C-reactive protein flare-response predicts long-term efficacy to first-line anti-PD-1-based combination therapy in metastatic renal cell carcinoma

Niklas Klümper; Philipp Schmucker; Oliver Hahn; Benedikt Höh; Angelika Mattigk; Severine Banek; Jörg Ellinger; Julia Heinzelbecker; Danijel Sikic; Markus Eckstein; Arne Strauß; Friedemann Zengerling; Michael Hölzel; Philip Zeuschner; Charis Kalogirou

doi:10.1002/cti2.1358

C-reactive protein flare-response predicts long-term efficacy to first-line anti-PD-1-based combination therapy in metastatic renal cell carcinoma

Clin Transl Immunology. 2021 Dec 6;10(12):e1358. doi: 10.1002/cti2.1358. eCollection 2021.

Authors

Niklas Klümper^{1

2}, Philipp Schmucker³, Oliver Hahn⁴, Benedikt Höh⁵, Angelika Mattigk⁶, Severine Banek⁵, Jörg Ellinger¹, Julia Heinzelbecker⁷, Danijel Sikic^{8

9}, Markus Eckstein^{9

10}, Arne Strauß⁴, Friedemann Zengerling⁶, Michael Hölzel², Philip Zeuschner⁷, Charis Kalogirou³

Affiliations

¹ Department of Urology and Paediatric Urology University Hospital Bonn (UKB) Bonn Germany.
² Institute of Experimental Oncology University Hospital Bonn (UKB) Bonn Germany.
³ Department of Urology and Paediatric Urology Julius Maximilians University Medical Center of Würzburg Würzburg Germany.
⁴ Department of Urology University Medical Center Göttingen Göttingen Germany.
⁵ Department of Urology University Hospital Frankfurt Goethe University Frankfurt am Main Frankfurt Germany.
⁶ Department of Urology and Paediatric Urology University Hospital Ulm Ulm Germany.
⁷ Department of Urology and Paediatric Urology Saarland University Homburg/Saar Germany.
⁸ Department of Urology and Pediatric Urology University Hospital Erlangen Friedrich-Alexander-University Erlangen-Nuremberg Erlangen Germany.
⁹ Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN) Erlangen Germany.
¹⁰ Institute of Pathology University Hospital Erlangen Friedrich-Alexander-University Erlangen-Nuremberg Erlangen Germany.

Abstract

Objectives: Immune checkpoint blockade (IO) has revolutionised the treatment of metastatic renal cell carcinoma (mRCC). Early C-reactive protein (CRP) kinetics, especially the recently introduced CRP flare-response phenomenon, has shown promising results to predict IO efficacy in mRCC, but has only been studied in second line or later. Here, we aimed to validate the predictive value of early CRP kinetics for 1st-line treatment of mRCC with αPD-1 plus either αCTLA-4 (IO+IO) or tyrosine kinase inhibitor (IO+TKI).

Methods: In this multicentre retrospective study, we investigated the predictive potential of early CRP kinetics during 1st-line IO therapy. Ninety-five patients with mRCC from six tertiary referral centres with either IO+IO (N = 59) or IO+TKI (N = 36) were included. Patients were classified as CRP flare-responders, CRP responders or non-CRP responders as previously described, and their oncological outcome was compared.

Results: Our data validate the predictive potential of early CRP kinetics in 1st-line immunotherapy in mRCC. CRP responders, especially CRP flare-responders, had significantly prolonged progression-free survival (PFS) compared with non-CRP responders (median PFS: CRP flare-responder: 19.2 months vs. responders: 16.2 vs. non-CRP responders: 5.6, P < 0.001). In both the IO+IO and IO+TKI subgroups, early CRP kinetics remained significantly associated with improved PFS. CRP flare-response was also associated with long-term response ≥ 12 months.

Conclusions: Early CRP kinetics appears to be a low-cost and easy-to-implement on-treatment biomarker to predict response to 1st-line IO combination therapy. It has potential to optimise therapy monitoring and might represent a new standard of care biomarker for immunotherapy in mRCC.

Keywords: CRP flare‐response; C‐reactive protein; biomarker; checkpoint inhibition; immunotherapy; metastatic renal cell carcinoma.