Immunotherapy Has Indelibly Changed the Treatment Paradigm in Urothelial Carcinoma

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Cora N. Sternberg, MD, FACP

Cora N. Sternberg, MD, FACP

Cisplatin-based combination chemotherapy is the preferred first-line therapy for metastatic urothelial cancer and the only treatment shown to improve survival in patients with previously untreated disease for many years. This chemotherapy also has proven to be beneficial in the neoadjuvant and adjuvant settings for muscle-invasive disease.

The treatment of bladder cancer has evolved, however, to include not only chemotherapy, but now immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guérin (BCG) vaccine, which has been the standard of care for non–muscle-invasive bladder cancer for many years.

Cutting-edge immunotherapy in bladder cancer has focused on inhibitors of checkpoint proteins, molecules that impede immune function, thereby allowing tumor cells to proliferate. Antibodies to several checkpoint targets such as programmed cell death ligand 1 (PD-L1), expressed on tumor cells and macrophages, and programmed cell death protein 1 (PD-1), expressed primarily on activated T cells in the tumor microenvironment, have been evaluated in the treatment of advanced or metastatic urothelial cancer of the bladder, renal pelvis, and ureter or urethra. Five of these antibodies have already received approvals in the United States both in cisplatin-ineligible patients and after cisplatin-based chemotherapy.

Approximately 50% of patients with metastatic urothelial cancer are ineligible for or decline cisplatin-based chemotherapy. This may be due to advanced age, performance status, kidney dysfunction, cardiac or hearing disabilities, peripheral neuropathy, or other comorbidities. The population of patients who are ineligible for cisplatin has also been underrepresented in clinical studies and generally have worse outcomes. Carboplatin-based doublets have been frequently used in these patients, although carboplatin is known to be inferior to cisplatin in this disease.

KEYNOTE-052 Trial

Based on the results of the phase II KEYNOTE-052 trial by Balar et al,1 reviewed in this issue of The ASCO Post, the U.S. Food and Drug Administration granted accelerated approval to the anti–PD-1 antibody pembrolizumab (Keytruda) for the front-line treatment of cisplatin-ineligible patients in May 2017, although only 307 of 370 enrolled patients had > 4 months of follow-up at that time.

Atezolizumab (Tecentriq), an anti–PD-L1 antibody, had received approval earlier for these patients,2 and three other immune checkpoint inhibitors have been shown to have similar significant activity in patients who have failed to respond to platinum-based chemotherapy in phase I and II trials and have gained regulatory approval: the anti–PD-1 antibody nivolumab (Opdivo)3 and the anti–PD-L1 antibodies durvalumab (Imfinzi)4 and avelumab (Bavencio).5

Both atezolizumab and pembrolizumab have shown encouraging durable response rates, survival, and tolerability, supporting their use in patients who have advanced or metastatic disease and are ineligible for cisplatin.
— Cora N. Sternberg, MD, FACP

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In an update of the KEYNOTE-052 II trial at the 2017 ASCO Annual Meeting, all patients had at least 6 months of follow-up. The overall response rate was 29%, including a complete response in 7% of patients; 82% of responders maintained a response for more than 6 months, and at the data cutoff, 67% of responses were ongoing.6 The median duration of response has not yet been reached (95% confidence interval = 12 months to not reached), and the median overall survival is not yet mature, making it difficult to compare mature overall survival with other studies.

The first 100 patients were part of a training set to evaluate the combined positive score, an immunohistochemistry method evaluating PD-L1 expression on both tumor and immune cells. The validation set included 265 patients: those with a combined positive score < 10% had a 23% response rate, and those with a combined positive score ≥ 10% had a 51% response rate and an 18% complete response rate.

The investigators also assessed the association of an 18-gene T-cell–inflamed gene-expression profile signature with overall response. The score was significantly associated with response, as were all 18 genes. The pattern of the joint distribution between the gene-expression profile score and immunohistochemistry evaluating the combined positive score revealed a moderate but highly significant association between the two biomarkers.

