Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics

Abstract

Immune checkpoint inhibitors (ICIs) are considered a new standard-of-care across many cancer indications. This review provides an update on ICIs approved by the Food and Drug Administration (FDA), with focus on monoclonal antibodies that target the programmed cell death 1 (PD-1) or its ligand, PD-1 ligand 1 (PD-L1), including information on their clinical indications and associated companion diagnostics. The information is further discussed with strategies for identifying predictive biomarkers to guide the clinical use of PD-1/PD-L1-targeted therapies.

Keywords: biomarker; cancer immunotherapy; companion diagnostic; immune checkpoint inhibitor.

Fig. 1

FDA approvals of PD-1/PD-L1 mAbs. As of December 2020, six anti-PD-1/PD-L1 mAbs have been approved with supplemental indications across 19 cancer types and two tissue-agnostic conditions. Shown are the approvals for each cancer indication, for Keytruda (pembrolizumab), Opdivo (nivolumab), Libtayo (cemiplimab), Tecentriq (atezolizumab), Bavencio (avelumab), and Imfinzi (durvalumab). Multiple approvals for a cancer indication within the same year are shown with only one symbol. The open symbols represent approvals without a biomarker (no BM). The full symbols represent approvals that incorporate a biomarker with an associated threshold for each indication (BM), which was measured using either a central laboratory test or complementary diagnostic that was not approved as a CDx for the drug. Symbols with a red outline represent approvals in which a companion diagnostic is indicated for biomarker measurement (BM + CDx). *: approval for MSI-H/dMMR colorectal cancer. PM, pleural mesothelioma; TNBC, triple-negative breast cancer; CSCC, cutaneous squamous cell carcinoma; TMB-H, tumor mutation burden high; CRC, colorectal cancer; BCG-BC, Bacillus Calmette-Guérin bladder cancer; EC, endometrial carcinoma; ESCC, esophageal squamous cell carcinoma; SCLC, small cell lung cancer; RCC, renal cell carcinoma; MCC, Merkel cell carcinoma; HCC, hepatocellular carcinoma; PMBCL, primary mediastinal large B cell lymphoma; CC, cervical cancer; GC, gastric cancer; MSI-H, microsatellite instability high; dMMR, mismatch repair-deficient; UC, urothelial carcinoma; cHL, classical Hodgkin’s lymphoma; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung cancer. Information on approvals and supplemental approvals was gathered from Drugs@FDA

Fig. 2

FDA approvals of companion and complementary diagnostic assays. As of December 2020, there are five companion diagnostics that have been approved to identify patients across seven tissue types and one tissue-agnostic condition who may benefit from treatment with an anti-PD-1/PD-L1 mAb. Shown are the approvals for each companion (indicated in red text) and complementary (indicated in blue text) device with the associated threshold per cancer type. Tumor proportion score (TPS) measured the membranous staining of tumors cells and is reported as a percentage of the total viable tumor cells. Combined proportion score (CPS) measures the membranous staining of tumor cells, lymphocytes, and macrophages and is reported as a percentage of the total viable tumor cells and multiplied by 100. PD-L1 percentage (as measured by the 28-8 pharmDx) reports the number of tumor cells with complete circumferential or partial linear plasma membrane staining of PDL1 out of 100 viable tumor cells. IC and TC measure the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (IC) or the percentage of PD-L1-positive tumor cells (TC) and is reported as a percentage of the tumor area. The percentage of immune cells present (ICP) is reported as the percentage of tumor area occupied by any tumor-associated immune cells. *The melanoma indication was withdrawn from the PD-L1 IHC 28-8 pharmDx label on 07 March 2019. TNBC, triple-negative breast cancer; TMB-H, tumor mutation burden high; ESCC, esophageal squamous cell carcinoma; CC, cervical cancer; GC, gastric cancer; UC, urothelial carcinoma; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung cancer. Information was collected from the “List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) (https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools)