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Last Updated: 05/10/2017

NCI-sponsored trials in precision medicine

What is “Precision Medicine?”

On January 30, 2015, President Obama unveiled details about the Precision Medicine Initiative, a bold new research effort to revolutionize how we improve health and treat disease. Precision medicine uses information about the genes, proteins, and other features of a person's cancer to diagnose or treat their particular disease. Genes code for information that allows normal growth and development. In cancer, these processes work abnormally, leading to abnormal growth and spread of cancerous disease. Even cancers that are thought of as similar (e.g. lung cancer) have been found to consist of cancers with different molecular make up, and different rates of progress and response to treatment. Each patient may share a molecular defect with only a few other patients among all patients with the same cancer. Genetic information about a particular person's cancer can be used to diagnose or treat their particular disease. Understanding the genetic changes in cancer cells can lead to precise treatments that target the specific changes in a person's tumor.

NCI-supported scientists are pursuing new technologies and collaborations, and conducting new kinds of clinical trials, to help fulfill precision medicine's promise.

The NCI is currently testing a new precision medicine strategy that includes both “genotype to phenotype” and “phenotype to genotype” initiatives. “Genotype to Phenotype” refers to clinical trials that screen for molecular features that may predict response to a drug with a given mechanism of action. “Phenotype to Genotype” is the retrospective genomic analysis of a patient's tumor to determine if molecular factors may explain why a patient responded particularly well to a particular treatment.

“Genotype to Phenotype” trials:


The NCI-MATCH (“Molecular Analysis for Therapy Choice”) trial will examine the molecular features of tumors in as many as 6,000 patients with solid tumors or lymphoma who have progressed on standard therapy, and hopes to match at least 1,000 of those patients to a treatment with a targeted drug or drug combination. Patients will need to have a biopsy, which will be used to screen for abnormalities in up to 143 genes known to be involved in cancer and/or to predict response to a particular drug or drug combination.

Because any one molecular abnormality may be present in only 5-10% of patients with solid tumors or lymphomas, NCI-MATCH will have more than 20 arms, each with a drug treatment for a particular molecular abnormality or group of molecular abnormalities. Each targeted therapy will be studied in a single-arm phase II trial, with NCI-MATCH functioning as an umbrella protocol for these trials. Patients with a match to a drug treatment will stay on that drug treatment until their disease progresses (or the treatment becomes toxic), at which point they will, if they desire, undergo another biopsy to look for additional molecular features that could match them to a new targeted drug. Under certain circumstances (e.g., non-response with rapid progression), patients who have more than one “actionable” genetic abnormality will be able to match to a treatment addressing the second molecular abnormality without a repeat biopsy. Additionally, NCI-MATCH will compare pre-treatment biopsies to post-treatment biopsies to study why some tumors develop resistance to cancer treatment.

Molecular tests to be performed on the tumors include genetic sequencing using a panel of about 143 genes (on the Ion Torrent PGM™ system), as well as other diagnostic assays for specific molecular features. Biopsies will be sent to a central laboratory at MD Anderson Cancer Center in Houston, TX. Four CLIA-certified laboratories will perform the tests — Frederick National Laboratory for Cancer Research, MD Anderson Cancer Center, Yale Cancer Center, and Massachusetts General Hospital.

The NCI-MATCH study is available through the National Clinical Trials Network (NCTN) and led by EGOG-ACRIN External Link and NCI. The trial was activated in August 2015. The protocol design incorporated a pause for review after enrollment of 500 patients for mutation screening. In late October 2015, the trial reached the 500 patient enrollment mark, which was five times the number of patients expected to enroll in the trial's first 3 months. Therefore, patient enrollment was paused in November 2015 for the planned review. The review allowed the investigators to examine how the trial was performing and guided them on how to improve tumor and drug match rates, among other factors. The Interim Analysis results were released at the 2016 Annual Meeting of the American Association for Cancer Research in April 2016. An Executive Summary of the Interim Analysis results is available. NCI-MATCH re-opened for patient enrollment to the screening phase in late May 2016.


