Checkpoint Inhibitors and Urothelial Carcinoma: The Translational Paradigm

The emergence of immune checkpoint inhibitors as effective cancer immunotherapy has effectively built a new “highway” connecting the promise of oncologic translational research to progress in treating advanced malignancies. However, despite the clear advances demonstrated in randomized trials of patients with melanoma, non–small-cell lung cancer (NSCLC), and renal cell carcinoma, the applicability of checkpoint inhibitors to other tumor types still sits squarely on the “promise” side. Case in point: metastatic urothelial carcinoma is a generally incurable disease that has had no new systemic treatment options or improvement in survival outcomes in decades.[1] Although systemic chemotherapy can achieve an overall survival (OS) ranging from 14.0 to 16.1 months with multi-agent chemotherapy, untreated patients have been reported to have an OS of only 5.2 months.[2-4] Thus, oncologists and patients alike are hoping new treatment options like checkpoint inhibitors will be their ticket from promise to progress.

Urothelial Carcinoma: Ripe for Immunotherapy?

In many ways, urothelial carcinoma represents a tumor subtype in which checkpoint inhibition may have ideal potential. In a landmark paper in the journal Nature in 2013, Alexandrov et al characterized the prevalence of somatic mutations across human cancer types. Leading the way with the highest mutational burden were melanoma and NSCLC (both adenocarcinoma and squamous cell carcinoma), the tumor types for which checkpoint inhibition have proven the most efficacious to date, followed closely by urothelial carcinoma.[5] One common thread between these cancers may be their association with chronic exposure to DNA-damaging carcinogens, such as smoking (NSCLC and urothelial carcinoma), chemical exposure (urothelial carcinoma), and ultraviolet radiation (melanoma). Mutational burden has, in fact, been associated with response to checkpoint inhibition in both melanoma and NSCLC,[6,7] and although total mutational load is likely only a surrogate marker for a more complex immunogenic relationship, the potential relevance to urothelial carcinoma is intriguing.

Another important signal of increased immunogenicity in urothelial carcinoma relates to the treatment of non–muscle invasive urothelial carcinoma (NMIUC). The standard of care for preventing tumor recurrence after maximal transurethral resection of bladder tumor in NMIUC is intravesical therapy with bacille Calmette-Guérin (BCG). Multiple clinical trials have established the superiority of BCG in preventing recurrence and progression of disease in the bladder, yet its mechanism is still not well understood.[8-10] What is clear, however, is that BCG efficacy depends on an intact immune system, while impaired humoral and cell-mediated immunity, as well as dysregulated cytokine profiles, can promote BCG failure.[11]

Initial Studies of Checkpoint Inhibitors in Urothelial Carcinoma

The first studies evaluating checkpoint inhibitors in urothelial carcinoma involved the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor ipilimumab. In a neoadjuvant “window of opportunity” study, 12 urothelial carcinoma patients with high-grade T1/2 disease received two doses of ipilimumab prior to radical cystectomy (RC).[12] The primary aim was exploratory, evaluating for increased levels of CD4+ICOShi T cells as a predictive biomarker, and indeed levels increased in a dose-dependent manner. However, no correlation to outcomes in urothelial carcinoma was reported in this study, although it was shown that increased ICOShi CD4+ cells retrospectively correlated with clinical benefit in a separate cohort of melanoma patients. In first-line metastatic urothelial carcinoma, a subsequent trial combining gemcitabine and cisplatin chemotherapy with four doses of ipilimumab has completed accrual, and preliminary correlative data were presented at the 2015 American Society of Oncology (ASCO) Annual Meeting (ClinicalTrials.gov identifier: NCT01524991).[13] The addition of ipilimumab to chemotherapy increased levels of circulating CD4+ and CD8+ cells, although not necessarily the ICOS+ cells, and induced a potentially more immunostimulatory environment. Updated safety and efficacy results were presented at the Genitourinary Cancers Symposium in January 2016.[14] The grade 3/4 adverse event (AE) rate was 72%, and autoimmune adverse events were noted. In 36 evaluable patients, the overall response rate (ORR) was 64%, with 5 patients (14%) achieving a pathologic complete response (CR). However, the study did not meet its primary endpoint of improved 1-year OS.

