Combos and Biomarkers Will Shape the Future of Bladder Cancer Immunotherapy

OncologyLive, Vol. 20/No.3, Volume 20, Issue 3

Although multiple checkpoint inhibitors have been introduced into the bladder cancer treatment paradigm during the past several years, their use in the malignancy remains an unfolding story.

Joaquim Bellmunt MD, PhD

Although multiple checkpoint inhibitors have been introduced into the bladder cancer treatment paradigm during the past several years, their use in the malignancy remains an unfolding story, according to Joaquim Bellmunt, MD, PhD. The future, Bellmunt believes, is in identifying biomarkers and exploring combination therapy. Bellmunt, a leading investigator in the field, recapped developments in bladder cancer during the 3rd Annual International Congress on Immunotherapies in Cancer™ that Physicians’ Education Resource® (PER®) sponsored in New York, New York, in December 2018.

“In diseases such as lung cancer and kidney cancer, we have seen that combining chemotherapy with immunotherapy—or 2 different types of immunotherapy—can improve patient outcomes,” said Bellmunt, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center at the DanaFarber Cancer Institute in Boston, Massachusetts. “The future of bladder cancer—specifically, for frontline treatment—will probably be in combinations. We cannot forget that chemotherapy is an active way of treating these patients.”

Status of Immunotherapy Drugs

The challenge, he said, is to move beyond chemotherapy. As the role of immunotherapy continues to grow in the first and second lines of treatment, so does the need for a more personalized and targeted approach.Bellmunt offered an overview of the state of treatment for metastatic urothelial cancer (mUC), the most common type of bladder cancer: There had been no major changes in frontline treatment from the 1990s until the introduction of immune checkpoint inhibitors for those who are not eligible for cisplatin. The standard of care remains cisplatin chemotherapy in the frontline setting for those who can tolerate the regimen.

For a long time, no established second-line options existed for patients whose disease recurred or who were refractory to the firstline chemotherapy. The discovery of MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) combination chemotherapy and the 2009 European Medicines Agency approval of vinflunine, according to Bellmunt, were the only options available before new drugs came into the picture in 2016.

Now, PD-1 and PD-L1 inhibitors are standard for the treatment of mUC in the second-line setting after cisplatin-based chemotherapy.1 In the next 1 or 2 years, these advances in immunotherapy could open the door to further improvements in care, Bellmunt said. This revolution is due in part to a surge of approvals between May 2016 and May 2017.2

“A wealth of new options has come after 25 to 30 years of research in metastatic bladder cancer,” Bellmunt said.

Five immune checkpoinnt inhibitors have been approved by the FDA since 2016 for patients with mUC in the second line: the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) and the PD-L1 inhibitors atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio). Atezolizumab and pembrolizumab also are approved as first-line therapy for cisplatin-ineligible patients.

There was a disappointment amid the wave of approvals. In May 2018, the FDA restricted the frontline use of atezolizumab and pembrolizumab in cisplatin-ineligible patients to those with elevated PD-L1 expression. The labels of the drugs were changed to reflect that, in this setting, patients receiving atezolizumab must show PD-L1 expression levels ≥5% on tumor and immune cells and those receiving pembrolizumab must have a combined positive score (CPS) of ≤10. (CPS is calculated through a formula that includes of PD-L1 staining on tumor cells, lymphocytes, and macrophages.)

The changes were made after data monitoringcommittees found a decrease in survival in patients with PD-L1—low status in the monotherapy arms of the atezolizumab (IMvigor130) and pembrolizumab (KEYNOTE-361) trials. Both trials stopped enrolling patients with PD-L1–low status and updated prescribing information was issued on August 16, 2018, along with approvals companion for a diagnostic assay for each drug.

The second-line indications in urothelial carcinoma for the 2 drugs are unchanged. Both drugs also are still approved for use in the first-line setting for patients who are not eligible for any platinum-containing therapy regardless of level of tumor PD-L1 expression.

