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A Blueprint Proposal for Companion Diagnostic Comparability
http://www.aacr.org/AdvocacyPolicy/GovernmentAffairs/Documents/FDA-AACR-ASCO-Complexities-in-Personalized-Medicine-Blueprint-Proposal.pdf

Introduction We are in an era of rapid incorporation of basic scientific discoveries into the drug development pipeline. Currently, numerous sponsors are developing therapeutic products that may use similar or identical biomarkers for therapeutic selection, measured or detected by an in vitro companion diagnostic device. The current practice is to independently develop a companion diagnostic for each therapeutic. Thus, the matrix of therapeutics and companion diagnostics, if each therapeutic were approved in conjunction with a companion diagnostic, may present a complex challenge for testing and decision making in the clinic, potentially putting patients at risk if inappropriate diagnostic tests were used to make treatment decisions. To address this challenge, there is a desire to understand assay comparability and/or standardize analytical and clinical performance characteristics supporting claims that are shared across companion diagnostic devices. Pathologists and oncologists also need clarity on how to interpret test results to inform downstream treatment options for their patients.

Clearly using each of the companion diagnostics to select one of the several available targeted therapies in the same class is not practical and may be impossible. Likewise, having a single test or assay as a sole companion test for all of the multiple therapeutic options within a class is also impractical since the individual therapies have differing modes of action, intended use populations, specificities, safety and efficacy outcomes. Thus, a single assay or test may not adequately capture the appropriate patient population that may benefit (or not) from each individual therapeutic option within a class of therapies. Furthermore, aligning multiple sponsors’ study designs and timelines in order that they all adopt a single companion test may inadvertently slow down development of critical therapeutic products and delay patient access to these life-saving products.

Any solution to this challenge will be multifaceted and will, by necessity, involve multiple stakeholders. Thus, the US Food and Drug Administration (FDA), the American Association for Cancer Research (AACR) and American Society of Clinical Oncology (ASCO) convened a workshop titled “Complexities in Personalized Medicine: Harmonizing Companion Diagnostics Across a Class of Targeted Therapies” to draw out and assess possible solutions. Recognizing that the complex scientific, regulatory and market forces at play here require a collaborative effort, an industry workgroup volunteered to develop a blueprint proposal of potential solutions using nonsmall cell lung cancer (NSCLC) as the use case indication.

Goal and Scope of Blueprint The imminent arrival to the market of multiple PD1 / PD-L1 compounds and the possibility of one or more associated companion diagnostics is unprecedented in the field of oncology. Some may assume that since these products target the same biological pathway, they are interchangeable; however, each PD1/PD-L1 compound is unique with respect to its clinical pharmacology and each compound is being developed in the context of a unique biological scientific hypothesis and registration strategy. Similarly, each companion diagnostic has been optimized within the individual therapeutic development programs to meet specific development goals, e.g., 1) validation for patient selection, 2) subgroup analysis as a prognostic variable, or 3) enrichment.

Further, each companion diagnostic test is optimized for its specific therapy and with its own unique performance characteristics and scoring/interpretation guidelines.

The blueprint development group recognizes that to assume that any one of the available tests could be used for guiding the treatment decision with any one or all of the drugs available in this class presents a potential risk to patients that must be addressed.

The goal of this proposal is to agree and deliver, via cross industry collaboration, a package of information /data upon which analytic comparison of the various diagnostic assays may be conducted, potentially paving the way for post-market standardization and/or practice guideline development as appropriate.

Presentation Time:	Monday, Apr 18, 2016, 8:00 AM -12:00 PM
Location:	Section 10
Poster Board Number:	18
Author Block:	Marianne J. Ratcliffe1, Alan Sharpe2, Anita Midha1, Craig Barker2, Paul Scorer2, Jill Walker2. 1AstraZeneca, Alderley Park, United Kingdom; 2AstraZeneca, Cambridge, United Kingdom
Abstract Body:	Background: PD-1/PD-L1 directed antibodies are emerging as effective therapeutics in multiple oncology settings. Keynote 001 and Checkmate 057 have shown more frequent response to PD-1 targeted therapies in NSCLC patients with high tumour PD-L1 expression than patients with low or no PD-L1 expression. Multiple diagnostic PD-L1 tests are available using different antibody clones, different staining protocols and diverse scoring algorithms. It is vital to compare these assays to allow appropriate interpretation of clinical outcomes. Such understanding will promote harmonization of PD-L1 testing in clinical practice. Methods: Approximately 500 tumour biopsy samples from NSCLC patients, including squamous and non-squamous histologies, will be assessed using three leading PD-L1 diagnostics assays. PD-L1 assessment by the Ventana SP263 assay that is currently being used in Durvalumab clinical trials (positivity cut off: ≥25% tumour cells with membrane staining) will be compared with the Dako 28-8 assay (used in the Nivolumab Checkmate 057 trial at the 1%, 5% and 10% tumour membrane positivity cut offs), and the Dako 22C3 assay (used in the Pembrolizumab Keynote 001 trial) at the 1% and 50% cut offs). Results: Preliminary data from 81 non-squamous patients indicated good concordance between the Ventana SP263 and Dako 28-8 assays. Optimal overall percent agreement (OPA) was observed between Dako 28-8 at the 10% cut off and the Ventana SP263 assay (OPA; 96%, Positive percent agreement (PPA); 91%, Negative percent agreement (NPA); 98%), where the Ventana SP263 assay was set as the reference. Data on the full cohort will be presented for all three assays, and a lower 95% confidence interval calculated using the Clopper-Pearson method. Conclusions: This study indicates that the patient population defined by Ventana SP263 at the 25% cut off is similar to that identified by the Dako-28-8 assay at the 10% tumour membrane cut off. This, together with data on the 22C3 assay, will enable cross comparison of studies using different PD-L1 tests, and widen options for harmonization of PD-L1 diagnostic testing.

