Immunotherapy Changes Early-Stage Urothelial Carcinoma Paradigm

Jason Harris
Published: Tuesday, Dec 11, 2018
Noah M. Hahn, MD

Noah M. Hahn, MD

Since 2016, the FDA has approved 5 immune checkpoint inhibitors (ICIs) to treat urologic cancers. Although that is a good thing for patients, the rise of these agents means that the role of the urologist in cancer is changing, Noah M. Hahn, MD, said during the 2018 Large Urology Group Practice Association (LUGPA) Annual Meeting, held November 1-3 in Chicago, Illinois. Newer agents are changing traditional strategies for care, resulting in higher levels of collaboration.

Hahn, director of the medical oncology bladder program at Johns Hopkins School of Medicine, has been working closely with Howard I. Scher, MD, the D. Wayne Calloway Chair in Urologic Oncology at Memorial Sloan Kettering Cancer Center, over the past few years as systemic anticancer therapies have moved from the metastatic setting into earlier stages of urologic disease. “It’s a very exciting time right now in both spectrums: urology and oncology,” Hahn said. “We’re going to be seeing a lot more cross-discipline care.”

The KEYNOTE-045 trial was the first to show an overall survival (OS) advantage over chemotherapy for an ICI in advanced bladder cancer and helped to start this revolution, Hahn said. The trial was stopped early, in 2016, after meeting its primary endpoint of OS. Two-year follow-up data from the phase III trial showed sustained improvements in OS with pembrolizumab (Keytruda) over chemotherapy in pretreated patients with locally advanced or recurrent urothelial cancer.

The median OS was 10.3 months with pembrolizumab versus 7.4 months for chemotherapy (HR, 0.73; 95% CI, 0.59-0.91; P = .002), according to the initial results, published in the New England Journal of Medicine. The 12-month OS rate was 43.9% (95% CI, 37.8%-49.9%) in the pembrolizumab group versus 30.7% (95% CI, 25.0%-36.7%) in the chemotherapy group.1

“What got immunotherapy approved in bladder cancer was the fact that this trial was the first trial to ever show an [OS] advantage versus chemotherapy in patients with advanced disease,” Hahn said. “We had never seen that despite the previous 30 years of trying with various chemotherapies and combinations.”

In KEYNOTE-045, patients with histologically or cytologically confirmed urothelial carcinoma who progressed after 1 to 2 lines of platinum-based chemotherapy were randomly assigned to 200 mg of pembrolizumab every 3 weeks (n = 270) or investigator’s choice of paclitaxel at 175 mg/m2, docetaxel at 75 mg/m2, or vinflunine at 320 mg/m2, each administered every 3 weeks (n = 272).

As assessed by blinded central review, the overall response rate was 21.1% versus 11.4% in favor of the pembrolizumab arm (P = .001). The median duration of response was not reached (range, 1.6-15.6 months) with pembrolizumab compared with 4.3 months (range, 1.4-15.4) with chemotherapy.

“What that trial showed was that immunotherapy with pembrolizumab resulted in about twice as many patients seeing their tumors shrink—about 20% compared with 10%,” Hahn said. “While that’s not a high percentage of patients, if you were in the group that responded, those responses tended to be durable.”

The trial also provided supporting evidence that immunotherapy is generally better tolerated that chemotherapy, Hahn pointed out. In KEYNOTE-045, the incidence of treatment-related adverse events (TRAEs) was lower with pembrolizumab for any grade (60.9% vs 90.2%) and grade 3/5 (15.0% vs 49.4%). The discontinuation rate resulting from TRAEs was 5.6% in the pembrolizumab arm and 11% in the chemotherapy arm.

Figure: Early Stage Bladder Cancer is Less Challenging to Treat

Figure: Early Stage Bladder Cancer is Less Challenging to Treat

Immunotherapy in MIBC and NMIBC

With the success of ICIs in metastatic disease—not just pembrolizumab, but also atezolizumab (Tecentriq), durvalumab (Imfinzi), and others—investigators have sought to determine if these agents can produce better outcomes in patients with earlier-stage bladder cancer, when the disease is less invasive (FIGURE). Several ongoing studies are exploring whether immunotherapy could be effective in patients with muscle invasive or nonmuscle invasive bladder cancer (MIBC/NMIBC).

Investigators are evaluating immunotherapy agents in the adjuvant setting in a pair of phase III trials: IMvigor010 (NCT02450331) is investigating atezolizumab versus observation in high-risk MIBC, and AMBASSADOR (NCT03244384) is investigating pembrolizumab versus observation in locally advanced bladder cancer. In addition, the phase II CheckMate 274 (NCT02632409) is investigating nivolumab (Opdivo) versus placebo in bladder or upper urinary tract cancer following surgery. Results from AMBASSADOR are expected in 2019. The other trials are expected to report in 2020.


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TitleExpiration DateCME Credits
Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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