ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) Study

ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) Study


Richard L. Schilsky, MD, FASCO
Twitter: @rschilsky

Key Points

  • A challenge facing oncologists who aim to provide patients personalized medicine services is obtaining the drug or drugs predicted to be beneficial based on the genomic testing of the tumor.
  • A potential solution to the problems of lack of access to drugs prescribed off label and lack of data collection on the safety and efficacy of such treatments is the creation of a registry to record and then share key clinical outcomes. Thus, ASCO is planning to launch the Targeted Agent and Profiling Utilization Registry (TAPUR) study
  • TAPUR is part of ASCO’s overarching goal to learn from observing the clinical practice of medicine using novel health information technology platforms, such as ASCO’s CancerLinQ™. TAPUR will simplify patient access to targeted agents predicted to provide benefit for them based on the genomic profile of their tumor and provide an opportunity to learn about the utility of matching drugs to tumor genomics.

Personalized cancer care is not a new concept, but its application has been enabled and enhanced by a far greater understanding than ever before of the biologic underpinnings of cancer. Our deeper knowledge of cancer at the genomic level, coupled with the increasingly widespread availability of affordable technologies to interrogate the genome, the transcriptome, the proteome, and other aspects of the tumor and host is leading to new paradigms of cancer care that rely increasingly on tumor molecular profiling throughout the course of care to refine prognosis and inform treatment decisions. A new generation of drugs, both anti-bodies and small molecules, that target specific molecules and pathways crucial for cancer survival or progression has revolutionized the treatment of some cancers and given hope to many patients with cancers that once lacked treatment options.

Evidence is building through reports of clinical trials, small research studies, case reports, and clinical anecdotes to suggest that patient outcomes are improved when a specific targeted agent can be matched to a tumor genomic variant.1 Such reports have fueled interest among patients and physicians to use genomic testing as a guide to treatment planning in patients with advanced cancer when standard treatment options have been exhausted, and commercial laboratories have begun to market such genomic tests to oncologists. Clinical reports, to date, suggest that 30%-80% of advanced solid tumors harbor potentially actionable genomic variants,2 but the outcomes of patients treated based on such tests remain largely anecdotal or unknown.

Previous Genetic-Profiling Studies

A pilot prospective study utilizing molecular profiling of tumors by immunohistochemistry, fluorescence in situ hybridization, and DNA microarray was conducted at nine sites across the United States and included patients with metastatic cancer who had progression of their tumors on their last systemic therapy and no remaining standard treatment options. The primary objective of the study was to compare progression-free survival (PFS) using a treatment regimen selected by molecular profiling versus the PFS observed for the patients’ most recent prior treatment regimen and then to calculate the PFS ratio (PFS on study/previous PFS). Eighty-six patients were profiled, and a molecular target was detected in 84 (98%) patients. Sixty-six patients were treated according to profiling results. Of these, 18 out of 66 (27%) patients had a PFS ratio greater than or equal to 1.3 (95% CI, 17%-38% one-sided, one sample, non-parametric test; p = 0.007). In addition to the PFS endpoint, there was one complete response by Response Evaluation Criteria In Solid Tumors (RECIST) guidelines, five partial responses, and 14 patients without progression at 4 months. In most patients with successful tumor molecular profiling, the profiling supported the use of a new treatment not contemplated initially by the investigator, in a patient population that was heavily pretreated and refractory to previous treatments.

The University of Texas MD Anderson Cancer Center investigators reported their experience of genomic profiling of patients with advanced solid tumors in the Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT) study.4 Of 1,144 patients analyzed, 40.2% had one or more genomic aberrations. For patients who received a targeted therapy matched to a genomic aberration, median PFS and overall survival were 4.1 months and 10.2 months, respectively, compared with 2.4 months and 8.2 months for patients who did not receive a matched treatment (p < 0.0001).

Recently, Lopez-Chavez and colleagues5 reported results of a basket trial conducted in patients with advanced non–small cell lung cancer, small cell lung cancer, and thymic malignancies. Six hundred forty-seven patients were enrolled, and their tumors were tested for 11 prespecified genomic alterations. Forty-five percent of patients had an alteration detected in at least one of the genes analyzed, and 4% had multiple genomic abnormalities. However, few patients actually received the protocol-specified matched targeted therapy, and, overall, only two of 15 treatment arms were successfully completed because of patient ineligibility or low frequency of the targets of interest. This trial clearly illustrates the challenges of trying to match drugs to specific genomic alterations in patients with advanced cancer: not all genomic tests will provide an informative result, not all tumors will harbor an actionable genomic variant, not all variants will be targeted by an available drug, not all patients will meet eligibility criteria for treatment, and not all patients will successfully complete the treatment prescribed. Such difficulties highlight the need for innovative trial designs to enhance accrual and improve study completion rates.

