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Figure.  Progression-Free and Overall Survival Following Treatment With Nivolumab, With or Without PBRM1 Truncating Mutations
Progression-Free and Overall Survival Following Treatment With Nivolumab, With or Without PBRM1 Truncating Mutations

A, Progression-free survival (PFS) with and without a PBRM1 mutation in patients treated with nivolumab. B, Overall survival (OS) with and without a PBRM1 mutation in patients treated with nivolumab. NE Indicates not estimable.

Table.  Demographic, Clinical Characteristics, and Tumor Response in the PBRM1 Truncating Mutant and Wild-Type Groups in the Nivolumab and Everolimus Treatment Groupsa
Demographic, Clinical Characteristics, and Tumor Response in the PBRM1 Truncating Mutant and Wild-Type Groups in the Nivolumab and Everolimus Treatment Groupsa
1.
Motzer  RJ, Escudier  B, McDermott  DF,  et al; CheckMate 025 Investigators.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.  N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665PubMedGoogle ScholarCrossref
2.
Miao  D, Margolis  CA, Gao  W,  et al.  Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.  Science. 2018;359(6377):801-806. doi:10.1126/science.aan5951PubMedGoogle ScholarCrossref
3.
Thorvaldsdóttir  H, Robinson  JT, Mesirov  JP.  Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration.  Brief Bioinform. 2013;14(2):178-192. doi:10.1093/bib/bbs017PubMedGoogle ScholarCrossref
4.
McDermott  DF, Huseni  MA, Atkins  MB,  et al.  Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.  Nat Med. 2018;24(6):749-757. doi:10.1038/s41591-018-0053-3PubMedGoogle ScholarCrossref
Research Letter
September 5, 2019

Clinical Validation of PBRM1 Alterations as a Marker of Immune Checkpoint Inhibitor Response in Renal Cell Carcinoma

Author Affiliations
  • 1Dana-Farber Cancer Institute, Boston, Massachusetts
  • 2Bristol-Myers Squibb, Lawrenceville, New Jersey
JAMA Oncol. 2019;5(11):1631-1633. doi:10.1001/jamaoncol.2019.3158

Nivolumab, an immune checkpoint inhibitor (ICI) targeting the programmed death-1 (PD-1) pathway, is approved for metastatic clear cell renal cell carcinoma (ccRCC).1 Loss-of-function (truncating) mutations in PBRM1, a PBAF-complex gene commonly mutated in ccRCC, were previously associated with clinical benefit from anti–PD-1 therapy in a smaller study,2 Herein, this association was examined in an independent cohort from a randomized clinical trial1 to determine whether PBRM1 alterations are a marker of response to ICI treatment.

Methods

Archival tumor tissue (collected before antiangiogenic therapy) was obtained from patients enrolled in a randomized, phase 3 trial that demonstrated improved overall survival (OS) with nivolumab vs everolimus in patients with ccRCC who received prior antiangiogenic therapy.1 This study was conducted under a secondary use protocol, approved by the Dana-Farber Cancer Institute. Written informed consent was obtained from participants. This post hoc analysis included 382 of 803 patients who were consented for genomic studies and passed quality control.2 This cohort was not significantly different from the other 421 patients in response or progression-free survival (PFS). Putative truncating mutations (frameshift insertion/deletion, nonsense, splice-site)2 in PBRM1 were manually reviewed using the Integrative Genomics Viewer.3

Clinical response (complete/partial remission by response evaluation criteria in solid tumours [RECIST]), clinical benefit (complementary to RECIST, defined previously as complete/partial response, or stable disease with tumor shrinkage and PFS ≥6 months)2 and survival data were available for all 382 patients. The proportions of patients with truncating PBRM1 mutations in responding (complete/partial response) vs nonresponding (progressive disease) patients, and clinical benefit vs no clinical benefit (progressive disease, PFS ≤3 months),2 were compared using Fisher exact test (1-sided, given prior association of PBRM1 mutations with clinical benefit2; R statistical software; v3.5.2; R Foundation). Other clinical characteristics were compared by χ2 testing. Participant PFS and OS were estimated using the Kaplan-Meier method, association with PBRM1 truncating mutations assessed using the log-rank test, and hazard ratio (HR) calculated using a Cox proportional hazard model (2-sided; R statistical software; survival/survminer packages v3.5.2; R Foundation).

Results

PBRM1 mutations were identified in 55 of 189 nivolumab-treated (29%) and of 45 of 193 everolimus-treated (23%) patients (Table). Among nivolumab-treated patients, 15 of 38 responding (39%) and 16 of 74 nonresponding (22%) patients had truncating PBRM1 mutations (odds ratio [OR], 2.34; 95% CI, 1.05-∞; P = .04). PBRM1 mutations were also associated with clinical benefit2 (18/52 with clinical benefit, 14/71 with no clinical benefit; OR, 2.14; 95% CI, 1.00-∞; P = .0497). PBRM1 mutation was associated with increased PFS (HR, 0.67; 95% CI, 0.47-0.96; P = .03) and OS (HR, 0.65; 95% CI, 0.44-0.96; P = .03) (Figure). Among patients treated with everolimus, 1 of 5 responding (20%) and 10 of 56 nonresponding (17.9%) patients had truncating PBRM1 mutations (OR, 1.15; 95% CI, 0.04-∞; P = .64). There was no evidence of an association between PBRM1 mutation and PFS (HR, 0.83; 95% CI, 0.58-1.2; P = .32) or OS (HR, 0.81; 95% CI, 0.56-1.18; P = .27) in patients treated with everolimus.

