FDA Updates Immunotherapy Labels for Bladder Cancer Treatment

The FDA has incorporated PD-L1 status into the labels for Keytruda (pembrolizumab) and Tecentriq (atezolizumab) for existing frontline approvals for platinum-ineligible patients with urothelial carcinoma, based on lower overall survival (OS) rates with the PD-1/PD-L1 inhibitors compared with platinum-based chemotherapy for patients with PD-L1—low expressing platinum-eligible urothelial carcinoma.

"In patients already receiving Keytruda or Tecentriq who are responding to treatment and are cisplatin-ineligible, continuation of treatment could be considered, regardless of PD-L1 status," the FDA advised in a safety alert. "The FDA has not changed the indications of Keytruda and Tecentriq for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment."

The FDA decision was based on an assessment conducted by a data monitoring committee (DMC) for the phase 3 KEYNOTE-361 study and the phase 3 IMvigor130 study. The KEYNOTE-361 (NCT02853305) and the IMvigor130 (NCT02807636) studies are exploring Keytruda and Tecentriq, respectively, with or without chemotherapy compared with chemotherapy or the immunotherapy alone.

The DMC identified that patients with PD-L1—low status had decreased overall survival in the single-agent immunotherapy arms compared with chemotherapy. Both trials have stopped enrolling patients with PD-L1–low status to the monotherapy arms. Other arms of the trials will remain open to patients with PD-L1–low tumors.

For Tecentriq, the frontline approval was restricted to patients with PD-L1 expression on immune cells (IC) of 5 percent or higher for those not eligible for cisplatin-containing therapy. For Keytruda, the label was restricted to patients with combined positive scores (CPS) 10 or higher for PD-L1 for cisplatin-ineligible patients. However, both labels remained broad for patients who are ineligible for any platinum-based agent, the label remained unconstrained by PD-L1 status.

"The FDA is reviewing the findings of ongoing analyses and will communicate new information regarding the PD-L1 assays and indications as it becomes available," the agency noted.

Single-arm phase 2 findings led to prior accelerated approvals for both Keytruda and Tecentriq as frontline therapies for cisplatin-ineligible patients with metastatic urothelial carcinoma. In these findings, and results from other phase 3 studies, responses were still observed in the PD-L1—negative populations.

In the larger phase 3 KEYNOTE-045 study of Keytruda in platinum-pretreated patients with urothelial carcinoma, PD-L1 expression by CPS did not appear to impact response. In the total population, the objective response rate (ORR) was 21.1 percent with Keytruda compared with 11.4 percent for chemotherapy. In those with a CPS of 10 percent or higher, the ORR for Keytruda was 21.6 percent compared with 6.7 percent for chemotherapy.

In the phase 2 KEYNOTE-052 trial, which explored frontline Keytruda for platinum-ineligible patients, the ORR across all groups was 24 percent, which included a complete response (CR) rate of 5 percent. Responses in this trial did appear to be impacted by PD-L1 status. For those with a CPS of more than 10 percent the ORR was 39 percent; however, in those with a score between 1 percent and 10 percent the ORR was 20 percent and for those with a score of less than 1 percent the ORR was 11 percent. Most CRs were seen in the ≥10 percent score range (10 of 11).

In the IMvigor210 trial of frontline Tecentriq for platinum-ineligible patients,³ the ORR was 23 percent, with a CR rate of 9 percent. In PD-L1 assessment via tumor infiltrating IC, the ORR was 21 percent in those with an IC0 score and 21 percent in those with an IC1 score. ORR was 28 percent in the IC2/3 group and 24 percent across all PD-L1—positive groups (IC1/2/3).

Several clinical trials exploring checkpoint inhibitors remain ongoing for patients with urothelial carcinoma. The single-arm phase 2 KEYNOTE-057 study is enrolling participants with high-risk non-muscle invasive bladder cancers (NMIBC) who are unresponsive to bacillus Calmette-Guérin (BCG) therapy (NCT02625961). Additionally, studies are ongoing to assess neoadjuvant treatment with Keytruda prior to cystectomy for patients with muscle-invasive bladder cancer (NCT02736266). These studies do not have strict PD-L1 testing requirements for entry.