Immune-mediated adverse events occurred in 21% of patients. Any-grade and grade ≥ 3 drug-related adverse events occurred in 66% and 19% of patients, respectively.

Other Relevant Studies

Pembrolizumab was well tolerated in the largest cisplatin-ineligible population studied to date, including elderly patients and those with a poor performance status. Pembrolizumab demonstrated a high overall response rate with a manageable safety profile, making it an attractive option for these patients. Pembrolizumab has also shown improved overall survival, better tolerability, and enhanced quality of life in patients who have failed to respond to cisplatin-based chemotherapy, in a phase III randomized trial comparing it with investigator’s choice of chemotherapy.7

The rapid expansion of therapeutic options in urothelial cancer has forever and indelibly changed our treatment paradigm.
— Cora N. Sternberg, MD, FACP

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Atezolizumab was approved prior to pembrolizumab, following a phase II trial (IMvigor 210; cohort 1) conducted in 119 untreated patients with metastatic urothelial carcinoma who were ineligible for cisplatin.2 In this trial, 70% of patients had renal impairment, and 20% had an Eastern Cooperative Oncology Group performance status of 2. At 17.2 months’ median follow-up, the objective response rate was 23%, including a complete response in 9% of patients. The median response duration had not been reached, with 70% of responses ongoing at 17.2 months. With longer follow-up, this cohort had a median overall survival of 15.9 months. Immune-mediated events occurred in 12% of patients, and treatment-related grade 3 or 4 events occurred in 16%.2 Tumor mutation load and data from The Cancer Genome Atlas subtypes correlated with immunotherapy response in this trial, as had already been noted by Rosenberg et al in the (IMvigor 210; cohort 2) trial of previously treated patients.8

Although it is impossible to compare across trials, the patient populations in KEYNOTE-052 and IMvigor 210 cohort 1 differ somewhat, and those in KEYNOTE-052 appear to be older and to have a poorer performance status and more visceral disease. Nevertheless, both atezolizumab and pembrolizumab have shown encouraging durable response rates, survival, and tolerability, supporting their use in patients who have advanced or metastatic disease and are ineligible for cisplatin.

Closing Thoughts

The checkpoint inhibitors offer an excellent alternative for patients for whom there were previously few options, patients who are ineligible for cisplatin-based regimens, and those who have failed to respond to these regimens. Research is ongoing to further categorize biomarkers and understand responses, better define ideal patient populations, and investigate combinations of checkpoint inhibitors with many different and varying agents such as chemotherapy ( identifier NCT02853305, NCT02807636), cytotoxic T-lymphocyte–associated protein 4 inhibitors (NCT02516241), and inhibitors of indoleamine 2,3-dioxygenase 1 such as epacadostat9 or poly (ADP-ribose) polymerase inhibitors.

The rapid expansion of therapeutic options in urothelial cancer has forever and indelibly changed our treatment paradigm. ■

Dr. Sternberg is Chief, Department of Medical Oncology, San Camillo Forlanini Hospital, Rome.

DISCLOSURE: Dr. Sternberg is a consultant for MSD, Roche, Pfizer, and -Bristol-Myers Squibb.


1. Balar AV, Castellano D, O’Donnell PH, et al: First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol. September 26, 2017 (early release online).

2. Balar AV, Galsky MD, Rosenberg JE, et al: Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet 389:67-76, 2017.

3. Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312-322, 2017.

4. Powles T, O’Donnell PH, Massard C, et al: Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncol 3:e172411, 2017.

5. Apolo AB, Infante JR, Balmanoukian A, et al: Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol 35:2117-2124, 2017

6. O’Donnell PH, Grivas P, Balar AV, et al: Biomarker findings and mature clinical results from KEYNOTE-052: First-line pembrolizumab in cisplatin-ineligible advanced urothelial cancer. 2017 ASCO Annual Meeting. Abstract 4502. Presented June 5, 2017. 

7. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015-1026, 2017.

8. 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: A single-arm, multicentre, phase 2 trial. Lancet 387:1909-1920, 2016.

9. Liu X, Shin N, Koblish HK, et al: Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115:3520-3530, 2010.

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