Twenty-five years with HER2 targeted therapy.

The development of trastuzumab is among the most significant cancer drug development projects in the 20th century. Trastuzumab became a gamechanger for the treatment of human epidermal growth receptor 2 (HER2) positive breast cancer, with a significant positive impact on disease recurrence and survival. The development of trastuzumab was the beginning of a new era of cancer drug development, which showed us the importance of understanding the molecular pathophysiology and drug mechanism of action. The drug-diagnostic codevelopment model, in which the drug is developed in parallel with a predictive biomarker assay, has had a significant impact on today's cancer drug development, and we are indebted to trastuzumab when it comes to the clinical enrichment trial design. Trastuzumab is not the only drug developed to target the HER2 protein. Over the past few decades, several new HER2 targeted therapies have been developed, including small-molecule tyrosine kinase inhibitors (TKI), monoclonal antibodies, and antibody-drug conjugates (ADC). In particular, the ADC trastuzumab deruxtecan seems to pave new avenues when it comes to HER2 targeted treatment not only for breast cancer, but also for gastric cancer and non-small cell lung cancer. With the development of trastuzumab as a reference point, this article will provide a brief summary of the efficacy of HER2 targeted therapy, including testing for HER2 positivity, as it has evolved over the past 25 years.

Twenty-five years with companion diagnostics.

For decades, pharmacotherapy has been hampered by significant patient variability, and the inability to predict outcomes at the individual patient level has negatively affected its value. However, progress in molecular medicine has led to an increased understanding of the pathophysiology and mechanisms of action of drugs, thereby enabling the development of predictive biomarkers. Companion diagnostics (CDx) belongs to the group of predictive biomarkers, which the Food and Drug Administration (FDA) defines as an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product. In September 1998, 25 years ago, the FDA approved the first CDx assay, the HercepTest, an immunohistochemical (IHC) assay for the detection of HER2 protein expression. This assay is linked to the use of the monoclonal antibody trastuzumab in the treatment of HER2 positive breast cancer. The HercepTest is not the only CDx developed. Currently, more than 60 drugs or drug combinations, primarily in hematology and oncology, have been approved by the FDA, with CDx assays linked to their use. The current article briefly discusses the subject of CDx and provides an overview of its evolution over the past 25 years, with particular emphasis on the United States.

The Different Roles of MET in the Development and Treatment of Cancer.

This Special Issue features contributions from leading international researchers in the field of MET (hepatocyte growth factor (HGF) receptor) biology and therapeutics [...].

The Potential of Trastuzumab Deruxtecan as a Tissue Agnostic Drug.

BACKGROUND: Many modern anticancer drugs are designed to target specific molecular alterations harbored by the cancer. If a specific drug is able to target these alterations, regardless of the organ or tissue in which the cancer originates, it will often be characterized as a tissue- or tumor agnostic drug. According to the Food and Drug Administration (FDA), a tissue-agnostic drug refers to a drug that targets a specific molecular alteration across multiple cancer types, as defined by organ, tissue, or tumor type. SUMMARY: Over the last 6 years, the FDA has approved seven tissue-agnostic drugs, and more are anticipated in the future. One promising candidate for a tissue-agnostic classification is the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). Currently, T-DXd is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive and HER2-low breast cancer, HER2-positive gastric or gastroesophageal junction adenocarcinoma, and non-small cell lung cancer with activating HER2 mutations. Ongoing clinical research is exploring the potential of T-DXd in various solid tumors that harbor specific HER2 molecular alterations, and encouraging results, including the interim data from the DESTINY-PanTumor02 trial, have been published, which suggest a tissue-agnostic potential. KEY MESSAGES: Published phase I data as well as the interim results from the phase II DESTINY-PanTumor02 trial indicates that patients with different HER2-positive advanced solid tumors may benefit from treatment with T-DXd. Based on the currently available data, it seems likely that T-DXd possesses pantumor activity. However, different clinical trials are ongoing, and it will be necessary to see the results from these trials before drawing a final conclusion. When discussing tissue-agnostic potential, it is important to add that for most of the patients enrolled in the DESTINY-PanTumor02 and other trials, few treatment alternatives seem to exist, and T-DXd might be able to cover an unmet medical need.

