1. Fuerst, Mark L.

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CHICAGO-The anti-programmed death-ligand 1 (PD-L1) agent atezolizumab has clinically meaningful activity as first-line therapy in cisplatin-ineligible metastatic urothelial carcinoma patients, with encouraging early survival data, according to a study presented at the 2016 American Society of Clinical Oncology Annual Meeting.

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Atezolizumab shrank tumors in about a quarter of patients and yielded a median survival of 14.8 months. Typically, patients in this setting have a survival of 9-10 months with carboplatin-based regimens.


"This is a compelling argument for atezolizumab as a new potential standard of care in cisplatin-ineligible advanced bladder cancer. The durable nature of response and favorable adverse events profile makes this an attractive alternative to chemotherapy," said lead author Arjun V. Balar, MD, Assistant Professor of Medicine at the New York University Langone Medical Center and Director of Genitourinary Medical Oncology at the NYU Perlmutter Cancer Center in New York, N.Y.


"Up to half of these patients are too frail to receive the only known survival-prolonging treatment, cisplatin. There is really no standard treatment for such patients. We are encouraged to see that atezolizumab immunotherapy may help address this major unmet need."


The standard upfront treatment for advanced bladder cancer is cisplatin-based chemotherapy. Patients receiving this therapy have a median survival of 12-15 months. However, for 30-50 percent of patients with advanced bladder cancer, cisplatin chemotherapy is not considered a safe option due to their advanced age, kidney function, and ongoing medical conditions. Such patients may receive carboplatin-based chemotherapy, which provides a median survival of 9-10 months.


Second-Line Therapy

The single-arm phase II study (Abstract LBA4500), called IMvigor210, included 119 patients with locally advanced or metastatic bladder cancer. All patients had urothelial cancer, which is the most common type of bladder cancer in the U.S.


The study included two cohorts. One cohort received atezolizumab as a second-line therapy and the other cohort received the drug upfront. The researchers have previously reported results from the second-line therapy group. Based on those results, the FDA recently granted accelerated approval for atezolizumab as second-line therapy after treatment with a platinum-based regimen.


With a median follow-up of 14.4 months, 28 out of 119 (24%) patients responded to the treatment. The longest duration of response is more than 18 months.


"The median duration of response was not yet reached in any predefined PD-L1 subgroup. Three-quarters of responses are ongoing," Balar said.


The median overall survival was 14.8 months. In terms of survival, "atezolizumab compares favorably with historic data from cisplatin-ineligible patients, both from clinical trials and real-word settings," he said. "Survival data are provocative, and suggest a population of patients is getting a long-term benefit. The tail of the curve will be important."


Overall, atezolizumab was well-tolerated, with only 10-15 percent of patients experiencing severe adverse effects. The most common toxicities were hypothyroidism, liver function abnormalities, rash, and diarrhea.


"The majority of our patients had few or no side effects from atezolizumab and only 6 percent of patients discontinued treatment because of toxicity. This is in stark contrast to the approximate 20 percent rate of treatment discontinuation from toxicity observed with carboplatin-based chemotherapy regimens. Immunotherapy appears to be much easier to tolerate than chemotherapy, and this is especially important for elderly patients," said Balar.


Most adverse events were grade 1 or 2. One patient had grade 5 sepsis.


About one-third of patients had an adverse event leading to dose interruption, he said, noting that about 20 percent of patients discontinue treatment due to toxicity with carboplatin-based chemotherapy regimens. Immunotherapy appears to be much easier to tolerate than chemotherapy, which is especially important for elderly patients, said Balar.


Atezolizumab is an antibody targeting PD-L1, a component of the PD-1/PD-L1 immune checkpoint. When atezolizumab attaches to PD-L1 on the surface of tumor cells, it prevents it from interacting with PD-1 receptors on immune cells and thus unleashes the immune system to attack the tumor.


Future PD-L1 Research

IMvigor210 is the first trial to test the efficacy of atezolizumab as the initial treatment in patients with advanced bladder cancer. The researchers are planning a randomized phase III trial of atezolizumab as upfront treatment for advanced bladder cancer, and a randomized clinical trial of atezolizumab as an adjuvant treatment for early-stage bladder cancer is also under way. Several ongoing clinical trials are exploring other immune checkpoint inhibitors, including nivolumab, durvalumab, and pembrolizumab, in localized and advanced bladder cancer.


In the future, PD-L1 may be used as a biomarker to direct therapy in cisplatin-ineligible advanced bladder cancer patients. Other factors, including sites of disease, performance status, and mutational burden, also have significant impact in defining responders, Balar concluded.


Mark L. Fuerst is a contributing writer.