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Visual Abstract. Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma
Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma
Figure 1.  Final Analysis of Overall Survival in the Intention-to-Treat (ITT) and Programmed Death Ligand 1–Positive (PD-L1+) Populations
Final Analysis of Overall Survival in the Intention-to-Treat (ITT) and Programmed Death Ligand 1–Positive (PD-L1+) Populations

In the ITT population, the event rates were 54.8% for the atezolizumab plus bevacizumab group and 55.3% for the sunitinib group, and the overall survivals were 36.1 months (95% CI, 31.5-42.3 months) for the atezolizumab plus bevacizumab group and 35.3 months (95% CI, 28.6-42.1 months) for the sunitinib group. In the PD-L1+ population, the event rates were 53.9% for the atezolizumab plus bevacizumab group and 56.5% for the sunitinib group, and the overall survivals were 38.7 months (95% CI, 29.0-49.7 months) for the atezolizumab plus bevacizumab group and 31.6 months (95% CI, 23.3-42.1 months) for the sunitinib group. HR indicates hazard ratio.

aPrespecified boundary of P = .02.

Figure 2.  Frequency of Treatment-Related Adverse Events (AEs)
Frequency of Treatment-Related Adverse Events (AEs)

Treatment-related AEs occurring with a frequency of 20% or greater in either arm are reported, with a greater than 5% difference between arms. The AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. PPE indicates palmar-plantar erythrodysesthesia.

Figure 3.  Overall Survival (OS) in Transcriptomic Clusters
Overall Survival (OS) in Transcriptomic Clusters

Kaplan-Meier analysis of OS for patients treated with atezolizumab plus bevacizumab and sunitinib and a forest plot showing the median OS hazard ratios (HRs) in the transcriptomic clusters. NC indicates not calculated; NR, not reported; snoRNA, small nucleolar RNA.

1 Comment for this article
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Renal cancer molecular clusters: the key for a tailored immunotherapy combinations use in favourable risk patients
marcello tucci, Medical Doctor | Medical Oncology, Cardinal Massaia Hospital, Corso Dante Alighieri 202, 14100, Asti, Italy
We read with interest the final results of IMmotion151 trial presented by Motzer et al., that did not show improved overall survival (OS) for the combination of atezolizumab plus bevacizumab vs sunitinib in metastatic renal cell carcinoma (mRCC) patients (pts), but provided intriguing insights about the potential role of RCC molecular classification. Biomarker analysis showed a prognostic role of several molecular clusters in pts treated with both sunitinib and the combinations of antiangiogenic drug and immune checkpoint inhibitor (ICI). ICI combinations nowadays are the standard first line treatment in all risk subgroups of pts (2). A broad range of combinations have been approved and consequently clinicians face with new challenges, the most important one is the choice of the best treatment for each patient. In particular, if the superior efficacy of ICI/anti-VEGFR drugs combinations compared to sunitinib is clearly shown in IMDC intermediate or poor risk subgroups, there are still doubts about the superiority in IMDC favourable risk pts. In this context, a meta-analysis of Ciccarese et al. showed that tyrosine kinase inhibitors (TKIs) + ICI combinations improve PFS (HR = 0.63; p < 0.00001) but not OS (HR = 0.99; p = 0.95) compared to sunitinib as first-line therapy in IMDC favourable risk pts (3). In addition, favourable risk mRCC represents a heterogeneous disease spectrum ranging from symptomatic and aggressive to truly indolent clinical pictures. In these last cases deferred therapy could be an advantageous option in terms of risk/benefit. Rini et al. reported a median time on surveillance from registration on study until systemic therapy start of 14.9 months showing that a subgroup of metastatic asymptomatic patients can safely undergo surveillance before starting first line therapy (4). ICI combinations may be therefore an overtreatment for some IMDC favourable risk pts. Patient selection according to molecular disease characteristics could permit to identify pts with more indolent disease who may really benefit from ICI + TKIs combinations, rather than TKIs monotherapy or surveillance, moving forward personalized medicine in RCC. Future studies will have to correlate treatment impact of investigational and approved therapeutic options not only with clinical risk models but also with molecular disease characterization in order to maximize therapy personalization.

