Urothelial Ca immunotherapy approved for first-line use

Editor’s note: Shortly after this article was published online, Urology Times learned of an announcement by Roche regarding updated phase III study data on atezolizumab (Tecentriq) in individuals with previously treated advanced bladder cancer. The study in people with locally advanced or metastatic urothelial cancer whose disease progressed during or after treatment with a platinum-based chemotherapy did not meet its primary endpoint of overall survival compared to chemotherapy. The article that follows primarily discusses the more recent FDA approval of atezolizumab in individuals with locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin chemotherapy.

The FDA has granted accelerated approval to atezolizumab (Tecentriq) for the treatment of locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin chemotherapy.

The regulatory agency’s decision makes atezolizumab the only cancer immunotherapy agent approved for initial treatment of urothelial carcinoma in patients who are ineligible for cisplatin. In May 2016, atezolizumab became the first immunotherapy agent approved for treatment of urothelial carcinoma when it was granted an indication for use in patients who had disease progression during or following any platinum-containing chemotherapy, or within 12 months of receiving chemotherapy before or after surgery.

Approval of atezolizumab in the first-line setting is based on results from the phase II, open-label, single-arm IMvigor210 clinical trial (Lancet 2017; 389:67-76).

Arjun V. Balar, MD, an investigator in IMvigor210 and lead author of the published article, noted that the durability of the responses, the promising survival data, and excellent safety profile of atezolizumab make it a very attractive treatment option for many patients with advanced urothelial carcinoma. He believes its approval for use in the first-line setting may have a broad impact on the management of advanced urothelial carcinoma that is perhaps larger than the effect of its initial approval.

Dr. Balar, of NYU Langone Medical Center, New York, told Urology Times, “It is estimated that as many as 50% to 70% of patients with advanced urothelial carcinoma are not eligible for cisplatin-based chemotherapy, and many of those individuals opt out of any form of cancer-directed treatment due to concerns about toxicity. With the new indication granted to atezolizumab, we expect that a higher proportion of patients with advanced urothelial carcinoma will receive treatment than ever before.”

Dr. Balar also commented on the ongoing revolution in treatment for advanced urothelial carcinoma.

“Two other immunotherapy agents, nivolumab (Opdivo) and durvalumab (Imfinzi), were also recently approved as second-line treatment for advanced urothelial carcinoma, and their efficacy and safety data were similar to atezolizumab,” he said. “More approvals are expected in the near term for agents in this class, and so the broader message is that modern immunotherapy is active in advanced urothelial carcinoma and represents the most important advancement in the treatment of this disease in over 30 years.”

IMvigor210 was comprised of two cohorts. Data from Cohort 1 provided the basis for the FDA approval of atezolizumab as first-line therapy for patients with advanced UC ineligible for cisplatin. Cohort 1 included 119 patients who were either treatment-naïve or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy. They were treated with atezolizumab 1,200 mg every 3 weeks until they developed unacceptable toxicity or disease progression.

Objective response rate was analyzed as the primary endpoint, and after a median follow-up of 17.2 months, the objective response rate was 23%, including 9% complete responses. Seventy percent of responses were ongoing at the data cut-off, and the median response duration was not reached.

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“The efficacy of atezolizumab thus far is striking, but it is not definitive. With long-term follow up, we may observe truly durable responses and possibly cures, suggesting that some patients may need only immunotherapy to treat their cancer. Data from at least 5 years of follow-up will be necessary to get a real understanding of the impact of atezolizumab on urothelial carcinoma.”

Subgroup analyses showed responses occurred regardless of the level of PD-L1 expression in immune cells. Patients with lymph node only metastases and overall lower disease burden were most likely to respond.

“Interestingly, patients with urothelial carcinoma who have these characteristics generally do well with any form of therapy tested so far, suggesting that the biology of cancer that is restricted to the lymph nodes is more favorable than that involving other organs such as the lung, bone, or the liver, in particular,” said Dr. Balar.

“In fact, patients with liver metastases had an 8% response rate to atezolizumab, and so they are a subgroup deserving of intense focus for alternative or combination immunotherapy options.”

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The only Grade 3-4 adverse events occurring at a rate ≥5% were fatigue (8%), anemia (7%), urinary tract infection (5%), diarrhea (5%), and increase in serum creatinine (5%).

Dr. Balar also suggested that the data from Cohort 1 in IMvigor210 signal a new paradigm in first-line treatment for urothelial carcinoma that may eventually expand to include use of atezolizumab in all patients. Data from the ongoing phase III IMvigor130 trial, however, are needed to define the scope of atezolizumab as initial therapy for advanced urothelial carcinoma. IMVigor130 is randomizing patients into three arms to receive platinum-chemotherapy or atezolizumab alone or in combination. It has a planned enrollment of approximately 1,200 patients and is including both cisplatin eligible and ineligible patients and will be the confirmatory study for atezolizumab’s accelerated first-line approval.

Dr. Balar is a paid consultant and receives research support from Genentech/Roche, Merck, and Astra Zeneca.

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