Atezolizumab in Platinum-Treated Advanced Urothelial Carcinoma: A New Standard of Care?


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Compared with a historic control rate, a phase II study of the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab (Tecentriq) has demonstrated clinically meaningful responses in patients with urothelial carcinoma who progressed after platinum-based chemotherapy.1 Hailed as a “major advancement” in the treatment of metastatic urothelial carcinoma, ­atezolizumab yielded clinical benefit in all subgroups, including heavily pretreated patients with multiple comorbidities and poor prognostic factors.

Atezolimumab recently received U.S. Food and Drug Administration approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease worsened during or after platinum-containing chemotherapy or within 12 months of receiving platinum-containing chemotherapy, either before or after surgical treatment.


Atezolizumab did not exacerbate renal toxicity in patients with impaired renal function. The drug is probably better tolerated than chemotherapy…and represents a major advancement in metastatic urothelial carcinoma.
— Robert Dreicer, MD

“With a median follow-up of 11.7 months in this updated analysis, clinically meaningful and durable responses continue to be observed,” said Robert Dreicer, MD, of the University of Virginia, Charlottesville. “Coupled with its favorable tolerability in a patient population with poor prognostic factors, atezolizumab is now the standard of care for patients with platinum-treated metastatic urothelial carcinoma.”

As Dr. Dreicer reported at the 2016 American Urological Association Annual Meeting, advanced urothelial carcinoma has few therapeutic options, characterized by poor response rates and significant toxicity. Atezolizumab, designed to reinvigorate antitumor immunity, works by inhibiting interactions between PD-L1 and its receptors, programmed cell death protein 1 (PD-1) and B7-1. The drug has demonstrated promising response rates in a variety of tumors, including metastatic urothelial carcinoma, non–small cell lung cancer, melanoma, and renal cell carcinoma.2-5

“In the past couple of years, there’s been a lot of enthusiasm with the role of checkpoint inhibitors,” said Dr. Dreicer. “Unless you’ve been living in a box, you realize that immune-modulatory therapy is here to stay.”

IMvigor 210 Study Design

IMvigor 210 is an open-label, multicenter, single-arm phase II study that evaluated the safety and efficacy of atezolizumab in people with locally advanced or metastatic urothelial carcinoma, regardless of PD-L1 expression.

Patients in the study were enrolled into one of two cohorts. Cohort 1 comprised those who had received no prior therapies for locally advanced or metastatic urothelial carcinoma but who were ineligible for first-line cisplatin-based therapy. The results for this cohort are not yet mature.

Cohort 2 included 310 patients with cancer of the bladder, kidney, pelvis, ureter, or urethra, during or after at least one prior platinum-containing regimen, and these formed the basis of this analysis. Patients received 1,200 mg of atezolizumab intravenously every 3 weeks until loss of clinical benefit.

The study’s co-primary endpoints included objective response rate per central review and per investigator review. Secondary endpoints included duration of response, progression-free survival, and overall survival.

Heavy Pretreatment Does Not Preclude Response

Although high expression of PD-L1 was associated with a higher overall response rate (26%), durable responses occurred in all predefined PD-L1 subgroups and in patients with poor prognostic factors. The objective response rate to atezolizumab in all patients was 15%. Data are consistent with the primary analysis, with the median duration of response still not reached, Dr. Dreicer reported.

Immunotherapy in Resistant Urothelial Carcinoma

  • In patients with urothelial carcinoma that progressed after platinum-based carcinoma, the objective response rate to atezolizumab was 15%.
  • A higher overall response rate was associated with higher PD-L1 status.
  • Responses with atezolizumab are durable, with 84% of responses still ongoing.

Complete responses were also seen in heavily pretreated patients with multiple comorbidities and poor prognostic factors. Complete responses occurred in all prespecified PD-L1 subgroups but were enriched in patients with a higher PD-L1 status (11%).

“Although there’s a higher likelihood of response in patients expressing more PD-L1 immune cells, it’s important to recognize there were responses in PD-L0 expression as well,” revealed Dr. Dreicer, who emphasized that these responses are at least comparable to other chemotherapy series. These responses are “very durable,” he added, with 39 of 45 (84%) responses ongoing at data cutoff (median follow-up, 11.7 months).

Toxicity

Finally, atezolizumab was generally well tolerated. The most common any-grade treatment-related adverse events included fatigue (30%), nausea (14%), and decreased appetite (12%). The most common immune-mediated adverse events included pneumonitis (2%) and increased liver enzymes, colitis, dyspnea, increased blood bilirubin, diarrhea, and rash (1% each).

“For clinicians, it’s also important to note that atezolizumab did not exacerbate renal toxicity in patients with impaired renal function,” remarked Dr. Dreicer. “The drug is probably better tolerated than chemotherapy…. Atezolizumab represents a major advancement in metastatic urothelial carcinoma.”

For more on atezolizumab and its approval on May 18, 2016, for treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy, see page 92 in this issue. ■

Disclosure: Dr. Dreicer is a consultant to Roche/Genentech, Asana Biosciences, Ferring Pharmaceuticals, Tokai Pharmaceuticals, Exelixis, Astellas Pharma, and Churchill Pharmaceuticals.

References

1. Dreicer R, van der Heijden MS, Grivas P, et al: Primary analysis of IMvigor 210: Atezolizumab in platinum-treated advanced urothelial carcinoma. 2016 AUA Annual Meeting. Abstract PD27-12. Presented May 8, 2016.

2. Ott PA, Hodi FS, Robert C: CTLA-4 and PD-1/PD-L1 blockade: New immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 19:5300-5309, 2013.

3. Rosenberg J, Petrylak D, Abidoye O, et al: Atezolizumab in patients with locally-advanced or metastatic urothelial carcinoma: IMvigor 210. 2015 European Cancer Congress. Abstract 21LBA. Presented September 27, 2015.

4. Vansteenkiste J, Fehrenbacher L, Spira AI, et al: Atezolizumab monotherapy vs docetaxel in 2L/3L non–small cell lung cancer: POPLAR. 2015 European Cancer Congress. Abstract 14LBA. Presented September 27, 2015.

5. McDermott DF, Sosman JA, Sznol M, et al: Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: Long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 34:833-842, 2016.


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