Systemic Immunotherapy Use Expanding Rapidly in Bladder Cancer

Daniel J. George, MD

Following a long drought in the development of bladder cancer treatments, the field is now poised to benefit from a series of rapid advances ushered in by highly effective immunotherapies, Daniel George, MD, told attendees at the 2016 Large Urology Group Practice Association (LUGPA) Annual Meeting.

George, director of genitourinary oncology at Duke Cancer Institute, called immunotherapy the “biggest, most promising innovation since the advent of platinum.” Although there have been fluctuations regarding which particular taxane to utilize in bladder cancer, “the general treatment paradigm has not changed and no major improvement in therapeutic efficacy has occurred for the past 30 years. Until recently,” he said.

In May 2016 the FDA granted accelerated approval to the immune checkpoint inhibitor atezolizumab (Tecentriq) as a treatment for patients with locally advanced or metastatic urothelial carcinoma post-platinum-based therapy. The agent demonstrated efficacy and safety in for urothelial carcinoma in the IMvigor210 trial, a phase II, single arm study, George said.

In 310 patients treated in cohort 2 of the study, the overall response rate (ORR) was 16%. In those with the highest level of PD-L1 expression the ORR was 28%. The median time to response was 2.1 months and the median duration of response was not yet reached.

“Responses were seen in all PD-L1 subgroups, but better ORR in higher PD-L1 status patients. This was a statistically significant improvement, compared to historical control ORR of 10%,” George said. “The duration of the response has been even more impressive than the effectiveness of response and that’s probably what swayed the FDA more than anything. It is a change in the natural history of this disease.”

Across all PD-L1 expression levels, the median overall survival (OS) was 7.9 months and the 12-month OS rate was 37%. Atezolizumab is also well-tolerated. “It’s reasonable to treat beyond disease progression in patients with evidence of clinical benefit and no clear signs/symptoms of disease progression,” he said. In those treated beyond progression (n = 134), 19% showed a subsequent tumor response. The 12-month OS rate was 50% and the median OS was 11.4 months.

In those with cisplatin-ineligible bladder cancer in cohort 1 of the IMvigor210 study, the ORR was 24% across all expression levels and 28% in those with high PD-L1 expressing tumors. Grade 3/4 adverse events were experienced by 15% of patients. However, this did not warrant an approval, George noted, since the ORR with gemcitabine and carboplatin in this setting is 36% and the rate of grade 3/4 events is 9.3%. Longer follow-up is needed for duration of response comparisons, however.

The NCCN guidelines list atezolizumab as a preferred second-line therapy for metastatic disease. Based off available data, George also summarized his management algorithm for metastatic urothelial carcinoma following atezolizumab’s approval:

• First-line, cisplatin-eligible: gemcitabine/cisplatin or aMVAC

• First-line, cisplatin-ineligible: gemcitabine/carboplatin
• Second-line/post-platinum: atezolizumab (regardless of PD-L1 status)
• Third-line and beyond: Clinical trial or single agent chemotherapy (docetaxel, paclitaxel, pemetrexed, gemcitabine, etc.)

In addition to atezolizumab, in February 2016 the PD-L1 inhibitor durvalumab (MEDI4736) received an FDA breakthrough therapy designation for PD-L1+ advanced urothelial carcinoma following unsuccessful treatment with platinum-based chemotherapy. Offering another therapy on the horizon.

Most recently, the anti-PD-1 therapy pembrolizumab (Keytruda) has grabbed headlines. On October 21, 2016, Merck announced that the phase III KEYNOTE-045 trial comparing pembrolizumab to chemotherapy in patients with advanced urothelial cancer following cisplatin had met the primary endpoint of improvement in overall survival (OS). Based on these results, the company decided to stop the trial early. A presentation of this data is expected soon.

In addition to these studies, a number of immunotherapy trials for bladder cancer are currently ongoing. For patients in the adjuvant post-cystectomy setting, there is phase III IMvigor010 study, which compares atezolizumab versus observation in T2-T4 muscle invasive bladder cancer (MIBC). The phase III CheckMate-274 study is testing the PD-1 inhibitor nivolumab (Opdivo) against placebo in high-risk transitional cell carcinoma (TCC) status post resection.

Overall, there are currently 3 phase III trials for first-line metastatic bladder cancer. The IMvigor130 trial is looking at gemcitabine/carboplatin with or without atezolizumab in platinum-ineligible metastatic TCC. The KEYNOTE-361 study is examining pembrolizumab with or without platinum-based chemotherapy versus chemotherapy for metastatic TCC. The DANUBE trial is looking at durvalumab with or without the CTLA-4 inhibitor tremelimumab versus standard chemotherapy.

Two trials are currently underway in high-risk non-muscle invasive TCC: the phase II KEYNOTE-057 trial of pembrolizumab in BCG-refractory bladder cancer and SWOG’s phase II trial of atezolizumab in BCG-refractory bladder cancer.

Given this surge of immunotherapy research, George addressed the question of whether urologists should be the physicians who administers checkpoints inhibitors to patients. “You can’t do it halfway. It has to become an integral part of your practice, like a surgeon doing the same procedure multiples times per week,” he said. “You’ll have to be willing to add infrastructure and practice in a multidisciplinary way, like we medical oncologists are used to doing. There will be a great deal of contextual information required for each patient to manage the inevitable side effects.”

He gave the example of a patient with bladder cancer who was receiving chemotherapy and went to the emergency department for severe diarrhea, in contrast to one on immunotherapy with the same complaint. “The first needs immodium, while the immunotherapy patient needs steroids,” he said. “You’re going to have to own all the serious adverse events, regardless of whether or not they’re immune-related.”

George summed up the potential for toxicity with systemic immunotherapy as “manageable but real,” noting that “if you treat patients you will see complications.”

Overall, he said, “Immunotherapy with checkpoint inhibitors is here to stay, post- chemotherapy and possibly in lieu of chemotherapy. Single-agent activity is real but likely to evolve into combination therapy.”

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