PD-1 and PD-L1 Inhibitors as Salvage Therapy for Urothelial Carcinoma

For more than two decades, the only therapy that was proven to extend overall survival among patients with advanced urothelial carcinoma was cisplatin-based combination chemotherapy.1 First-line cisplatin-based chemotherapy yields a median overall survival of 14 to 15 months, coupled with 5-year survival among 5 to 15% of patients. Historically, salvage chemotherapy with vinflunine or a taxane after the receipt of platinum-based chemotherapy has resulted in a response in only approximately 10% of patients, with a dismal median overall survival of 6 to 8 months.2,3 Vinflunine was approved in multiple countries on the basis of a phase 3 trial that showed prolonged overall survival, as compared with best supportive care, in a multivariate analysis and in the trial-eligible population after the exclusion of patients who had major protocol violations at baseline. However, it did not extend survival in the intention-to-treat population and is not approved in the United States. Taxanes have not been investigated in phase 3 trials or approved by regulatory agencies, although they are considered by many clinicians to be acceptable salvage agents.

Given this backdrop, the Food and Drug Administration (FDA) approvals of atezolizumab, a programmed death 1 ligand (PD-L1) inhibitor, in May 2016 and nivolumab, a programmed death 1 (PD-1) inhibitor, in February 2017 in patients who have a relapse after platinum-based therapy constitute major advances. In the context of cancer therapy, PD-L1 and PD-1 inhibitors may be aptly described as the metaphorical rising tide that lifts all boats. These monoclonal antibodies have yielded major advances across multiple malignant conditions by unleashing the antitumor activity of T lymphocytes by targeting this T-cell inhibitory pathway. Atezolizumab and nivolumab were granted accelerated approvals on the basis of the nonrandomized phase 2 trials IMvigor210 and CheckMate275, respectively.4,5 These agents yielded responses in 15% and 20% of patients, respectively, in these two trials, as well as prolonged response durations. Furthermore, severe toxic effects were observed in only 16% and 18% of patients, respectively. Accelerated approvals are defined as the early approval of drugs to address unmet needs, and confirmatory trials are required in order to grant full approvals. Another PD-L1 inhibitor, durvalumab, has also shown activity in a phase 2 trial.6

Bellmunt et al. now report in the Journal the results of a phase 3 trial (KEYNOTE-045) that assessed overall survival among patients who have a relapse after receiving a platinum-based regimen.7 This trial enrolled 542 patients and showed a longer median overall survival with pembrolizumab, a PD-1 inhibitor, than with taxane or vinflunine chemotherapy (10.3 months vs. 7.4 months; hazard ratio for death, 0.73; P=0.002). The response rate was higher with pembrolizumab than with chemotherapy (21.1% vs. 11.4%), and the estimated rate of duration of response of 12 months or longer was also higher with pembrolizumab (68% vs. 35%). However, no significant difference in median progression-free survival was observed (2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group). Pembrolizumab was also less toxic than chemotherapy for all adverse events (60.9% vs. 90.2% of patients had an event) and severe adverse events (15.0% vs. 49.4%). On the basis of these encouraging results, pembrolizumab is expected to gain regulatory approval.

These results provoke some questions. First, is there a preferred agent among pembrolizumab, nivolumab, and atezolizumab? Second, when should PD-1 or PD-L1 inhibitor therapy be discontinued? And third, can a biomarker inform the selection of patients? In the absence of a randomized trial comparing these agents, it is not possible to choose among them objectively. The fact that pembrolizumab is the only agent with proven efficacy in a phase 3 trial should be considered. Nomograms that are constructed to predict survival on the basis of prognostic factors at baseline may assist in the interpretation of the clinical outcomes seen in nonrandomized trials.8 Patients with disease progression, as assessed radiologically, could continue therapy if they were clinically stable, in order to account for the possibility of pseudoprogression (the temporary enlargement of lesions due to lymphocyte infiltration). Indeed, the extension of survival without the extension of progression-free survival that was observed with pembrolizumab suggests a delayed benefit in the majority of patients. None of the above trials selected patients on the basis of a biomarker (e.g., PD-L1 expression in the tumor). The KEYNOTE-045 trial identified a survival benefit regardless of tumor PD-L1 expression. The results of the IMvigor210 and CheckMate275 trials collectively suggest that tumor PD-L1 expression, genomic subtype, interferon-

γ gene expression, chemokine signature, and mutation burden may be prognostic for response.4 However, these biomarkers require validation before their use in the clinic.

The KEYNOTE-045 trial will have a practice-changing effect. The longer survival and lower rates of toxic effects with pembrolizumab than with chemotherapy confer an improved therapeutic index in these generally elderly patients with coexisting conditions. As we celebrate the major advance that is provided by pembrolizumab, it is important to remember that this remains an incremental advance overall, although the responses were remarkably durable. Patients who require salvage therapy remain incurable. Studies have highlighted the extraordinary molecular heterogeneity of urothelial carcinoma.9 Therefore, clinical trials evaluating biologic agents for rationally selected patients who have an elevated level of the molecular target of the drug in the tumor, potentially in combination with PD-1 and PD-L1 inhibitors, may yield further increments and are being pursued (ClinicalTrials.gov number, NCT02546661). Moreover, PD-1 and PD-L1 inhibitors are active as first-line therapy.10 Indeed, they are being investigated in randomized phase 3 trials assessing their use as first-line therapy in combination with platinum-based chemotherapy (NCT02853305 and NCT02807636) and cytotoxic T-lymphocyte

–associated 4 (CTLA-4)–inhibiting immune modulators (NCT02516241 and NCT03036098) and as adjuvant therapy after surgery for high-risk disease (NCT02450331 and NCT02632409).

New England Journal of Medicine , éditorial, 2016

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