Although checkpoint inhibitor therapy has expanded the options for patients with mUC, the benefit has been seen in a subset of patients. Bellmunt said that clinical trial data show overall response rates (ORRs) in the platinum-refractory setting ranging from 15% to 21.1%, with atezolizumab demonstrating a 23% ORR in patients in the PD-L1—high arm of 1 trial. In the frontline setting for cisplatin-ineligible patients, Bellmunt said clinical trial data showed ORRs of 23% for atezolizumab and 29% for pembrolizumab.

Future Directions

“We initially thought that immunotherapy would replace chemotherapy, but we have seen that only about 20% of patients respond to immunotherapy,” Bellmunt said. Only about half of patients who respond to treatment have a durable response, and just a small number of patients are seeing benefits from this treatment approach, he added.Promising data have been seen in the neoadjuvant setting. The phase II ABACUS trial (NCT02662309) tested the efficacy of atezolizumab before cystectomy in patients with operable transitional cell carcinoma. Results presented at the 2018 American Society for Clinical Oncology Annual Meeting showed a 40% pathological complete response rate (95% CI, 21%-62%) in patients who were PD-L1—positive.

Bellmunt predicts that combinations building on the cisplatin backbone will be further enhanced. One place to start those improvements, he said, involves identifying the molecular subtypes in bladder cancer. In a paper published in Cell, investigators who analyzed 412 muscle-invasive bladder cancers identified 5 subtypes: luminal-papillary (35%), luminal-infiltrated (19%), luminal (6%), basal-squamous (35%), and neuronal (5%).3 The results led to a hypothesis for treatment and point to the development of clinical trials that may lead to personalized therapies.

Identifying the subgroups is just the first step—rational clinical trial designs and relevant correlative analysis of clinical trials are key, said Bellmunt.

Figure. Biomarker-Directed Study Using Durvalumab Plus Targeted Therapy In mUC4

One ongoing trial that is paving the way for personalized treatments is the phase IB BISCAY study (NCT02546661), a multidrug, biomarker-directed trial involving patients with mUC (Figure).4 Patients will be placed in subgroups based on the genomic alteration expressed in their tumors and according to disease progression following prior therapy.

BISCAY investigators will consider patients for these arms: FGFR3 mutations or fusions, ATM, BRCA 1/2, and HRR gene alterations, CDKN2A loss, RB1 loss, CCNE1 amplification, MYC amplification; and RICTOR amplification, and TSC 1/2 mutations. Participants will be assigned to 1 of 5 arms and treated with either durvalumab as a monotherapy (for those without an identifiable genomic alteration) or durvalumab in combination with novel anticancer agents for the identified alteration.

The primary endpoints are safety, toxicity, and dose-limiting toxicity. Other endpoints include biomarker analysis of the blood and tissue.

“Combinations need to be explored in new trials with select patients who are enriched with biomarkers. We do not have a final answer in terms of biomarkers, but we need to prospectively design trials in which patients are enriched with tumor mutational burden and PD-L1 staining,” Bellmunt said. “We could also be genomically profiling the patients before they undergo treatment. The future involves biomarker-driven trials and combinations.”


  1. Bukhari N, Al-Shamsi HO, Azam F. Update on the treatment of metastatic urothelial carcinoma. ScientificWorldJournal. 2018;2018:5682078. doi: 10.1155/2018/5682078.
  2. Bellmunt J. Immunotherapy in bladder cancer: a sudden wealth of options. Slides presented at: International Congress on Immunotherapies in Cancer®: Focus on Practice-Changing Application; December 15, 2018; New York, NY.
  3. Robertson AG, Kim J, Al-Ahmadie H, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer [erratum in Cell. 2017;171(3):540-556.e25. doi: 10.1016/j.cell.2017.09.007.] Cell 2018;174(4):1033. doi: 10.1016/j.cell.2018.07.036].
  4. Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (BISCAY). Updated January 10, 2019. Accessed January 19, 2019.