1) Motzer RJ, Powles T, Atkins MB, et al; Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2021 Dec 23. doi: 10.1001/jamaoncol.2021.5981
2) Powles T, Albiges L, Bex A, et al; ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma. Ann Oncol. 2021 Dec;32(12):1511-1519. doi: 10.1016/j.annonc.2021.09.014
3) Ciccarese C, Iacovelli R, Porta C, et al; Efficacy of VEGFR-TKIs plus immune checkpoint inhibitors in metastatic renal cell carcinoma patients with favorable IMDC prognosis. Cancer Treat Rev. 2021 Nov;100:102295. doi: 10.1016/j.ctrv.2021.102295
4) Rini BI, Dorff TB, Elson P, et al; Active surveillance in metastatic renal-cell carcinoma:a prospective, phase 2 trial. Lancet Oncol. 2016 Sep;17(9):1317-24. doi: 10.1016/S1470-2045(16)30196-6

Authors:
Marcello Tucci(1), Marco Donatello Delcuratolo(2), Consuelo Buttigliero(2)
1)Medical Oncology,Cardinal Massaia Hospital,Asti,Italy
2)Department of Oncology,University of Turin,Orbassano,Turin,Italy
CONFLICT OF INTEREST: None Reported
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Brief Report
December 23, 2021

Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma

Author Affiliations
  • 1Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Barts Cancer Institute and the Royal Free Hospital, Queen Mary University of London, London, UK
  • 3Georgetown Lombardi Comprehensive Cancer Center, Washington, DC
  • 4Department of Medical Oncology, Vall d’Hebron Institute of Oncology, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  • 5Biologic Therapy and Cutaneous Oncology Programs, Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 6P. Herzen Oncology Research Institute, Moscow, Russia
  • 7Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
  • 8Vall d’Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain
  • 9Moscow City Oncology Hospital, Moscow, Russia
  • 10IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, Meldola, Italy
  • 11Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
  • 12Hospital Clínic of Barcelona, Medical Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
  • 13Genentech Inc, South San Francisco, California
  • 14F. Hoffmann-La Roche Ltd, Basel, Switzerland
  • 15Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
JAMA Oncol. 2022;8(2):275-280. doi:10.1001/jamaoncol.2021.5981
Key Points

Question  Does combined programmed death ligand 1 and vascular endothelial growth factor inhibition with atezolizumab and bevacizumab improve overall survival (OS) with an acceptable safety profile vs sunitinib for patients with metastatic renal cell carcinoma?

Findings  This phase 3 randomized clinical trial of 915 patients with metastatic renal cell carcinoma found similar OS with atezolizumab plus bevacizumab vs sunitinib, with an acceptable safety profile. Atezolizumab plus bevacizumab demonstrated improved OS when patients with tumors characterized by T-effector/proliferative, proliferative, and small nucleolar RNA transcription profiles were combined.

Meaning  While OS showed no difference between randomized treatment groups, exploratory subanalysis findings suggest that biomarker analyses may identify patients likely to benefit from combined anti−programmed death ligand 1 and anti–vascular endothelial growth factor therapy.

Abstract

Importance  Interim analyses of the IMmotion151 trial (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) reported improved progression-free survival (PFS) for patients with programmed death ligand 1–positive (PD-L1+) metastatic renal cell carcinoma (mRCC) receiving the PD-L1 inhibitor atezolizumab plus the vascular endothelial growth factor (VEGF) inhibitor bevacizumab vs the receptor tyrosine kinase inhibitor sunitinib. Overall survival (OS) results were immature at interim analyses.

Objective  To report the final OS results, safety, and exploratory biomarker analyses of the association of transcriptomic subgroups with OS in the IMmotion151 trial.

Design, Setting, and Participants  IMmotion151 was a multicenter, open-label, phase 3 randomized clinical trial that compared the efficacy and safety of atezolizumab plus bevacizumab vs sunitinib in patients with untreated mRCC. IMmotion151 included patients from 152 academic medical centers and community oncology practices in 21 countries. Adult patients with mRCC with components of clear cell or sarcomatoid histologic features, measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1.1), adequate performance status, hematologic and end organ function, and tumor tissue available for PD-L1 testing were included. IMmotion151 was initiated on May 20, 2015, and the study is ongoing. This final analysis was performed from May 20, 2015, to February 14, 2020.

Interventions  Receipt of 1200 mg of intravenous (IV) atezolizumab every 3 weeks and 15 mg/kg of IV bevacizumab every 3 weeks or 50 mg orally once daily of sunitinib (4 weeks on and 2 weeks off).

Main Outcomes and Measures  The coprimary end points were PFS (previously reported) in patients with PD-L1+ disease and OS in the intention-to-treat population. Additional exploratory outcomes included OS in the PD-L1+ population, association with transcriptomic subgroups, and safety.