Inhibiting both ends of the programmed death 1 (PD-1) pathway has also been investigated in urothelial carcinoma. The PD-1 inhibitor pembrolizumab (MK-3475) was studied in a large, multi-arm phase I trial, KEYNOTE-012, and the results of the urothelial carcinoma arm were updated at the 2015 ASCO Annual Meeting.[15] Patients on this arm needed to have recurrent or metastatic urothelial carcinoma and ≥ 1% positive staining for programmed death ligand 1 (PD-L1) on tumor cells or tumor infiltrating lymphocytes (TILs). Thirty-three patients were evaluable for response, with an ORR of 28%. The median OS was reported as 12.7 months and 52.9% of patients were alive at 12 months. Three patients achieved a CR. Data have also emerged for atezolizumab (MPDL3280A), the first PD-L1 inhibitor studied in urothelial carcinoma, with the results from the urothelial carcinoma cohort of this large, multi-arm phase Ia study also reported at the 2015 ASCO Annual Meeting.[16] This study accepted patients with any level of PD-L1 staining of immune cells (IC) only (graded IC 0–3). The ORR was 34%, with 87 total patients evaluable, but notably, the response rate was 50% in the 46 IC 2–3 patients, with nine CRs. Based on these results, the US Food and Drug Administration (FDA) granted atezolizumab “breakthrough therapy designation” status. Following up on these promising results, data from the phase II IMvigor 210 study were reported in September at the 2015 European Cancer Congress in Vienna, Austria. This was a single-arm trial of patients with locally advanced or metastatic urothelial carcinoma, with separate cohorts for platinum-ineligible, treatment-naive patients and patients with progression on or after platinum-based therapy. Data on 311 patients in the platinum-refractory cohort were presented. The ORR was 15% in the entire cohort, but 27% in the IC 2 and IC 3 groups combined. Median OS for the entire cohort was 7.9 months and not yet reached for the IC 2 and IC 3 groups, but with a median follow-up of only 7 months these data are somewhat premature. With regard to toxicity, although many patients feel well on these drugs, immune-related AEs can be severe, but are usually treatable if recognized and managed expeditiously. In the studies mentioned, grade 3/4 AEs occurred in 15% of the pembrolizumab-treated urothelial carcinoma patients, and in 8% to 15% of the atezolizumab-treated urothelial carcinoma patients.

Notably, although the toxicity profile and durability of response favor checkpoint inhibitors over chemotherapy, in an unselected population, the ORR and OS reported in the atezolizumab phase II trial do not differ much from values seen in historical chemotherapy comparisons. Albeit with a caveat to be cautious when comparing across studies and eras, second-line trials of chemotherapeutics in urothelial carcinoma have produced an ORR of about 12% and an OS of 7 months, values that are not markedly different from those seen in IMvigor210. Clearly, however, questions remain. The atezolizumab phase III study will help clarify this issue a bit, but controversies over optimal patient selection are likely to linger. Higher PD-L1 staining seems to increase the likelihood of response, but lack of standardization in assay platforms and staining thresholds limits its clinical applicability as a predictive biomarker. Better biomarkers are certainly needed and are embedded in many ongoing studies, but the story may get more complicated before any clarity is achieved.

