Atezolizumab Plus Bevacizumab Shows Encouraging Clinical Activity in mRCC

Thomas Powles, MD

Atezolizumab (Tecentriq) with bevacizumab (Avastin) provided improved progression-free survival (PFS) over sunitinib in patients with untreated metastatic renal cell carcinoma (mRCC), according to findings presented during the 2017 ESMO Congress in Madrid, Spain.

Importantly, the clinical benefit of atezolizumab plus bevacizumab did not come at the expense of increased symptom burden. Co-blockade of VEGF with bevacizumab and PD-L1 with atezolizumab also improved patient response compared to tyrosine kinase inhibition with sunitinib (Sutent) in the overall population and in patients with tumors expressing PD-L1.

Median PFS by RECIST was 7.8 months with sunitinib, versus 5.5 with monotherapy compared to sunitinib (hazard ratio [HR], 1.13; P = 0.45), versus 11.0 months with atezolizumab and bevacizumab compared to sunitinib (HR, 0.88; P = 0.44). By immune-modified RECIST (imRECIST) criteria, median PFS was 9.9 months with sunitinib, versus 8.5 with monotherapy (HR, 1.05; P = 0.77), versus 17.3 months with atezolizumab and bevacizumab (HR, 0.78; P = 0.16).

PFS event-free rates at 6 months were 56.4%, 45.6%, versus 63.2%, and 66.4%, 63.3%, versus 75.0% across the sunitinib, monotherapy, and atezolizumab and bevacizumab treatment arms in the overall and imRECIST populations, respectively. The median follow-up in phase II IMmotion150 (NCT01984242) trial was 25.7 months.

According to lead author Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology at Barts Cancer Institute, London, United Kingdom, RESIST and imRECIST criteria differ in several aspects including the appearance of new lesions, which define the former but are added to the total tumor burden and followed in imRECIST.

“As a result of crossover, efficacy outcomes by imRECIST are provided for descriptive purpose only,” Powles said.

“Interleukin-2 is an approved cancer immunotherapy for first-line metastatic renal cell carcinoma that is associated with long-term responses; however, it is limited by toxicity and the development of resistance, making the development of new therapies necessary,” he said. “Atezolizumab has demonstrated anti-tumor activity and, in combination with bevacizumab, may reactivate the cancer immunity cycle.”

The trial randomized treatment-naïve patients with mRCC to oral sunitinib at 50 mg daily for a 4 week on, 2 week off cycle (n = 101), atezolizumab monotherapy at 1200 mg IV every 3 weeks (n = 103), or to atezolizumab at 1200 mg IV plus bevacizumab at 15 mg/kg IV (n = 101) both given every 3 weeks. Treatment beyond progression was allowed in the atezolizumab arms, but not the sunitinib arm. Crossover upon progression was allowed for non-European patients.

Three-quarters of patients were male, 96% in the sunitinib arm, 92% in the monotherapy arm, and 96% in the combination arm had clear cell histology, and 69%, 67%, and 61% of patients were at intermediate risk of recurrence, respectively.

PD-L1 expression was scored on tumor-infiltrating immune cells (IC) using the VENTANA SP142 immunohistochemistry assay. The co-primary endpoints were PFS by independent review according to RECIST v1.1 in the intention to threat population and in the subgroup of patients with PD-L1 expression ≥1% on IC. Other endpoints included PFS by investigator according to RECIST and imRECIST plus patient-reported outcomes (PROs).

“The updated results remained consistent with the primary analysis, showing clinically meaningful benefit in PFS with atezolizumab versus sunitinib in PD-L1 positive patients,” said Powles.

The investigator=assessed overall response rate (ORR) was 32% with sunitinib, 24.3% with monotherapy, and 34.7% with atezolizumab and bevacizumab versus 28.3%, 27.8%, and 48.0% in the overall population versus the PD-L1 positive population, respectively. The rates of complete response (CR), partial response (PR), and stable disease were similar, but lower in the overall population compared to the PD-L1-positive cohort, where the CR rates were 1.7% versus 7.4%, versus 2.0%; PR rates were 26.7%, 20.4%, versus 46.0%; and SD rates were 40%, 31.5%, and 28.0% with sunitinib, atezolizumab monotherapy, and combination treatment, respectively.

“Safety of combined atezolizumab plus bevacizumab was consistent with the known safety profile of each agent alone; further follow-up showed no new safety signals,” Powles commented.

Both atezolizumab and bevacizumab were more well-tolerated than sunitinib. Treatment related serious adverse events (AEs) occurred in 12.0%, 14.6%, and 23.8% of patients receiving sunitinib, atezolizumab, and atezolizumab plus bevacizumab, respectively. Study withdrawal due to an AE occurred in 13.0%, 6.8%, and 21.8% of patients, and dose modification or interruption due to AEs occurred in 70.0%, 27.2%, and 61.4% of patients on sunitinib, monotherapy and combination treatment, respectively.

Two (2%) patients on sunitinib and one (1%) patient receiving combined atezolizumab plus bevacizumab died due to an AE.

“Patients receiving atezolizumab reported less symptom severity and interference in daily functioning on the MD Anderson Symptom Severity Inventory,” Powles noted. For example, the median time to symptom deterioration was 3.6 months with sunitinib, not reached with atezolizumab monotherapy, and 7.6 months with combined atezolizumab and bevacizumab.

This study was funded by F. Hoffmann-La Roche, Ltd.

Powles T, McDermotee SF, Rini B, et al. IMmotion150: Novel radiological endpoints and updated data from a randomized phase II trial investigating atezolizumab (atezo) with or without bevacizumab (bev) vs sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC). Abstract presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA39.