The immune checkpoint inhibitor atezolizumab showed promising, lasting efficacy in patients with locally advanced or metastatic urothelial cancer, according to results of a phase II clinical trial conducted by an international team including Cleveland Clinic Cancer Center oncologist Petros Grivas, MD, PhD.
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The findings represent the first significant improvement in the systemic treatment of metastatic urothelial cancer in 30 years — a very encouraging development for patients whose prognosis after relapse has been dismal.
“These are practice-changing results that confirm data from the phase I trial of atezolizumab,” Dr. Grivas says. “Although the overall response rate was lower compared to what was noted in the phase I trial, it still compares favorably to historical second-line cytotoxic chemotherapy. The Food and Drug Administration’s approval of atezolizumab on May 18, 2016, provides a new standard treatment option for platinum-resistant advanced/metastatic urothelial cancer.”
Trying to break a therapeutic logjam
Urothelial carcinoma is by far the most common type of bladder cancer, and the ninth most common cancer worldwide. It kills more than 165,000 people each year, including an estimated 15,000 Americans in 2015. It causes significant morbidity and healthcare expenses.
There have been no major advances in the systemic treatment of urothelial cancer since the development of combination platinum-based chemotherapy three decades ago. Median overall survival in previously untreated patients with metastatic urothelial cancer who receive platinum-based chemotherapy is approximately 15 months. Prognosis for patients who relapse is grim, with median survival of 5 to 7 months.
Response rates to cytotoxic chemotherapy are low in patients with platinum-resistant advanced urothelial cancer, and side effects may reduce patients’ quality of life and may make treatment intolerable. There is no FDA-approved second-line chemotherapy agent.
Immunotherapy offers the potential to overcome this therapeutic impasse. Immune checkpoint inhibitors that enhance anti-tumor immunity already have shown breakthrough results in treating metastatic renal cell carcinoma, melanoma, non-small cell lung cancer and Hodgkin lymphoma.
Dr. Grivas and colleagues at 70 academic medical centers in the United States, Canada and Europe sought to determine the safety and efficacy of atezolizumab, a humanized monoclonal antibody against programmed death ligand 1 (PD-L1), in patients with advanced urothelial carcinoma whose disease had progressed after platinum-based chemotherapy (cohort 2) or who were ineligible for cisplatin (cohort 1). The FDA’s approval of atezolizumab was based on published results from cohort 2.
Negating tumor-mediated immunosuppression
Urothelial carcinoma has high rates of somatic mutations, which should enhance the host immune system’s ability to identify tumor cells as foreign due to increased numbers of neoantigens. However, these cancers also possess the ability to evade immune surveillance and eradication through the overexpression of PD-L1.
PD-L1’s presence in the tumor microenvironment is an immune checkpoint that negatively regulates T-cell function, leading to decreased T-cell proliferation and survival. PD-L1 binds to programmed death 1 (PD-1) and B7-1 receptors on activated T lymphocytes and other immune cells, delivering an inhibitory signal that enables tumors to avoid destruction.
Atezolizumab selectively binds to PD-L1, preventing its interaction with PD-1 and B7-1 and thereby negating tumor-mediated immunosuppression. Atezolizumab has demonstrated durable responses in patients with metastatic urothelial cancer in a phase I trial,3 with higher response rates in patients with elevated PD-L1 expression levels on tumor-infiltrating immune cells.
To assess atezolizumab’s anti-tumor activity in advanced urothelial carcinoma, researchers at Cleveland Clinic and the phase II study’s 69 other sites enrolled patients with inoperable locally advanced or metastatic tumors whose disease had progressed after platinum-based therapy (cohort 2). Many had adverse prognostic indicators such as visceral or liver metastasis and baseline hemoglobin < 10 g/dL.
Between May and November 2014, 310 patients were treated with at least one dose of atezolizumab. At data cutoff in September 2015, 202 (65 percent) had discontinued treatment. Of those, 193 had died, eight had withdrawn and one had stopped for other reasons. Patients’ tumors were evaluated with cross-sectional computed tomography every nine weeks for a year and every 12 weeks thereafter. Tumor tissue obtained by surgical resection or biopsy was assayed for PD-L1 expression, assessing the percentage of PD-L1-positive immune cells in the tumor microenvironment.
Durable responses and few adverse events
The researchers reported that treatment with atezolizumab produced “striking” and durable responses as determined by primary investigator-assessed analysis and longer-term independent radiological review. Responses were noted even in patients with poor prognostic features, though at a lower rate than patients who lacked unfavorable indicators.
For all evaluable patients, the objective response rate as independently assessed was 15 percent (95 percent confidence interval [CI] 11-19) compared with an overall response rate of 10 percent among historical controls. A complete response was recorded in 15 (5 percent) of 310 patients.
With a median follow-up of 11.7 months (95% CI, 11.4–12.2), ongoing responses were recorded in 38 (84 percent) of 45 responders.
Increased levels of PD-L1 expression on immune cells (IC) measured by immunohistochemistry were associated with increased response. In addition to PD-L1 expression levels, patients’ mutation load of cancer-related genes and luminal II molecular (TCGA) subtype were strongly indicative of their response to atezolizumab.
The median treatment duration was 12 weeks. Median progression-free survival was 2.1 months. Median overall survival was 11.4 months in patients with IC2/3 PD-L1 expression, 8.8 months in patients with IC1/2/3 PD-L1 expression and 7.9 months in the entire cohort. Twenty (17 percent) of 121 patients treated beyond progression experienced reductions of at least 30 percent of the size of their tumors.
Atezolizumab was generally well-tolerated. Treatment-related serious (grade 3/4) adverse events occurred in 16 percent of patients. There were no treatment-related deaths. Most treatment-related adverse events were mild to moderate (primarily fatigue). Only 5 percent of patients had serious (grade 3/4) immune-related adverse events. This low incidence is encouraging, since patients with metastatic urothelial cancer often have renal dysfunction and/or other conditions that could be exacerbated by an adverse treatment reaction.
The need for more clinical and translational research
More research is needed to evaluate the predictive value of patients’ PD-L1 immune cell expression levels, to better determine which patients will benefit from atezolizumab treatment and to develop future treatment strategies. The associations between PD-L1 expression, molecular subtype, mutation load and response to atezolizumab suggest that the presence of additional neoantigens may correlate with immune system response, and that combination immunotherapies may further enhance therapeutic effects. More clinical trials are needed to define further new therapies in this challenging cancer; trial accrual is critical.
“The prior absence of a standard-of-care treatment option in patients with platinum-resistant advanced urothelial cancer, in conjunction with the shown efficacy and relatively favorable toxicity profile of immune checkpoint inhibitors, contributed to the recent FDA approval that rendered atezolizumab the new standard of care for patients with platinum-resistant advanced urothelial cancer,” Dr. Grivas says. “More clinical and translational research is critical to further understand the immunologic mechanisms and potential treatment combinations and sequences, and to develop prognostic and predictive biomarkers that can aid in optimal patient selection.”