Testing PD-1/PD-L1 Expression in Cancer Therapy: Pathologic Insights and Economic Sustainability

We read with considerable interest the 2 editorials written by Philip T. Cagle, MD, and Eric H. Bernicker, MD, in the November and December 2015 issues of the Archives of Pathology & Laboratory Medicine, entitled “A New Immunotherapy Drug Creates a Watershed for the Surgical Pathologist's Role in Patient Care” 1 and “Challenges to Biomarker Testing for PD-1/PD-L1 Checkpoint Inhibitors for Lung Cancer.” 2 They have led us, a transnational group of closely collaborating pathologists and oncologists, to some considerations concerning our role in this new era of cancer immunotherapy.We fully agree with the authors of these 2 editorials that the recent approval of pembrolizumab by the US Food and Drug Administration (FDA) to treat patients with metastatic non–small cell lung cancer (NSCLC), based on PD-L1 immunohistochemical (IHC) expression, will lead very soon to an exponential and further increase of the importance of surgical pathology in the clinical practice. It represents a milestone toward the incorporation of anti–PD-1 (programmed death receptor-1)/PD-L1 (programmed death ligand-1) agents into the paradigm of personalized oncology and medicine (see Figure; its legend gives an overview of the cell location of PD-1 and PD-L1 and of the link with the related antibodies). However, we have to remember that, contrary to pembrolizumab in NSCLC, the FDA approved this drug in melanoma and nivolumab in NSCLC, in melanoma and, more recently, in renal cell carcinoma (RCC), independently from tissue PD-L1 IHC expression, that is, from PD-L1 IHC testing.3The practical predictive and prognostic role of PD-L1 IHC expression merits some thoughts about recently published data. In a meta-analysis of 1475 patients with cancer (including melanomas, lung and genitourinary tumors) treated with nivolumab, pembrolizumab, or the anti–PD-L1 agent atezolizumab, Carbognin et al4 reported a clinical response in 239 of 702 patients with PD-L1–positive tumors (34.1%) and in 154 of 773 patients with PD-L1–negative tumors (19.9%), respectively. A significant difference in response according to PD-L1 IHC expression was seen for melanoma and NSCLC but not for genitourinary tumors (renal cell carcinoma and bladder carcinoma).4 However, the overall survival (OS) of RCC patients with PD-L1–positive tumors treated with nivolumab is very similar to the OS of patients with PD-L1–negative tumors treated with everolimus (21.8 versus 21.3 months, respectively). Moreover, Motzer et al5 observed that the OS benefit in favor of nivolumab is significantly higher in patients with PD-L1 expression below 1% than in patients with PD-L1 expression of 1% or greater (6.2 versus 3.0 months).We are aware of the paramount effort requested of the pathology community to cope with the rapid expansion of immunotherapies in a day-by-day widening scenario of novel targets and therapeutic strategies. In this new era of cancer immunotherapy, the activity of surgical pathologists has to change from the traditional morphology-based routine to a fully clinically oriented interaction with medical oncologists, surgeons, and radiotherapists, that is, to become multidisciplinary. This is absolutely fundamental to carefully select those patients who, based on clinical and tumor features, are the best candidates for immunotherapeutic approaches and should receive IHC testing for multiple targets. Refinement of scoring criteria and critical analysis of interpretation pitfalls are mandatory.Last but not least, the selection of patients with cancer who may benefit from immune checkpoint blockade will be dramatically crucial to guarantee proper use of economic resources in the worldwide health care scenario. The World Health Organization has estimated there was approximately 1.8 million new lung cancer cases in 2012. Non–small cell lung cancers represented 85% of all cases, with 70% of patients having metastatic disease.6 If we consider that 1-year treatment with pembrolizumab costs $131 300 per patient, the total amount for all 1 071 000 patients with metastatic NSCLC will be $140 billion, strongly supporting the need to optimize the current methods of cost-effectiveness evaluation, patient selection for treatment, and drug reimbursement. This represents a key factor to reach the goal of economic sustainability in the era of precision oncology and medicine.