The New Generation of Prospective Clinical Trials

A new generation of prospective clinical trials exemplified by the recently launched National Cancer Institute (NCI) Molecular Profiling based Assignment of Cancer Therapeutics (M-PAC) study, The University of Texas MD Anderson IMPACT2 study, the Lung Cancer Master Protocol (Lung-MAP) study, the NCI Molecular Analysis for Therapy Choice (MATCH) trial, the FOCUS4 study, the Novartis Signature Trial Program, the Genentech My Pathway Trial, and the Stand Up to Cancer Melanoma Study will provide a more definitive test of the value of matching drugs to genomic alterations. Obtaining these results will likely take years. Until then, the opportunity exists to capture data from prescribing targeted agents in the context of clinical practice. Although imperfect, these data might still be informative to guide the development of this promising treatment strategy. 

A substantial challenge facing oncologists who aim to provide personalized medicine services to their patients is obtaining the drug or drugs predicted to be beneficial based on the genomic testing of the tumor. In the great majority of cases, such drugs will either be marketed agents that could be prescribed off label or investigational agents that are available only through participation in a clinical trial. Off-label prescribing is frequently not reimbursed by insurance companies because of its unproven effectiveness in many cases and the high cost of recently introduced targeted agents. Thus, patients face substantial financial risk if treatment costs are not reimbursed and expend considerable time and effort in discussions with drug manufacturers and insurance companies to obtain the desired treatment at an affordable cost. In addition, few oncologists or pathologists have expertise or access to experts to interpret genomic test reports and guide scientifically informed decisions about the optimal use of targeted agents. Furthermore, when clinicians and patients use targeted agents off label, efficacy and safety is generally not recorded and analyzed. As a result, the research and clinical communities have a limited understanding of the clinical outcomes of patients who receive these treatments outside of formal clinical trials.

There are now more than 30 commercially available drugs that target the molecular pathways frequently aberrant in human tumors, thus providing many opportunities to match drugs to the genomic profile of a tumor. Table 1 lists some of the targeted agents approved for use in the United States, the labeled indication, and the putative drug target(s).

Table 1. FDA-Approved Targeted Agents for Cancer Treatment

Drug

FDA-Approved Indication

Target(s)*

Ado-trastuzumab emtansine

Breast cancer

HER2

Afatinib

NSCLC

EGFR

Axitinib

RCC

VEGFR

Bevacizumab

Colorectal, NSCLC, RCC, cervix, GBM

VEGF-A

Bosutinib

CML

Bcr-abl

Cabozantinib

MTC

RET, VEGFR, MET, TRKB, TIE2

Ceritinib

NSCLC

ALK, ROS

Cetuximab

Colon, NSCLC, HNC

EGFR

Crizotinib

NSCLC

EML4-ALK, ROS1, MET

Dabrafenib

Melanoma

BRAFV600E

Dasatinib

CML

Bcr-abl, SRC, cKIT, PDGFR

Erlotinib

NSCLC

EGFR

Everolimus

RCC, breast, pNET

mTOR, TSC1, TSC2

Ibrutinib

MCL, CLL

BTK

Imatinib

CML, GIST

Bcr-abl, cKIT

Lapatinib

Breast

EGFR

Lenvatinib

Thyroid

VEGFR, FGFR, RET, KIT, PDGFR

Nilotinib

CML

Bcr-abl

Olaparib

Ovary

BRCA

Palbociclib

Breast

CDK 4/6

Panitumumab

Colon

EGFR

Pazopanib

RCC, STS

VEGFR, PDGFR, FGFR, KIT

Pertuzumab

Breast

HER2

Ramucirumab

Gastric

VEGFR2

Regorafenib

Colon

VEGFR, TIE2, PDGFR, RET, cKIT

Ruxolitinib

Myelofibrosis

JAK1, JAK2

Sorafenib

RCC, HCC, DTC

BRAF, KIT, FLT-3, RET, VEGFR, PDGFR

Sunitinib

RCC, GIST, pNET

PDGFR, VEGFR, KIT, FLT-3, RET

Temsirolimus

RCC

mTOR

Trametinib

Melanoma

MEK1, MEK2

Trastuzumab

Breast, gastric

HER2

Vandetanib

MTC

RET, EGFR, VEGFR, TIE2

Vemurafenib

Melanoma

BRAFV600E

Vismodegib

BCC

SMO

*Drug targets obtained from review of FDA-approved package insert for each drug. Abbreviations: BBC, basal-cell carcinoma; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; DTC, differentiated thyroid cancer; GBM, glioblastoma; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HNC, head and neck cancer; MCL, mantle cell lymphoma; MTC, medullary thyroid carcinoma; NSCLC, non–small cell lung cancer; pNET, pancreatic neuroendocrine tumor; RCC, renal cell carcinoma; STS, soft-tissue sarcoma.

