The therapeutic landscape of metastatic urothelial carcinoma (mUC) is rapidly changing with the introduction of immune checkpoint inhibitors (ICIs). Nevertheless, mUC remains a challenging cancer to treat, and the selection of a suitable therapy is dependent on factors including comorbidities and specific goals of care, which may focus on the survival advantage of treatment, quality of life, and patient preferences. Options for mUC treatment include chemotherapy with cisplatin, carboplatin, taxanes, or vinflunine; anti-programmed death-1 (PD-1) receptor and anti-programmed death-ligand 1 (PD-L1) ICIs; radiotherapy; and clinical trials. In Canada, cisplatin-based chemotherapy is the standard of care for fit patients with advanced mUC in the first-line setting. For patients who are cisplatin-ineligible due to renal dysfunction, neuropathy, hearing deficit, or poor performance status, carboplatin chemotherapy is an alternative. Before the introduction of ICIs, second-line treatment options for mUC were chemotherapy with taxanes (in Ottawa, we use paclitaxel) or vinflunine (not typically used in Canadian practice). However, recent data regarding ICIs suggest that both anti–PD-1 and anti–PD-L1 treatments likely have similar or improved antitumour activity over chemotherapy, with improved tolerability.

The international phase III KEYNOTE-045 trial examined the efficacy and safety of pembrolizumab (200 mg every three weeks [q3w]) in comparison with investigator’s choice of paclitaxel (175 mg/m2 q3w), docetaxel (75 mg/m2 q3w), or vinflunine (320 mg/m2 q3w) in patients with advanced mUC that recurred or progressed following platinum-based chemotherapy.1 The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response (DOR), and safety.

The main result of this study was the significant improvement in median OS with pembrolizumab compared to investigator’s choice of chemotherapy (10.3 months vs. 7.4 months, respectively; hazard ratio [HR] = 0.70; p = 0.0003). This result is particularly important as this is the first study to demonstrate improved survival in the second-line setting of UC therapy. There was no significant difference in PFS between the two arms, but patients in the pembrolizumab group exhibited a longer DOR (not reached vs. 4.4 months) and higher ORR (21.1% vs. 11.0%) compared to chemotherapy. Finally, the treatment-related adverse event profile was improved in the pembrolizumab treatment group (62.0%) compared to the chemotherapy group (90.6%).

In a post hoc analysis of the KEYNOTE-045 trial, the efficacy and safety of pembrolizumab was compared to each chemotherapy (paclitaxel, docetaxel, and vinflunine).2 The benefit in median OS obtained with pembrolizumab compared to each chemotherapy was consistent with original findings, as paclitaxel (7.0 months), docetaxel (7.4 months), and vinflunine (7.4 months) exhibited similar results.

Though there was no significant difference in median PFS between pembrolizumab and each chemotherapy arm, it is important to consider the different mechanisms of action of chemotherapy and anti–PD-1 antibody therapy. Though chemotherapy initially shrinks the tumour by eliminating sensitive cancer cells, it is later followed by an expansion of chemotherapy-resistant tumour cells, resulting in a PFS curve with an initial plateau followed by a gradual drop. In contrast, anti–PD-1 antibody therapy augments the pre-existing inflammatory response to the tumour, specifically benefiting a small group of patients with this response. As many patients have very little to no benefit in PFS, the PFS curve shows an initial sharp drop, followed by a plateau, representing the group experiencing therapeutic benefit. Thus, the absence of a significant difference does not indicate the lack of a therapeutic effect; rather, these results suggest that median PFS is not an effective parameter to assess patient benefit following this type of therapy.

Data from the KEYNOTE-045 study demonstrate evidence of patient benefit in all subgroups, with an impressive OS benefit and manageable safety profile exhibited with pembrolizumab treatment, compared to chemotherapy. In the similarly-designed phase III IMvigor211 trial, which evaluated atezolizumab (a PD-L1 inhibitor) compared to single-agent chemotherapy in a similar patient population as KEYNOTE-045, the results favoured atezolizumab in the intention-to-treat population (OS: 8.6 vs. 8.0 months; HR: 0.85; p = 0.038).3 While the IMvigor211 study did not meet its primary endpoint of improved median OS in a patient cohort with high PD-L1 expression, there was still evidence of benefit for patients including good tolerability of treatment, antitumour activity, long DOR, and a benefit of atezolizumab over taxane chemotherapy.3 These results demonstrate that anti–PD-1/PD-L1 ICIs are a new standard treatment strategy in the second-line setting for mUC.

Pembrolizumab has also been evaluated in the first-line setting for patients with advanced mUC who are ineligible for cisplatin therapy. The phase II KEYNOTE-052 study investigated the efficacy and safety of first-line pembrolizumab in a cisplatin-ineligible patient population with advanced mUC, poor Eastern Cooperative Oncology Group performance status (ECOG PS), a creatinine clearance (CrCl) rate of ≥30 to <60 mL/min, and grade ≥2 neuropathy or hearing loss.4 The patient inclusion criteria address an important patient demographic seen in my clinic, including geriatric patients with comorbidities, patients with chronic vasculopathy due to diabetes or hypertension leading to renal dysfunction, and patients with upper tract UC post nephroureterectomy and disease recurrence.

Patients included in the KEYNOTE-052 study received 200 mg pembrolizumab every 3 weeks for 24 months or until confirmed disease progression, intolerable toxicity, or withdrawal. The primary endpoint was ORR, and the secondary endpoints were DOR, OS, PFS, and safety.

The median ORRs were 29% in patients aged ≥65 years, 27% in patients aged ≥75 years, 29% in patients aged ≥65 years with an ECOG PS of 2, and 32% in patients aged ≥75 years with an ECOG PS of 2. Interestingly, higher ORRs were exhibited by patients with PD-L1 combined positive scores ≥10 in all subgroups (50%–55%). In terms of safety, the rates of grade 3–5 treatment-related adverse events were 20%, 18%, 20%, and 19% in patients aged ≥65 years, ≥75 years, ≥65 years with an ECOG PS of 2, and ≥75 years with an ECOG PS of 2, respectively. These results indicated that pembrolizumab was highly active and well tolerated in the first-line setting in cisplatin-ineligible patients.

Considering data from both KEYNOTE trials, the safety profile of pembrolizumab is an improvement over standard chemotherapy in the majority of patients. Though unexpected and more serious toxicities requiring management are possible, grade 5 events were extremely rare in these studies and there were no concerning safety signals presented. However, it is important to consider the conservative language of clinical trial inclusion criteria, as it may not reflect the scope of patients seen in the “real world”. Thus, vigilance is necessary when applying data from clinical trials in broader practice.

While the clinical trial data for pembrolizumab as a new standard of care for post-platinum and platinum-ineligible patients are compelling, the cost associated with this therapy remains an obstacle, as public reimbursement is not available at this time (at least in Ontario).

Furthermore, there are several unmet needs in this disease setting. Though there is a significant improvement in survival outcomes with anti–PD-1 therapy, the number of patients benefiting with disease response remains relatively low (approximately 20%); thus, clinical trials with new or combination therapies are required for further improvement. Additional clinical trials are also necessary to determine the ideal duration of therapy and tolerability in patients with modest autoimmune comorbidities (i.e., psoriasis/psoriatic arthritis).

The higher ORRs demonstrated in the KEYNOTE-052 study, compared to KEYNOTE-045, should also prompt the examination of clinical characteristics that may assist in the selection of patients most likely to benefit from anti–PD-1/PD-L1 antibody therapy. For example, in patients with Lynch syndrome, presence of upper tract disease and mismatch repair deficiencies are strongly correlated with an enhanced benefit from ICI therapy.5 In some analyses, a high burden of cigarette smoking was also associated with treatment benefit.

Naturally there is significant interest in biomarker development, such as PD-L1 status and tumour mutational burden, to improve patient selection and enhance patient benefit. PD-L1 expression is likely both prognostic and predictive, but current clinical trial data are conflicting in terms of the utility of PD-L1 as a biomarker. Data from the KEYNOTE-045 study suggested that tumour PD-L1 expression was not associated with enhanced benefit from therapy, whereas data from the KEYNOTE-052 trial suggested a connection between a higher ORR and PD-L1 combined positive score of ≥10.1,4 Though a similar positive association has also been demonstrated in other studies, results may have been influenced by study inclusion criteria and additional research is required prior to routine use.

Overall, results from the KEYNOTE-045 study support the use of pembrolizumab as a new standard of care in advanced mUC in the second-line setting. For cisplatin-ineligible patients with advanced mUC, the KEYNOTE-052 study also demonstrated compelling results for the use of pembrolizumab in the first-line setting. However, access to pembrolizumab may be heterogeneous without standard public funding for these new therapy indications, and a number of suitable alternatives (i.e., atezolizumab, clinical trials, and systemic chemotherapy) are available. Hopefully the treatment paradigm of today will soon be another page in history as clinical trials evaluate ICIs and ICI combinations in the first-line and (neo)adjuvant settings.

