Daniel P. Petrylak, MD
The explosion of new checkpoint immunotherapy drugs has changed the paradigm of care for patients with urothelial carcinoma, the most common form of bladder cancer, according to experts who participated in a recent OncLive® Peer Exchange® panel. Although chemotherapy regimens may still be the best first-line approach for some patients, other patients may benefit more from a checkpoint inhibitor.
Since May 2016, the FDA has approved 5 immunotherapy agents for patients with urothelial carcinoma: avelumab (Bavencio), atezolizumab (Tecentriq), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda). The drugs, which are all PD-1 or PD-L1 inhibitors, have all been approved for patients with locally advanced or metastatic urothelial carcinoma that has progressed during or after platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant treatment. Atezolizumab and pembrolizumab also are indicated for patients who are not eligible for cisplatin-containing chemotherapy. Other checkpoint inhibitors that inhibit PD-1/PDL-1 or cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) have also shown activity in urothelial carcinoma.1
Peer Exchange® moderator Daniel P. Petrylak, MD, and other experts in the field of genitourinary oncology discussed how immunotherapy is changing outcomes for patients with advanced bladder cancer.
Heterogeneity of Bladder Cancer
“Bladder cancer is a very heterogeneous disease, even within the metastatic state,” Petrylak said. Bladder cancers are broadly described as papillary or nonpapillary.2 Dean F. Bajorin, MD, explained that they are further subdivided into 3 main categories: metastatic bladder cancer, muscle-invasive bladder cancer (MIBC) without metastasis, and nonmuscle-invasive bladder cancer (ie, carcinoma in situ). The 3 types occur with different frequencies and require different management approaches.
Genomic studies like The Cancer Genome Atlas (TCGA) project have revealed numerous molecular subtypes and genetic signatures within the 3 main categories of bladder cancer.2 Bajorin said, “We know that there are a substantial number of mutations that we see in this disease. In fact, the mutation rate is right up there, with non–small cell lung cancer and melanoma.” He said the tumor’s genetic makeup appears to evolve over time. As a result, Bajorin said, metastatic bladder cancer has the highest prevalence of genetic mutations and “is poised for sensitivity to immune therapy.”
Elizabeth R. Plimack, MD, said multiple studies support a correlation between higher mutation load and greater likelihood of treatment response in bladder cancer. Plimack said she and colleagues investigated DNA repair genes in MIBC and found that “tumors with the highest number of alterations [had] the best response to cisplatin.”3 On the immunotherapy side, Rosenberg et al found that a higher mutational load predicted a good response to atezolizumab.4 Plimack said more data are needed to determine whether those likely to respond well to cisplatin and those likely to immunotherapy are the same people.
Patients with bladder cancer are also heterogeneous, and tend to be older. Bajorin said choice of treatment currently depends on the patient’s disease state and performance status. On one end, Bajorin said, “there are patients who are so-called good risk—that is, nodal-only disease, good performance status—and then at the other end of the spectrum are the patients who do very poorly, those who have visceral disease and have a poor performance status.”
“From a societal perspective, 10% to 15% of all bladder cancers in the United States don’t get treated at all,” said Robert Dreicer, MD. He said 1 reason many patients with advanced bladder cancer never receive treatment is because of tolerability issues with cisplatin, which forms the backbone of first-line chemotherapy. Thus, identifying a biomarker predictive of response to cisplatin would not render more patients eligible for chemotherapy.