FDA Warning Advises Against Single-Agent Checkpoint Inhibition for PD-L1-Low Untreated Urothelial Carcinomas


A drug safety notification warning has been issued by the FDA against the use of the single-agent immune checkpoint inhibitors in the first-line setting for patients with PD-L1–low expressing platinum-eligible urothelial carcinoma.  This follows findings of a decrease in overall survival with pembrolizumab and atezolizumab versus a platinum-based chemotherapy.

A drug safety notification warning has been issued by the FDA against the use of single-agent immune checkpoint inhibitors in the first-line setting for patients with PD-L1—low expressing platinum-eligible urothelial carcinoma. This warning follows findings of a decrease in overall survival with pembrolizumab (Keytruda) and atezolizumab (Tecentriq) versus a platinum-based chemotherapy.

The FDA issued the warning based on results from an assessment conducted by a data monitoring committee (DMC) for the phase III KEYNOTE-361 study (NCT02853305) and the phase III IMvigor130 study (NCT02807636). Both of these studies are exploring pembrolizumab and atezolizumab, respectively, with or without chemotherapy versus treatment of either chemotherapy or immunotherapy alone.

Patients with PD-L1—low status had decreased overall survival rates in the single-agent immunotherapy arms verus chemotherapy, according to the assessment by the DMC. Both trials are no longer enrolling patients with PD-L1–low status to the monotherapy arms. However, other arms remain open to patients with PD-L1–low tumors.

"FDA issues an alert that preliminary data analysis shows a decrease in survival for bladder cancer patients receiving immunotherapy with pembrolizumab or atezolizumab versus chemotherapy as first-line therapy," read a tweet from Andrea Apolo, MD, chief of the Bladder Cancer Section, Genitourinary Malignancies Branch, NCI, NIH. "This is not surprising as chemotherapy is very active in this setting."

Both studies utilized different techniques and cutoff points to define the PD-L1 status among patients. The KEYNOTE-361 trial used a combined positive score (CPS), the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells. The immunohistochemistry-based Ventana PD-L1 (SP142) assay has been approved as a complementary diagnostic for atezolizumab.

A score between 1% and 10% is considered low for the CPS test. However, an expression level of 1 is considered low for the ventana test. Additional data from the assessment will be available at a presentation of the results and was not released by the FDA.

A larger analysis of the PD-L1 assessment techniques in each trial is required after the FDA warning, Apolo said.

"The initial bladder cancer first-line cisplatin-ineligible single-arm studies showed no difference in ORR for pembrolizumab or atezolizumab in PD-L1—positive versus PD-L1–negative patients," Apolo added.

Findings from a single-arm phase II led to previous accelerated approvals for both pembrolizumab and atezolizumab as frontline therapies for cisplatin-ineligible patients with metastatic urothelial carcinoma. In these findings as well as 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,1PD-L1 expression by CPS did not appear to have an impact on response. The objective response rate (ORR) in the total population 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,2that explored pembrolizumab in the first-line setting for platinum-ineligible patients, the ORR across all groups was 24%, which included a complete response (CR) rate of 5%. Those with a CPS of >10% for PD-L1 had an ORR of 39%. 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).

The FDA alert highlighted an overall lack of efficacy in the PD-L1—low expressing group in the frontline setting, regardless of platinum eligibility, according to Alison Birtle, MB BS, MD. Although there were not comparator arms in the KEYNOTE-052 and IMvigor210 studies, the phase II/III EORTC 30986 study showed higher ORRs for gemcitabine and carboplatin for patients with advanced platinum-ineligible urothelial carcinoma.4The ORR in this study was 41.2% with gemcitabine/carboplatin.

"For first-line treatment I'd still give gemcitabine/cisplatin or gemcitabine/carboplatin, based on current data. This alert backs up that approach further," Birtle, consultant Clinical Oncologist and honorary clinical senior lecturer at the Lancashire Teaching Hospitals, noted on Twitter.

The current FDA announcement pertains only to the two phase III studies, it remains unclear whether the FDA will mandate stricter testing for other early-stage clinical trials for the checkpoint inhibitors in urothelial carcinoma, as studies are beginning to explore these agents in patients with non-muscle invasive bladder cancers (NMIBC).

KEYNOTE-057, a single-arm phase II study, is currently enrolling participants with high-risk 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.
  4. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986.J Clin Oncol. 2012;30(2):191-199.

The ORR was 23%, with a CR rate of 9% in the IMvigor210 trial of frontline atezolizumab for platinum-ineligible patients.3In PD-L1 assessment via tumor infiltrating immune cell (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).

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