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FDA Updates Frontline Pembrolizumab, Atezolizumab Urothelial Carcinoma Labels to Include PD-L1 Status

Silas Inman
Published Online:2:08 PM, Thu June 21, 2018
The FDA has added PD-L1 status to the labels for pembrolizumab (Keytruda) and atezolizumab (Tecentriq) for existing frontline approvals for platinum-ineligible patients with urothelial carcinoma. The addition was made 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 III KEYNOTE-361 study and the phase III IMvigor130 study. The KEYNOTE-361 (NCT02853305) and the IMvigor130 (NCT02807636) studies are exploring pembrolizumab and atezolizumab, 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 atezolizumab, the frontline approval was restricted to patients with PD-L1 expression on immune cells (IC) of ≥5% for those not eligible for cisplatin-containing therapy. For pembrolizumab, the label was restricted to patients with combined positive scores (CPS) ≥10 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 II findings led to prior accelerated approvals for both pembrolizumab and atezolizumab as frontline therapies for cisplatin-ineligible patients with metastatic urothelial carcinoma. In these findings, and results from other phase III studies, responses were still observed in the PD-L1–negative populations.

In the larger phase III KEYNOTE-045 study of pembrolizumab in platinum-pretreated patients with urothelial carcinoma,1 PD-L1 expression by CPS did not appear to impact response. In the total population, the objective response rate (ORR) was 21.1% with pembrolizumab compared with 11.4% for chemotherapy. In those with a CPS of ≥10%, the ORR for pembrolizumab was 21.6% compared with 6.7% for chemotherapy.

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

In the IMvigor210 trial of frontline atezolizumab for platinum-ineligible patients,3 the ORR was 23%, with a CR rate of 9%. In PD-L1 assessment via tumor infiltrating IC, the ORR was 21% in those with an IC0 score and 21% in those with an IC1 score. ORR was 28% in the IC2/3 group and 24% 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 II 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 pembrolizumab prior to cystectomy for patients with muscle-invasive bladder cancer (NCT02736266). These studies do not have strict PD-L1 testing requirements for entry.
  1. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi: 10.1056/NEJMoa1613683.
  2. Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
  3. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.

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