Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma

doi:10.1016/j.xcrm.2023.100947

. 2023 Feb 21;4(2):100947.

doi: 10.1016/j.xcrm.2023.100947.

Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma

Affiliations

¹ Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
² Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA; The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21287, USA.
³ Department of Surgery, Johns Hopkins University, Baltimore, MD, USA; The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21287, USA.
⁴ Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Dermatology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁵ Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Bristol-Myers Squibb, Princeton, NJ, USA.
⁸ Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁰ Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
¹² Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Dermatology, Johns Hopkins University, Baltimore, MD 21287, USA; The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: jtaube1@jhmi.edu.

PMID: 36812889
PMCID: PMC9975323
DOI: 10.1016/j.xcrm.2023.100947

Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma

Julie Stein Deutsch et al. Cell Rep Med. 2023.

. 2023 Feb 21;4(2):100947.

doi: 10.1016/j.xcrm.2023.100947.

Authors

Affiliations

¹ Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
² Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA; The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21287, USA.
³ Department of Surgery, Johns Hopkins University, Baltimore, MD, USA; The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21287, USA.
⁴ Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Dermatology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁵ Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Bristol-Myers Squibb, Princeton, NJ, USA.
⁸ Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁰ Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
¹² Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Dermatology, Johns Hopkins University, Baltimore, MD 21287, USA; The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: jtaube1@jhmi.edu.

PMID: 36812889
PMCID: PMC9975323
DOI: 10.1016/j.xcrm.2023.100947

Abstract

With a rapidly developing immunotherapeutic landscape for patients with metastatic clear cell renal cell carcinoma, biomarkers of efficacy are highly desirable to guide treatment strategy. Hematoxylin and eosin (H&E)-stained slides are inexpensive and widely available in pathology laboratories, including in resource-poor settings. Here, H&E scoring of tumor-infiltrating immune cells (TIL^plus) in pre-treatment tumor specimens using light microscopy is associated with improved overall survival (OS) in three independent cohorts of patients receiving immune checkpoint blockade. Necrosis score alone does not associate with OS; however, necrosis modifies the predictive effect of TIL^plus, a finding that has broad translational relevance for tissue-based biomarker development. PBRM1 mutational status is combined with H&E scores to further refine outcome predictions (OS, p = 0.007, and objective response, p = 0.04). These findings bring H&E assessment to the fore for biomarker development in future prospective, randomized trials, and emerging multi-omics classifiers.

Keywords: H&E; PBRM1; PD-1; RCC; TIL; biomarker; immunotherapy; irPRC; necrosis; pathologic response.

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Conflict of interest statement

Declaration of interests Dr. Taube reports grants and consulting from Bristol-Myers Squibb and Akoya Biosciences, consulting for Merck, AstraZeneca, Genentech, GlaxoSmithKline, Regeneron, Lunaphore, and Compugen outside the submitted work. Dr. Deutsch and Dr. Taube report an institutional patent filed on machine learning for scoring pathologic response to immunotherapy. Dr. Topalian reports research grants from Bristol Myers Squibb; personal fees from AstraZeneca and Immunocore; and personal fees and stock options from Five Prime Therapeutics and Dragonfly Therapeutics. Dr. Topalian’s spouse has financial relationships with the following entities: Amgen, Bristol Myers Squibb, Compugen, DNAtrix, Dracen Pharmaceuticals, Enara Bio, Immunomic Therapeutics, Janssen Pharmaceuticals, ManaT Bio, RAPT Therapeutics, Tizona LLC, Trieza Therapeutics, TRex Bio Ltd, and WindMIL. Dr. Lipson receives institutional research grant funding from Bristol-Myers Squibb, Merck, and Regeneron, and during the past 2 years, has consulted for Bristol-Myers Squibb, Eisai, Genentech, Instil Bio, MacroGenics, Merck, Natera, Nektar Therapeutics, Odonate, OncoSec, Pfizer, Rain Therapeutics, Regeneron, and Sanofi Genzyme. Dr. Choueiri reports institutional and personal, paid and/or unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, and others), outside the submitted work. Institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA. Equity: Tempest, Pionyr, Osel, Precede Bio. CureResponse. Committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, KidneyCan. Medical writing and editorial assistance support may have been funded by Communications companies in part. No speaker’s bureau. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. Dr. Atkins reports personal support for, advisory boards and consultancy from Bristol Myers Squibb, Merck, Eisai, Aveo, Pfizer, Werewolf, Fathom, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Genentech-Roche, Exelixis, Iovance, COTA, Idera, Agenus, Asher Bio, Neoleukin, AstraZeneca, Calithera, SeaGen, Sanofi, SAB Bio, OncoRena, Pliant Therapeutics, Up-To-Date, and GlaxoSmithKline. Institutional Research support from BMS, Merck, and Pfizer and Stock or Stock options from Werewolf, Pyxis Oncology, and Elpis outside the submitted work. Dr. Signoretti reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis, and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; and receives royalties from Biogenex. Saurabh Gupta is a full-time employee of Bristol-Myers Squibb and owns BMS stock. Dr. Motzer reports clinical trial support (institutional) from BMS for this manuscript; advisory board fees from AstraZeneca, AVEO, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and fees (institutional) for coordinating PI from AVEO, BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. Dr. Ged reports advisory roles and has received honoraria from Aveo, Bristol Myers Squibb, BostonGene, and Exelixis. Drs. Baraban, Singla, Jedrych, and Danilova declare no competing interests.

