Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q.

BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

Umbrella and basket trials in oncology: ethical challenges.

BACKGROUND: Novel precision oncology trial designs, such as basket and umbrella trials, are designed to test new anticancer agents in more effective and affordable ways. However, they present some ethical concerns referred to scientific validity, risk-benefit balance and informed consent. Our aim is to discuss these issues in basket and umbrella trials, giving examples of two ongoing cancer trials: NCI-MATCH (National Cancer Institute - Molecular Analysis for Therapy Choice) and Lung-MAP (Lung Cancer Master Protocol) study. MAIN BODY: We discuss three ethical requirements for clinical trials which may be challenged in basket and umbrella trial designs. Firstly, we consider scientific validity. Thanks to the new trial designs, patients with rare malignancies have the opportunity to be enrolled and benefit from the trial, but due to insufficient accrual, the trial may generate clinically insignificant findings. Inadequate sample size in study arms and the use of surrogate endpoints may result in a drug approval without confirmed efficacy. Moreover, complexity, limited quality and availability of tumor samples may not only introduce bias and result in unreliable and unrepresentative findings, but also can potentially harm patients and assign them to an inappropriate therapy arm. Secondly, we refer to benefits and risks. Novel clinical trials can gain important knowledge on the variety of tumors, which can be used in future trials to develop effective therapies. However, they offer limited direct benefits to patients. All potential participants must wait about 2 weeks for the results of the genetic screening, which may be stressful and produce anxiety. The enrollment of patients whose tumors harbor multiple mutations in treatments matching a single mutation may be controversial. As to informed consent - the third requirement we discuss, the excessive use of phrases like "personalized medicine", "tailored therapy" or "precision oncology" might be misleading and cause personal convictions that the study protocol is designed to fulfill the individual health-related needs of participants. CONCLUSIONS: We suggest that further approaches should be implemented to enhance scientific validity, reduce misunderstandings and risks, thus maximizing the benefits to society and to trial participants.

The NCI-MATCH trial and precision medicine in gynecologic cancers.

The Precision Medicine Initiative is a National Cancer Institute (NCI) driven interdisciplinary collaborative effort to test the feasibility of trials incorporating genomic profiling when choosing patient therapies. The goal of the initiative is to generate the scientific evidence needed to move the concept of precision medicine, or targeted therapy, into clinical practice. The rapid development and widespread availability of next generation sequencing provides access to information regarding an individual's tumor at various times during the course of their disease. Translating the aberrations specific to a patient's tumor into personalized treatment is the concept behind "basket" trials, and thus categorize patients' cancers based on the sequencing of the tumor, rather than the organ of origin. The NCI Molecular Analysis for Therapy Choice (MATCH) trial [NCT02465060] is a multi-site, collaborative effort between the NCI and several pharmaceutical companies that is beginning to clarify the significance of molecular alterations in tumors. This trial was designed to assign targeted treatment based on molecular alterations identified from a tumor biopsy obtained after study enrollment and determine the efficacy of this treatment. This review article will briefly discuss known genomic aberrations in gynecologic cancers, and then provide an overview of the NCI-MATCH trial with an update on accrual and recent interim analysis. We will also review current FDA-approved precision therapies for gynecologic malignancies, such as poly (ADP ribose) polymerase (PARP) inhibitors.

Is the NCI MATCH trial a match for gynecologic oncology?

The Precision Medicine Initiative is an NCI driven program in cancer to generate the scientific evidence needed to move the concept of precision medicine into clinical practice. The rapid development and widespread availability of next generation sequencing and other molecular interrogation of tumors has heralded a new era of knowledge about each individual's tumor at a point in time. In some instances, this information has led to new therapeutic discoveries, in most instances, this information has been uninformative or of unclear significance. The NCI Molecular Analysis for Therapy Choice (MATCH) trial [NCT02465060] which screens for molecular features that may predict response to a drug with a given mechanism of action, is a multi-study, collaborative effort between the NCI and many pharmaceutical companies to begin to clarify the significance of molecular alterations in tumors not previously studied. This trial design is in response to the recent appreciation that certain driver mutations which may be common in a particular tumor type are mutated in other diseases at low frequency (<10%). In low frequency mutations, testing the utility of certain targeted therapy requires screening large numbers of patients. This review article will discuss the types of novel trial designs that led to the development and launch of the NCI MATCH.

Perspectives on research activity in the USA on Cancer Precision Medicine.

