Portal de Periódicos da CAPES

Time is up for PD-L1 testing standardization in lung cancer

2018; Elsevier BV; Volume: 29; Issue: 4 Linguagem: Inglês

10.1093/annonc/mdy069

1569-8041

Sanja Đačić,

Colorectal Cancer Treatments and Studies

The treatment options for patients with advanced non-small-cell lung carcinoma have undergone major changes in the recent years, particularly after the FDA approval of PD-1/PD-L1 immune checkpoint inhibitors nivolumab, pembrolizumab and atezolizumab) [1.Borghaei H. Paz-Ares L. Horn L. et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639Crossref PubMed Scopus (6814) Google Scholar, 2.Brahmer J. Reckamp K.L. Baas P. et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135Crossref PubMed Scopus (6273) Google Scholar, 3.Garon E.B. Rizvi N.A. Hui R. et al.Pembrolizumab for the treatment of non-small-cell lung cancer.N Engl J Med. 2015; 372: 2018-2028Crossref PubMed Scopus (4392) Google Scholar, 4.Herbst R.S. Baas P. Kim D.W. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4578) Google Scholar, 5.Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6279) Google Scholar, 6.Rittmeyer A. Barlesi F. Waterkamp D. et al.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.Lancet. 2017; 389: 255-265Abstract Full Text Full Text PDF PubMed Scopus (3193) Google Scholar, 7.Carbone D.P. Reck M. Paz-Ares L. et al.First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.N Engl J Med. 2017; 376: 2415-2426Crossref PubMed Scopus (1737) Google Scholar, 8.Hui R. Garon E.B. Goldman J.W. et al.Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial.Ann Oncol. 2017; 28: 874-881Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar]. Each PD-1/PD-L1 inhibitor was approved together with a specific PD-L1 immunohistochemistry assay used in the clinical trials. In addition to unique primary antibody, each assay is optimized for use with a different detection system (i.e. Dako Link 48 and Ventana BenchMark) and a different diagnostic kit. Furthermore, the unique scoring algorithms for immunohistochemical assays were co-developed with each immune checkpoint inhibitor based on predictive values shown in the clinical trials. The one drug–one assay approach is challenging to implement in clinical practice as most laboratories do not use all of the staining platforms and such practice leads to avoidable escalation of laboratory testing cost and health care in general. The main question is whether laboratories will make effort to implement the FDA approved predictive assays for one or more anti-PD-1/PD-L1 checkpoint inhibitors or implement one or more affordable laboratory developed tests (LDTs) using already available testing platforms. To find the answer to this question it is essential to determine analytical concordance between commercially available PD-L1 immunohistochemical assays. Several studies showed an excellent analytical concordance between either FDA approved or LDTs [9.Hirsch F.R. McElhinny A. Stanforth D. et al.PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project.J Thorac Oncol. 2017; 12: 208-222Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar, 10.Ratcliffe M.J. Sharpe A. Midha A. et al.Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein expression cutoffs in non-small cell lung cancer.Clin Cancer Res. 2017; 23: 3585-3591Crossref PubMed Scopus (244) Google Scholar, 11.Rimm D.L. Han G. Taube J.M. et al.A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer.JAMA Oncol. 2017; 3: 1051-1058Crossref PubMed Scopus (565) Google Scholar, 12.Scheel A.H. Dietel M. Heukamp L.C. et al.Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas.Mod Pathol. 2016; 29: 1165-1172Crossref PubMed Scopus (292) Google Scholar, 13.Ilie M. Khambata-Ford S. Copie-Bergman C. et al.Use of the 22C3 anti-PD-L1 antibody to determine PD-L1 expression in multiple automated immunohistochemistry platforms.PLoS One. 2017; 12: e0186537Crossref PubMed Scopus (1) Google Scholar]. Three assays SP263, 22C3 and 28-8 showed a high concordance in percentage of PD-L1 membrane staining of tumor cells at any intensity. In contrast, lower expression of PD-L1 on tumor cells was observed with SP142 clone. In terms of interpretation, interobserver concordance was high for tumor cell PD-L1 expression, while it was low for immune cells. In the current issue, Adam et al. report the results of the French harmonization study that compared the analytical performance of five PD-L1 antibodies (SP263, SP142, 22C3, 28-8 and E1L3N) and three staining platforms (Dako Autostainer Link 48, Leica Bond and Ventana BenchMark Ultra), using both FDA approved/reference and LDTs [14.Adam J. Le Stang N. Rouquette I. et al.Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer.Ann Oncol. 2018; 29: 953-958Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. Tumor cell staining was highly concordant for 28-8, 22C3 and SP263 across the Dako or Ventana platforms. Of 27 LDTs carried out at seven laboratories, only 14 (51.8%) showed concordance for tumor cell staining with reference assays. Furthermore, there was variability in the performance of different LDTs. The most concordant results for both tumor and immune cells were observed with SP263 clone (κ = 0.81 and 0.64, respectively) across all platforms. High concordance for tumor cells was also observed with E1L3N (κ = 0.78), followed with 28-8 and 22C3 (κ = 0.73 each). Similar to other harmonization studies, the lowest concordance for tumor cells was observed with SP142 clone (κ = 0.64) except for assays run on the Leica Bond platform (κ = 0.78–0.81). Overall, this study suggests that SP263 clone is probably the least challenging assay for implementation as LDT. Most importantly, the study highlights the importance of rigorous validation that should be carried out for all assays, and particularly for LDTs. Assay validations are not standardized and may differ between countries. The College of American Pathologists (CAP) requirement for laboratory accreditation defines validation prerequisites for immunohistochemical assays (20 positive and 20 negative cases), which is adequate for diagnostic markers, but is suboptimal for most of predictive biomarkers [15.Wolff A.C. Hammond M.E. Hicks D.G. et al.Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.Arch Pathol Lab Med. 2014; 138: 241-256Crossref PubMed Scopus (811) Google Scholar]. This relatively straightforward validation rule can be applied to predictive assays that are interpreted as positive or negative such as ALK immunohistochemical assay. However, the PD-L1 expression is not interpreted in binary fashion, but rather as percentage of tumor cells with any intensity of PD-L1 expression. Therefore, one would expect that the validation should reflect a range of expression (from 0% to 100%) rather than randomly defined positive and negative cases. Since it is impractical and not cost-effective to collect samples for every possible result, obtaining the samples with the PD-L1 expression close to cut-off points determined by reference assay should be adequate. The question remains what is the adequate number of samples to be considered for a reliable validation which should depend on the variety of possible results and the amount of variation in results. Statistically driven comparison suggests about 800 cases with 85% concordance with the validated reference assay [16.Thunnissen E. de Langen A.J. Smit E.F. PD-L1 IHC in NSCLC with a global and methodological perspective.Lung Cancer. 2017; 113: 102-105Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. For clinical laboratories this number is unrealistic and would cause a sky-high cost for the test implementation. In the absence of a validation guideline for predictive biomarkers, clinical laboratories should aim to design the validation that will reflect clinical practice with a new LDT showing at least 95% concordance with the validated assay to which it is compared. The current study by Adam et al. indicates that misclassification of patients based on PD-L1 results may be in a large number of cases caused by assay limitations and inadequate laboratory practices that are difficult to control or regulate. The present research is focused on identifying novel biomarkers representing tumor microenvironment as well as tumor mutation burden which may show better predictive value than a single PD-L1 assay [17.Rizvi N.A. Hellmann M.D. Snyder A. et al.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science. 2015; 348: 124-128Crossref PubMed Scopus (5567) Google Scholar, 18.McGranahan N. Furness A.J. Rosenthal R. et al.Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.Science. 2016; 351: 1463-1469Crossref PubMed Scopus (1962) Google Scholar, 19.Rizvi H. Sanchez-Vega F. La K. et al.Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand (PD-L)-ligand 1 blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing.J Clin Oncol. 2018; 36: 614-633Crossref Scopus (830) Google Scholar]. Until new biomarkers pave their way into routine clinical practice, accreditation agencies together with pathologists and treating physicians should make every effort to standardize implementation of currently available PD-L1 assays. Study by Adams et al. certainly provides a strong foundation for such effort. None declared.