Discussion

The association of PBRM1 truncating mutations with response to anti–PD-1 therapy was confirmed in an independent ccRCC cohort. However, key limitations restrict use of PBRM1 mutations as a clinical biomarker. First, the PBRM1 mutation effect on response and survival was modest. Second, the effect was observed in patients who received prior antiangiogenic therapy, whereas associated studies of PBRM1 mutations in the first-line setting had negative results.2,4 Third, PBRM1 alterations may also be associated with benefit from antiangiogenic therapies.4 Moreover, there are inherent limitations to the current study, including use of archival tissue, lack of data regarding time on initial antiangiogenic therapy, and inclusion of only clear cell histology. The concomitant presence of other cellular or molecular features may further influence the findings described herein. Nonetheless, this validated association between PBRM1 alterations and ICI response in a large randomized study represents a further step toward the development of genomic predictors for immunotherapies in advanced RCC.

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Article Information

Corresponding Author: Toni K. Choueiri, MD, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 (toni_choueiri@dfci.harvard.edu).

Accepted for Publication: June 18, 2019.

Published Online: September 5, 2019. doi:10.1001/jamaoncol.2019.3158

Author Contributions: Drs Shukla and Braun had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Shukla and Choueiri contributed equally.

Study concept and design: Braun, Ishii, Van Allen, Wu, Shukla, Choueiri.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Braun, Van Allen, Wu, Shukla, Choueiri.

Critical revision of the manuscript for important intellectual content: Braun, Ishii, Walsh, Van Allen, Shukla, Choueiri.

Statistical analysis: Braun, Walsh, Van Allen, Shukla.

Obtained funding: Ishii, Choueiri.

Administrative, technical, or material support: Ishii, Walsh, Van Allen, Choueiri.

Study supervision: Van Allen, Wu, Shukla, Choueiri.

Conflict of Interest Disclosures: Dr Braun reported nonfinancial support from Bristol-Myers Squibb during the conduct of the study, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of the submitted work. Dr Walsh is an employee and owns stock in Bristol-Myers Squibb. Dr Van Allen reported personal fees from Tango Therapeutics, Genome Medical, Invitae, Illumina, and Dynamo; grants from Novartis, Bristol-Myers Squibb-IION, nonfinancial support from Genentech, personal fees from Syapse and Microsoft outside the submitted work. In addition, Dr Van Allen and Dr Choueiri had a patent to association of mutations in PBAF genes and response to cancer immunotherapy pending. Dr Wu is a founder of Neon Therapeutics and a member of its scientific advisory board. Dr Shukla reported nonfinancial support from Bristol-Myers Squibb during the conduct of the study; and equity in 152 Therapeutics outside the submitted work. In addition, Dr Shukla had a patent to compositions and methods predicting response and resistance to CTLA4 blockade in melanoma using a gene expression signature pending. Dr. Choueiri reports grants and personal fees from Astra Zeneca, personal fees from Bayer, grants and personal fees from Bristol-Myers Squibb, personal fees from Cerulean, grants and personal fees from Eisai, personal fees from Foundation Medicine Inc, grants and personal fees from Exelixis, grants and personal fees from Genentech, personal fees from Roche, grants and personal fees from GlaxoSmithKline, grants and personal fees from Merck, from Novartis, Peloton, and Pfizer, personal fees from Prometheus Labs, grants and personal fees from Corvus, personal fees from Ipsen, grants from Tracon, grants from Astellas outside the submitted work. No other conflicts were reported.

Funding/Support: This work was supported with funding from the DOD CDMRP (W81XWH-18-1-0480) and in part by Bristol-Myers Squibb. Dr Braun is supported by the John R. Svenson Fellowship. Dr Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at the Dana-Farber Cancer Institute. Dr Shukla acknowledges support by the National Cancer Institute (R50RCA211482). Dr Wu acknowledges support from the Parker Institute for Cancer Immunotherapy, the Mathers Foundation, and is a Scholar of the Leukemia and Lymphoma Society. Dr Van Allen acknowledges support by the National Cancer Institute (R01 CA227388 and U01 CA233100).

Role of the Funder/Sponsor: Bristol-Myers Squibb had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Sabina Signoretti, MD, Brigham and Women’s Hospital, Harvard Medical School; David McDermott, MD, Beth Israel Deaconess Medical Center, Harvard Medical School; Ziad Bakouny, MD, MSc, Dana-Farber Cancer Institute; Megan Wind-Rotolo, PhD, Bristol-Myers Squibb; Petra Ross-Macdonald, PhD, Bristol-Myers Squibb; and Maxine Sun, PhD, MPH, Dana-Farber Cancer Institute; for helpful discussion on data analysis. We also thank Ashton Berger, BS, Broad Institute of MIT and Harvard; for assistance with data analysis; Stefan Kirov, PhD, Bristol-Myers Squibb; and Ariella Sasson, PhD, Bristol-Myers Squibb; for assistance with data collection, transfer, and quality control. They were not compensated.

References
1.
Motzer  RJ, Escudier  B, McDermott  DF,  et al; CheckMate 025 Investigators.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.  N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665PubMedGoogle ScholarCrossref
2.
Miao  D, Margolis  CA, Gao  W,  et al.  Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.  Science. 2018;359(6377):801-806. doi:10.1126/science.aan5951PubMedGoogle ScholarCrossref
3.
Thorvaldsdóttir  H, Robinson  JT, Mesirov  JP.  Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration.  Brief Bioinform. 2013;14(2):178-192. doi:10.1093/bib/bbs017PubMedGoogle ScholarCrossref
4.
McDermott  DF, Huseni  MA, Atkins  MB,  et al.  Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.  Nat Med. 2018;24(6):749-757. doi:10.1038/s41591-018-0053-3PubMedGoogle ScholarCrossref
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