ONCAlert | 2017 San Antonio Breast Cancer Symposium

Next Generation Diagnostics for Immuno-Oncology

Sarah E. Warren, PhD, Lisa Macera, PhD, and Alessandra Cesano, MD, PhD
Published Online: Jul 07,2016

The Current Immuno-Oncology Diagnostics

The first checkpoint inhibitors to be developed in conjunction with diagnostics are the programmed cell death protein 1 (PD-1)-targeting antibodies nivolumab (Opvido) and pembrolizumab (Keytruda). Other agents targeting the same pathway are in late-stage development and are expected to become commercially available in the near future (TABLE 1). Although the two commercially available monoclonal antibodies (mAbs) share the target and mechanism of action, their current indications for use are not identical, reflecting the different clinical development plans. They are both approved in advanced melanoma as single agents, and nivolumab is also approved in melanoma in combination with ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]). Both are approved in non–small cell lung cancer (NSCLC), although pembrolizumab indication is limited to patients whose tumors express programmed death-ligand 1 (PD-L1) by immunohistochemistry (IHC); nivolumab has also been approved in renal cell cancer.

There are nine drugs in development targeting the PD-1/PD-L1 pathway, and the current practice of pharmaceutical companies is to independently develop an anti-PD-L1 IHC diagnostic assay.1 Therefore, if each therapeutic drug was approved in conjunction with a companion diagnostic one, the matrix of therapeutics and diagnostics would present a complex challenge for testing and decision-making in the clinic. In addition, the purpose of each assay has been shaped by clinical experience. As a result, the PD-L1 IHC 22C3 pharmDx, which was used as an inclusion criteria for patient enrichment in advance NSCLC trials with pembrolizumab, is required for clinical use of the drug in this indication, whereas the PD-L1 IHC 28-8 pharmDx, retrospectively evaluated in the same patient population, is used to inform on the risk-benefit assessment for different patient subgroups as defined by the biomarker positivity.

Compounding the issues with the current PD-L1 IHC assays, evaluating PD-L1 as a single analyte biomarker is less than ideal. Cellular, spatial, and temporal heterogeneity all contribute to the poor prediction accuracy of this biomarker in the clinic (ie, lack of both positive and negative predictive value), as it has been shown that the majority of PD-L1+ tumors fail to respond to a PD-1 blockade, and a subset of patients whose tumor biopsies are PD-L1 achieve clinical benefit.2 TABLE 1 summarizes the PD-1 and PD-L1 antibodies currently in clinical development together with a companion diagnostic.

Clearly, the existing diagnostics that rely solely on measuring PD-L1 expression in the tumor environment are suboptimal for informing treatment decisions regarding treatment PD-1 pathway blockades. The multiplicity of antibodies being used to target the PD-1/PD- L1 pathway, the requirement for a clinical lab to select a single staining platform or to adopt multiple platforms, and the need for a pathologist to review patient samples and render a subjective judgement all impair the efficacy of these assays. This is further compounded by the wide range of values that constitute “PD-L1 positivity” associated with each test. There is no consensus in the literature about what degree of PD-L1 expression is adequate to elicit biological activity, and therefore, each test has its own cut-offs. Overall, there is evidence that higher levels of PD-L1 expression correlate to better response to PD-1 blockades.

In the clinical trial for pembrolizumab in advanced NSCLC, patients whose tumors were at least 50% positive had better overall survival and progression-free survival, but there was minimal difference in outcomes between patients whose tumors were <1% or 1-49% PD-L1+2. For nivolumab, for which PD-L1 IHC was developed as a complementary diagnostic and is not required for drug prescribing, the cut-off for PD- L1 positivity is much lower (1% of tumor cells), and for durvalumab is intermediate at 25%.5 Scoring for atezolimumab is unique, because it considers PD-L1 expression on both tumor cells and immune cells to generate a score.5 Despite the most restrictive cutoffs for PD-L1 positivity (ie, 50%), response rates for pembrolizumab in advanced NSCLC are approximately 40%, indicating that the biology of immune response is more complicated than previously believed, and additional work needs to be done to understand how the degree of PD-L1 expression affects the tumor-immune response.

Furthermore, that complexity exists entirely within diagnostics developed for a single immune checkpoint axis—PD-1 and PD-L1. The other approved immune checkpoint inhibitor for treatment of melanoma, ipilimumab (Yervoy), a CTLA-4 blocking antibody, does not have an accompanying diagnostic. CTLA-4 is a central negative regulator of T cell activation, and CLTA-4 blockades induce profound T cell activation and accompanying immunotoxicity that can be dose-limiting in some patients.6 Additionally, CLTA-4 blockades are only efficacious in a minority of patients. Therefore, a companion or complementary diagnostic with predictive power to identify patients likely to respond would be extremely informative—patients who are likely to respond could enter treatment with greater confidence that the treatment will be beneficial, and patients unlikely to benefit from the drug could be spared the side effects and cost in favor of another treatment plan. However, a companion diagnostic to accompany ipilimumab therapy would be even less straightforward to develop than an anti-PD-L1 diagnostic, as CTLA-4-mediated suppression occurs in secondary lymphoid organs rather than at the site of the tumor, and the ligands for CTLA-4, namely CD80 and CD86, which are expressed on antigen presenting cells, are also the ligands for the T cell costimulatory receptor CD28.7 Consequently, their expression may not always correlate with immune suppression. Therefore, development of an ipilimumab companion diagnostic would be complicated by the need to select the appropriate marker and profile non-tumor tissue.

Beyond CLTA-4 and PD-1/PD-L1, other checkpoint inhibitors are rapidly being advanced to the clinic setting and will likely require new diagnostics for rational use. Additional immuno-oncology approaches are also in development, including cancer vaccines, adoptive cell therapy with chimeric antibody receptor expressing T cells (CAR-T), small molecule modulators of immune response (e.g. TLR agonists), and nucleic acid-based therapies. These potential treatments will need diagnostics to select patients and biomarkers to monitor immune responses. This critical need for new diagnostic solutions has led to the development of a number of new technologies or redeployment of existing technologies as alternative diagnostic platforms for the immuno-oncology field.

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