Atezolizumab-bevacizumab combination extends PFS in PD-L1-positive metastatic renal cell carcinoma

Sumanta Kumar Pal

MIAMI — The combination of atezolizumab and bevacizumab demonstrated encouraging activity as first-line treatment for PD-L1-positive metastatic renal cell carcinoma, according to updated results from the randomized phase 2 IMmotion150 trial presented at International Kidney Cancer Symposium.

Researchers observed a statistically significant PFS benefit with the combination in this subgroup as assessed by RECIST version 1.1 criteria and immune-modified RECIST criteria.

“Assessment by immune-modified criteria also showed a trend toward benefit in the intention-to-treat population,” researcher Sumanta Kumar Pal, MD, medical oncologist and co-director of the kidney cancer program at City of Hope and a HemOnc Today Editorial Board Member, said during a presentation.

IMmotion150 was the first randomized study of PD-1/PD-L1-directed therapy and VEGF pathway inhibition in the first-line setting of metastatic renal cell carcinoma.

The trial included 305 patients with treatment-naive locally advanced or metastatic renal cell carcinoma.

Researchers randomly assigned patients to one of three regimens:

101 patients received 15 mg/kg bevacizumab (Avastin, Genentech), a humanized anti-VEGF monoclonal antibody, plus 1,200 mg IV atezolizumab (Tecentriq, Genentech), a PD-L1 inhibitor, every 3 weeks;
101 patients received 1,200 mg IV atezolizumab every 3 weeks; and
103 patients received 50 mg sunitinib (Sutent, Pfizer) — which targets multiple tyrosine kinases — in a conventional 4-weeks-on, 2-weeks-off schedule.

Patients assigned atezolizumab monotherapy or sunitinib monotherapy had the opportunity to cross over to the combination regimen upon progression.

Stratification factors included prior nephrectomy, PD-L1 expression and Memorial Sloan Kettering Cancer Center risk category.

Independent review facility-assessed PFS in both the intention-to-treat population and PD-L1-positive subgroup served as coprimary endpoints. The threshold for PD-L1 positivity changed from 5% or higher to 1% or higher during the study period based on relevant data from a phase 1 clinical trial.

Secondary endpoints included investigator-assessed PFS by RECIST version 1.1 and immune-modified RECIST, objective response rate and patient-reported outcomes.

As HemOnc Today previously reported, data presented at this year’s Genitourinary Cancer Symposium showed the combination conferred no significant PFS benefit compared with sunitinib monotherapy in the overall cohort. However, the combination demonstrated antitumor activity in PD-L1-positive patients. In that population, PFS favored the combination by independent review facility assessment (median, 14.7 months vs. 7.8 months; HR = 0.64; 95% CI, 0.38-1.08) and investigator assessment (median, 11.7 months vs. 7 months; HR = 0.6; 95% CI, 0.37-0.97).

At the International Kidney Cancer Symposium, Pal presented updated PFS outcomes and data on additional endpoints based on median follow-up of 25.7 months.

PAGE BREAK

In the full cohort, investigator-assessed PFS by RECIST version 1.1 criteria in the intention-to-treat population showed a benefit with the combination (11 months) compared with sunitinib monotherapy (7.8 months) and atezolizumab monotherapy (5.5 months); however, the PFS difference between the combination and sunitinib monotherapy did not reach statistical significance (HR = 0.88; 95% CI, 0.64-1.22).

In the PD-L1-positive subgroup, investigator assessment showed median PFS of 11.1 months with the combination, 6.8 months with sunitinib monotherapy and 5.5 months with atezolizumab monotherapy. Among these patients, the PFS difference between the combination and sunitinib monotherapy reached statistical significance (HR = 0.6; 95% CI, 0.3-0.94).

Investigator-assessed PFS measured by immune-modified RECIST criteria showed a more substantial PFS benefit with the combination (17.3 months) compared with sunitinib monotherapy (9.9 months) and atezolizumab monotherapy (8.5 months). However, the difference did not reach statistical significance (HR = 0.78; 95% CI, 0.55-1.11).

In the PD-L1 subgroup, results of PFS assessment by immune-modified RECIST criteria strongly favored the combination (21.9 months) compared with atezolizumab monotherapy (10.9 months) and sunitinib monotherapy (8.4 months; HR = 0.47; 95% CI, 0.29-0.78).

Pal and colleagues reported a higher ORR among combination-treated patients in the PD-L1-positive subgroup than the intention-to-treat population (48% vs. 35%).

“The safety profile with the combination appears consistent with the profile of each agent alone,” Pal said.

Treatment-related grade 3/grade 4 events were lower with atezolizumab and bevacizumab than with sunitinib, Pal said. In addition, patients assigned the combination regimen and atezolizumab monotherapy appeared associated with delays in symptom interference compared with those assigned sunitinib.

“These updated efficacy data confirm the encouraging activity of atezolizumab with bevacizumab for first-line treatment of PD-L1-positive metastatic renal cell carcinoma,” Pal said. “Analysis of these data by immune-modified RECIST criteria contributes to our understanding of the clinical activity of immunotherapy in this disease.”

The phase 3 IMmotion151 study, designed to further evaluate atezolizumab plus bevacizumab with sunitinib monotherapy, is underway. Data are expected next year.

“We, of course, eagerly await these results, Pal said. – by Mark Leiser

For more information:

Pal SK. IMmotion150: Novel radiological endpoints and updated data from a randomized phase II trial investigating atezolizumab with or without bevacizumab vs. sunitinib in untreated metastatic renal cell carcinoma. Presented at: International Kidney Cancer Symposium; Nov. 3-4, 2017; Miami.

Disclosure: Pal reports honoraria from Genentech, as well as consultant roles with Astellas, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Novartis and Pfizer. Please see the abstract for a list of all other authors' relevant financial disclosures.