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Background: The Idylla™ EGFR Mutation Test is an ultra-rapid single-gene test that detects epidermal growth factor receptor (EGFR) mutations using formalin-fixed paraffin-embedded specimens. Here, we compared the performance of the Idylla EGFR Mutation Test with the Cobas® EGFR Mutation Test v2. Methods: Surgically resected NSCLC specimens obtained at two Japanese institutions (N = 170) were examined. The Idylla EGFR Mutation Test and the Cobas EGFR Mutation Test v2 were performed independently and the results were compared. For discordant cases, the Ion AmpliSeq Colon and Lung Cancer Research Panel V2 was performed. Results: After the exclusion of five inadequate/invalid samples, 165 cases were evaluated. EGFR mutation analysis revealed 52 were positive and 107 were negative for EGFR mutation in both assays (overall concordance rate: 96.4%). Analyses of the six discordant cases revealed that the Idylla EGFR Mutation Test was correct in four and the Cobas EGFR Mutation Test v2 was correct in two. In a trial calculation, the combination of the Idylla EGFR Mutation Test followed by a multi-gene panel test will reduce molecular screening expenses if applied to a cohort with EGFR mutation frequency >17.9%. Conclusions: We demonstrated the accuracy and potential clinical utility of the Idylla EGFR Mutation Test as a molecular screening platform in terms of turnaround time and molecular testing cost if applied to a cohort with a high EGFR mutation incidence (>17.9%).

Purpose The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA- mutated ( PIK3CA mut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2−), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2− advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. Results Patients with PIK3CA mut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CA mut BC. Among patients with double PIK3CA mut tumors (12% of all PIK3CA mut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CA mut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2− BC were not part of the therascreen panel. Conclusion PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CA mut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.

The emergence of companion diagnostic devices has been spurred by drug discovery and development efforts towards targeted therapies, particularly in oncology. Companion diagnostics and their corresponding therapeutics are often codeveloped, or developed in parallel, to ensure the safe and effective use of the products. The regulatory framework for companion diagnostics has gradually evolved as a result of the essential role of diagnostic tests to identify the intended population for a corresponding treatment. Here, we describe the current regulatory model for companion diagnostics in the US and outline key strategies for a successful codevelopment program from the device perspective. We also discuss how technological advances and changes in clinical management may challenge the regulatory model in the future.

Imaging plays a key role in the preclinical evaluation of nanomedicine-based drug delivery systems and it has provided important insights into their mechanism of action and therapeutic effect. Its role in supporting the clinical development of nanomedicine products, however, has been less explored. In this review, we summarize clinical studies in which imaging has provided valuable information on the pharmacokinetics, biodistribution, and target site accumulation of nanomedicine-based drug delivery systems. Importantly, these studies provide convincing evidence on the uptake of nanomedicines in tumors, confirming that the enhanced permeability and retention (EPR) effect is a real phenomenon in patients, albeit with fairly high levels of inter- and intraindividual variability. It is gradually becoming clear that imaging is critically important to help address this high heterogeneity. In support of this notion, a decent correlation between nanomedicine uptake in tumors and antitumor efficacy has recently been obtained in two independent studies in patients, exemplifying that image-guided drug delivery can help to pave the way towards individualized and improved nanomedicine therapies.

Purpose Early detection of hepatocellular carcinoma (HCC) remains a clinical challenge. Glypican 3 (GPC3) is a proteoglycan highly specific for HCC and is a potential diagnostic and therapeutic target for HCC. This work aims to develop GPC3-targeted immuno-positron emission tomography (immunoPET) imaging strategies and to assess the diagnostic values in preclinical HCC models. Methods Flow cytometry was used to screen GPC3-positive HCC cell lines. The expression of GPC3 in HCCs was detected by immunohistochemistry on tissue microarray. A novel GPC3-specific single domain antibody (sdAb) was produced and labeled with gallium-68 ( 68 Ga, T 1/2  = 1.1 h) and fluorine-18 ( 18 F, T 1/2  = 1.8 h) to develop radiotracers with different half-lives. The diagnostic efficacies of the developed probes (i.e., [ 68 Ga]Ga-NOTA-G2, [ 18 F]F-G2, and [ 68 Ga]Ga-NOTA-ABDG2) were interrogated in preclinical HCC models bearing varying GPC3 levels. Results GPC3 was strongly expressed on HCC cell lines and patients with poorly differentiated HCC. [ 68 Ga]Ga-NOTA-G2 immunoPET imaging specifically delineated the subcutaneous HCC lesions, outperforming the traditional 18 F-fluorodeoxyglucose PET and the nonspecific [ 68 Ga]Ga-NOTA-NbGFP immunoPET. ImmunoPET imaging with [ 18 F]F-G2 also efficiently diagnosed the tumors with clarity. Moreover, the fusion of G2 to an albumin-binding domain (ABD) significantly increased the tumor uptake and decreased kidney accumulation of the radiotracer when compared to [ 68 Ga]Ga-NOTA-G2. Conclusions In the work, we successfully developed sdAb-derived GPC3-targeted immunoPET imaging strategies and characterized the superior diagnostic accuracies in preclinical HCC models. Furthermore, we synthesized a fusion protein ABDG2 with improved targeting and pharmacokinetic properties, serving as a promising candidate for developing radioimmunotherapy agents.

