First Look at Combo With Immunotherapy in Untreated mRCC

Nick Mulcahy

February 27, 2017

ORLANDO, Florida – Use of the immunotherapy atezolizumab (Tecentriq, Roche) in combination with bevacizumab (Avastin, Roche) nearly doubled progression-free survival (PFS) compared with sunitinib (Sutent, Pfizer) as a first-line treatment in patients with locally advanced or metastatic renal cell carcinoma (mRCC).

These results come from a subgroup analysis of a phase 2 trial presented here at the Genitourinary Cancers Symposium (GUCS) 2017.

It is important to note that atezolizumab is an inhibitor of programmed death ligand 1 (PD-L1), and this PFS result with the combination therapy was found only among the subgroup of patients with PD-L1 expression and not in the larger group trial participants.

Despite having "provocative data," this phase 2 randomized trial does not allow conclusions to be drawn about the results because it was hypothesis generating, said lead study author Thomas Powles, MD, of the Barts Cancer Institute in London, United Kingdom.

Still, the study is notable because it is the first randomized trial to compare an immune checkpoint inhibitor vs a "benchmark control" in untreated mRCC, said Dr Powles.

Furthermore, Dr Powles said the trial results "support" the ongoing phase 3 study in this setting, IMmotion151, which involves the same three drugs and includes only patients with detectable PD-L1. "We hope [this trial] will change the way we treat kidney cancer in the not too distant future," he enthused.

Currently, the only immunotherapy approved for the treatment of mRCC in the United States is nivolumab (Opdivo, Bristol-Myers Squibb), but it is a monotherapy in second-line treatment, and its use is not guided by a biomarker.

Not every everyone at the meeting was as gung ho as Dr Powles about the possibility of using the combination of atezolizumab and bevacizumab, an angiogenesis inhibitor, in this setting.

Jose Karam, MD, of the University of Texas MD Anderson Cancer Center in Houston, pointed out that "about half" of patients with locally advanced and metastatic RCC "probably don't need anything," referring to adjuvant treatment.

He was also concerned about adding bevacizumab to atezolizumab because, in the current trial, the toxicity with the combination was greater than with atezolizumab alone (40% vs 17% in grade 3 and 4 adverse events). "That's a big jump," he said. Whatever treatment is chosen for these patients needs to have "acceptable toxicity," he said during a panel discussion at the meeting.

Dr Powles acknowledged that adverse events were important. "Quality of life for our patients, who have a limited life expectancy, is very important," he said.

Doubling of PFS, but Not Statistically Significant

Atezolizumab is approved in the United States for use in previously treated metastatic non–small cell lung cancer and previously treated advanced urothelial cancer.

In the new 305-patient, three-arm study, atezolizumab alone or in combination with bevacizumab was compared with sunitinib in patients with previously untreated mRCC. The atezolizumab arms were not compared with each other.

Median follow-up was 20.7 months.

Coprimary endpoints were PFS (RECIST v1.1 by independent review) in intention-to-treat patients and patients with PD-L1 expression on ≥1% of immune cells (aka, PD-L1+).

The intention-to-treat analysis among all patients found no statistically significant difference in PFS between patients treated with the combination of atezolizumab and bevacizumab and those treated with sunitinib. Atezolizumab alone also did not improve PFS vs sunitinib.

In the subgroup analysis of patients PD-L1-positive tumors, the median PFS with the combination was 14.7 months; it was 7.8 months with sunitinib, and 5.5 months with atezolizumab monotherapy. The combination was associated with a 36% reduction in disease progression or death compared with sunitinib, but the result was not statistically significant (hazard ratio, 0.64; P = .095).

The overall response rate was highest with the combination (32%), followed by sunitinib (29%) and atezolizumab alone (25%).

However, among the PD-L1+ patients, the response rate was 46% with the combination, 28% with atezolizumab alone, and 27% with sunitinib.

As noted above, treatment-related grade 3-4 adverse events were seen in 40%, 16%, and 57% of patients in the combination, atezolizumab, and sunitinib arms, respectively. Adverse events leading to death occurred in 3%, 2%, and 2% of patients, respectively.

Data on duration of response were not yet available.

"In the era of immunotherapy, we are actually more interested in long-term durable remissions and overall survival" than in PFS, which has been the measure for evaluating and approving sunitinib and other antiangiogenic therapies, said Dr Powles.

The study was funded by Roche. Dr Powles has financial ties to Roche, BMS, Merck Novartis, AstraZeneca, and other companies. Dr Kara has financial ties to Roche, Novartis, Pfizer, and EMD Serano.

Genitourinary Cancers Symposium (GUCS) 2017. Abstract 431, presented February 18, 2017.

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