Results  The IMmotion151 trial assessed 915 patients with metastatic renal cell carcinoma. Mean (IQR) age was 62 (56-69) years for patients receiving atezolizumab plus bevacizumab and 60 (54-66) years for patients receiving sunitinib; 669 (73.1%) were male and 246 (26.9%) were female. The final analysis showed similar median OS in patients receiving atezolizumab plus bevacizumab vs sunitinib in the intention-to-treat (36.1 vs 35.3 months) and PD-L1+ (38.7 vs 31.6 months) populations. No new safety signals were reported. The additional exploratory outcome of atezolizumab plus bevacizumab vs sunitinib showed improved median OS trends in patients whose tumors were characterized by T-effector/proliferative, proliferative, or small nucleolar RNA transcriptomic profiles (35.4 vs 21.2 months; hazard ratio, 0.70; 95% CI, 0.50-0.98).

Conclusions and Relevance  The primary end point of PFS was met at interim analyses, although no improvement in OS was observed with atezolizumab plus bevacizumab at the final analysis. Biomarker analyses provided insight into which patients with mRCC may benefit from combined anti−PD-L1 and anti-VEGF therapy.

Trial Registration  ClinicalTrials.gov Identifier: NCT02420821

Introduction

IMmotion151 (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) was a multicenter, open-label, phase 3 randomized clinical trial that compared atezolizumab plus bevacizumab with sunitinib as first-line treatment for patients with metastatic renal cell carcinoma (mRCC). Interim analyses showed a prolonged progression-free survival (PFS) and favorable safety profile with atezolizumab plus bevacizumab but no significant difference in overall survival (OS).1,2

Integrated multiomics evaluation of tumors from IMmotion151 identified 7 molecular subsets with distinct angiogenesis, immune, cell cycle, metabolism, and stromal transcription profiles.3 Atezolizumab plus bevacizumab improved PFS compared with sunitinib in patients whose tumors had high T-effector/proliferative, proliferative, and small nucleolar RNA (snoRNA) profiles.3 The final PFS results, interim OS results, and associations between transcriptomics and PFS but not OS have been previously reported.1,2 In this article, we report the final OS, safety, and exploratory analyses of the association of transcriptomic subsets with OS from IMmotion151.

Methods
Patients and Trial Design

Detailed methods of IMmotion151 were previously reported.1 Briefly, patients with mRCC, measurable disease, and tumor tissue available for programmed death ligand 1 (PD-L1) testing were included. IMmotion151 was initiated on May 20, 2015, and the study is ongoing. This final analysis was performed on data obtained from May 20, 2015, to February 14, 2020. IMmotion151 and all subsequent analyses were approved by the institutional review board or independent ethics committee at each site and performed in accordance with the Guideline for Good Clinical Practice and the Declaration of Helsinki.4 All patients provided written informed consent.1 All data were deidentified. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The trial protocol can be found in Supplement 1.

Patients received 1200 mg of intravenous (IV) atezolizumab and 15 mg/kg of IV bevacizumab every 3 weeks or 50 mg of sunitinib orally once daily (4 weeks on and 2 weeks off). The intention-to-treat (ITT) population (n = 915) included all randomly assigned patients. The safety population (n = 897) included patients in the ITT population who received 1 dose or more of any component of study drug. The PD-L1–positive (PD-L1+) population (n = 362) included patients in the ITT population whose PD-L1 expression was 1% or greater of tumor-infiltrating immune cells at randomization. Coprimary end points included PFS in patients with PD-L1+ disease and OS in the ITT population. Secondary objectives included OS in the PD-L1+ population and safety. Stratified Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs. The stratification factors were presence of liver metastasis (yes/no); tumor PD-L1 status (IC0 vs IC1/2/3); and the Memorial Sloan Kettering Cancer Center/Motzer risk score (0 [favorable], 1-2 [intermediate], and ≥3 [poor]). The Kaplan-Meier method was used to estimate survival.

