PFS Improvement With Atezolizumab Combination in Metastatic Renal Cell Carcinoma

Robert J. Motzer, MD

Robert J. Motzer, MD

As stated in findings from IMmotion151, a phase III open-label study, the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) induced a 26% reduction in the risk of progression or death compared with sunitinib (Sutent) for patients with untreated PD-L1—positive metastatic renal cell carcinoma (mRCC). This study was released ahead of the 2018 Genitourinary Cancers Symposium.¹

Median progression-free survival (PFS) by investigator assessment for those with PD-L1 expression on ≥1% of immune cells (n = 362) was a co-primary endpoint of the study along with overall survival (OS) in the full intent-to-treat (ITT) population (n = 915). After 15 months of median follow-up, the median PFS was 11.2 months (95% CI, 8.9-15.0) with atezolizumab and bevacizumab compared with 7.7 months (95% CI, 6.8-9.7) with sunitinib (HR, 0.74; 95% CI, 0.57-0.96;P= .0217).

OS data remained immature at the time of the interim analysis. In the PD-L1 cohort, the median OS was not yet reached with the combination compared with 23.3 months for sunitinib, representing an early 32% reduction in the risk of death with the combination versus monotherapy (HR, 0.68; 95% CI, 0.46-1.00;P= .05). In the ITT group, median OS was not reached in both arms (HR, 0.81; 0.63-1.03;P= .09).

In addition to improvements in efficacy, the atezolizumab/bevacizumab combination demonstrated fewer serious adverse events (AEs) compared with sunitinib in the ITT analysis. Overall, treatment-related grade 3/4 AEs occurred in 40% of patients in the combination arm versus 54% of those treated with sunitinib.

“The side effects of atezolizumab plus bevacizumab were decidedly less harsh than sunitinib. And because progression-free survival was also better, I am confident that this relatively easy-to-administer combination will be a strong treatment choice in all medical practices,” lead study author Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said in a statement.

“For an aggressive cancer like this, where less than 20% of people survive 5 years after diagnosis, we think a 3.5-month longer progression-free survival, given the tolerability for this new combination treatment regimen, is an important development,” added Motzer, anOncLiveGiant of Cancer Care in Genitourinary Cancer.

Early findings have suggested that anti-VEGF treatments, like bevacizumab, could help sensitize tumors to PD-L1 inhibitors, in the presence of sufficiently activated cytotoxic infiltrating T cells. Additionally, PD-L1 inhibitors have been shown to sensitize tumors to antiangiogenic therapy, suggesting synergistic mechanisms of action.²

“With the introduction of checkpoint inhibitors, clinicians started looking at combinations of these medicines with antiangiogenic medicines like bevacizumab,” said Motzer. “Bevacizumab may affect the local immune response in the tumor and help prime the response of tumor and immune cells to immune-system activators like atezolizumab.”

In the open-label study, 915 patients were randomized to receive the combination (n = 454) or sunitinib (n = 461). In the investigational arm, atezolizumab was administered at 1200 mg and bevacizumab was given at 15 mg/kg every 3 weeks. Oral sunitinib was given at 50 mg once daily for 4 weeks followed by 2 weeks of rest. All patients had a Karnofsky performance score of ≥70 and clear cell and/or sarcomatoid histology.

In the ITT analysis, median PFS with the combination was 11.2 months (95% CI, 9.6-13.3) compared with 8.4 months (95% CI, 7.5-9.7) with sunitinib (HR, 0.83; 95% CI, 0.70-0.97;P= .0219). The PFS improvement experienced with bevacizumab and atezolizumab was similar across patient subgroups, including MSKCC risk, liver metastases, and sarcomatoid histology, Motzer noted.

In the PD-L1—positive group, the objective response rate (ORR) was 43% with the atezolizumab/bevacizumab combination compared with 35% with sunitinib. In the combination group, 9% of patients had a complete response (CR) compared with 4% in the sunitinib arm. The duration of response (DOR) was not yet reached with the immunotherapy/VEGF doublet versus 12.9 months for sunitinib.

