- Email: [email protected]
Precision medicine in oncology
Curr Probl Cancer ] (2017) ]]]–]]]
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
Precision medicine in oncology Advancements in cancer genomics have led to a new era of precision medicine in oncology. It is now commonplace for a patientʼs tumor to be extensively profiled for molecular abnormalities, and anticancer treatments to be based mainly on the identified underlying alterations, rather than just cancer histology. This capability is a critical advance in cancer medicine, as molecularly targeted agents may ultimately only benefit patients when their tumors are molecularly characterized and rationally matched with an antitumor agent with known mechanisms of action. Despite the initial promise of individualizing antitumor treatments for all patients, the management of most cancers still remains generally imprecise. Given the growing collection of cancer genomic data publicly available in The Cancer Genome Atlas (TCGA) program, which was started in 2006 under the direction of the National Cancer Institute (NCI) of the National Institutes of Health (NIH), a number of academic institutions across the globe has launched pilot studies investigating if a precision medicine approach can truly improve outcomes for patients with advanced solid tumors. Some of these institutions have now published their clinical trial data, but these clinical studies are still going on in most institutions with only limited information available. One of these precision medicine trials is the genomic-based US national clinical trial NCIMolecular Analysis for Therapy Choice (MATCH), which began accrual in 2015 as the ECOGACRIN/NCI collaborative study, with the primary aim of investigating the effect of novel antitumor agents based on genetic abnormalities that are believed to be the main drivers of progressing cancers. It is notable that the trial has maximized the use of the NCI-Cancer Therapy Evaluation Program (CTEP) infrastructure, whereby drug management and delivery of a significant number of investigational agents will occur at more than 1000 study sites across the country. These sites include members of the National Clinical Trials Network (NCTN) and a significant numbers of NCI Community Oncology Research Program (NCORP) sites. Apart from the NCI-MATCH and other precision medicine trials, in the United States, an increasing number of oncology patients are now getting molecularly characterized and screened for antitumor therapies routinely using either commercially available or academically derived next-generation sequencing (NGS) platforms. This resource has now led to an exponential increase in interest among oncologists to use genetic profiling as a screening tool to identify potential antitumor treatments for their patients. There is also an increasing number of industry-sponsored basket and umbrella trials conducted by cooperative groups and academic institutions, and more recently, even basket and umbrella http://dx.doi.org/10.1016/j.currproblcancer.2017.01.001 0147-0272/& 2017 Published by Elsevier Inc.
Precision medicine in oncology / Curr Probl Cancer ] (2017) ]]]–]]]
2
Table Definition and Examples of Basket and/or Umbrella Clinical Trials. PM trial type
Characteristics of trial
Basket
Targeting a single genetic alteration (indels, SNV, CNV, and fusions) using a single drug in multiple histologies
A study of vemurafenib in patients
Targeting multiple genetic alterations using multiple agents in a single cancer type
BATTLE trials (NCT004409968)
Umbrella
Example trials
with BRAFV600 mutation-positive cancers (NCT01524978)
I-SPY2 (NCT01042379) LungMap-S1400 (NCT00410189) National Lung Matrix Trial (NCT02664935) Basket and umbrella hybrid
Each subprotocol arm is designed to target a single genetic alteration using a single drug in multiple histologies, but 1 clinical trial is consisted of multiple subprotocol arms so that it is capable of testing multiple agents and multiple genetic alterations in multiple histologies in a single clinical trial
NCI-MATCH/EAY131 (NCT01827384) SHIVA (NCT01771458) TAPUR (NCT02693535) MPACT (NCT01827384)
ASCO, American Society of Clinical Oncology; BATTLE, Biomarker-Integrated Targeted Therapy Study; CNV, copy number variation; EAY, ECOG-ACRIN, Eastern Cooperative Oncology Group and American College of Radiology Imaging Network; indels, insertion deletions; ISPY, Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis; LungMap, Lung Cancer Master Protocol; MPACT, Molecular Profiling-Based Assignment of Cancer Therapy for Patients With Advanced Tumors; NCI-MATCH, National Cancer Institute-Molecular Analysis for Therapy Choice; PM, precision medicine; SNV, single nucleotide variant; TAPUR, Targeted Agent and Profiling Utilization Registry.