Biomarker Analyses

Detailed exploratory biomarker analysis methods were previously reported.3 Briefly, pretreatment tumors (n = 823) were transcriptionally profiled by RNA sequencing (TruSeq RNA Access; Illumina). Seven molecular clusters (cluster 1: angiogenic/stromal; cluster 2: angiogenic; cluster 3: complement/Ω-oxidation; cluster 4: T-effector/proliferative; cluster 5: proliferative; cluster 6: stromal/proliferative; and cluster 7: snoRNA) were identified using unsupervised transcriptomic analysis with nonnegative matrix factorization. Validation of the molecular subsets was conducted in tumor samples from patients in the IMmotion150 trial. Analyses were conducted using R statistical software, version 3.6.1 (R Foundation for Statistical Computing).3

Results
Patient Disposition

This final analysis of the IMmotion151 trial assessed 915 patients with metastatic renal cell carcinoma (mean [IQR] age, 62 [56-69] years for patients receiving atezolizumab plus bevacizumab and 60 [54-66] years for patients receiving sunitinib; 669 [73.1%] overall were male, and 246 [26.9%] were female). At the time of data cutoff (February 14, 2020), the minimum follow-up was 40 months. The median duration of treatment was 12.7 months (range, 0-54.1 months) for safety-evaluable patients receiving atezolizumab, 11.8 months (range, 0-52.2 months) for patients receiving bevacizumab, and 9.2 months (range, 0-54.7 months) for patients receiving sunitinib. Of the 451 patients in the atezolizumab plus bevacizumab arm, 397 patients (88%) discontinued atezolizumab treatment, and 410 (91%) discontinued bevacizumab treatment; 405 patients (91%) discontinued sunitinib treatment (eTable 1 and eFigure in Supplement 2). Disease progression was the leading cause of treatment discontinuation for all study drugs.

Overall Survival

The OS in the ITT population was mature, with an event rate of 55% (504 of 915 patients). The median OS in the ITT population was 36.1 months (95% CI, 31.5-42.3 months) in the atezolizumab plus bevacizumab arm and 35.3 months (95% CI, 28.6-42.1 months) in the sunitinib arm (HR, 0.91; 95% CI, 0.76-1.08) (Figure 1A). For the PD-L1+ population, median OS was 38.7 months (95% CI, 29.0-49.7 months) for the atezolizumab plus bevacizumab arm and 31.6 months (95% CI, 23.3-42.1 months) for the sunitinib arm (HR, 0.85; 95% CI, 0.64-1.13) (Figure 1B).

Safety

Any-grade adverse events (AEs) were reported for 442 of 451 (98%) patients from the safety population receiving atezolizumab plus bevacizumab and 441 of 446 (99%) patients receiving sunitinib. Adverse events leading to withdrawal from any study treatment occurred in 128 of 451 patients (28%) in the atezolizumab plus bevacizumab arm and 52 of 446 patients (12%) in the sunitinib arm (eTable 2 in Supplement 2). Grade 3/4 treatment-related AEs were reported in 205 of 451 patients (46%) receiving atezolizumab plus bevacizumab; proteinuria was the most frequently reported grade 3/4 treatment-related AE, occurring in 35 of the 451 patients (8%) (≥2% higher in the atezolizumab plus bevacizumab arm) (Figure 2).

Biomarker Analyses

Previously, unsupervised transcriptomic analysis identified 7 molecular subsets characterized by distinct gene expression profiles, and associations of PFS within and across treatment arms in these subsets were reported.3 Overall survival was evaluated in these molecular subsets. Similar to the PFS results,3 patients in angiogenic/stromal (cluster 1) and angiogenic (cluster 2) clusters showed longer OS in both treatment arms relative to other subsets, whereas those in the proliferative (cluster 5) and stromal/proliferative (cluster 6) subsets had shorter relative OS (Figure 3A and B). Improved OS was observed with sunitinib in the angiogenic (cluster 2) subset and with atezolizumab plus bevacizumab in T-effector/proliferative (cluster 4), proliferative (cluster 5), and snoRNA (cluster 7) subsets (Figure 3C). When these latter 3 subgroups were combined, atezolizumab plus bevacizumab exhibited improved OS vs sunitinib (median OS, 35.4 vs 21.2 months; HR, 0.70; 95% CI, 0.50-0.98) (Figure 3C).

Discussion

Although the combination of atezolizumab plus bevacizumab showed a PFS benefit versus sunitinib,1 the final analysis from the IMmotion151 study did not demonstrate improved OS for patients with mRCC in the ITT or PD-L1+ populations. The final safety analysis was consistent with previously reported safety profiles of atezolizumab plus bevacizumab in mRCC.1,2 Increased incidences of proteinuria were observed, which was consistent with extended treatment time; proteinuria was the leading cause of treatment withdrawal for patients receiving long-term treatment. The safety profile of the combination aligned with that of the individual agents, and incidences of immune-related AEs remained low. Three phase 3 trials of antivascular tyrosine kinase inhibitors (TKI) plus anti–PD-1 inhibitors showed benefit in PFS and OS compared with sunitinib in first-line therapy.5-7 A phase 3 trial of an antivascular TKI plus the anti–PD-L1 inhibitor, avelumab, showed benefit in PFS but has yet to show an OS benefit.8 We currently do not have a clear explanation as to the lack of OS benefit with atezolizumab when combined with bevacizumab. The 3 trials with reported OS benefit all use a small molecule inhibitor of the VEGF pathway as sunitinib is, while bevacizumab is an antibody, which may lack similar efficacy when combined with an antibody targeting the PD-L1 pathway. These differences in targeting molecule, as well as differences in study design, population, conduct, and access to subsequent therapy may account for the lack of survival benefit with atezolizumab plus bevacizumab.

