An update on companion and complementary diagnostic assays for PD-1/PD-L1 checkpoint inhibitors in NSCLC

ABSTRACT

Introduction: Development within molecular medicine has given us an increased understanding of the pathophysiology of malignant diseases. This understanding has been the key to a development of a number of new effective target-specific drugs, including the PD-1/PD-L1 checkpoint inhibitors.

Areas covered: This review will focus on the clinical validation and utility of the commercially available IHC PD-L1 expression assays linked to the different PD-1/PD-L1 checkpoint inhibitors indicated for treatment of NSCLC. For the discussion of this subject, mainly data from studies where the PD-1/PD-L1 checkpoint inhibitors have been given as monotherapy will be reported.

Expert opinion: Although PD-L1 expression is not the perfect biomarker; the different IHC PD-L1 expression assays have had major impact on the clinical development of PD-1/PD-L1 checkpoint inhibitors for treatment of NSCLC. A number of clinical studies in NSCLC have shown that the efficacy of the PD-1/PD-L1 checkpoint inhibitors are positively correlated to the level of PD-L1 expression. Based on studies presented in this review, the recommendation is that monotherapy should mainly be used for treatment of NSCLC patients with a high PD-L1 expression, as defined by the cutoff values for the individual assays linked to the specific PD-1/PD-L1 checkpoint inhibitor.

KEYWORDS:

• Atezolizumab
• durvalumab
• nivolumab
• pembrolizumab
• ventana PD-L1 (SP142)
• ventana PD-L1 (SP263)
• PD-L1 IHC 28-8 pharmDx
• PD-L1 IHC 22c3 pharmDx
• companion diagnostics
• complementary diagnostic

Article highlights

• Four commercially PD-L1 expression assays linked to different PD-1/PD-L1 checkpoint inhibitor for treatment of NSCLC are currently available. These assays are the PD-L1 IHC 22C3 pharmDx, PD-L1 IHC 28-8 pharmDx, VENTANA PD-L1 (SP142) Assay, and the VENTANA PD-L1 (SP263) Assay. All these assays have undergone an extensive clinical validation.

• The drug-diagnostic codevelopment model has had a significant impact on the clinical development of the PD-1/PD-L1 checkpoint inhibitors for treatment of NSCLC. For pembrolizumab, the 22C3 assay played an absolutely critical role in the development of both the first- and second-line indications.

• For any CDx assay, the selection of a proper assay cut-off value is of key importance. Based on test results and clinical outcome data, ROC analysis can be used to estimate the assay cut-off values and hence the clinical sensitivity and specificity. The clinicians who make treatment decisions based on a CDx result must know the clinical sensitivity and specificity in order to evaluate the probability of a false positive and false negative test result.

• For the PD-1/PD-L1 checkpoint inhibitors developed for treatment of patients with NSCLC, a positive correlation between the level of PD-L1 expression and the clinical outcome has been demonstrated in a number of studies. Based on the studies presented in this review, it is recommended that monotherapy for NSCLC should mainly be recommended for patients with a high PD-L1 expression, as defined by the cut-off values for the individual assays linked to the different PD-1/PD-L1 checkpoint inhibitors.

• The different PD-L1 expression assays approved by the FDA as CDx or CoDx are all developed for a single PD-1/PD-L1 checkpoint inhibitor. For most pathological laboratories, it is unlikely that they will have access to all available assays and staining platforms. Attempts have been made to harmonize the different commercial assays, and analytical concordance studies have been performed; however, such harmonization must also include a clinical validation. Analytical concordance it not the same as clinical concordance.

• Based on the clinical sensitivity and specificity data from 22C3 and SP263 assays, it is clear that a proportion of the NSCLC patients will be classified as false negative and false positive. We have to realize that the current available PD-L1 expression assays are not perfect and improvements or alternatives need to be developed in order to increase the predictability of treatment with the PD-1/PD-L1 checkpoint inhibitors.

Declaration of interest

Jan Trøst Jørgensen has worked as a consultant for Agilent/Dako, Euro Diagnostica, Oncology Venture, Azanta, Alligator Biosciences and Leo Pharma and has given lectures at meetings sponsored by AstraZeneca, Merck Sharp & Dohme, and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article was not funded.