[Predictive biomarkers in medical treatment].

Use of predictive biomarkers plays a promising role in stratifying patients to a more effective medical treatment with less side effects. This review provides a brief overview in a Danish context of the potential of applying pharmacogenomics (PGx) including companion diagnostics (CDx) in daily clinical practice based on the current knowledge and regulation from the FDA and EMA, Summary of Product Characteristics (SPC), PharmGKB (pharmacogenomics knowledge resource providing clinical dosing guidelines) and partly promedicin.dk. Also, the barriers to more widespread use are being addressed.

Missing Companion Diagnostic for US Food and Drug Administration-Approved Hematological and Oncological Drugs.

Within hematology and oncology, companion diagnostics (CDxs) play an increasing role in securing an optimal therapy for individual patients, and the US Food and Drug Administration (FDA) consider this type of assay essential for the safe and effective use of a corresponding therapeutic product. Most CDxs are developed prospectively using the drug-diagnostic codevelopment model, which normally secures the simultaneous approval of both drugs and diagnostics. A CDx assay is an important treatment decision tool that needs to be available simultaneously with the drug. However, within the past few years, several targeted drugs and new indications have been approved by the FDA without a CDx, despite the use of a predictive biomarker assay for patient selection during clinical development. A missing analytical and clinically validated CDx assay could affect the correct use of these drugs and ultimately patient safety. An alternative to FDA-approved or FDA-cleared CDxs could be to use a laboratory-developed test, which will normally miss documentation on the clinical validity. On the basis of the information available from different publicly available FDA databases, this article briefly discusses the issue of missing CDx assays in relation to the approval of hematological and oncological drugs and new indications.

Companion Diagnostics and Predictive Biomarkers for MET-Targeted Therapy in NSCLC.

Dysregulation of the MET tyrosine kinase receptor is a known oncogenic driver, and multiple genetic alterations can lead to a clinically relevant oncogenesis. Currently, a number of drugs targeting MET are under development as potential therapeutics for different cancer indications, including non-small cell lung cancer (NSCLC). However, relatively few of these drugs have shown sufficient clinical activity and obtained regulatory approval. One of the reasons for this could be the lack of effective predictive biomarkers to select the right patient populations for treatment. So far, capmatinib is the only MET-targeted drug approved with a companion diagnostic (CDx) assay, which is indicated for the treatment of metastatic NSCLC in patients having a mutation resulting in MET exon 14 skipping. An alternative predictive biomarker for MET therapy is MET amplification, which has been identified as a resistance mechanism in patients with EGFR-mutated NSCLC. Results obtained from different clinical trials seem to indicate that the MET/CEP7 ratio detected by FISH possesses the best predictive properties, likely because this method excludes MET amplification caused by polysomy. In this article, the concept of CDx assays will be discussed, with a focus on the currently FDA-approved MET targeted therapies for the treatment of NSCLC.

Oncology drug-companion diagnostic combinations.

With the development of trastuzumab for metastatic breast cancer a new era began in cancer drug development. The drug-diagnostic codevelopment model with its clinical enrichment trial design has enabled development of target specific drugs for molecular defined subsets of patients. Since the simultaneous approval of trastuzumab and the HercepTest in 1998, the number of FDA-approved drug-companion diagnostic combinations within oncology and hematology have steadily increased. By June 2021, the number of drugs that have a companion diagnostic (CDx) linked to its use has reached 46. For these drugs, the CDx assays play an important role in defining the patient population likely to respond and without the assay they will often lose their value. This short article is based on an analysis of the FDA List of Cleared or Approved Companion Diagnostic Devices and relevant information in the Drugs@FDA, and will focus on the drug-CDx combinations, drug classes, clinical development, and the regulatory path and status.

A Companion Diagnostic With Significant Clinical Impact in Treatment of Breast and Gastric Cancer.