In the ITT analysis, the ORR was 37% with atezolizumab/bevacizumab versus 33% for sunitinib. The CR rates were 5% and 2%, in the combination and sunitinib groups, respectively. The DOR was 16.6 months for the doublet and 14.2 months for the monotherapy.

"Response outcomes and encouraging immature OS results support improved efficacy for atezolizumab plus bevacizumab in patients with PD-L1—positive disease," Motzer said.

Efficacy findings differed significantly in an independent review of the data, which Motzer noted was being investigated further. In the PD-L1—positive cohort by independent review, the median PFS was 8.9 months (95% CI, 6.9-12.5) with atezolizumab plus bevacizumab compared with 7.2 months (95% CI, 6.1-11.1) for sunitinib alone, which was not a statistically significant improvement (HR, 0.93; 95% CI, 0.72-1.21). Similar findings were seen in the ITT analysis (9.6 vs 8.3 months; HR, 0.88; 95% CI, 0.74-1.04). "Independent review of PFS and response differed from investigator assessment, and further analyses are underway to identify why there was a difference," he said.

Across the study, the most common grade 3/4 AEs with atezolizumab plus bevacizumab were hypertension, proteinuria, asthenia, and diarrhea. In the sunitinib arm, the most common grade 3/4 AEs were hypertension, palmar-plantar erythrodysesthesia, fatigue, diarrhea, asthenia, stomatitis, decreased appetite, and vomiting.

The number of patients discontinuing treatment due to AEs was higher in the combination arm at 12% compared with 8% in the sunitinib group. Sixteen percent of patients in the combination arm required concomitant treatment with corticosteroids for immune-related AEs, which is lower than in studies for other immunotherapy combinations, Motzer said.

"Atezolizumab plus bevacizumab had fewer high-grade treatment-related AEs, and there was a relatively low use of steroids to treat immune-related side effects," said Motzer. "There was delayed symptom interference with daily life for the combination versus sunitinib, and patients treated with atezolizumab plus bevacizumab had better quality of life than compared with sunitinib."

Findings from the study are likely to be submitted to the FDA for a potential approval. Moreover, the magnitude of benefit coupled with the mild toxicity profile in the study suggests that atezolizumab and bevacizumab could become a standard frontline treatment for some patients with mRCC, said ASCO Expert Sumanta K. Pal, MD, during a press briefing.

"This study represents an important breakthrough in kidney cancer therapy. For several years now, we have hosted debates on which treatment strategy is best for our patients—targeted therapy or immune therapy," said Pal, co-director of the Kidney Cancer Program at City of Hope. "This treatment, which is really a first of its kind, points to a combination of both as being highly effective at delaying cancer growth and there's an early trend toward improving survival as well."

Pal compared the findings from the IMmotion151 study with data from the phase III CheckMate 214 trial. In the ITT analysis from this trial,³the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not improve PFS compared with sunitinib (12.4 vs 12.3 months; HR, 0.98; 99.1% CI, 0.79-1.23;P= 0.8498); however, the combination did significantly reduce the risk of death by 32%. Better outcomes were experienced by patients in high- and intermediate-risk groups.

Outside of efficacy, one differentiator between the trials, Pal noted, was the need for steroid administration to address immune-related AEs. In CheckMate 214, nearly 60% of patients required steroid treatment, which was significantly higher than in IMmotion151.

"Another important piece of this data is the tolerability of combining targeted therapy and immune therapy with bevacizumab and atezolizumab, respectively," said Pal. "In my opinion, the side effect profile compares favorably to a dual immunotherapy regimen…I would agree with Dr Motzer that this data supports considerations of bevacizumab and atezolizumab as a first-line option.

References

1. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC).J Clin Oncol.2018;36 (suppl 6S; abstr 578).
2. Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti—PD-L1 therapy stimulates tumor immunity through HEV formation.Sci Transl Med.2017;9(385). doi: 10.1126/scitranslmed.aak9679.
3. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.