A Phase III Randomized Trial of Pembrolizumab in Combination with Sacituzumab Govitecan vs. Standard of Care in Anti-PD(L)1-Resistant Advanced Urothelial Cancer

Bladder cancer (urothelial carcinoma) is the fifth most common cancer in the United States. About 80% of cases are diagnosed in the early stage, and advances in frontline treatment are rapidly occurring. However, treatment-refractory advanced bladder cancer remains challenging to treat with limited options. The 5-year survival rate for patients with locally advanced disease is about 40%, and lower (9%) for metastatic disease. The KEYNOTE-045 phase 3 study that led to US Food and Drug Administration approval in 2017 for pembrolizumab in this setting, found only a 21% overall response rate. More effective therapies in this setting are desperately needed.

Some studies have shown that the targeted drug therapy, sacituzumab govitecan*, may play a role in improving outcomes for these patients. The phase 3 TROPiCS-04 trial (NCT0452799) showed that the drug is active and effective in this setting; however, the study did not show a statistically significant improvement in overall survival compared to chemotherapy. In another study, the phase 2 TROPHY-U-01 study (NCT03547973), the combination treatment of sacituzumab govitecan and pembrolizumab showed some efficacy and a manageable toxicity profile. The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) has opened a phase 3 trial, EA8231, which aims to further evaluate this combination.

Sacituzumab govitecan is an antibody-drug conjugate. It is in a class of cancer treatments that target the TROP-2 protein, which is found on the surface of cancer cells and is associated with a poor prognosis. TROP-2 expression can cause resistance to drugs that block the PD-L1 protein. In combination with pembrolizumab, sacituzumab govitecan has been shown to help patients with other PD-L1-positive cancers live longer without cancer progression.

EA8231 will target anti-PD-L1-resistant advanced urothelial carcinoma. Investigators hypothesize that re-inhibition of the PD-L1 pathway when patients start sacituzumab govitecan will improve survival outcomes compared to salvage chemotherapy alone—the usual treatment for patients with progression following all other available treatments.

All patients who participate in EA8231 must have received: at least one dose of anti-PD-L1 monotherapy or combination therapy; at least one line of systemic therapy given in the advanced/metastatic setting for urothelial cancer; and enfortumab vedotin, another antibody-drug conjugate, in any setting (unless contraindicated). Patients are not eligible if they have already received sacituzumab govitecan, other TROP-2 directed therapies, or an antibody-drug conjugate containing topoisomerase I inhibitor (such as trastuzumab deruxtecan).

Participants will be randomized to either Arm A, to receive standard of care chemotherapy of the physician’s choice, or Arm B, to receive sacituzumab govitecan and pembrolizumab combination therapy. Treatment will continue until disease progression or unacceptable toxicity, except for the Arm A platinum doublet regimens, which may be given for up to 6 cycles, and Arm B pembrolizumab which may be given for a maximum of 35 cycles or 2 years. All patients will be followed for response until progression, and for survival for 5 years from the date of randomization. The study’s primary endpoint is overall survival.

As drug development continues to rapidly change frontline bladder cancer therapy, survival rates for advanced disease remain low. Therefore, it is necessary to evaluate new drug combinations quickly for safety and increased efficacy. One such priority is to gain insight into the role of immune checkpoint re-inhibition in the refractory setting. The results of this phase 3 trial may open the door to better treatment options and help guide further research.

Learn more about EA8231 at ecog-acrin.org.

*Also known as sacituzumab govitecan-hziy

The study chair for this trial is Monika Joshi, MD (Penn State Cancer Institute) and the co-chair is Petros Grivas, MD, PhD (University of Washington/Fred Hutchinson Cancer Center).