Advanced sequencing methods have led to the identification of numerous molecular markers in urothelial carcinoma that can be exploited with targeted therapies.
In May 2016, cancer immunotherapy, atezolizumab (TECENTRIQ™) received accelerated FDA approval for the treatment of individuals with previously treated or locally advanced or metastatic urothelial cancer (mUC). This approval represented the first of its kind for this cancer in decades.
Here, Arjun V. Balar, MD, Director of Genitourinary Medical Oncology, NYU Perlmutter Cancer Center, speaks to Urotoday about the meaning of this advance in treatment and about important findings he reported for first-line treatment of advanced or metastatic urothelial cancer at the 2016 ASCO Annual Meeting, held June 3-7, in Chicago, IL.
Urotoday: The current therapeutic landscape for patients with advanced or metastatic urothelial cancer has been quite bleak. Can you explain how you would treat patients with this stage of the disease?
The standard of care for patients with locally advanced or metastatic urothelial cancer is cisplatin-based chemotherapy, which is the only therapy ever shown to improve survival in this setting. However, nearly half of patients diagnosed with this disease will not be eligible for cisplatin-based therapy due to poor renal function, performance status, or other medical problems, which would render the therapy too toxic. For these patients, we commonly use carboplatin-based therapy, which is considered less toxic. However, it is less efficacious.
Regardless, for the vast majority of patients, the cancer will progress despite this therapy. And, in the second-line setting, there are no approved treatments and survival is very poor. New treatment advances for this patient population were sorely needed.
Urotoday: What is the mode of action of atezolizumab—Tecentriq—the cancer immunotherapy recently approved by the FDA?
Atezolizumab is an engineered antibody that targets protein called PD-L1, or programmed death-ligand 1. PD-L1 is expressed on cancer cells and other types of cells such as immune cells that infiltrate a tumor, and it works to inactivate immune cells and prevent them from attacking cancer cells. Atezolizumab blocks that “off “ switch, so to speak. This allows the immune system to do its job and recognize and fight cancer cells. This is the core goal of immunotherapy—to help the immune system fight the cancer for you.
Urotoday: Can you comment about the importance of this approval to patient care?
Atezolizumab is the first and only immunotherapy approved for people with advanced bladder cancer. This approval is important because atezolizumab is the first major treatment advance in more three decades for patients with advanced bladder cancer. It represents a potential change in our overall approach for the treatment of this disease moving forward.
Urotoday: Would you describe the IMvigor 210 study design and endpoints?
IMvigor 210 is a multinational phase II study that evaluated the safety and efficacy of atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (mUC) that focused on two specific cohorts. Cohort 1 focused on patients who had not received any chemotherapy for locally advanced or mUC and who were ineligible for first-line (initial) cisplatin-based chemotherapy. Cohort 2 included people whose disease progressed during or following previous treatment with a platinum-based chemotherapy regimen (second-line or later).
The primary endpoint of the study was objective response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival (OS), progression-free survival (PFS) and safety.
Patients were not selected based on PD-L1 expression; however it was assessed on immune cells in archival tumor tissue from all patients to correlate expression levels (by immunohistochemisty) with response.
The approval of atezolizumab was based on data from Cohort 2 (second-line or later).
At the 2016 ASCO Annual Meeting, I presented the results I led, from Cohort 1 (first-line).
Urotoday: What were the requirements for patients to be termed “cisplatin-ineligible”—(your Cohort 1)?
Half of all patients with advanced bladder cancer will not be eligible for cisplatin-based chemotherapy because of poor renal function, performance status or other medical conditions. IMVigor210 cohort 1 focused specifically on these patients, and defined ineligible for cisplatin as having 1 or more of the following: ECOG performance status of 2, impaired renal function (estimated GFR < 60 cc/min, and > 30 cc/min), or grade 2 or worse peripheral neuropathy or hearing loss.
Urotoday: You presented data for a median follow-up of 14.4 months— Cohort 1. What did you and your colleagues find?
The key findings of the study were that for the 119 patients enrolled in cohort 1, we observed an objective response rate of 24% and a complete response rate of 7%.
When we looked at response rates by PD-L1 expression levels in the infiltrating immune cells, we observed responses at all levels of expression, including a 21% response rate and 8% complete response rate in the group with the lowest expression level (IC0). Patients with the highest PD-L1 expression level (IC 2/3) had a response rate of 28%.
Further, at a median follow up of 14.4 months, 75% of these responses were still ongoing, suggesting that responses with immunotherapy can be durable.
Lastly, treatment was very well tolerated, with only 15% of patients developing a grade 3 or 4 treatment-related toxicity, and only 6% of patients discontinuing treatment for toxicity.
In comparison to the toxicities we typically observe with chemotherapy, this safety profile is highly favorable. This is particularly important for elderly patients who are diagnosed with this disease. In fact, 21% of patients in cohort 1 were age 80 or greater.
Urotoday: What was the median overall survival for Cohort 1?
The estimated median overall survival was 14.8 months, and the 12-month landmark OS was 57%. It is important to note that this data is still immature, as only 47% of the events had occurred at the time of the analysis.
In comparison, the survival outcomes for cisplatin-ineligible patients treated with carboplatin-based therapies is in the range of 9-10 months.
Urotoday: What conclusions did you arrive at from the IMvigor 210 Cohort 1 study, and what are next steps?
The data from this trial makes a very compelling argument for atezolizumab as a potential new standard of care for cisplatin-ineligible patients with metastatic urothelial cancer. The efficacy demonstrated in this trial coupled with the safety of atezolizumab, in my opinion, signals the beginning of a profound change in our treatment approach for all patients with metastatic urothelial cancer, irrespective of their ability to tolerate cisplatin.
Trials to definitively compare atezolizumab to chemotherapy in the first-line setting are underway and I am optimistic [they] will confirm our findings.
Balar AV, Galsky MD, Loriot Y, et al. Atezolizumab (atezo) as first-line (1L) therapy in cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (mUC)