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.
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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