Evidence Builds for Targeting PD-1/PD-L1 Pathway in Bladder Cancer

Andrea Necchi, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Andrea Necchi, MD

As the number of tumor types with approved PD-1/PD-L1 pathway inhibitors continues to expand, bladder cancer has become a robust area of development. In less than a year, 2 new checkpoint immunotherapy agents have been approved and 3 others remain under study.

The pathway has emerged as a rational target in urothelial carcinoma (UC), the most common form of bladder cancer, because of the presence of PD-L1 expression and a comparatively high mutation load, researchers have concluded.¹

Moreover, patients diagnosed with bladder cancer are in need of new treatment options. Although a role for immunotherapy has been established for non-muscle invasive UC since the approval of the Bacillus Calmette-Guérin vaccine in 1976, there were no such agents available for advanced disease until the approval of the PD-L1 inhibitor atezolizumab (Tecentriq) in May 2016. The armamentarium expanded in February with the approval of the PD-1 inhibitor nivolumab (Opdivo) for patients with advanced or metastatic UC (mUC) that has progressed during or after platinum-containing chemotherapy.

Checkpoint Inhibitors in Action

Atezolizumab

Clinical trial findings presented in recent weeks at major oncology conferences have added to the body of evidence building for these agents. The following is a summary of the latest findings.The FDA granted atezolizumab accelerated approval as a treatment for patients with locally advanced or mUC whose disease progressed during or after platinum-based chemotherapy either before or after surgery based on the data from the phase II IMvigor 210 study. The overall response rate (ORR) in that trial was 15% among all patients and 26% among participants with PD-L1 expression ≥5% on infiltrating immune cells in the tumor microenvironment.¹

In January, investigators presented data about the impact of prior therapies on outcomes with atezolizumab treatment at the 2017 Genitourinary Cancers Symposium.²

Patients with UC in the platinum-pretreated cohort of the IMvigor 210 study (NCT02108652) received 1200 mg of atezolizumab intravenously (IV) on day 1 of a 21-day cycle. Of the evaluable patients (n = 310), the median age was 66 years, and 82% of patients had received prior systemic treatment, with the lines of prior regimens ranging from 1 to 4 or more. Of those patients who received prior therapy, 73% received prior cisplatin-based chemotherapy, and 26% received carboplatin-based chemotherapy.²

Table 1. Clinical Benefit of Atezolizumab in the IMvigor 210 Study¹

Responses occurred regardless of the number of prior therapies, and were ongoing in 65% of responding patients at the data cutoff date (July 4, 2016). A clinically meaningful benefit was observed, with minimally and heavily pretreated patients experiencing durable responses (Table 1).² In a phase Ia study of the long-term impact of atezolizumab in previously treated patients with mUC (NCT01375842), atezolizumab was well tolerated without new safety signals in this patient population. The study concluded that the durability of responses, including complete response (CR) rates and an extended OS, confirm atezolizumab as a new standard therapy for previously treated patients with mUC.³

In this investigation, evaluable patients (n = 95) received 15 mg/kg or 1200 mg of atezolizumab through an IV every 3 weeks. The median age was 66 years, 76% of patients were male, 80% had primary bladder tumors, and 61% had an ECOG performance status of 1. The median treatment duration was 3 months, and 24% of patients were treated for 1 year or longer.

Pembrolizumab

Treatment-related adverse events (AEs) occurred in 66% (all-grade AEs) and 9% (grade 3-4 AEs) of patients, with no treatment-related deaths reported. The ORR was 27%, and the CR rate was 10%. The median duration of response was 22.1 months in all patients, and 56% of the responses were ongoing at the data cutoff date (December 15, 2015). With a median 24-month follow-up, the 1-year OS rate was 46%, and the 2-year OS rate was 30%, with a median OS of 10.6 months.³Treatment with PD-1 inhibitor pembrolizumab (Keytruda) significantly prolonged OS over investigators’ choice of chemotherapy in patients with recurrent advanced UC, according to results reported at the 19th European Cancer Congress.⁴

Findings from the phase III KEYNOTE-045 study (NCT02256436) support pembrolizumab as a new standard of care for patients with advanced UC that progressed during or after platinum-based chemotherapy, investigators said (Table 2).