The National Cancer Institute-Molecular Analysis for Therapy Choice trial is a clinical trial that will analyze various genetic statuses of patients' tumors to determine whether they contain abnormalities which can be a target for an available drug. National Cancer Institute-Molecular Analysis for Therapy Choice seeks to determine whether improved outcomes can be achieved when cancer treatments are personalized based on molecular abnormalities found in individual patients. As a master protocol, or basket trial, National Cancer Institute-Molecular Analysis for Therapy Choice can add or remove treatments as indicated over the duration of the study. Each treatment will be used in a unique arm, or sub-study, of the trial. The trial initially has 10 arms, each of which will enroll patients to a specific molecularly targeted treatment. It is ultimately anticipated that 20-25 drugs or combination treatments will be tested. To be eligible for the study, participants must have an advanced solid tumor or lymphoma that is no longer responding or never responded to the standard therapy. National Cancer Institute-Molecular Analysis for Therapy Choice investigators plan to obtain tumor biopsy specimens from as many as 3000 patients initially. To identify multiple genetic abnormalities that may respond to the targeted drugs selected for the trial, next-generation deoxyribonucleic acid and ribonucleic acid sequencing will be done in the genetic testing laboratories, analyzing for >4000 different variants across 143 genes. The drugs included in the trial have all either been approved by the US Food and Drug Administration for another cancer indication or are still being tested in other clinical trials, but have shown some clinical levels of evidence against tumors with a particular genetic alteration.

Precision Oncology: Evolving Clinical Trials across Tumor Types.

Advances in molecular technologies and targeted therapeutics have accelerated the implementation of precision oncology, resulting in improved clinical outcomes in selected patients. The use of next-generation sequencing and assessments of immune and other biomarkers helps optimize patient treatment selection. In this review, selected precision oncology trials including the IMPACT, SHIVA, IMPACT2, NCI-MPACT, TAPUR, DRUP, and NCI-MATCH studies are summarized, and their challenges and opportunities are discussed. Brief summaries of the new ComboMATCH, MyeloMATCH, and iMATCH studies, which follow the example of NCI-MATCH, are also included. Despite the progress made, precision oncology is inaccessible to many patients with cancer. Some patients' tumors may not respond to these treatments, owing to the complexity of carcinogenesis, the use of ineffective therapies, or unknown mechanisms of tumor resistance to treatment. The implementation of artificial intelligence, machine learning, and bioinformatic analyses of complex multi-omic data may improve the accuracy of tumor characterization, and if used strategically with caution, may accelerate the implementation of precision medicine. Clinical trials in precision oncology continue to evolve, improving outcomes and expediting the identification of curative strategies for patients with cancer. Despite the existing challenges, significant progress has been made in the past twenty years, demonstrating the benefit of precision oncology in many patients with advanced cancer.

Considerations of developing an NGS assay for clinical applications in precision oncology: The NCI-MATCH NGS assay experience.

Next generation sequencing (NGS) technologies have been widely adapted in clinical oncology by utilizing the profiled genetic mutation information to select patients and to guide the choice of target therapy. To fulfill the regulatory compliance, development of an NGS assay that will be used in clinical trials requires an analytical validation to meet its intend clinical use. NCI-MATCH trial is the largest precision oncology basket trial which uses a single NGS assay (NCI-MATHC NGS assay) to screen the actionable mutations in 6000 patients, who have relapsed/refractory solid tumors and lymphomas after standard systemic treatment, and assigns matched treatment. This article reviews on the critical considerations during development and validation of NGS assays as an investigational device for genomic based clinical trials and provides the experiences from the development of NCI-MATCH NGS assay.

An overview of the NCI precision medicine trials-NCI MATCH and MPACT.

The concept of oncogene addiction was first proposed by Weinstein in 2002, postulating that tumors rely on a single dominant mutation, the oncogenic "driver", for growth and survival. We have since come to realize that the genomic landscape of tumors is heterogeneous and more complex than previously thought. Advances in biotechnology and bioinformatics over the past decade have shifted treatment paradigms with regard to the development of molecular targeted therapeutics to identify and target the presumptive dominant lesion. As such, the decision of choosing targeted treatment strategies has become increasingly more reliant on the reporting of genomic screens of patients' tumor tissue. Whether this change in treatment paradigm will translate into improved clinical benefit, remains to be seen. To this end, the United States National Cancer Institute (NCI) has launched precision-based medicine trials to address this question. NCI Molecular Analysis for Therapy Choice (MATCH), a genomic pre-screening study, was designed to explore the efficacy of using targeted agents to target specific molecular aberrations and whether these same therapies have comparable activity across different tumor subtypes. Molecular Profiling-based Assignment of Cancer Therapy (MPACT), is a smaller, provocative trial designed to address whether targeting an oncogenic "driver" would be more efficacious than one not. The Exceptional Responders' initiative further aims to evaluate patients who have derived an unexpected durable benefit to these therapies, with retrospective analysis of their tumors to delineate potential predictive biomarkers which could predict response. The results of these trials will serve to help guide the field of precision medicine and personalized care.