Metastatic Urothelial Carcinoma: A Model Malignancy for Immune ­Checkpoint Blockade

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“After several decades without advances, nivolumab is now the second drug to receive regulatory approval for the treatment of metastatic urothelial cancer within 12 months.”
— Matthew D. Galsky, MD

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Platinum-based combination chemotherapy became a mainstay of first-line treatment for metastatic urothelial cancer in the 1980s. With combination platinum-based regimens, 40% to 50% of patients achieve an objective response to treatment. However, aside from approximately 5% to 10% of patients who achieve more durable disease control with chemotherapy (with or without consolidative surgical resection of residual disease), responses to chemotherapy are generally transient, and long-term outcomes remain suboptimal.

Treatment Options Limited Historically

For patients with metastatic urothelial cancer progressing despite platinum-based chemotherapy, treatment options have historically been quite limited. Decades of clinical investigation, mostly exploring cytotoxic chemotherapeutic agents or a handful of “targeted therapies,” have yielded disappointing results. The majority of these trials have been small and have not met prespecified levels of activity to warrant further study, leading to a paucity of randomized phase III trials in this space. Only the randomized trial of vinflunine vs best supportive care for patients with metastatic urothelial cancer progressing despite prior platinum-based chemotherapy1 has led to regulatory approval in some parts of the world; however, prior to 2016, there had been no drugs approved by the U.S. Food and Drug Administration (FDA) for this disease state.

In retrospect, metastatic urothelial cancer is a model malignancy for the clinical development of programmed cell death protein 1/ programmed cell death ligand 1 (PD-1/PD-L1) blockade: (1) This is a disease with historically few treatment options; (2) Urothelial cancers typically harbor a high burden of nonsynonymous somatic mutations; (3) DNA-damaging cytotoxic chemotherapy is standard treatment, which could theoretically further increase a tumor’s mutational load; and (4) A subset of urothelial cancers are infiltrated with T lymphocytes, which has been correlated with a better prognosis.2,3 However, in reality, the striking responses in heavily pretreated patients with metastatic urothelial cancer seen early in expansion cohorts of phase I trials exploring PD-1 or PD-L1 inhibition caught most of the bladder cancer research community by surprise and have led to an entirely new era of clinical investigation in this disease.4-7

Where Does CheckMate 275 Fit?

How do the results of CheckMate 275—reported by Sharma et al8 and reviewed in this issue of The ASCO Post—fit in with the explosion of data centered on immune checkpoint blockade in metastatic urothelial cancer? CheckMate 275 enrolled 270 patients with metastatic urothelial cancer; incidentally, this was an identical number to the treatment arm of the recently reported phase III trial of pembrolizumab (Keytruda) vs chemotherapy in metastatic urothelial cancer.9 The trial was designed to evaluate the objective response rate with nivolumab (Opdivo) in all treated patients, in addition to biomarker-defined populations based on different thresholds of PD-L1 expression as assessed by immunohistochemistry on tumor cells.

In the entire treatment population, nivolumab was associated with an objective response rate of 19.6% (95% confidence interval [CI] = 15.0%–24.9%), and despite a slight numerical increase in response rate in subgroups of patients with higher levels of tumor cell PD-L1 expression, the lower bound of the 95% confidence interval for objective response rate exceeded the 10% threshold of minimal desirable activity (based on historical controls treated with chemotherapy), even in patients with tumor PD-L1 expression of < 1%. Similar to the experience in other solid tumors, and with other PD-1 or PD-L1 inhibitors, responses were durable.

At the time of the data lock, responses to nivolumab were ongoing in 77% of patients. There were no new safety signals detected in CheckMate 275, as compared with the experience with single-agent nivolumab in other advanced solid tumors. For patients remaining on treatment longer term, quality of life was stable or improved. Based on these data, on February 2, 2017, nivolumab became the first PD-1 inhibitor approved by the FDA for the treatment of patients with metastatic urothelial cancer progressing despite platinum-based chemotherapy.

In addition to the clinical results, exploratory biomarker analyses from CheckMate 275 contribute further to our understanding of response and resistance to immune checkpoint blockade in the context of intrinsic urothelial cancer biology. Several groups have now demonstrated that, as with other malignancies, urothelial cancer is not one disease but may be subcategorized based on gene expression into subtypes of potential clinical relevance.2,10-12 

Among the 270 patients enrolled in the trial, gene-expression profiling data were generated from archival tumors in 177 patients and used to classify patients into 1 of 4 molecular subtypes defined by The Cancer Genome Atlas. Interestingly, patients with cluster III (also known as basal 1) tumors had the highest response rate to nivolumab (30%), although responses were observed in patients among all four subtypes. A similar analysis from the IMVigor 210 study demonstrated that patients with cluster II (also known as luminal 2) tumors had the highest response rate to atezolizumab (Tecentriq).13 Together, these analyses underscore the need for further exploration of the relationship between intrinsic urothelial cancer subtypes and treatment response and highlight the complexities of tumor-intrinsic and -extrinsic characteristics in driving antitumor immune responses.

After several decades without advances, nivolumab is now the second drug to receive regulatory approval for the treatment of metastatic urothelial cancer within 12 months. Trials moving immune checkpoint blockade into earlier clinical states of urothelial cancer, such as the adjuvant setting for muscle-invasive disease (eg, identifiers NCT02632409 and NCT02450331), are poised to further impact the course of this disease. 

Disclosure: Dr. Galsky was the senior author of the CheckMate 275 article; has been a consultant for Genentech, Merck, Novartis, and Astellas; and has received research funding from Bristol-Myers Squibb, Dendreon, Janssen, Novartis, and Merck.


1. Bellmunt J, Théodore C, Demkov T, et al: Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 27:4454-4461, 2009.

2. Cancer Genome Atlas Research Network: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315-322, 2014.

3. Sharma P, Shen Y, Wen S, et al: CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci U S A 104:3967-3972, 2007.

4. Plimack ER, Bellmunt J, Gupta S, et al: Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012). Lancet Oncol 18:212-220, 2017.

5. Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558-562, 2014.

6. Massard C, Gordon MS, Sharma S, et al: Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol 34:3119-3125, 2016.

7. Sharma P, Callahan MK, Bono P, et al: Nivolumab monotherapy in recurrent meta­static urothelial carcinoma (CheckMate 032). Lancet Oncol 17:1590-1598, 2016.

8. Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275). Lancet Oncol 18:312-322, 2017.

9. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. February 17, 2017 (early release online).

10. Choi W, Porten S, Kim S, et al: Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152-165, 2014.

11. Damrauer JS, Hoadley KA, Chism DD, et al: Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A 111:3110-3115, 2014.

12. Sjödahl G, Lauss M, Lövgren K, et al: A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 18:3377-3386, 2012.

13. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy. Lancet 387:1909-1920, 2016.