The development of trastuzumab (Herceptin®) was one of the most significant cancer drug development projects of the 20th century. Not only was it a scientific and medical achievement but it also paved the way for the drug-diagnostic codevelopment model, where a predictive biomarker assay is developed in parallel to the drug. One of the challenges in the development of trastuzumab was to select the right patient population likely to respond and here, it was critical to have access to an accurate, robust and reliable assay for detection of HER2 overexpression in tumors. In the clinical development of trastuzumab, a clinical trial assay (CTA), developed by Genentech, was used for selection of HER2 positive patients. However, during the phase III trial with trastuzumab, a new optimized IHC assay, HercepTest™ was designed and developed by Dako. In the final stage of its development, a comparative study with the CTA was conducted in order to show concordance between the two assays. In September 1998, the Food and Drug Administration (FDA) simultaneously granted approval to trastuzumab and HercepTest™. The assay has been used for patient selection in a number of significant breast cancer clinical trials such as the HERA, CLEOPATRA, EMILIA and more. In these trials, HercepTest™ demonstrated its clinical utility in the neoadjuvant, adjuvant, and metastatic setting as well as in relation to different types of HER2 targeted therapies. Likewise, the assay was used for selection of HER2 positive gastric cancer patients in the important ToGA trail. HercepTest™ was the first companion diagnostic ever approved by the FDA, and more than 20 years of use has documented its clinical impact.

An update on companion and complementary diagnostic assays for PD-1/PD-L1 checkpoint inhibitors in NSCLC.

Introduction: Development within molecular medicine has given us an increased understanding of the pathophysiology of malignant diseases. This understanding has been the key to a development of a number of new effective target-specific drugs, including the PD-1/PD-L1 checkpoint inhibitors.Areas covered: This review will focus on the clinical validation and utility of the commercially available IHC PD-L1 expression assays linked to the different PD-1/PD-L1 checkpoint inhibitors indicated for treatment of NSCLC. For the discussion of this subject, mainly data from studies where the PD-1/PD-L1 checkpoint inhibitors have been given as monotherapy will be reported.Expert opinion: Although PD-L1 expression is not the perfect biomarker; the different IHC PD-L1 expression assays have had major impact on the clinical development of PD-1/PD-L1 checkpoint inhibitors for treatment of NSCLC. A number of clinical studies in NSCLC have shown that the efficacy of the PD-1/PD-L1 checkpoint inhibitors are positively correlated to the level of PD-L1 expression. Based on studies presented in this review, the recommendation is that monotherapy should mainly be used for treatment of NSCLC patients with a high PD-L1 expression, as defined by the cutoff values for the individual assays linked to the specific PD-1/PD-L1 checkpoint inhibitor.

Predictive biomarkers and clinical evidence.

Predictive biomarkers play an important role in our efforts to individualize pharmacotherapy, and within recent years, a number of different types of assays have been introduced. These biomarkers may potentially support the selection and dosage of specific drugs in order to maximize efficacy and minimize adverse reactions in the individual patient. However, in many instances, the scientific and clinical evidence is insufficient to support the prescribing decision. When predictive biomarkers are used to guide pharmacotherapy, it is important to secure that decisions are based on solid clinical evidence. Here, the regulatory authorities, especially the FDA, have been at the forefront in relation to regulate this type of biomarker assay in order to secure patient safety. The approval process for companion diagnostics is an example of this effort, where the scientific validity of the biomarker and assay is in focus. With the approaching implementation of the new IVD Regulation, greater attention will also be paid to analytical and clinical validity of biomarker assays in the EU. For any type of predictive biomarker assay, including pharmacogenetic and tumour profiling tests, the clinical evidence needs to be in place before they are used routinely in the clinic.

MET deletion is a frequent event in gastric/gastroesophageal junction/esophageal cancer: a cross-sectional analysis of gene status and signal distribution in 1,580 patients.

