Parminder Singh, MD, hematologist/oncologist, Mayo Clinic, discusses potential implications of the phase III IMvigor130 trial in advanced bladder cancer.

According to data from the IMvigor130 trial, the frontline combination of atezolizumab (Tecentriq) and chemotherapy demonstrated a 1.9-month improvement in median progression-free survival versus placebo/chemotherapy in patients with locally advanced or metastatic urothelial carcinoma. Moreover, at the interim analysis, the median overall survival (OS) was 16.0 months and 13.4 months with atezolizumab/chemotherapy and placebo/chemotherapy, respectively (HR, 0.83; 95% CI, 0.69-1.00; 

Although these data were clinically meaningful, the OS data did not cross the prespecified interim efficacy boundary for significance. If the OS meets the prespecified endpoint with longer follow-up, the combination will likely be approved, says Singh. However, there are a lot of data that have yet to be presented which will impact how patients are treated in the frontline setting.

Singh is hopeful that with more mature data, immunotherapy will find its place in the first-line setting—in combination with either a traditional chemotherapy like gemcitabine and cisplatin or gemcitabine and carboplatin, or with a newer drug like enfortumab vedotin.

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Parminder Singh, MD, discusses potential implications of the phase III IMvigor130 trial in advanced bladder cancer.

Dr. Singh on Potential Implications of the IMvigor130 Trial in Bladder Cancer

Parminder Singh, MD, hematologist/oncologist, Mayo Clinic, discusses the improvement in overall response rates (ORR) with immunotherapy, targeted therapy, and antibody-drug conjugates (ADCs) in advanced urothelial cancer. 

Traditionally, patients who progress on chemotherapy have a median survival of 6 to 8 months, says Singh. The approval of 5 checkpoint inhibitors: atezolizumab (Tecentriq), pembrolizumab (Keytruda), nivolumab (Opdivo), avelumab (Bavencio), and durvalumab (Imfinzi), as well as the FGFR inhibitor erdafitinib (Balversa), have changed the paradigm. 

Checkpoint inhibitors have shown an objective response rate (ORR) of 15% to 20%, says Singh. Notably, 70% to 80% of patients who respond have durable responses. Furthermore, patients expressing PD-L1 have higher response rates. 

Regarding erdafitinib, investigators reported an ORR of 32.2% in patients with 

-positive locally advanced or metastatic bladder cancer in the phase II BLC2001 trial. The data from the trial served as the basis for the agent’s accelerated approval in patients with locally advanced or metastatic bladder cancer with an 

 alteration that has progressed on platinum-containing chemotherapy. 

Finally, the ADC enfortumab vedotin demonstrated an ORR of 44% in previously treated patients with locally advanced or metastatic disease in the phase II EV-201 trial. In September 2019, the FDA granted a priority review designation to a biologics license application for the agent in this indication. 

Parminder Singh, MD, discusses the improvement in overall response rates with immunotherapy, targeted therapy, and antibody-drug conjugates in advanced urothelial cancer. 
 

Dr. Singh on Novel Therapies in Advanced Urothelial Cancer

Parminder Singh, MD, hematologist/oncologist, Mayo Clinic, discusses combination treatments that are being evaluated in localized bladder cancer.

The natural progression of drugs that are approved in the advanced setting is to move them into earlier stages of disease, and bladder cancer is no exception, says Singh. Several combination treatments that have been approved for use in the advanced setting are already being evaluated in the frontline space. Investigators at Mayo Clinic recently opened the SWOG 1806 trial, which is looking at the combination of chemotherapy with radiation and atezolizumab (Tecentriq) in localized bladder cancer. Several other clinical trials are combining chemoimmunotherapy in the neoadjuvant space, adds Singh.

Combinations of chemotherapy and immunotherapy are poised to move into earlier lines of therapy, but they are not the only treatment strategies with this potential, says Singh. Clinical trials combining FGFR3 inhibitors with chemotherapy in earlier-line settings are also ongoing. As the understanding of these newer agents and the comfort surrounding their use grows, there will be a natural progression of these agents into early-stage disease, concludes Singh. 

Parminder Singh, MD, discusses combination treatments that are being evaluated in localized bladder cancer.

Dr. Singh on Combination Therapy in Localized Bladder Cancer

Parminder Singh, MD, hematologist/oncologist, Mayo Clinic, discusses research being done with antibody-drug conjugates (ADCs) in advanced bladder cancer.

The majority of patients who receive a checkpoint inhibitor will progress, says Singh. In general, the response rate among all checkpoint inhibitors is approximately 15% to 20%. This has left a large unmet need and has prompted research with ADCs, such as enfortumab vedotin and sacituzumab govitecan, adds Singh. There are several ongoing trials with these agents.

