No Survival Benefit for Atezolizumab in
PD-L1–Positive Urothelial Cancer


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As reported in The Lancet by Thomas Powles, MD, of Barts Cancer Institute, Queen Mary University of London, and colleagues, the phase III IMvigor211 trial showed no survival benefit for atezolizumab vs physician’s choice of chemotherapy in platinum-treated locally advanced or metastatic urothelial carcinoma with programmed cell death ligand 1 (PD-L1) expression ≥ 5%.1

Study Details

In the open-label trial, 931 patients with disease progression after platinum-based therapy from 198 sites primarily in Europe, North America, and the Asia-Pacific region were randomized between January 2015 and February 2016 to receive atezolizumab (Tecentriq) 1,200 mg every 3 weeks (n = 467), or physician’s choice of chemotherapy (n = 464). Chemotherapy consisted of vinflunine at 320 mg/m2 (55% of patients), paclitaxel at 175 mg/m2 (33%), or docetaxel at 75 mg/m2 (12%) every 3 weeks.


Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1.
— Thomas Powles, MD, and colleagues

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Randomization was stratified by PD-L1 expression (expression of < 1% [IC0] or 1% to < 5% [IC1] of tumor-infiltrating immune cells vs ≥ 5% of tumor-infiltrating immune cells [IC2/3]), chemotherapy type, liver metastases, and number of prognostic factors. The primary endpoint was overall survival, tested hierarchically in prespecified populations—ie, IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. A total of 234 patients (116 in the atezolizumab group, 118 in the chemotherapy group) were in the IC2/3 population.

For the atezolizumab vs chemotherapy patients in the IC2/3 population: 70% vs 81% were male; 74% vs 75% were white and 14% vs 10% were Asian; 30% vs 27% were never-users of tobacco; 73% vs 75% had the bladder as the primary tumor site; 85% vs 94% had metastatic disease (67% vs 69% with visceral metastases); Eastern Cooperative Oncology Group performance status was 0 or 1 in all patients; 15% vs 16% had a hemoglobin level < 10 g/dL; 62% vs 65% had at least one risk factor; 49% vs 49% had previous cystectomy; 64% vs 65% had at least one prior systemic therapy in the metastatic setting; and 32% vs 31% had neoadjuvant/adjuvant chemotherapy with disease progression within 12 months.

Survival Outcomes

In the IC2/3 population, the median overall survival was 11.1 months in the atezolizumab group vs 10.6 months in the chemotherapy group; the stratified hazard ratio (HR) was not significant (0.87, P = .41), precluding further formal statistical analysis. Confirmed objective response rates among evaluable patients in the IC2/3 population were 23% vs 22%, with median response durations of 15.9 months vs 8.3 months (HR = 0.57, 95% confidence interval = 0.26–1.26). The median progression-free survival in the IC2/3 population was 2.4 months vs 4.2 months (HR = 1.01, 95% CI = 0.75–1.34).

ATEZOLIZUMAB VS CHEMOTHERAPY IN UROTHELIAL CANCER

  • Atezolizumab did not improve overall survival vs chemotherapy in patients with PD-L1 expression ≥ 5%.
  • Atezolizumab was associated with fewer severe adverse events.

In the intent-to-treat population, 23% of the atezolizumab group vs 25% of the chemotherapy group received nonprotocol treatment after disease progression, with 6% of the chemotherapy group receiving immunotherapy. The median duration of follow-up was 17.3 months. In an exploratory analysis, overall survival at 12 months was 39.2% with atezolizumab and 32.4% with chemotherapy; the median overall survival was 8.3 months with atezolizumab vs 7.5 months with taxanes and 9.2 months with vinflunine.

Adverse Events

In theintent-to-treat population, grade 3 or 4 treatment-related adverse events occurred in 20% of the atezolizumab group vs 43% of the chemotherapy group; the most common adverse events in the atezolizumab group were fatigue, anemia, and asthenia (2% each), and the most common adverse event in the chemotherapy group were neutropenia (11% vs < 1%) and febrile neutropenia (6% vs < 1%). Treatment-related adverse events of any grade occurring in at least 10% of both groups were fatigue, asthenia, decreased appetite, and diarrhea; treatment-related fatigue (26% vs 15%), nausea (26% vs 10%), constipation (33% vs 6%), and alopecia (27% vs 0%) occurred in at least 20% of chemotherapy patients. Treatment-related deaths occurred in 1% vs 2%.

The investigators concluded: “Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favorable compared with chemotherapy. Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting.” ■

DISCLOSURE: The study was funded by F. Hoffmann-La Roche and Genentech. For full disclosures of study authors, visit www.thelancet.com.

REFERENCE

1. Powles T, Durán I, van der Heijden MS, et al: Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial. Lancet 391:748-757, 2018.


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