Ongoing and Future Trials

Looking down the translational highway, there is still much to be optimistic about. The international phase III IMvigor211 trial comparing atezolizumab with physician’s choice chemotherapy in the second-line setting in platinum-refractory urothelial carcinoma is currently recruiting patients (ClinicalTrials.gov identifier: NCT02302807). KEYNOTE-045 (ClinicalTrials.gov identifier: NCT02256436) is a phase III trial of pembrolizumab with a design and patient population similar to those of IMvigor 211, while KEYNOTE-052 (ClinicalTrials.gov identifier: NCT02335424) is a single-arm phase II study evaluating first-line pembrolizumab in platinum-ineligible patients. Another PD-1 inhibitor, nivolumab, is currently being studied in a phase II single-arm study in platinum-refractory metastatic urothelial carcinoma patients. The next steps involve combining checkpoint inhibitors in rational combinations in an attempt to increase the number of patients that benefit, as well as exploring the role of these drugs in other settings or at other time points in the disease process. In treatment-naive metastatic melanoma patients, dual checkpoint blockade with ipilimumab and nivolumab has already demonstrated superior efficacy over either single agent, but at the cost of excess toxicity.[17] However, due to the exceptional efficacy, this combination has received FDA approval and has arguably become the standard of care in that setting. This combination is being tested in urothelial carcinoma as part of a single-arm phase Ib study (ClinicalTrials.gov identifier: NCT01928394) in previously treated patients, and in another phase Ib trial (ClinicalTrials.gov identifier: NCT02496208) that randomizes metastatic urothelial carcinoma patients in the second-line setting to nivolumab plus the c-Met and vascular endothelial growth factor receptor 2 inhibitor cabozantanib (XL-184) or the triple combination of ipilimumab/nivolumab/cabozantanib.

The efficacy of combined checkpoint blockade in melanoma has illustrated the potential of immunotherapy. However, with grade 3/4 treatment-related AEs eclipsing 50%, one has to wonder how we can maintain that benefit while minimizing the fallout. Checkpoint inhibitors work to unleash the immune system, but once unleashed, if there are no tumor antigens to recognize, the antitumor effect is likely nil. So combining PD-1 inhibitors with therapies that destroy tumor cells and cause an efflux of antigens may complement checkpoint blockade. Accordingly, trials looking at various combinations of PD-1/PD-L1 inhibitors with chemotherapy, radiation, and targeted therapy are in various stages of planning or accrual. Combining PD-1 inhibitors with other immune checkpoint blockers that may be less toxic than CTLA-4 inhibitors, or with immunomodulators that prime the tumor microenvironment to be more hospitable to an immune response, may also prove to be viable strategies. Modulating the tumor milieu may well be the way in which BCG works in NMIUC, and combining such strategies with PD-1 inhibition in metastatic urothelial carcinoma could bring the treatment paradigm full circle. Some examples of this include a combination of the anti-CD27 monoclonal antibody varlilumab (CDX-1127) with atezolizumab (ClinicalTrials.gov identifier: NCT02543645) and a combination of the cytokine interferon-γ with nivolumab, both of which are planned but not yet open to accrual.

Conclusions

After years of dead ends in the treatment of metastatic urothelial carcinoma, the road is now paved with optimism. Single-agent immune checkpoint inhibitors are in phase III trials that aim to extend the lean armamentarium available for patients with this disease. At this time, PD-L1 staining does not suffice as a reliable predictive marker with which to make treatment decisions for our patients, but hopefully innovative correlative studies embedded in many of the ongoing and upcoming trials will further elucidate candidate biomarkers to inform treatment decisions and optimize patient selection. Furthermore, studies of rational combination strategies should be supported to increase response rates while minimizing toxicity. While we await phase III data to hopefully confirm the superiority of these agents for patients with urothelial carcinoma, tremendous opportunities currently exist to refer patients for clinical trials that will provide access to promising new drugs and combinations that may one day become the standard of care. It is too early to assume that the gains that are now a reality in metastatic melanoma will translate fully to the treatment of metastatic urothelial carcinoma, but the immunogenic features of this tumor and promise of the initial trials justify expectations that new and better treatment options are in sight for our patients.

Financial Disclosure:Dr. Plimack has consulted on issues relevant to bladder cancer for Bristol-Myers Squibb, Eli Lilly, Genentech, Novartis, Pfizer, and Roche; she has also received funding for the conduct of clinical trials relevant to bladder cancer from Bristol-Myers Squibb, Horizon Pharma, and Merck. Dr. Zibelman has received funding for the conduct of clinical trials relevant to bladder cancer from Horizon Pharma.

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