hybrid-type trials, such as the SHIVA trial (Table). Conversely, the rapid entry of novel therapeutics into routine oncology practice clearly underscores the urgent need for physicians to develop a sound understanding of the concepts of precision medicine and NGS assays. This current special issue “Precision Medicine in Oncology” was assembled to help physicians understand this rapidly growing field in oncology. The international nature of the journal finds articles from investigators based globally, covering the United States, Europe, and Asia, where precision medicine clinical trials and associated NGS assays, which are the foundation of such research will be discussed. Despite the promise that this new era of cancer medicine brings, intertumor and intratumor heterogeneity, the rewiring of complex signaling networks and other escape mechanisms inevitably lead to treatment resistance. Current strategies are, therefore, focused on the incorporation of rational combination regimens of molecular-targeted agents, so as to achieve durable cancer responses. Hypothesis-generating preclinical testing will continue to be a critical element in the identification of analytically validated and clinically qualified predictive markers for drug development to achieve true precision medicine. In addition, a rational drug development approach involves the assessment of combination therapies through the in vitro and in vivo testing of patient-derived xenografts. We should also consider the development of novel predictive biomarkers, such as genome-wide gene expression profiling signatures and systematic proteomic profiling. The development of NGS assays for use on cell-free DNA will also provide us with an alternative strategy to relatively more invasive tumor biopsies. These are exciting times in cancer medicine, with impressive gains in the development of multiple antitumor agents matched against patient tumors with
Precision medicine in oncology / Curr Probl Cancer ] (2017) ]]]–]]]
3
robust predictive biomarkers. We now need to widen the application of precision medicine, so as to truly individualize the management of all patients, with an ultimate goal of defeating cancer.
Naoko Takebe, MD, PhD Associate Editor National Cancer Institute, Division of Cancer Treatment and Diagnosis, Bethesda, MD [email protected]
Timothy A. Yap, MBBS, MRCP, PhD The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Department of thoracic/head and neck medical oncology Houston, TX
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
Precision medicine in oncology Advancements in cancer genomics have led to a new era of precision medicine in oncology. It is now commonplace for a patientʼs tumor to be extensively profiled for molecular abnormalities, and anticancer treatments to be based mainly on the identified underlying alterations, rather than just cancer histology. This capability is a critical advance in cancer medicine, as molecularly targeted agents may ultimately only benefit patients when their tumors are molecularly characterized and rationally matched with an antitumor agent with known mechanisms of action. Despite the initial promise of individualizing antitumor treatments for all patients, the management of most cancers still remains generally imprecise. Given the growing collection of cancer genomic data publicly available in The Cancer Genome Atlas (TCGA) program, which was started in 2006 under the direction of the National Cancer Institute (NCI) of the National Institutes of Health (NIH), a number of academic institutions across the globe has launched pilot studies investigating if a precision medicine approach can truly improve outcomes for patients with advanced solid tumors. Some of these institutions have now published their clinical trial data, but these clinical studies are still going on in most institutions with only limited information available. One of these precision medicine trials is the genomic-based US national clinical trial NCIMolecular Analysis for Therapy Choice (MATCH), which began accrual in 2015 as the ECOGACRIN/NCI collaborative study, with the primary aim of investigating the effect of novel antitumor agents based on genetic abnormalities that are believed to be the main drivers of progressing cancers. It is notable that the trial has maximized the use of the NCI-Cancer Therapy Evaluation Program (CTEP) infrastructure, whereby drug management and delivery of a significant number of investigational agents will occur at more than 1000 study sites across the country. These sites include members of the National Clinical Trials Network (NCTN) and a significant numbers of NCI Community Oncology Research Program (NCORP) sites. Apart from the NCI-MATCH and other precision medicine trials, in the United States, an increasing number of oncology patients are now getting molecularly characterized and screened for antitumor therapies routinely using either commercially available or academically derived next-generation sequencing (NGS) platforms. This resource has now led to an exponential increase in interest among oncologists to use genetic profiling as a screening tool to identify potential antitumor treatments for their patients. There is also an increasing number of industry-sponsored basket and umbrella trials conducted by cooperative groups and academic institutions, and more recently, even basket and umbrella http://dx.doi.org/10.1016/j.currproblcancer.2017.01.001 0147-0272/& 2017 Published by Elsevier Inc.
