Michael B. Atkins, MD

THE COMBINATION of atezolizumab (Tecentriq) plus bevacizumab (Avastin) showed promising results as first-line treatment of patients with metastatic renal cell carcinoma, according to a phase II trial called IMmotion 150. Based on these results, the phase III IMmotion 151 trial is comparing atezolizumab/bevacizumab vs sunitinib (Sutent) as front-line treatment of patients with metastatic renal cell carcinoma. 

Combinations of immunotherapy checkpoint inhibitor plus vascular endothelial growth factor (VEGF) pathway inhibitors are being studied in metastatic renal cell carcinoma, with varying degrees of success. Atezolizumab/bevacizumab is one of the more promising ones, with less toxicity than some of the other combinations that have been studied, namely, pembrolizumab (Keytruda)/pazopanib (Votrient) and nivolumab (Opdivo)/pazopanib or sunitinib (Sutent). 

“Atezolizumab plus bevacizumab achieved encouraging efficacy vs sunitinib in programmed cell death ligand 1 (PD-L1)–positive patients treated in the first-line setting for metastatic renal cell carcinoma. In addition, in a unique aspect of this trial, the clinical activity of this combination was seen in patients who crossed over to the combination regardless of whether they received prior first-line atezolizumab or first-line sunitinib,” explained Michael B. Atkins, MD, Deputy Director of the Georgetown-Lombardi Comprehensive Cancer Center and Professor at Georgetown University School of Medicine in Washington, DC. 

Crossover Cohort 

AT THE 2017 ASCO Annual Meeting, Dr. Atkins presented the results of patients enrolled in the phase II trial who crossed over to atezolizumab/bevacizumab from either atezolizumab monotherapy or sunitinib monotherapy at disease progression.¹ 

The objective response rate was 26% in all crossover patients, and the progression-free survival was 8.8 months in all crossover patients. PD-L1 expression ≥ 1% modestly enriched for response. “The efficacy of the combination is better in crossover patients than with the monotherapies in the same patients as front-line treatment,” he said. 

Study Details 

IMMOTION 1 50 is the first randomized front-line trial to explore PD-L1 blockade with atezolizumab as monotherapy and in combination with bevacizumab vs sunitinib in metastatic renal cell carcinoma. The study randomized 305 patients with untreated metastatic renal cell carcinoma to receive atezolizumab/bevacizumab vs atezolizumab vs sunitinib. 

A unique feature of the trial was that patients with progressive disease on monotherapy could cross over to the combination arm after an optional biopsy. Crossover was not permitted in Europe, so only some of the originally enrolled patients were included in the crossover analysis. 

The front-line clinical results, previously presented in 2016, showed overlapping progression-free survival curves in an intent-to-treat analysis. Median progression-free survival was 11.7 months in the combination arm, 6.1 months for atezolizumab monotherapy, and 8.4 months for sunitinib. 

In the subset of patients who were PD-L1–positive (as defined by > 1% expression of PD-L1 on tumor-infiltrating cells), progression-free survival favored the combination early on. There was a doubling of progression-free survival in the combination arm: 14.7 vs 5.5 months for atezolizumab and 7.8 months for sunitinib (a 36% improvement for the combination). 

Crossover Details 

SEVENTY-SEVEN PERCENT of the first-line sunitinib group and 75% of the first-line atezolizumab group who had progressive disease and were eligible based on geography, crossed over to the combination arm. This totaled 101 patients (57 after first-line sunitinib and 44 after first-line atezolizumab). 

The demographics of the overall crossover population were similar to those of the front-line patients and similar between the two crossover cohorts. Patients who crossed over were less likely to respond to first-line therapy and more likely to progress early than the overall front-line population. 

Prior to crossover, after first-line therapy in crossover patients, the overall response rates was 21% for sunitinib, 9% for atezolizumab, and 16% overall. Median progression-free survival was 5.4 months. 

After crossing over to the combination arm, the overall response rate was 26% (28% for crossovers post sunitinib and 24% post atezolizumab). 

“These response rates compare favorably with first-line response rates for these patients as well as the previously reported response rates for second-line atezolizumab or bevacizumab monotherapy,” Dr. Atkins said. 

At the time of his presentation, 72% of responses were ongoing, and the median duration of response was not estimable. “Response rates appeared slightly higher in the few patients who had a brief response to sunitinib or atezolizumab monotherapy relative to those with no response,” he added. 

“As with response rates, median progression-free survival was longer in transient responders to monotherapy.”

— Michael B. Atkins, MD

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Median progression-free survival was 8.8 months for all crossover patients: 8.3 months post sunitinib and 12.6 months post atezolizumab. 

“As with response rates, median progression-free survival was longer in transient responders to monotherapy,” Dr. Atkins said. 

PD-L1 Expression 

BASED ON PD-L1 expression, irrespective of prior therapy, slightly higher responses were observed in the PD-L1–positive patients at baseline: 28% vs 20% for low or no expression of PD-L1 at baseline. A similar trend was seen for PD-L1 expression in patients who had tumor biopsies at time of disease progression: 33% for the PD-L1–positive patients vs 22% for < 1% of PD-L1 expression. 

There was no apparent difference in progression-free survival in the crossover group based on PD-L1 expression at baseline or in the progression biopsy. “There was no discernible difference in the safety profile between front-line atezolizumab/bevacizumab treatment or crossover treatment with the combination,” Dr. Atkins said. 

Tumor Microenvironment 

AN EXPLORATORY endpoint examined the association between outcome and tumor microenvironment gene signatures, dividing patients’ tumors into three subsets: angiogenesis, preexisting immunity (T-effector signature), or myeloid inflammation. 

“In the front-line setting, reduced atezolizumab monotherapy activity in the T-effector–high and myeloid inflammatory–high patients suggests a potential mechanism of immune escape, which may be rescued by the addition of bevacizumab,” Dr. Atkins said. 

In a small group of nine patients who crossed over from front-line bevacizumab, a trend was observed for improved progression-free survival, stable disease, and response in patients whose tumors were T-effector–high and myeloid inflammatory–high, but the numbers are very small. 

“Analysis of disease biology suggests a distinct association with first-line progression-free survival for the combination, with reduced activity for atezolizumab alone in T-effector–high and myeloid–high patients. The response rates in the crossover patients after first-line atezolizumab suggests the combination [with bevacizumab] may be important in rescuing some patients who can’t respond to atezolizumab monotherapy. The biomarker data suggest, surprisingly, that a lot of the effect of the combination might be an immune effect, and that immunosuppressive factors in the microenvironment need to be blocked, in this case by bevacizumab, to see a response,” Dr. Atkins elaborated during a question-and-answer period following his presentation. 

“The hypothesis generated from these data will inform the ongoing IMmotion151 trial and other combination trials,” he stated. ■

DISCLOSURE: Dr. Atkins received honoraria from Bristol-Myers Squibb and served as a consultant or advisor for Alkermes, Amgen, Bristol-Myers Squibb, Genentech, Genoptix, GlaxoSmithKline, Infinity Pharmaceuticals, Lilly, Merck, Nektar, Novartis, Pfizer, Peleton, and X4 Pharmaceuticals.

REFERENCE 

1. Atkins MB, McDermott DF, Powles T, et al: IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma patients of atezolizumab and bevacizumab vs and following atezolizumab or sunitinib. 2017 ASCO Annual Meeting. Abstract 4505. Presented June 5, 2017.