BACKGROUND: MET gene aberrations are found in several human cancers including gastric, ovarian and lung. In a large multinational cohort of patients with gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma we assessed the MET status with respect to amplification and deletion and correlate the results with the phenotypical gene signal distribution pattern. METHODS: Tissue specimens from 1,580 patients were analyzed using a novel fluorescence in situ hybridization (FISH) assay employing a MET/CEN-7 IQFISH Probe Mix. MET amplification and deletions were defined as a MET/CEN-7 ratio ≥2.0 and a MET/CEN-7 ratio <0.8, respectively. Furthermore, the link between the MET gene status and the phenotypical signal distribution was investigated. RESULTS: The prevalence of MET amplification and deletions was found to be 7.2% and 8.7%, respectively. Significant differences were observed with regard to geographic regions and sex. The Asian population had the highest percentage of MET amplification (9.4%) and the lowest percentage of deletions (3.2%). MET deletions was found more frequently among males (10.1%) compared to females (5.3%) and in esophagus (17.6%) compared to the stomach (5.7%). More than 50% of the patients who harbored MET gene amplification had a heterogeneous distribution of the FISH signals. Patients with a focal signal distribution were solely to be found among the MET amplified population. MET deletion were mainly observed in the group of patients with a homogenous signal distribution. CONCLUSIONS: The screening data from this cross-sectional study showed that MET deletion and amplification are frequent events in G/GEJ/E cancer, which are linked to different phenotypical signal distribution patterns. The role of MET deletion in relation to tumor development is not fully understood but it is likely to play a role in the oncogenic transformation of the cells.

The current landscape of the FDA approved companion diagnostics.

Predictive biomarker is an important element in the realization of precision medicine and with the introduction of the drug-diagnostic codevelopment model, the number of regulatory approved companion diagnostics (CDx) have steadily increased. This short perspective is based on an analysis of the FDA List of Cleared or Approved Companion Diagnostic Devices and focus on the biomarkers, drugs, clinical indications, analytical platforms, regulatory paths and status related to the different assays. By the end of 2020, the total number of CDx assays approved by the FDA had reached 44. These assays are almost exclusively linked to different hematological and oncological drugs. Without an accurate and reliable CDx assay these drugs will lose their value. The analytical platforms are diverse and cover technologies like immunohistochemistry, in situ hybridization, polymerase chain reaction, next generation sequencing, and imaging. CDx assays are high risk devices and the regulatory path almost exclusively requires submission of a Premarket Application (PMA); however, a relatively large group of the CDx assays is PMA approved Laboratory Developed Test.

Site-agnostic biomarker-guided oncology drug development.

INTRODUCTION: Advances within molecular diagnostics have enabled us to identify a number of oncogenic drivers across different cancers. Many cancers can now be divided into subgroups based on molecular characteristics, and an increasing number of targeted anticancer drugs have been developed together with a predictive biomarker assay using the drug-diagnostic codevelopment model. With the recent approval of entrectinib, larotrectinib, and pembrolizumab for site-agnostic indications, biomarker-guided drug development has entered into a new phase. AREAS COVERED: The review focuses on the general principles of drug-diagnostic codevelopment, especially basket trials and site-agnostic drug development. Special attention is paid to entrectinib, larotrectinib, and pembrolizumab. EXPERT OPINION: The recent approval of entrectinib, larotrectinib, and pembrolizumab must be regarded as a paradigm shift in biomarker-guided oncology drug development. For a site-agnostic indication, it is important to have in mind the central role of the companion diagnostic (CDx), as the assay defines the 'disease' and the patient population to be treated. A number of site-agnostic drugs are currently in development and here, it is important that CDx assay development is given high priority, so an analytical and clinical validated assay is available at the time of drug approval.

A paradigm shift in biomarker guided oncology drug development.

Over the past couple of decades, biomarker driven enrichment clinical trials have proven to be an important tool in clinical drug development, especially for targeted anti-cancer drugs. By the end of 2018, more than 30 drugs have been developed in conjunction with a biomarker test and have a regulatory approved companion diagnostic linked to their use. With the recent approval of larotrectinib (Vitrakvi, Loxo Oncology/Bayer) for patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion and pembrolizumab (Keytruda, MSD) for microsatellite instability-high (MSI-H) and mis-match-repair-deficient (dMMR) positive patients, we are experiencing a paradigm shift in biomarker guided drug development. In contrast to the previous drugs, they are not developed for a conventional cancer indication defined by tumor histology and anatomical location, but solely on their effect related to specific molecular aberrations. For larotrectinib efficacy was demonstrated across 12 different conventional cancer indications and for pembrolizumab the number was 15. Due to the low prevalence of the different molecular aberrations, data from several small "basket" trials was pooled in order to document the efficacy of the two drugs. With the approval of larotrectinib and the MSI-H/dMMR indication for pembrolizumab, the translational research methodology has demonstrated its potential in relation to drug development and made the way for a more precise and individualized anti-cancer therapy.