Precision medicine in oncology / Curr Probl Cancer ] (2017) ]]]–]]]
2
Table Definition and Examples of Basket and/or Umbrella Clinical Trials. PM trial type
Characteristics of trial
Basket
Targeting a single genetic alteration (indels, SNV, CNV, and fusions) using a single drug in multiple histologies
A study of vemurafenib in patients
Targeting multiple genetic alterations using multiple agents in a single cancer type
BATTLE trials (NCT004409968)
Umbrella
Example trials
with BRAFV600 mutation-positive cancers (NCT01524978)
I-SPY2 (NCT01042379) LungMap-S1400 (NCT00410189) National Lung Matrix Trial (NCT02664935) Basket and umbrella hybrid
Each subprotocol arm is designed to target a single genetic alteration using a single drug in multiple histologies, but 1 clinical trial is consisted of multiple subprotocol arms so that it is capable of testing multiple agents and multiple genetic alterations in multiple histologies in a single clinical trial
NCI-MATCH/EAY131 (NCT01827384) SHIVA (NCT01771458) TAPUR (NCT02693535) MPACT (NCT01827384)
ASCO, American Society of Clinical Oncology; BATTLE, Biomarker-Integrated Targeted Therapy Study; CNV, copy number variation; EAY, ECOG-ACRIN, Eastern Cooperative Oncology Group and American College of Radiology Imaging Network; indels, insertion deletions; ISPY, Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis; LungMap, Lung Cancer Master Protocol; MPACT, Molecular Profiling-Based Assignment of Cancer Therapy for Patients With Advanced Tumors; NCI-MATCH, National Cancer Institute-Molecular Analysis for Therapy Choice; PM, precision medicine; SNV, single nucleotide variant; TAPUR, Targeted Agent and Profiling Utilization Registry.
hybrid-type trials, such as the SHIVA trial (Table). Conversely, the rapid entry of novel therapeutics into routine oncology practice clearly underscores the urgent need for physicians to develop a sound understanding of the concepts of precision medicine and NGS assays. This current special issue “Precision Medicine in Oncology” was assembled to help physicians understand this rapidly growing field in oncology. The international nature of the journal finds articles from investigators based globally, covering the United States, Europe, and Asia, where precision medicine clinical trials and associated NGS assays, which are the foundation of such research will be discussed. Despite the promise that this new era of cancer medicine brings, intertumor and intratumor heterogeneity, the rewiring of complex signaling networks and other escape mechanisms inevitably lead to treatment resistance. Current strategies are, therefore, focused on the incorporation of rational combination regimens of molecular-targeted agents, so as to achieve durable cancer responses. Hypothesis-generating preclinical testing will continue to be a critical element in the identification of analytically validated and clinically qualified predictive markers for drug development to achieve true precision medicine. In addition, a rational drug development approach involves the assessment of combination therapies through the in vitro and in vivo testing of patient-derived xenografts. We should also consider the development of novel predictive biomarkers, such as genome-wide gene expression profiling signatures and systematic proteomic profiling. The development of NGS assays for use on cell-free DNA will also provide us with an alternative strategy to relatively more invasive tumor biopsies. These are exciting times in cancer medicine, with impressive gains in the development of multiple antitumor agents matched against patient tumors with
Precision medicine in oncology / Curr Probl Cancer ] (2017) ]]]–]]]
3
robust predictive biomarkers. We now need to widen the application of precision medicine, so as to truly individualize the management of all patients, with an ultimate goal of defeating cancer.
Naoko Takebe, MD, PhD Associate Editor National Cancer Institute, Division of Cancer Treatment and Diagnosis, Bethesda, MD [email protected]
Timothy A. Yap, MBBS, MRCP, PhD The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Department of thoracic/head and neck medical oncology Houston, TX