A potential solution to the problems of lack of access to drugs prescribed off label and lack of data collection on the safety and efficacy of such treatments is the creation of a registry to record and then share key clinical outcomes. Thus, ASCO is planning to launch the Targeted Agent and Profiling Utilization Registry (TAPUR) study. TAPUR will focus on facilitating access to approved targeted therapies that are prescribed to patients with advanced cancer for whom standard treatment options have been exhausted and for whom treatment is selected based on results of a genomic test of their tumor performed in a qualified laboratory. ASCO will appoint a Molecular Tumor Board supported by a comprehensive knowledge base to help physicians understand the genomic profiling test results and possible treatment options and will capture patient outcomes in a registry to enable insights about the utility of this approach. ASCO will collaborate with a number of pharmaceutical companies that will provide drugs for the study. The study will be reviewed by a central institutional review board and overseen by an ASCO-appointed Steering Committee. In a unique international collaboration, a parallel clinical trial with identical objectives, eligibility criteria, and endpoints will be conducted by the Netherlands Cancer Institute, and the data will be shared across studies.

TAPUR Objectives

Primary objectives:

  • To describe the antitumor activity and toxicity of commercially available, targeted anticancer drugs used for treatment of patients with advanced solid tumors, multiple myeloma, or B cell non-Hodgkin lymphoma with a genomic variant known to be a drug target or to predict sensitivity to a drug.
  • To facilitate patient access to commercially available, targeted anticancer drugs of potential efficacy for treatment of patients with an advanced solid tumor, multiple myeloma, or B cell non-Hodgkin lymphoma for whom standard treatment options have been exhausted and whose tumor harbors a genomic variant known to be a drug target or to predict sensitivity to a drug.

Secondary objectives:

  • To record the treatment-related adverse events experienced by patients receiving treatment with commercially available, targeted anticancer drugs.
  • To create a prospective registry of patient outcomes following treatment of patients with advanced solid tumors, multiple myeloma, or B cell non-Hodgkin lymphoma that harbors a genomic variant known to be a target of an approved anticancer drug or to enhance sensitivity to a drug.
  • To create a prospective registry of commercially available tumor genomic tests used by clinical oncologists in the usual care setting.
  • To determine the concordance of the treatment plan proposed by the treating oncologist with that recommended by the Molecular Tumor Board in applicable situations.

TAPUR Endpoints and Analysis Plan

The primary outcome of interest is antitumor activity, as assessed by objective response. Response is defined as complete or partial response by RECIST version 1.1. Serious adverse events will be recorded, and grades 3-5 treatment-related toxicity will be described using the NCI Common Terminology Criteria for Adverse Events version 4.0 criteria. Each tumor type/genomic target/drug treatment group will define a separate cohort, and each cohort will be monitored using a two-stage design to identify tumor/target/drug cohorts with evidence of activity. A true response rate of less than 10% will be considered to be of no clinical interest. A response rate of 30% or more will be considered to be of sufficient interest to warrant further study in a confirmatory trial.

TAPUR is being launched by ASCO as part of the Society’s overarching goal to learn from observing the clinical practice of medicine using novel health information technology platforms, such as ASCO’s CancerLinQ™. TAPUR is also an attempt to provide guidance, education, and support to oncologists who wish to provide precision medicine services to their patients but do not have the expertise or resources to do so. TAPUR is expected to begin patient enrollment at a limited number of clinical sites in Michigan and North Carolina by the end of this year and to then expand participation in 2016. TAPUR will simplify patient access to targeted agents predicted to provide benefit for them based on the genomic profile of their tumor and will provide valuable insights to the clinical, pharmaceutical, regulatory, and payer communities about the value of matching drugs to genomic alterations in patients with advanced cancer.

About the Author: Dr. Schilsky is the chief medical officer of ASCO. Formerly the chief of Hematology/Oncology in the Department of Medicine and deputy director of the University of Chicago Comprehensive Cancer Center, he is a highly respected leader in the field of clinical oncology who specializes in new drug development and treatment of gastrointestinal cancers. Dr. Schilsky is a past president of ASCO, having served in the role during 2008-2009, and also a past chair of one of the NCI’s Cooperative Groups, Cancer and Leukemia Group B (CALGB).