Combination May Move to the Frontline for Kidney Cancer

There was a 36 percent reduction in the risk of progression or death for patients with PD-L1-positive metastatic renal cell carcinoma (mRCC) who were treated in the first line with Tecentriq (atezolizumab) and Avastin (bevacizumab) compared to Sutent (sunitinib), according to the 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 2 results made a compelling case for a randomized phase 3 evaluation of the Tecentriq-Avastin combination, which has already begun, Thomas Powles, M.D., 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 3 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 2 IMmotion150 trial, which evaluated Tecentriq alone or in combination with Avastin versus Sutent in patients with previously untreated mRCC. The trial compared both Tecentriq arms against Sutent, but not with each other.

The trial had two 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 percent or more expression. Following results of a phase 1a trial, they amended the protocol to define PD-L1-positive as at least 1.

Data analysis included 305 patients. The ITT analysis showed a median PFS of 11.7 months with the combination, 8.4 months with Sutent, and 6.1 months with single-agent Tecentriq. Neither the comparison of the combination nor Tecentriq monotherapy versus single-agent Sutent 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 Sutent, and 5.5 months with Tecentriq monotherapy. The comparison of the combination versus Sutent resulted in a hazard ratio (HR) of .64, which still did not achieve statistical significance. A subgroup analysis favored the combination over Sutent for all categories of PD-L1 expression: at least 1 percent to 5 percent (76 patients) with a HR of .87; 5 percent to 10 percent (22 patients) with a HR of .50; more than 10 percent (12 patients) with a HR of .23.

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

The median duration of treatment also favored the combination: 11.8 months for Tecentriq and 10.3 months for Avastin; 7.6 months for Tecentriq monotherapy; and 6.7 months for Sutent.

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

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