References: 1. De Wit R, Vaughn DJ, Fradet Y, et al. Pembrolizumab versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer: mature results from the phase 3 KEYNOTE-045 trial. ESMO Annual Congress Abstracts 2017:LBA37. 2. Petrylak DP, Vogelzang NJ, Fradet Y, et al. Subgroup analyses from KEYNOTE-045: Pembrolizumab (pembro) versus individual investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (uc). ESMO Annual Congress Abstracts 2017:851PD. 3. Ramos JD and Yu EY. Immuno-oncology in urothelial carcinoma: who or what will ultimately sit on the iron throne. Immunotherapy 2017;9(12):951–4. 4. Grivas P, Plimack ER, Balar AV, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: outcomes from KEYNOTE-052 in senior patients with poor performance status. ESMO Annual Congress Abstracts 2017:857P. 5. Viale G, Trapani D, Curigliano G. Mismatch repair deficiency as a predictive biomarker for immunotherapy efficacy. Biomed Res Int 2017;2017:4719194. doi:10.1155/2017/4719194. [Epub ahead of print].

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Dr. Abla
Oussama Abla, MD
Dr. Oussama Abla is a staff oncologist at the Division of Hematology/ Oncology in The Hospital for Sick Children in Toronto, where he has been on faculty since the year 2000. He is also an Associate Professor in the Department of Pediatrics at the University of Toronto. He received his medical degree from the University of Genoa, Italy in 1989. His post-graduate training included a pediatric residency at the Gaslini Children’s Hospital in Genoa and a pediatric hematology/oncology fellowship at the Hospital for Sick Children.

Dr. Abla’s clinical and research interests include pediatric leukemias and lymphomas with a special focus on acute promyelocytic leukemia (APL), pediatric primary central nervous system lymphoma and other rare pediatric lymphomas, as well as Langerhans cell histiocytosis (LCH) and rare histiocytic disorders. He is the chair of the Histiocyte Society “Rare Histiocytoses Steering Committee” and the primary investigator for the International Registry for Rare Histiocytic Disorders, as well as the Canadian Coordinator of the LCH-IV trial. He is also the co-editor of an upcoming textbook on Histiocytic Disorders. In addition, Dr. Abla is a member of the Children’s Oncology Group-APL study committee and co-editor of an upcoming textbook on APL. He is also a member of the international- BFM study group committees on non-Hodgkin lymphoma and acute myeloid leukemia. Dr. Abla has more than 80 scientific publications and book chapters in the fields of supportive care, leukemias, lymphomas, and histiocytic disorders.

Dr. Jillella
Anand Prasad Jillella, MBBS
Dr. Anand Jillella is currently Director of the Georgia Cancer Center (GCC) Clinic, Ambulatory Services, Network and Outreach, GCC Associate Director of Medical Oncology Services, and Chief of the Division of Hematology/ Oncology and Bone Marrow Transplant (BMT). He has also been appointed to the first J. Harold Harrison, MD Distinguished Chair in Medical Oncology.

Dr. Jillella’s professional training included a fellowship in hematology/oncology at Yale University School of Medicine and intensive training in Bone Marrow Transplantation at Johns Hopkins Oncology Center. In 1996, he was appointed Assistant and then Associate Professor and Director of the BMT Program at Medical College of Georgia (MCG). He then became Associate Professor at Temple University and Associate Director of the Fox Chase-Temple BMT Program in 2002. Dr. Jillella returned to MCG at Georgia Health Sciences University in 2005 as Professor of Medicine and Chief of the Division of Hematology/Oncology and BMT, and Director of the Bone Marrow/Stem Cell Transplant Program, and then became Associate Director for Clinical Affairs of the Georgia Regents University (GRU) Cancer Center Service Line. In 2013, Dr. Jillella left GRU to become Associate Director for Community Affairs and Outreach at the Winship Cancer Institute of Emory University in Atlanta.

Dr. Seftel
Matthew Seftel, MD, MPH, MRCP, FRCPC
Dr. Matthew Seftel is the Department Head of Hematology and Oncology at CancerCare Manitoba and the Section of Hematology/Oncology, Department of Internal Medicine at the University of Manitoba in Winnipeg, Manitoba. He is also an Associate Professor at the University of Manitoba. Dr. Seftel’s research interests include leukemia epidemiology and clinical trials in leukemia and lymphoma (including blood and marrow transplantation). He is an investigator with the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Centre for International Blood and Marrow Transplant Research (CIBMTR).

Dr. Ong
Michael Ong, MD
Dr. Ong is a medical oncologist who specializes in genitourinary malignancies, malignant melanoma, and experimental therapeutics. His training has included an undergraduate medicine degree in Ottawa, as well as an internal medicine and medical oncology residency at Western University, and further fellowship training in experimental therapeutics at the Royal Marsden Hospital in London, U.K., before being recruited to The Ottawa Hospital Cancer Centre.

Dr. Ong’s research interests primarily include development of anticancer drug combination strategies including immunotherapy and targeted therapies, dose-optimization and sequencing-optimization of currently developed therapeutics, and development of non-invasive biomarker strategies. Dr. Ong is the lead investigator for a number of clinical trials for bladder and prostate cancers, and the main investigator for novel experimental therapeutics for genitourinary cancers and melanoma, in Ottawa.