Figures

**Figure 1**
Examples of TIL^plus and necrosis scoring in patients with metastatic ccRCC treated with anti-PD-1 Left: photomicrograph of a pre-treatment specimen with TIL^plus = 0, i.e., no evidence of pre-existing immune response to tumor, with a substantial amount (≥10% of surface area) of necrosis (demarcated by dashed line). Scale bar, 400 μm. Right: sample TIL^plus = 1 with evidence of infiltrating immune cells (black arrows) and no necrosis present. Scale bar, 200 μm. H&E staining, both panels.

**Figure 2**
Pathologic scoring of H&E slides from metastatic specimens biopsied within 1 year of anti-PD-1 treatment initiation associates with OS (A) Left: in the discovery cohort of n = 63 pre-treatment tumor biopsies from metastases (CheckMate 009), OS was significantly increased in patients with a TIL^plus score of 1 as compared with 0 (log rank test, p = 0.008). Middle: these same findings are validated in an independent cohort of pre-treatment specimens from metastases in patients with ccRCC treated with anti-PD-1 therapy (CheckMate 025) (p < 0.0001). Right: the findings were then extended into the pre-treatment specimens from metastases in patients with ccRCC treated with combination anti-PD-1/CTLA-4 blockade (CheckMate 214), although the analysis was limited due to the small number of pre-treatment biopsies available from metastatic lesions. (B) Meta-analysis from the three trial cohorts (p = 0.0006). (C) Notably, there was no significant association between TIL^plus score and OS in patients treated with the mTOR inhibitor everolimus on the control arm of CheckMate 025.

**Figure 3**
Pathologic scoring of H&E slides in pre-treatment specimens from patients receiving nivolumab in CheckMate 009 and CheckMate 025 and everolimus in CheckMate 025 (A) In the n = 63 pre-treatment mCCRCC specimens from CheckMate 009, OS was significantly increased in patients with a TIL^plus score of 1 (blue line) as compared with 0 (black line). When the presence of substantial necrosis (>10% of tumor surface area on slide) was taken into account (dashed lines), patients showed inferior OS than their counterparts with the same immune infiltrate score but who lacked necrosis (solid lines) (log rank test, p = 0.03). (B) Similar findings were observed in metastases from n = 19 patients from an independent cohort, CheckMate 025, who received anti-PD-1, p < 0.0001. (C) In contrast, these findings did not predict patient outcomes for n = 39 patients receiving everolimus from CheckMate 025. This relationship could not be tested in patients receiving anti-PD-1 + CTLA-4 dual blockade, as none of the specimens contained geographic necrosis.

**Figure 4**
Combining TIL^plus and necrosis scores on H&E with *PBRM1* mutation status in pre-treatment biopsies from metastases improves OS prediction after anti-PD-1 Patients with score = 3 (TIL^plus, no or minimal necrosis, and *PBRM1* mutation) showed significantly improved survival when compared with those with only a single feature (score = 1). There were no patients that had a combinatorial score of zero. A statistically distinct intermediate prognostic group was also identified for patients whose tumors harbored any two of these features (score = 2) log rank test, p < 0.0001). Patient level data are provided for H&E TIL^plus and necrosis score and *PBRM1* mutation status. Information regarding objective response status and the trial cohort is also provided (A, CheckMate 009; B, CheckMate 025; C, CheckMate 214). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

**Figure 5**
Multimodality biomarker studies identified by literature review Each line in this network represents a study that tested multimodality biomarkers in pre-treatment tissue specimens for an association with patient outcomes following anti-PD-(L)1-based therapy. Each individual solid, curved line represents a single study combining the modalities shown in the green node. Each triangle indicates studies that combined three modalities (DNA sequencing, RNA sequencing, and IHC). The orange lines show studies that were conducted using specimens from patients with RCC. The blue lines show studies conducted in other tumor types, including NSCLC, melanoma, urothelial carcinoma, gastric/gastroesophageal carcinoma, Merkel cell carcinoma, triple-negative breast cancer, and head and neck squamous cell carcinoma. The dotted orange line represents this study. The 38 studies identified upon literature review and included in the network diagram are listed in Table S3.

