Antibody-Drug Conjugates Changed the Standard of Care in Bladder Cancer

Padcev and Keytruda now set the standard for advanced bladder cancer, surpassing older single-agent immunotherapy approaches.

An international team of researchers has published their findings detailing potential predictors of response to immunotherapy among patients with advanced bladder cancer that were determined via a meta-analysis of six independent cohorts of patients.

While researchers, who published their findings in Nature Communications, analyzed the data of 466 patients who had received single-agent immunotherapy treatment for advanced, metastatic bladder cancer, “nowadays that’s not the way that we treat bladder cancer,” as study co-author Dr. Joaquim Bellmunt explained.

Bellmunt is an associate professor at Harvard Medical School and director of the Bladder Cancer Center at Genitourinary Oncology Program of Dana-Farber Cancer Institute, both in Boston.

“We have moved ahead, and the landscape has changed,” Bellmunt said in an interview with CURE. “And now, for example, in first line we are using still immunotherapy that is, for example, [Keytruda (pembrolizumab)], the PD-1 inhibitor. But this is combined with a new type of chemotherapy, a personalized or let's say more targeted chemotherapy, that are antibody-drug conjugates.

“And the antibody-drug conjugate that we are giving together with immunotherapy is named [Padcev (enfortumab vedotin-ejfv)]. It is like a carrier of a payload that is a chemotherapy. And this antibody, that is a carrier, is looking, searching for the cancer cell. The cancer cell is identified because this antibody is detecting or targeting what is called NECTIN-4, that is an antigen highly expressed in tumor cells, and then this antibody arrives to the cancer cell, and the cancer cell engulfs the antibody-drug conjugate, and then the chemotherapy is released inside the cell.”

The Food and Drug Administration (FDA) approved the combination of Padcev and Keytruda for patients with locally advanced or metastatic bladder cancer in December 2023, less than a year after the regulatory agency granted the drug combination accelerated approval for the treatment of patients who were ineligible for treatment with cisplatin-based chemotherapy.

Regarding patients’ response to single-agent immunotherapy, Bellmunt and his colleagues found that, in addition to tumor mutational burden, enrichment in the APOBEC mutational signature and an abundance of pro-inflammatory macrophages were all major factors that were associated with response, as they noted in their study.

“The antibody-drug conjugate combined with immunotherapy is now the standard of care, so meaning that all these studies that we have published are helpful, but — and this is good news —because we are adding another agent, likely we will need to design new tools to say, well, this combination of [Padcev] and [Keytruda] is getting like a 65% response rate in patients with metastatic disease.

“And then, obviously, we will like to know which patients might need other therapies instead of these combinations. And then obviously we will need to do genomic profiling of these patients that are receiving this combination. And maybe some of these predictors that have been described with single agent immunotherapy are going to prevail, so likely the tumor mutational burden like this going to prevail. But there might be other [predictive factors] that will be overcome with the addition within another agent. And those are predictive factors are no longer to be valid.”

Reference:

“Predicting immunotherapy response of advanced bladder cancer through a meta-analysis of six independent cohorts” by Lilian Marie Boll et al., Nature Communications.

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