Use of Checkpoint Inhibitors in Urothelial Carcinoma

Studies presented in the last year demonstrated a revolutionary role for immune checkpoint inhibitors.
Studies presented in the last year demonstrated a revolutionary role for immune checkpoint inhibitors.

ORLANDO After limited advancements in the treatment of urothelial carcinoma over the last 3 decades, studies presented in the last year demonstrated a revolutionary role for immune checkpoint inhibitors among patients resistant to platinum-containing chemotherapy and those ineligible to receive cisplatin.

At the 2017 Genitourinary Cancers Symposium, Matthew I. Milowsky, MD, associate professor in the department of medicine, division of hematology and oncology at University of North Carolina-Chapel Hill, discussed clinical trials that supporting the efficacy of immuno-oncology agents among patients with urothelial carcinoma.1

Cohort 2 of the open-label, phase 2 IMvigor210 trial (ClinicalTrials.gov Identifier: NCT02108652) showed that median overall survival was 7.9 months (95% CI, 6.7-9.3) with atezolizumab, a PD-L1 blocking antibody, among patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following prior treatment with platinum-based chemotherapy.

"Median survival was higher in those patients with higher PD-L1 expression as well as in those with lymph node only disease, and this compares quite favorably to patients historically treated with chemotherapy in the post-platinum space with relatively poor prognostic features," explained Dr Milowsky. "These findings led to FDA [U.S. Food and Drug Administration] approval in May of 2016."

The FDA also approved nivolumab as second- or subsequent-line therapy for patients with locally advanced or metastatic urothelial carcinoma in February 2017. Approval was based on findings from the phase 2 CheckMate 275 study (ClinicalTrials.gov Identifier: NCT02387996), which showed a confirmed objective response rate of nearly 20% of 265 patients with nivolumab every 2 weeks and a median duration of response of 10.2 months.

"Once again, there was durability to these responses with median duration of response not reached and ongoing responses seen in 77% of patients," Dr Milowsky added. "Median survival was 8.74 months, and again, this compares favorably to historical patients treated with post-platinum chemotherapy with relatively poor prognostic features."

Data from the open-label, phase 3 KEYNOTE-045 study (ClinicalTrials.gov Identifier: NCT02256436) of pembrolizumab vs investigator's choice of chemotherapy among patients with previously treated advanced urothelial cancer showed that PD-1 blockade reduced the risk of death by 27% compared with chemotherapy regardless of PD-L1 expression status (hazard ratio, 0.73; 95% CI, 0.59-0.91).

"Once again, these responses are durable and this was the first phase 3 study of immune checkpoint blockade to demonstrate a significant survival benefit."

Durvalumab monotherapy in (Study 1108; ClinicalTrials.gov Identifier: NCT01693562) and nivolumab plus ipilimumab (CheckMate 032; ClinicalTrials.gov Identifier: NCT01928394) may also be effective strategies for patients with advanced disease who have previously received platinum-based chemotherapy.

For frontline treatment of cisplatin-ineligible patients, cohort 1 of the IMvigor 210 trial (ClinicalTrials.gov Identifier: NCT02951767) showed an overall response rates of 23% and a median overall survival of 15.9 months with atezolizumab monotherapy. Interim results of the KEYNOTE-052 trial (ClinicalTrials.gov Identifier: NCT02335424) of pembrolizumab in 100 cisplatin-ineligible patients with unresectable or metastatic disease demonstrated a response rate of 24%, with 6% achieving complete responses. Durable responses were observed in both studies.

"The rapid development of new checkpoint inhibitors has felt at times like a pharmaceutical arms race, and this must not cloud efforts to chart the way forward with basic, translational, and clinical research toward the next major advancement in the field," said Dr Milowsky.

Reference

1. Milowsky MI. Urothelial Carcinoma: Year in Review. Lecture presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL.

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