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32 C-reactive protein (CRP) as a prognostic biomarker in advanced non-small cell lung cancer treated with immune checkpoint inhibitors. Results from a multi-center international observational study
  1. Abdul Rafeh Naqash1,
  2. Alessio Cortellini2,
  3. Emma Mi3,
  4. Sanna Livanainen4,
  5. Daria Gramenitskaya3,
  6. James Clark3,
  7. Kevin O’Brien5,
  8. Jussi Koivunen4,
  9. Shravanti Macherla5,
  10. Sweta Jonnalagadda5,
  11. Shanker Polsani5,
  12. Rahim Jiwani5,
  13. Nitika Sharma5,
  14. Chipman Stroud6,
  15. Mahvish Muzaffar5,
  16. Paul Walker7 and
  17. David Pinato3
  1. 1National Cancer Institute, Silver Spring, MD, USA
  2. 2University of L’Aquila, L’Aquila, Italy
  3. 3Imperial College London, London, UK
  4. 4University of Oulu, MRC Oulu, Oulu, Finland
  5. 5East Carolina University, Greenville, NC, USA
  6. 6Genentech, San-Francisco, CA, USA
  7. 7Circulogene, Birmingham, AL, USA


Background CRP is an acute-phase protein produced primarily in response to interleukin IL-6 via transcriptional activation of the STAT3. Recent data have provided mechanistic insights into the immune suppressive role of elevated CRP by elucidating its influence on effector T-cell function and antigen presentation.1 Furthermore, melanoma patients in Checkmate-064 and 067 with high baseline and on-treatment CRP were seen to have a lower response rate and shorter survival to immune checkpoint inhibitors (ICIs).2 Given these observations, we sought to evaluate the role of CRP as a prognostic biomarker in advanced NSCLC treated with ICIs from a multi-center international cohort.

Methods Between 2015–2019, 420 adult patients with advanced NSCLC treated with ICIs alone or with concurrent chemotherapy (Chemo-ICI) were identified at four (1 US and 3 European) academic centers. CRP level in peripheral blood samples collected up to 2 weeks before starting ICI based treatments was considered as baseline. Based on previously validated data, a CRP cutoff of 10 mg/l was used to define CRP-normal (CRP-N) and CRP-high (CRP-H). Association of baseline CRP with median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and multivariate proportional hazards regression adjusted for multiple variables.

Results Baseline CRP value was available in 75.5% of patients, with 66% having CRP-H. The median CRP was 21.0 mg/l. Single-agent nivolumab (44%) and Chemo-ICI (33.3%) were the two most common therapies. CRP-H showed a trend for stronger association with squamous histology (73.7% vs 63.3%; p= 0.063) and female sex (70.8 vs 60.0%; p=0.062) but did not show an association with PD-L1 status (0%, 1–49%, or ≥50%). Patients with CRP-H had a lower objective response rate compared with patients with CRP-N (26.9% vs. 47.6% PR; p=0.029). Compared to those with CRP-N (figure 1), patients with CRP-H had a significantly shorter median PFS [3.9 vs. 6.6 months, HR 1.41 95% CI: (1.07–1.86); p=0.0138] and OS (8.6 vs. 14.8 months, HR 1.55 95% CI [1.13- 2.14]; p=0.0060). In Cox regression analysis, CRP-H was again found to be independently associated with shorter median PFS and OS.

Conclusions This is the largest international real-world dataset demonstrating significantly inferior outcomes associated with CRP > 10 mg/l in NSCLC patients treated with ICI based therapies. The potential influence of the immune suppressive effects of elevated CRP and IL-6 on the anti-tumor efficacy of ICIs needs prospective evaluation and could potentially be exploited as a therapeutic avenue in NSCLC.

Abstract 32 Figure 1

Kaplan-Meier Curves with 95% CI for PFS and OSSignificantly inferior median PFS and OS were seen for patients with CRP-H vs. CRP-N.

Acknowledgements Susan Eubanks and Sue-Ann Joyner at the ECU IRB for their help and support.

Ethics Approval The primary IRB approval for this study was conducted under an ECU (P-MAIT- UMCIRB-15-001400). Individual approval was also obtained from the respective IRB of each participating institution.


  1. Yoshida T, Ichikawa J, Giuroiu I, et al. C reactive protein impairs adaptive immunity in immune cells of patients with melanoma. Journal for ImmunoTherapy of Cancer 2020.

  2. Weber, et al. Journal of Clinical Oncology37, no. 15_suppl (May 20, 2019) 100–100

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