Biomarker-driven Phase 2 study of Nivolumab in Advanced Metastatic NSCLC Open Access

Abstract

Background: Non-small cell lung cancer (NSCLC) is the most lethal one among various human cancer. Nivolumab is a new effective anti-cancer treatment as a monoclonal antibody, which can bind PD-1 and prevent the combination of PD-L1 and PD-1. It’s easy to obtain peripheral blood and to observe changes of immune response to nivolumab by sampling peripheral blood at different time points. After the treatment of PD-1 and PDL-1 inhibitors, there will be a proliferation of CD8 T cells, and we could treat the sustained proliferation of T cell as a predictive biomarker of response to nivolumab.

Methods and Materials: We enrolled a total of 48 patients (36 to 87 years) for the retrospective study, 25 in biomarker positive group and 23 in biomarker negative group. Both groups had been treated with nivolumab 240 mg per two weeks and the response had been assessed by the sample of peripheral blood. The primary endpoint was the response rates between two groups. T-test, Wilcoxon rank sum test, Chi-square test, Mantel-Haenszel test, Log-rank test, and Cox proportional-hazards model were used for statistical analysis.

Results: The number of patients with objective response is 7 out of 25 in biomarker positive group (expected rate = 0.280, p-value = 0.03). The hazard ratio of groups stratified by biomarker is 0.281 (0.088, 0.900) with the reference of negative group (p-value = 0.023). Two variables of biomarker and IRAE are included in the final model. The hazard rate of biomarker positive group is 0.232 (0.066, 0.819) (p-value = 0.023), IRAE group between grades 2-4 is 0.091 (0.017, 0.482) (p-value = 0.005), and patients in biomarker positive and IRAE group between grades 2-4 have the highest survival probability. 

Conclusion: There are more patients with objective response in biomarker positive group and patients in biomarker positive group have significantly higher survival probability than those in biomarker negative group due to the greater immune response with the proliferation of CD8 T cells. Therefore, the sustained proliferation of CD8 T cells can be treated as a predictive biomarker of response to Nivolumab.

Table of Contents

1.INTRODUCTION ............................................................................................................1

2. METHODS AND MATERIALS ........................................................................................3

  2.1 Study Design..............................................................................................................3

  2.2 Population and Observation parameter ....................................................................3 

  2.3 Statistical Analysis ...................................................................................................5

    2.3.1 Descriptive analysis .............................................................................................5 

    2.3.2 Statistical analysis ...............................................................................................5 

    2.3.3 Univariate and Multivariate Survival analysis......................................................5

3. RESULTS .......................................................................................................................7

  3.1 Results of Descriptive analysis .................................................................................7 

  3.2 Results of Statistical analysis ...................................................................................8 

  3.3 Results of Univariate and Multivariate Regression Analysis ...................................11

    3.3.1 Results of univariate regression .........................................................................11

    3.3.2 Results of multivariate regression ......................................................................13

4. DISCUSSION ...............................................................................................................14

5. CONCLUSION .............................................................................................................15

6. REFERENCE ................................................................................................................16

7. FIGURES AND TABLES ................................................................................................18

About this Master's Thesis

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School	Rollins School of Public Health
Department	Biostatistics
Subfield / Discipline	Biostatistics - MPH & MSPH
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Biology, Cell Biology, Biostatistics
Keyword	nivolumab non-small cell lung cancer
Committee Chair / Thesis Advisor	Zhengjia (Nelson) Chen, University of Illinois at Chicago
Committee Members	Yuan Liu, Emory University

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