatin or carboplatin plus gemcitabine. The coprimary end points for the trial were OS and PFS. Secondary end points were response, disease control rate, and safety.

In the study, the media PFS was 8.3 months with P + C, compared with 3.9 months and 7.1 months with P alone and C alone, respectively.2 The hazard ratio for PFS for P + C versus C was 0.78 (P = .0033). The median OS was 17.0 months for P +C, compared with 15.6 months with P alone and 14.3 months with C alone. The hazard ratio for OS for P + C versus C was 0.86 (P = .0407). The objective response rates were 54.7%, 30.3%, 44.9% for P + C , P, and C, respectively.

Regarding safety, 75.1% of the P + C arm experienced grade 3-5 treatment-related adverse events, compared with 16.9% in the P arm and 71.6% in the C arm. The AE-related discontinuation rates of any drug were 30.9%, 15.9%, and 18.1% in the 3 arms, respectively.


1. FDA Approves Updated Indication for Merck’s KEYTRUDA® (pembrolizumab) for Treatment of Certain Patients With Urothelial Carcinoma (Bladder Cancer). Published online August 31, 2021. Accessed August 31, 2021. https://bwnews.pr/3kF1dw6.

2. Merck Provides Update on Phase 3 KEYNOTE-361 Trial Evaluating KEYTRUDA® (pembrolizumab) as Monotherapy and in Combination with Chemotherapy in Patients with Advanced or Metastatic Urothelial Carcinoma. Published June 10, 2020. https://bit.ly/3cQzLWe. Accessed May 4, 2021.

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