Table 2. Efficacy of Pembrolizumab Versus Chemotherapy in KEYNOTE-045⁴

“Pembrolizumab is the first agent to demonstrate OS improvement compared with chemotherapy in patients with advanced urothelial carcinoma after failure of platinum-based chemotherapy,” said Andrea Necchi, MD, medical oncologist at Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy. “This is the first immunotherapy to demonstrate OS bene t over an active comparator in urothelial carcinoma.”

Treatment-related adverse events (TRAEs) were less frequent with pembrolizumab compared with chemotherapy. The rates of all-grade TRAEs were 60.9% and 90.2%, respectively; grade 3-5 TRAEs occurred in 15% of patients treated with pembrolizumab and in 49.9% of patients treated with chemotherapy. TRAEs with pembrolizumab occurring at an incidence of ≥10% were pruritus (20%), fatigue (10%), nausea (10%), and diarrhea (10%). Treatment discontinuation due to TRAEs was reported for 15 patients in the pembrolizumab arm compared with 28 patients in the chemotherapy arm. Four deaths due to a TRAE occurred in each arm.⁴

The full results of the phase II KEYNOTE-052 study (NCT02335424), presented at the 2017 GU Cancers Symposium, showed that pembrolizumab had clinically meaningful and durable responses in cisplatin-ineligible patients with mUC, including those with poor ECOG performance status. In total, 370 patients were enrolled in the trial, with a median age of 74 years. The ORR was 24%, the CR rate was 5%, and the OS rate at 6 months was 67%.⁵

However, pembrolizumab has also been shown to have clinical significance when combined with chemotherapy. According to preliminary data presented at the 2017 GU Cancer Symposium, combining pembrolizumab with chemotherapy induced objective responses in one-third of patients with previously treated mUC. The study is still ongoing, but encouraging antitumor activity was observed.⁶

Patients received pembrolizumab and were assigned to also receive either docetaxel or gemcitabine (n = 12). Treatment consisted of pembrolizumab at 200 mg on day 1 every 3 weeks plus either docetaxel at 75 mg/m2 on day 1 or gemcitabine at 1000 mg/m2 on days 1 and 8. Six patients were accrued to each treatment arm.⁶

Nivolumab

Based on data from these studies, the FDA is evaluating pembrolizumab under its priority review program in 2 treatment settings, according to Merck, the developer of the drug. Pembrolizumab is being considered in the second- line setting for the treatment of patients with locally advanced or mUC who progress following platinum-containing chemotherapy and as a treatment for cisplatin-ineligible patients with locally advanced or mUC.In February, the FDA granted an accelerated approval to nivolumab as a treatment for patients with locally advanced unresectable or mUC following progression on a platinum-containing therapy, based on findings from the phase II CheckMate-275 study (NCT02387996; Table 3).

Table 3. Outcomes With Nivolumab in CheckMate-275 Study⁷

“In previously treated patients with metastatic urothelial carcinoma, for whom there is no standard of care, we provide the first evidence of substantial clinical activity with nivolumab, regardless of PD-L1 expression,” said Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center, in a presentation at the 2016 ESMO Annual Meeting. “In this heavily pretreated population, the safety profile of nivolumab monotherapy is manageable and consistent with previous reports in other tumor types.”

The open-label study enrolled 270 patients with unresectable or mUC. Patients had received a platinum-based agent in the metastatic setting or were within 1 year of neoadjuvant/adjuvant platinum therapy. In the trial, nivolumab was administered at 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The FDA recommended a at dose for the UC indication of 240 mg IV every 2 weeks.⁷

Notably, nivolumab is being studied in combinations with other treatments. In combination with ipilimumab (Yervoy), a inhibitor, patients with mUC saw a bene t after having no response to single- agent nivolumab, according to findings reported at the 2017 GU Cancers Symposium.⁸

Ten patients who were refractory to nivolumab monotherapy were treated with the combination of nivolumab and ipilimumab. Of the 8 evaluable patients, 1 patient achieved a confirmed partial response (PR) and 4 additional patients experienced stable disease (SD) by immune-related response criteria.8 The combination was associated with a modest increase in toxicity, but was generally well tolerated.