Data with enfortumab vedotin, which were presented at the 2019 ASCO Annual Meeting, showed a significant response rate of approximately 44% in patients who had received prior immunotherapy and chemotherapy. Up to 12% of patients achieved a complete response, which is very promising among a pretreated patient population. Singh anticipates that the agent will move forward and become a definitive therapeutic option for this patient population. In July 2019, a biologics license application was submitted to the FDA for the agent for patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-based chemotherapy.

Dr. Singh on Research With Antibody-Drug Conjugates in Advanced Bladder Cancer

Parminder Singh, MD, hematologist/oncologist, Mayo Clinic, discusses investigational immunotherapy combinations in urothelial cancer.

Combination strategies are emerging, says Singh. At the 2019 ASCO Annual Meeting, Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center, presented data regarding the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in previously treated patients with metastatic disease. The expansion cohort results of the phase I/II CheckMate-032 trial showed that the objective response rate was 38.0% in patients who received 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab.

In addition to combinations of double immunotherapy agents, combinations of immunotherapy and antibody-drug conjugates and chemotherapy are being explored. These combinations may broaden the utility of immunotherapy in the field to targeted agents such as erdafitinib (Balversa) and enfortumab vedotin, says Singh.

Dr. Singh on Investigational Immunotherapy Combinations in Urothelial Cancer

Parminder Singh, MD, hematologist/oncologist, Mayo Clinic, discusses the prevalence of genomic testing in urothelial cancer.

Most medical oncologists have incorporated various genomic assays into their practices, says Singh. Some of the commonly used assays include FoundationOne, Caris, and newer platforms from Tempus. These platforms can shed light on a patient’s PD-L1 status, tumor mutational burden, in addition to 

 and DNA damage repair mutations. Genetic testing is recognized as a standard of care in urothelial cancer, but the ways in which these markers are tested for may change in the future, adds Singh.

For example, the technology behind circulating tumor DNA (ctDNA) is developing at a rapid pace which may provide a means of testing for these markers during treatment, says Singh. In the next few years, the field is likely to move beyond baseline testing and incorporate sequential testing with ctDNA in practice.

Dr. Singh on the Prevalence of Genomic Testing in Urothelial Cancer

Parminder Singh, MD, hematologist/oncologist, Mayo Clinic, discusses the evolving role of chemotherapy in the treatment of bladder cancer.

The rise of immunotherapy in bladder cancer gave oncologists optimism that they could shy away from chemotherapy, Singh says, but right now it appears that not enough patients are responding to checkpoint inhibitors. In other disease types like lung cancer, data show that chemotherapy in combination with immunotherapy is improving outcomes for patients. As a result, chemotherapy is likely to make a comeback in bladder cancer in terms of sensitizing the immune system to immunotherapy.

Chemotherapy is believed to be immunosuppressive, but recent findings indicate it can make a tumor “hot,” meaning that it will allow the body to naturally fight the disease with its immune system. Singh concludes that chemotherapy will evolve in bladder cancer treatment to be used with immunotherapy.

Dr. Singh on the Role of Chemotherapy in Bladder Cancer

Parminder Singh, MD, hematologist/oncologist, Mayo Clinic, discusses treatment selection for patients with bladder cancer.

At this point, patient selection is based on the approval or labeling indications of the drug, where the patient lies in the spectrum of disease, and whether or not they have any alternative options.

Pembrolizumab (Keytruda) and atezolizumab (Tecentriq) are both approved in first-line and second-line treatment. Durvalumab (Imfinzi), nivolumab (Opdivo), and avelumab (Bavencio) are approved for patients who have progressed on platinum-based chemotherapy.

Although physicians now have immunotherapy agents, chemotherapy responses remain to be higher. There is a chance of achieving remission with cisplatin-based chemotherapy, and physicians don't want to take away a cisplatin-ineligible patient's option with newly diagnosed metastatic disease. At the same time, once a patient progresses on cisplatin, the second-line options are limited, and responses are minimal with chemotherapy.

That's one setting in which physicians routinely use immunotherapy. Additionally, bladder cancer occurs in older patients who may not be good candidates for platinum-based chemotherapy; in those situations, immune therapy is a reasonable first-line option.

Parminder Singh, MD, Hematologist/Oncologist, Mayo Clinic, discusses treatment selection for patients with bladder cancer. At this point, patient selection is based on the approval or labeling indications of the drug, where the patient lies in the spectrum of disease, and whether or not they have any alternative options.

Parminder Singh, MD

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