Exploratory biomarker analyses suggested that OS trends in molecular subgroups were similar to previously described PFS outcomes. Comparison of OS across treatment arms suggested that sunitinib showed a trend of improved OS in tumors with a higher prevalence of angiogenesis, whereas atezolizumab plus bevacizumab showed a trend of improved OS in angiogenesis poor but immune and/or cell cycle enriched clusters 4 and 5. Patients whose tumors showed higher proliferative gene expression profiles (clusters 5 and 6) exhibited worse prognosis, suggesting investigation of novel therapeutic approaches for these patients. Patients with tumors characterized by snoRNA (cluster 7) who received atezolizumab plus bevacizumab exhibited a relatively long OS compared with the sunitinib group, albeit the number of patients in this cluster was quite small.

Limitations

Although the biomarker results were promising, further evaluation and validation of these molecular subsets in additional datasets are required to inform applicability to other anti-angiogenesis plus checkpoint inhibitor combinations, to other clinical settings, such as in adjuvant therapy, and to add value to existing clinical risk group models.

Conclusions

While the combination of atezolizumab plus bevacizumab did not show improved OS vs sunitinib, the biomarker analyses provide insight into the molecular basis of differential survival outcomes and inform development of personalized approaches for treatment with antiangiogenics, checkpoint inhibitors, and their combinations in mRCC.

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Article Information

Accepted for Publication: September 11, 2021.

Published Online: December 23, 2021. doi:10.1001/jamaoncol.2021.5981

Corresponding Author: Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (motzerr@mskcc.org).

Author Contributions: Dr Motzer had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Motzer, Powles, Atkins, Escudier, McDermott, Suarez, Hamidi, Khan, Huseni, Rini.

Acquisition, analysis, or interpretation of data: Motzer, Atkins, McDermott, Alekseev, Lee, Stroyakovskiy, De Giorgi, Donskov, Mellado, Banchereau, Hamidi, Craine, Huseni, Flinn, Dubey, Rini.

Drafting of the manuscript: Motzer, Powles, Escudier, Suarez, Hamidi, Huseni, Flinn, Dubey, Rini.

Critical revision of the manuscript for important intellectual content: Motzer, Powles, Atkins, Escudier, McDermott, Alekseev, Lee, Stroyakovskiy, De Giorgi, Donskov, Mellado, Banchereau, Hamidi, Khan, Craine, Huseni, Flinn, Dubey, Rini.

Statistical analysis: Powles, Banchereau, Hamidi, Craine, Huseni.

Administrative, technical, or material support: Motzer, Escudier, Lee, De Giorgi, Hamidi, Flinn, Dubey, Rini.

Supervision: Motzer, Powles, Escudier, Alekseev, Suarez, Khan, Huseni, Dubey, Rini.

Conflict of Interest Disclosures: Dr Motzer reported receiving personal fees for consulting and advisory board work from Genentech/Roche, Pfizer, Novartis, Easai, Exelixis, Lilly, Incyte, EMD Serono, Merck, grants for clinical trial support from Genentech/Roche, Bristol Myers Squibb, Novartis, Isai, Exelixis, and Merck during the conduct of the study, and personal fees from Aveo consulting/advisory board outside the submitted work. No other disclosures were reported.

Funding/Support: This work was sponsored by F. Hoffmann-La Roche Ltd. and Genentech, Inc. Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by core grant P30 CA008748 from the Memorial Sloan Kettering Cancer Center.

Role of the Funder/Sponsor: F. Hoffmann-La Roche Ltd and Genentech, Inc. provided support for the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Jessica Swanner, PhD, of Health Interactions Inc, provided writing assistance. She was compensated by F. Hoffmann-La Roche Ltd. We thank the patients and their families who participated in this study.

Data Sharing Statement: See Supplement 3.

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