Since the discovery of immune checkpoint proteins, there has been a special interest in developing antibodies that block programmed cell death 1 receptor (PD-1) and programmed cell death receptor ligand 1 (PD-L1) for a subset of cancer patients. PD-1 signaling negatively regulates T cell-mediated immune responses and serves as a mechanism for tumors to evade an antigen-specific T cell immunologic response. It plays a role in promoting cancer development and progression by enhancing tumor cell survival. With this background, PD-1 signaling represents a valuable therapeutic target for novel and effective cancer immunotherapy. Clinical data shows that blockade of this PD-1 signaling significantly enhance antitumor immunity, produce durable clinical responses, and prolong survival. Currently, there are three FDA-approved PD-L1 inhibitors for various malignancies ranging from non-small cell lung cancer to Merkel cell carcinoma. This review is to summarize many ongoing phase II/III trials of atezolizumab, durvalumab, avelumab, and new PD-L1 inhibitors in clinical developments. In particular, we focus on key trials that paved the pathway to FDA-approved indications for atezolizumab, durvalumab, and avelumab. Despite the popularity and accelerated FDA approval of PD-L1 inhibitors, further considerations into predictive biomarkers, mechanisms of resistance, treatment duration, immune-related toxicities, and PD-L1 expression threshold are needed to optimize anticancer potential in this class of immunotherapy.

Cancer immunotherapy by chimeric antigen receptor-modified T (CAR-T) cells has shown exhilarative clinical efficacy for hematological malignancies. Recently two CAR-T cell based therapeutics, Kymriah (Tisagenlecleucel) and Yescarta (Axicabtagene ciloleucel) approved by US FDA (US Food and Drug Administration) are now used for treatment of B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) respectively in the US. Despite the progresses made in treating hematological malignancies, challenges still remain for use of CAR-T cell therapy to treat solid tumors. In this landscape, most studies have primarily focused on improving CAR-T cells and overcoming the unfavorable effects of tumor microenvironment on solid tumors. To further understand the current status and trend for developing CAR-T cell based therapies for various solid tumors, this review emphasizes on CAR-T techniques, current obstacles, and strategies for application, as well as necessary companion diagnostics for treatment of solid tumors with CAR-T cells.

Medical history has not wandered far from its original aspirations of being personalized. Diagnostic capability has evolved from the metaphysical to the anatomical to the cellular and ultimately to the molecular level. Now that diseases can be subclassified into categories that indicate the course of disease and in some cases its likely response to treatment, there is a responsibility to act on that information. As more predictive biomarkers become clinically validated and as more targeted therapies become available, single marker companion diagnostics for specific drugs will be replaced by multiplex and multiparameter diagnostics that may be applicable across disease entities preserving sample, time, money and enabling rapid molecular taxonomy. We call this an ensemble relationship model between diagnostics and medicines.

In the era of precision medicine, digital technologies and artificial intelligence, drug discovery and development face unprecedented opportunities for product and business model innovation, fundamentally changing the traditional approach of how drugs are discovered, developed and marketed. Critical to this transformation is the adoption of new technologies in the drug development process, catalyzing the transition from serendipity-driven to data-driven medicine. This paradigm shift comes with a need for both translation and precision, leading to a modern Translational Precision Medicine approach to drug discovery and development. Key components of Translational Precision Medicine are multi-omics profiling, digital biomarkers, model-based data integration, artificial intelligence , biomarker-guided trial designs and patient-centric companion diagnostics. In this review, we summarize and critically discuss the potential and challenges of Translational Precision Medicine from a cross-industry perspective.

Prostate cancer (PCa) remains one of the most prominent forms of cancer for men. Since the early 1990s, Prostate-Specific Antigen (PSA) has been a commonly recognized PCa-associated protein biomarker. However, PSA testing has been shown to lack in specificity and sensitivity when needed to diagnose, monitor and/or treat PCa patients successfully. One enhancement could include the simultaneous detection of multiple PCa-associated protein biomarkers alongside PSA, also known as multiplexing. If conventional methods such as the enzyme-linked immunosorbent assay (ELISA) are used, multiplexed detection of such protein biomarkers can result in an increase in the required sample volume, in the complexity of the analytical procedures, and in adding to the cost. Using companion diagnostic devices such as biosensors, which can be portable and cost-effective with multiplexing capacities, may address these limitations. This review explores recent research for multiplexed PCa protein biomarker detection using optical and electrochemical biosensor platforms. Some of the novel and potential serum-based PCa protein biomarkers will be discussed in this review. In addition, this review discusses the importance of converting research protocols into multiplex point-of-care testing (xPOCT) devices to be used in near-patient settings, providing a more personalized approach to PCa patients’ diagnostic, surveillance and treatment management.