http://www.abstractsonline.com/Plan/ViewAbstract.aspx

Table 1

	Reference: Ventana SP-263 (≥25% tumour membrane staining)
Dako 28-8 assay cut off	PPA (%)	NPA (%)	OPA (%)
>1%	58	100	81
>5%	72	100	90
>10%	91	98	96

UPDATED 5/19/2019

Incidence of Adverse Events for PD-1/PD-L1 Inhibitors Underscores Toxicity Risk

https://www.cancernetwork.com/immuno-oncology/incidence-adverse-events-pd-1pd-l1-inhibitors-underscores-toxicity-risk

• Christina Bennett, MS

May 7, 2019

• Immuno Oncology, News

Approximately two-thirds of cancer patients who received a programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor in clinical trials experienced treatment-related adverse events, according to a systematic review and meta-analysis recently published in JAMA Oncology. The study findings may facilitate discussions with cancer patients who are considering PD-1 or PD-L1 therapy.

“The vast majority of patients with advanced cancer want to be on the [PD-1 or PD-L1] therapy,” Eric H. Bernicker, MD, a thoracic medical oncologist with Houston Methodist Cancer Center, told Cancer Network. Not involved in the current study, Bernicker explained that patients perceive these therapies to have “very different” side effects and risks from chemotherapy.

While they do, Bernicker explained, it’s important to underscore, which this study does, that these are not “completely innocuous” therapies. The study findings allow physicians to give numbers to patients and families when counseling them about the risks involved, he said.

The systematic review and meta-analysis is based on data from 125 clinical trials and 20,128 participants. Clinical trials were identified by systematically searching for published clinical trials that evaluated single-agent PD-1 and PD-L1 inhibitors and reported treatment-related adverse events in PubMed, Web of Science, Embase, and Scopus. The majority of trials evaluated nivolumab (n = 46) or pembrolizumab (n = 49), and the most common cancer types were lung cancer (n = 26), genitourinary cancer (n = 22), melanoma (n = 16), and gastrointestinal cancer (n = 14).

In all, 66.0% of clinical trial participants reported at least 1 adverse event of any grade, and 14.0% reported at least 1 grade 3 or higher adverse event. The most frequently reported adverse events of any grade were fatigue (18.26%), pruritus (10.61%), and diarrhea (9.47%). As for grade 3 or higher events, the most commonly reported were fatigue (0.89%), anemia (0.78%), and aspartate aminotransferase (AST) increase (0.75%).

Frequently reported immune-related adverse events of any grade included diarrhea (9.47%), AST increase (3.39%), vitiligo (3.26%), alanine aminotransferase (ALT) increase (3.14%), pneumonitis (2.79%), and colitis (1.24%). Grade 3 or higher immune-related adverse events included AST increase (0.75%), ALT increase (0.70%), pneumonitis (0.67%), diarrhea (0.59%), and colitis (0.47%).

If present, certain adverse events had increased likelihood of being grade 3 or higher, including hepatitis (risk ratio [RR], 50.59%), pneumonitis (RR, 24.01%), type 1 diabetes (RR, 41.86%), and colitis (RR, 37.90%).

“In terms of the rough percentage of side effects and the breadth of the side effects, this is pretty much what most of us see in the clinic,” Bernicker said, noting that none of the findings were particularly surprising.

Although no differences in adverse event incidence were found across different cancer types, differences were found between PD-1 and PD-L1 inhibitors in a subgroup analysis. Overall, compared with PD-L1 inhibitors, PD-1 inhibitors had a higher mean incidence of grade 3 or higher events (odds ratio [OR], 1.58; 95% CI, 1.00–2.54). Specifically, nivolumab had a higher mean incidence of grade 3 or higher events (OR, 1.81; 95% CI, 1.04–3.01) compared with PD-L1 inhibitors.

Bernicker commented that these incidence differences on the basis of drug type were “intriguing” but not clinically useful, given that PD-1 and PD-L1 inhibitors are not interchangeable. He said the finding “needs to be further looked at.”