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Abstract
Background Despite significant advances in the prevention, diagnosis and treatment of colorectal carcinoma (CRC), it remains one of the leading causes of cancer deaths worldwide.1 Recent results from MK4280–001 phase I clinical study (NCT02720068) have demonstrated clinical activity of a combined therapy regimen of the anti-LAG3 antibody favezelimab plus pembrolizumab in patients with microsatellite stable metastatic CRC whose tumors express PD-L1 with a Combined Positive Score (CPS) ≥ 1.2 In this external reproducibility study, we give evidence of the reproducibility of PD-L1 expression determination in CRC using PD-L1 IHC 22C3 pharmDx at the CPS ≥ 1 cutoff.
Methods The external reproducibility study was a three site, blinded and randomized reproducibility study of PD-L1 IHC 22C3 pharmDx on formalin-fixed paraffin-embedded human CRC specimens. The endpoints assessed in the study were inter-site, intra-site/inter-day, inter-observer and intra-observer reproducibility at the CPS ≥ 1 cutoff. To evaluate inter-site and intra-site reproducibility, five replicate sets of pre-qualified unstained specimens were stained and evaluated at each of three testing sites. To assess inter-observer and intra-observer reproducibility, one pre-stained specimen set was evaluated three times at each of the three testing sites. The primary statistical analysis calculated analytical agreements of the diagnostic outcome (positive/negative) by evaluating negative percent agreement (NPA), positive percent agreement (PPA), and overall percent agreement (OA) based on comparisons to the consensus diagnostic outcome with corresponding percentile bootstrap confidence intervals. The pre-determined acceptance criteria for all reproducibility endpoints required at least 85.0% for the lower-bound (LB) of a two-sided 95% confidence interval (CI) on NPA, PPA, and OA.
Results All endpoints at the CPS ≥ 1 cutoff within the context of the evaluation of CRC cases met pre-determined acceptance criteria. The inter- and intra-site reproducibility endpoints had 95% CI LB values of 98.7% for NPA, 96.0% for PPA, and 98.0% OA for both endpoints. The inter- and intra-observer reproducibility 95% CI LB values were 98.9% for NPA, 98.6% for PPA, and 99.4% OA for both endpoints.
Conclusions This study demonstrates high external lab reproducibility of PD-L1 IHC 22C3 pharmDx with respect to PD-L1 expression in CRC at the CPS ≥ 1 cutoff.
Acknowledgements Armita Bahadori is the co-first author of this abstract.
References
Colorectal cancer. https://www.iarc.who.int/cancer-type/colorectal-cancer/#:~:text=Summary%20Colorectal%20cancer%20is%20the%20third%20most%20common,leading%20to%20almost%201%20million%20deaths%20per%20year. (accessed 2023 March 15).
Garralda E, Sukari A, Lakhani NJ, Patnaik A, Lou Y, Im SA, Golan T, Geva R, Wermke M, de Miguel M, et al. A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer. ESMO Open 2022; 7 (6):100639. DOI: 10.1016/j.esmoop.2022.100639 From NLM.
Ethics Approval The external reproducibility study was approved by WCG IRB, study numbers 1319546, 1318969, 1319133.
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