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References

1. Motzer R.J., Jonasch E., Boyle S., Carlo M.I., Manley B., Agarwal N., Alva A., Beckermann K., Choueiri T.K., Costello B.A., et al. NCCN guidelines insights: kidney cancer, version 1.2021. J. Natl. Compr. Canc. Netw. 2020;18:1160–1170. - PMC - PubMed
1. Rini B.I., Battle D., Figlin R.A., George D.J., Hammers H., Hutson T., Jonasch E., Joseph R.W., McDermott D.F., Motzer R.J., et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC) J. Immunother. Cancer. 2019;7:354. - PMC - PubMed
1. Motzer R.J., Escudier B., McDermott D.F., George S., Hammers H.J., Srinivas S., Tykodi S.S., Sosman J.A., Procopio G., Plimack E.R., et al. Nivolumab versus everolimus in advanced renal cell carcinoma. N. Engl. J. Med. 2015;373:1803–1813. - PMC - PubMed
1. Reck M., Rodríguez-Abreu D., Robinson A.G., Hui R., Csőszi T., Fülöp A., Gottfried M., Peled N., Tafreshi A., Cuffe S., et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N. Engl. J. Med. 2016;375:1823–1833. - PubMed
1. Hakimi A.A., Attalla K., DiNatale R.G., Ostrovnaya I., Flynn J., Blum K.A., Ged Y., Hoen D., Kendall S.M., Reznik E., et al. A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response. Nat. Commun. 2020;11:4168. - PMC - PubMed

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[1] Motzer R.J., Jonasch E., Boyle S., Carlo M.I., Manley B., Agarwal N., Alva A., Beckermann K., Choueiri T.K., Costello B.A., et al. NCCN guidelines insights: kidney cancer, version 1.2021. J. Natl. Compr. Canc. Netw. 2020;18:1160–1170. - PMC - PubMed

[2] Motzer R.J., Jonasch E., Boyle S., Carlo M.I., Manley B., Agarwal N., Alva A., Beckermann K., Choueiri T.K., Costello B.A., et al. NCCN guidelines insights: kidney cancer, version 1.2021. J. Natl. Compr. Canc. Netw. 2020;18:1160–1170. - PMC - PubMed

[3] Rini B.I., Battle D., Figlin R.A., George D.J., Hammers H., Hutson T., Jonasch E., Joseph R.W., McDermott D.F., Motzer R.J., et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC) J. Immunother. Cancer. 2019;7:354. - PMC - PubMed

[4] Rini B.I., Battle D., Figlin R.A., George D.J., Hammers H., Hutson T., Jonasch E., Joseph R.W., McDermott D.F., Motzer R.J., et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC) J. Immunother. Cancer. 2019;7:354. - PMC - PubMed

[5] Motzer R.J., Escudier B., McDermott D.F., George S., Hammers H.J., Srinivas S., Tykodi S.S., Sosman J.A., Procopio G., Plimack E.R., et al. Nivolumab versus everolimus in advanced renal cell carcinoma. N. Engl. J. Med. 2015;373:1803–1813. - PMC - PubMed

[6] Motzer R.J., Escudier B., McDermott D.F., George S., Hammers H.J., Srinivas S., Tykodi S.S., Sosman J.A., Procopio G., Plimack E.R., et al. Nivolumab versus everolimus in advanced renal cell carcinoma. N. Engl. J. Med. 2015;373:1803–1813. - PMC - PubMed

[7] Reck M., Rodríguez-Abreu D., Robinson A.G., Hui R., Csőszi T., Fülöp A., Gottfried M., Peled N., Tafreshi A., Cuffe S., et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N. Engl. J. Med. 2016;375:1823–1833. - PubMed

[8] Reck M., Rodríguez-Abreu D., Robinson A.G., Hui R., Csőszi T., Fülöp A., Gottfried M., Peled N., Tafreshi A., Cuffe S., et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N. Engl. J. Med. 2016;375:1823–1833. - PubMed

[9] Hakimi A.A., Attalla K., DiNatale R.G., Ostrovnaya I., Flynn J., Blum K.A., Ged Y., Hoen D., Kendall S.M., Reznik E., et al. A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response. Nat. Commun. 2020;11:4168. - PMC - PubMed

[10] Hakimi A.A., Attalla K., DiNatale R.G., Ostrovnaya I., Flynn J., Blum K.A., Ged Y., Hoen D., Kendall S.M., Reznik E., et al. A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response. Nat. Commun. 2020;11:4168. - PMC - PubMed

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Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma

Affiliations

Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma

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Abstract

Conflict of interest statement

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