Selected Clinical Trials PD-1/PD-L1 Inhibitors in Urothelial Carcinoma

Avelumab

In another study, a preliminary clinical investigation demonstrated that the combination of cabozantinib and nivolumab, with or without ipilimumab, proved safe and active in advanced genitourinary cancers, particularly UC. Almost one-third of patients responded to the combination therapy, including 3 CRs. More than half of the patients had SD, as only 7 patients had progressive disease as a best response. Of those patients with UC (n = 16), 56% achieved SD, 25% had PRs, 6% had CRs, and the ORR was 38%.⁹Avelumab, a fully human monoclonal PD-L1 anti-body of isotope immunoglobulin G1 (IgG1), has also demonstrated promising efficacy and safety in patients with mUC. In a report on the interim pooled analysis of 2 cohorts from the large phase Ib JAVELIN trial (NCT01772004), the clinical activity of avelumab was further shown to be well tolerated and to have durable responses, regardless of PD-L1 expression.

The trial is ongoing, but as of March 19, 2016, patients with mUC (n = 241) received avelumab at a dose of 10 mg/kg every 2 weeks, for a median duration of 8 weeks (range 2-80 weeks). In 153 patients with at least 6 months of follow-up, the confirmed ORR was 17.6% (95% CI, 12.0-24.6), including 9 CRs and 18 PRs, and 88.9% of patients in ongoing treatment. The disease control rate was 41.2%, with 36 patients experiencing SD as the best response. The median PFS was 6.4 weeks, and the median OS was 7 months.¹⁰

Durvalumab

TRAEs of any grade occurring in 10% or more of patients were infusion-related reaction (22.8%) and fatigue (12%), with 7.5% of patients experiencing grade 3/4 TRAEs. One treatment-related death was reported in a patient with pneumonitis.¹⁰Durvalumab (MEDI4736) is a selective, high-affinity human IgG1 monoclonal antibody against PD-L1, binding to both PD-1 and CD80. The anti- body does not interfere with interaction between PD-1 and PD-L2.

Safety and efficacy results of durvalumab treatment in patients with advanced UC bladder cancer were presented at the 2016 ASCO Annual Meeting. The ORR was 31% (95% CI, 17.6-47.1) in the 42 evaluable patients, 46% (95% CI, 28-66) in the high PD-L1—positive subgroup (≥25% in the tumor cells or immune cells), and 0% in the PD-L1 low/negative subgroup.¹¹ Durvalumab had a manageable safety profile and showed evidence of significant clinical activity in heavily pretreated PD-L1— positive patients.

Table 4. Clinical Benefit of Durvalumab by PD-L1 Expression¹²

Durvalumab also demonstrated compelling clinical activity and a manageable safety profile as second-line therapy for locally advanced or mUC, according to updated phase I/II data presented at the 2017 GU Cancers Symposium. Following treatment with durvalumab at a dose of 10 mg/ kg every 2 weeks, one-fourth of 103 patients (24%) remained alive without disease progression at 6 months, as did 17% at 12 months. The OS rate was 60% at 6 months and 51% at 12 months. Durvalumab led to an ORR of 20.4%, and patients with and without PD-L1 expression had responses to the drug (Table 4).¹²

References

1. Rosenberg JE, Ho man-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcino- ma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920. doi:10.1016/S0140-6736(16)00561-4.
2. Perez-Gracia JL, Loriot Y, Rosenberg JE, et al. Atezolizumab (atezo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): outcomes by prior therapy. Presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 323. meetinglibrary.asco.org/content/179258-197.
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10. Patel MR, Ellerton JA, Infante JR, et al. Avelumab in patients with metastatic urothelial carcinoma: pooled results from two cohorts of the phase 1b JAVELIN solid tumor trial. Presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 330. meetinglibrary.asco.org/content/178781-197.
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