In the real world, many patients are excluded from clinical trials of novel treatments and therapies for a host of reasons, ranging from diabetes and high blood pressure to psoriasis. The situation invariably leaves patients who are deemed ineligible for these trials with an unmet clinical need.
In response, researchers who conducted the international SAUL study examined atezolizumab in an expanded “real-world” population of patients with comorbidities that typically excluded them from clinical trials with immunotherapy, such as renal impairment, autoimmune disease, and central nervous system (CNS) metastases, to name a few.
The SAUL study is the first large prospective real-world clinical trial of immunotherapy in patients with advanced urinary tract carcinoma. And it is the first and only clinical trial of immunotherapy in this setting.
In the study, researchers analyzed clinical outcomes irrespective of age, expression of PD-L1 status, and histology, said lead investigator, Cora N. Sternberg, MD, FACP, Clinical Director of the Caryl and Israel Englander Institute for Precision Medicine and Professor of Medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine.
“These data support the use of atezolizumab in urinary tract carcinoma patients, including those with limited treatment options,” said Sternberg, who is the winner of a 2020 Excellence in Oncology award from Oncology Times in recognition of her work on the SAUL study. The results of the clinical trial are “confirmatory in nature and practice-defining,” she noted.
An Uncommon Approach
Urothelial carcinoma is the most common type of bladder cancer, accounting for about 90 percent of all cases. The disease also is known as transitional cell cancer since urothelial cells are found in the urethra, ureters, renal pelvis, and other areas of the urinary tract.
Atezolizumab is a type of immunotherapy approved for the treatment of locally advanced or metastatic urothelial carcinoma based on previous clinical trials. Some bladder cancer patients have achieved complete and long-lasting responses using this agent.
A checkpoint inhibitor and humanized IgG1 monoclonal antibody, atezolizumab targets PD-L1 by blocking the binding of PD-L1 and mPDL-1 receptors, and also blocks binding with B7 immune regulatory ligands (Nature 2014;515(7528):558-562).
In the U.S., atezolizumab may be used to treat patients with bladder cancer who have failed to respond to cisplatin-based or carboplatin-based chemotherapy. It is approved also for patients ineligible for cisplatin-based chemotherapy, particularly those with 5 percent or more immunocompromised cells which are PD-L1 staining.
After earning FDA approval for patients with bladder cancer, atezolizumab was investigated around the globe in a series of registration trials. Enrollment in those studies, however, was limited to highly selective patients who met stringent safety criteria that excluded many patients.
Without employing the real-world approach, in fact, 35 percent of the patients included in the pivotal SAUL study would have been excluded for having failed in one of the categories of ineligibility for the landmark IMvigor211 phase III clinical trial that evaluated atezolizumab versus chemotherapy, results from which were published in The Lancet in 2017 (https://doi.org/10.1016/S0140-6736(17)33297-X).
Data from “Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract” were published last summer in European Oncology (2019;76(1):73-81). All age groups, including the elderly, tolerated the immunotherapy well in the SAUL study, Sternberg noted.
“The SAUL study was designed to assess atezolizumab in a broader population of patients, including those typically excluded from phase III trials because of comorbidities, autoimmune disease, poor performance, and so on,” she explained. “We often see these patients in our clinical practice, but there is little or no information on outcomes in these patients.”
The phase IIIb, multicenter, international SAUL study included 1,004 patients with locally advanced or metastatic urothelial or non-urothelial urinary tract carcinoma in 32 countries in Europe, Asia, South America, Australia, and Canada (NCT02928406).
The real-world approach allowed SAUL study researchers to enroll patients with immunological disease, elevated creatinine, poor performance status, ECOG PS 0-2 (10% of patients), progression on non-platinum treatment, creatinine clearance greater than or equal to 15 mL/min, stable CNS metastases, steroid treatment ongoing at baseline, autoimmune disease, HIV-positive status (two patients), and individuals with renal failure and on dialysis.
All of the patients in the SAUL study had experienced disease progression during or after 1-3 prior therapies for inoperable, locally advanced, or metastatic disease, and 98 percent had prior platinum-based chemotherapy (Eur Urol 2019;76(1):73-81).
Between November 2016 and March 2018 (median follow-up 12.7 months), the patients received atezolizumab dosed at 1,200 mg every 3 weeks until either progression or unacceptable toxicity occurred or death. The median treatment duration was 2.8 months (range 0-19); 22 percent remained on treatment and 8 percent discontinued because of toxicity.
Grade ≥3 adverse events occurred in 45 percent of the patients, with the most common being fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7 months (95% CI 7.8-9.9). The 6-month OS rate was 60 percent (95% CI 57-63%), median PFS was 2.2 months (95% CI 2.1-2.4), and the ORR was 13 percent (95 CI 11-16%; 3% complete responses).
Among IMvigor211-like patients (from the registration trial criteria, excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0 months (95% CI 8.8-11.9) and 6-month OS was 65 percent (95% CI 61-69%), according to the researchers.
“It is important that investigators work in a multidisciplinary team to manage any potent side effects of immunotherapy,” Sternberg said. “In general, safety in the subgroups of special interest was very similar to the overall population and very few patients discontinued treatment due to adverse events.”
The primary endpoint of the SAUL study was safety, Sternberg said. Secondary endpoints included OS, response rate and duration of response. Both the response and OS rates were the same 8.7 months, which was the same as what was seen in the registration trials, she said. Atezolizumab was also well-tolerated by elderly patients (ages 65-80, and some even slightly older) with no increases in toxicity.
“The safety profile was consistent with the well-established profile of immunotherapy in previous trials in urothelial carcinoma. There were very few grade 4/5 treatment-related adverse events,” Sternberg said. “Overall, SAUL showed that atezolizumab was well-tolerated in this broader population.”
Not all patients in the SAUL study fared as well as the majority, Sternberg said. “The 10 percent of patients with ECOG performance status 2 are difficult to treat and they did less well than the overall population. Similarly, the patients with CNS metastases had a poor prognosis,” she explained.
“On the other hand, patients with autoimmune disease, usually not permitted in registration trials, seemed to do very well on atezolizumab,” Sternberg added. What's more, “patients with upper tract urothelial cancer did as well as those patients with a primary tumor that initiated in the bladder,” she noted.
Additionally, the researchers found that efficacy overall as well as in the IMvigor211-like sub group was consistent with the previous anti-PD-L1/PD-1 urothelial carcinoma trials, Sternberg said.
Looking ahead, the real-world SAUL study opens myriad avenues to further research.
“Analysis of data in this large real-life cohort provides the opportunity to further investigate the role of potential biomarkers in locally advanced or metastatic urothelial and non-urothelial cancer of the urinary tract treated with atezolizumab,” she noted.
Chuck Holt is a contributing writer.
2020 Excellence in Oncology