Novel Therapies in Urothelial Carcinoma

A Biomarker-Driven Approach

G. Iyer; J. E. Rosenberg


Ann Oncol. 2018;29(12):2302-2312. 

In This Article

Immunotherapy for Metastatic Urothelial Malignancies: Current State-of-the-art

Immunotherapy has fundamentally altered the treatment paradigm for metastatic UC. Until recently, patients with metastatic disease had few treatment options after failure of platinum-based chemotherapy strategies. Single agent chemotherapies in the second-line setting generally display response rates of <30%, and more frequently 10%–15%. An analysis of studies investigating doublet chemotherapy regimens as salvage therapy after initial platinum-based treatment showed no extended survival benefits compared with single agents[15] and such regimens are frequently limited by toxicity.[16] In 2009, vinflunine, a fluorinated Vinca alkaloid, was approved by the European Medicines Agency (EMA) as monotherapy for the treatment of adult patients with advanced or metastatic UC after failure of a prior platinum-containing regimen[17] and is a recommended therapy in treatment guidelines.[4] This approval is based upon a phase III study of vinflunine plus best supportive care versus best supportive care alone for patients with metastatic UC who had progressed on platinum-based chemotherapy. A 2-month median survival advantage was observed for vinflunine plus best supportive care (6.9 months versus 4.3 months for best supportive care alone, P = 0.040) in the eligible patient population. Significant improvements in overall response rate (ORR) and progression-free survival were also noted with the addition of vinflunine.

In 2016, atezolizumab, a programmed death ligand 1 (PD-L1)-blocking antibody, received accelerated United States Food and Drug Administration (FDA) approval for locally advanced or metastatic UC in patients with disease progression during or following platinum-containing chemotherapy or within 12 months of peri-operative platinum-containing chemotherapy.[18] This approval was based on a phase II study in patients with metastatic UC who had progressed on prior platinum-based chemotherapy.[19] In this trial, the ORR was 15%, significantly higher than a historical response rate of 10% with chemotherapy. Responses were also organized based upon PD-L1 expression (using the Ventana SP142 assay) on immune infiltrating cells (ICs) and were found to be highest in patients with ≥5% infiltration (IC2/3, 26%); notably, responses were also observed in IC0 (8%) and IC1 (10%) patients. At 11.7 months median follow-up, 84% of responders continued to show objective responses, underscoring a durability not usually seen with standard chemotherapy. In April 2017, accelerated approval was also granted for atezolizumab as a first-line treatment of patients with locally advanced or metastatic UC who are ineligible for cisplatin-based chemotherapy or who have disease progression at least 12 months after receiving perioperative chemotherapy.[20] In a phase II study of atezolizumab in this patient population, the objective response rate was 23%, including a 9% complete response rate, with a median overall survival of 15.9 months, all significantly higher than observed with carboplatin-based chemotherapy. In both studies, tumor mutation load was significantly higher in responders.

Following the approval of atezolizumab, the results of an open-label, multi-center phase III study were reported (IMvigor211) in which patients with progressive metastatic UC following platinum chemotherapy were randomized to receive either atezolizumab or treating investigator's choice of paclitaxel, docetaxel, or vinflunine.[21] The primary end point of overall survival within a predefined patient population with IC2/3 PD-L1 expression was not significantly different between atezolizumab and chemotherapy (median OS 11.1 versus 10.6 months, respectively, HR 0.87, P = 0.41). The objective response rate was also similar in both groups, but the rate of ongoing responses was higher with atezolizumab therapy (62% versus 20% with chemotherapy). Potential reasons for the lack of improvement in OS include the observation that survival with vinflunine was higher than expected within the statistical model for this study and the fact that IC2/3 patients displayed improved survival and response independent of treatment modality. The association of tumor mutation burden with survival was evaluated in an exploratory analysis of the intent to treat patient population. High tumor mutation burden (defined as being higher than the median total mutation burden within assessable patients) was associated with a nonsignificant improvement in overall survival with atezolizumab therapy (11.3 versus 8.3 months with chemotherapy, HR 0.68). Comparison of survival between treatment arms within high total mutation burden patients with IC2/3 PD-L1 expression showed a longer median survival with atezolizumab (17.8 months) versus chemotherapy (10.6 months).

Nivolumab, a PD-1 immune checkpoint inhibitor antibody, received accelerated approval from the FDA in February 2017 in patients with locally advanced or metastatic UC whose disease has progressed on platinum chemotherapy.[22] The phase II CHECKMATE 275 study explored nivolumab monotherapy in patients with metastatic, pre-treated UC and showed a response rate of 19.6% across all patient subgroups. When segregated by PD-L1 expression status on tumor cells, the response rate was 28.4% in patients with ≥5% expression versus 16.1% in patients with <1% PD-L1 expression. The median overall survival was 8.74 months (11.3 months in patients with ≥1% PD-L1 expression versus 5.95 months in patients with <1% expression). Nivolumab has also been studied in two dose combinations with ipilimumab (an anti-CTLA-4 antibody) in patients with locally advanced or metastatic UC previously treated with platinum-based chemotherapy; interim results showed that high response rates were achieved with combination therapy, but with higher toxicity[23] rates, which is similar to observations in treatment-naive melanoma patients.[24,25] Further study is needed to evaluate the clinical utility of this combination.

