Combination Makes First-Line Case for Metastatic PD-L1+ RCC

Thomas Powles, MD

Patients with PD-L1-positive metastatic renal cell carcinoma (mRCC) had a 36% reduction in the risk of progression or death when treated in first line with the combination of atezolizumab and bevacizumab instead of sunitinib, according to results of a randomized trial.

The median progression-free survival (PFS) was almost twice as long with the combination therapy, 14.7 months versus 7.8 months. Although the combination failed to improve PFS in the overall population (primary endpoint), the phase II results made a compelling case for a randomized phase III evaluation of the atezolizumab-bevacizumab combination, which has already begun, Thomas Powles, MD, reported at the 2017 Genitourinary Cancers Symposium in Orlando, FL.

“The combination of atezolizumab and bevacizumab, in that PD-L1 positive population, looks really attractive,” said Powles, a medical oncologist at Barts Cancer Institute and Queen Mary University of London. “It was well tolerated, and importantly, we have that randomized, phase III study that is powered to explore that PFS endpoint in that PD-L1-positive population. This trial has had a direct impact on the subsequent study, which we hope will change the way we treat kidney cancer in the not-too-distant future.”

“It’s important to underline that this was a hypothesis-generating trial,” he added. “It was not designed for registration or approval. In a situation where we have provocative data, it is important to stress that the trial had interim analyses and therefore we can’t be jumping to conclusions with the data before us, as it stands.”

The findings came from the randomized phase II IMmotion150 trial, which evaluated atezolizumab alone or in combination with bevacizumab versus sunitinib in patients with previously untreated mRCC. The trial compared both atezolizumab arms against sunitinib, but not with each other.

The trial had 2 primary endpoints: PFS by intention-to-treat (ITT) analysis (determined by independent review), and in the subgroup of patients with PD-L1-positive tumors. Investigators initially defined PD-L1 positive as ≥5% expression. Following results of a phase Ia trial, they amended the protocol to define PD-L1-positive as ≥1.

Data analysis included 305 patients. The ITT analysis showed a median PFS of 11.7 months with the combination, 8.4 months with sunitinib, and 6.1 months with single-agent atezolizumab. Neither the comparison of the combination nor atezolizumab monotherapy versus single-agent sunitinib resulted in a significant difference.

The analysis of patients with PD-L1-positive tumors yielded a median PFS of 14.7 months with the combination, 7.8 months with sunitinib, and 5.5 months with atezolizumab monotherapy. The comparison of the combination versus sunitinib resulted in a hazard ratio (HR) of .64, which still did not achieve statistical significance (HR, .38-1.08, P = .095). A subgroup analysis favored the combination over sunitinib for all categories of PD-L1 expression: ≥1 to <5% (n = 76) with a HR of .87; ≥5% to <10% (n = 22) with a HR of .50; ≥10% (n = 12) with a HR of .23.

The overall response rate differed little among the three groups in the ITT analysis: 32% with the combination, 29% with sunitinib, and 25% with atezolizumab monotherapy. An analysis of patients with ≥1% PD-L1 expression showed response rates of 46% with the combination, 28% with atezolizumab alone, and 27% with sunitinib.

The median duration of treatment also favored the combination: 11.8 months for atezolizumab and 10.3 months for bevacizumab; 7.6 months for atezolizumab monotherapy; and 6.7 months for sunitinib.

Treatment-related grade 3/4 adverse events (AEs) occurred more often with sunitinib (57%) than with the combination (40%) or single-agent atezolizumab (17%). The incidence of AEs leading to withdrawal was 9% with sunitinib and the combination and 3% with single-agent atezolizumab. AEs leading to dose modification or interruption occurred in 70% of the sunitinib group, 60% of the combination group, and 27% of the single-agent atezolizumab arm.

The most common AEs (all grades) in the combination arm were fatigue (about 60%), and diarrhea, nausea, headache, arthralgia, and proteinuria (30-40% each). In the sunitinib group the most common AEs were fatigue (70%), diarrhea (60%), nausea (50%), hand-foot syndrome (40%), and mucositis, dysgeusia, and decreased appetite (30% each).

McDermott D, Atkins M, Motzer R, et al. A phase II study of atezolizumab with or without bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma patients. Abstract presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 431.

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