Durvalumab was investigated in 191 patients with advanced or metastatic UC following progression on prior chemotherapy or who were ineligible or refused chemotherapy in a phase I/II multi-center trial.[26] In the latest evaluation, patients with stage IV disease [98 PD-L1-positive, 79 PD-L1-negative (1 patient with unknown PD-L1 status)] were treated with intravenous durvalumab 10 mg/kg every 2 weeks for up to 12 months, and 99.5% had received one or more prior therapies. After a median follow-up of 5.8 months, the ORR was 17.8% (27.6% in the PD-L1-positive subgroup versus 5.1% in the PD-L1-negative subgroup). The initial 20 patients on study were enrolled regardless of PD-L1 expression, while subsequent patients were required to have ≥5% PD-L1 expression (using the Ventana SP263 assay) on tumor cells for enrolment. PD-L1 expression was defined as positive if either ≥25% of tumor cells or ≥25% of immune cells expressed PD-L1. Using this definition, the ORR in PD-L1 positive patients was 46.4% versus 0% in PD-L1 negative patients.

Avelumab, a fully humanized monoclonal PD-L1 antibody, is in phase Ib investigation in patients with solid tumors (JAVELIN trial program); an analysis of patients with metastatic UC showed promising and durable clinical activity in heavily pre-treated patients.[27] In this study, the unconfirmed ORR was 17.4%, and 25.4% in PD-L1-positive patients (defined using a ≥5% cut-off for tumor cell staining, Dako PD-L1 IHC kit) versus 13.2% in PD-L1-negative patients. Avelumab is also being assessed in a study (JAVELIN Bladder 100) as maintenance treatment of patients with locally advanced/metastatic UC whose disease did not progress after first-line platinum-based treatment,[28] with primary outcome results expected in the latter half of 2019.

Pembrolizumab is a humanized monoclonal antibody directed against PD-1. In a phase III study of pembrolizumab as second-line therapy in patients with advanced UC that recurred or progressed after platinum-based chemotherapy versus investigator's choice of docetaxel, paclitaxel, or vinflunine (KEYNOTE 045), pembrolizumab was associated with significantly longer overall survival (10.3 versus 7.4 months, hazard ratio 0.70, P < 0.001).[29,30] Notably, the median duration of response was longer (not reached) in the pembrolizumab treated patients versus 4.4 months with chemotherapy. PD-L1 expression using a 10% or greater combined positive score in tumor and infiltrating immune cells (22C3 pharmDx assay, Dako) was not associated with a statistically significant difference in response rate. This led to full FDA approval for patients previously treated with platinum-based chemotherapy. The phase II KEYNOTE 052 study investigated pembrolizumab in cisplatin-ineligible patients; the ORR was 24%, including 5% complete responses.[31] At an 8-month median follow-up, 74% of patients continued to respond and the median response duration was not reached. The results of this study supported an accelerated FDA approval in cisplatin-ineligible metastatic UC patients.

The observation that patients without PD-1 or PD-L1 expression may still exhibit responses to immune checkpoint inhibitors underscores the fact that these biomarkers cannot be used in isolation to make treatment decisions. Moreover, several caveats to the application of routine PD-1/PD-L1 staining exist, including the use of different assays to test for PD-1 and PD-L1 expression, variability in the definitions and cutoffs for positivity (the use of tumor-cell versus immune cell surface expression), differences in familiarity with interpreting test results, intratumor heterogeneity of expression, and the impact of prior treatments upon expression levels over time. As discussed below in more detail, several other tumor-specific factors likely contribute to checkpoint blockade sensitivity in UC, including expression subtyping and mutation profile (e.g. the presence of DNA damage response gene alterations or FGFR3 alterations). Additionally, host-specific factors, such as T-cell receptor clonality, tumor-infiltrating lymphocytes, and others, also modulate response to checkpoint blockade. A significant challenge will be to understand the relative impact of each of these biomarkers in predicting for checkpoint blockade sensitivity and resistance and implementing testing for these biomarkers in a rapid, prospective fashion before initiation of therapy.

Immunotherapies in Development

A number of other checkpoint inhibitors, interleukins (ILs), and novel immune molecules have been identified as potential immunotherapeutic agents in muscle-invasive and metastatic urothelial cancer (Figure 1).

Figure 1.

Immunotherapeutic targets in urothelial malignancies [33].