The ALCHEMIST (“Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial”) trial will screen several thousand patients with operable, non-squamous, non-small-cell lung cancer to determine if their tumors contain specific molecular alterations that may make them eligible for treatment trial of therapy that targets that alteration:

  • Eligible patients with the ALK rearrangement would enroll on a randomized trial studying crizotinib (trial # E4512, led by ECOG-ACRIN).
  • Eligible patients with the EGFR mutation would enroll on a randomized trial studying erlotinib (trial #A081105, led by Alliance).

The screening portion will take place via Alliance trial #A151216.

In addition to the two randomized trials, ALCHEMIST will also contain a large discovery component:

  • Genomic analysis of primary tumor and blood on all screened patients, no matter if they have the ALK or EGFR alterations or not.
  • Genomic analysis of relapse tumor in patients who relapse.
  • Collection of plasma for circulating tumor DNA.
  • Epidemiological questionnaire.

The genomic analyses will be performed by research labs run by the NCI Center for Cancer Genomics. Genomic information will be linked to clinical and epidemiological information in a public database, enabling researchers to perform further studies on the data. (Data will be de-identified.)


The Lung-MAP (“Lung Cancer Master Protocol”) trial will test the tumors of patients with advanced squamous cell lung cancer whose disease has progressed after one line of chemotherapy to determine if they contain certain genomic features, to match patients to one of the arms studying therapy for that target.

Lung-MAP is a phase II/III trial containing several such arms, each randomized to a control arm of a standard therapy. Patients not testing positive for one of the genomic features will be enrolled in the arm testing immunotherapy. Lung-MAP is a SWOG-led Intergroup trial (trial #S1400) funded through a public-private partnership via the Foundation for the NIH, involving NCI, SWOG, Friends of Cancer Research, Foundation Medicine, and several pharmaceutical companies. The trial will screen up to 1,000 patients per year. The genetic test used will be the Foundation Medicine genetic panel.


NCI’s MPACT (“Molecular Profiling-Based Assignment of Cancer Therapy”) seeks to determine if patients with a mutation in a certain genetic pathway are more likely to benefit from a treatment that targets that pathway, as opposed to another cancer treatment not targeting that pathway.

A multi-center trial led by the NCI, MPACT will analyze tumor biopsies of hundreds of advanced cancer patients to determine if they have mutations in specific genetic pathways that are the target of certain drugs. Eligible patients who have those mutations will be randomized 2:1 to a drug that targets that mutated pathway versus a drug that is not known to target the pathway. Patients on the non-targeted therapy arm whose disease progresses will be allowed to cross over to a drug targeting their mutation(s). It is expected that MPACT will enroll about 180 patients.

Current targeted drugs studied in MPACT include the following (additional arms are expected to be added):

  • ABT-888 (PARP inhibitor) with temozolomid: Targets mutations in the DNA repair pathway
  • AZD1775 (MK-1775) (Wee1 inhibitor) with carboplatin: Targets mutations in the DNA repair pathway
  • Everolimus (mTOR inhibitor): Targets mutations in the PI3K pathway
  • Trametinib DMSO (MEK inhibitor): Targets mutations in the RAS/RAF/MEK pathway


The NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) trial will enroll children and adolescents with advanced cancers that have not responded to treatment or have progressed on standard therapy.

As in the adult NCI-MATCH trial, DNA sequencing will be used to identify children and adolescents whose tumors have a genetic abnormality for which either an approved or investigational targeted therapy exists. Pediatric MATCH provides a tremendous opportunity to test molecularly targeted therapies in children and adolescents with advanced cancers who have few other treatment options. With the genomic data captured in the trial, it will also produce an invaluable resource for studying the genetic basis of pediatric cancers.

Pediatric MATCH, which will be led by the NCI-funded Children's Oncology Group, a member of the NCTN, is still under development and aims to start in 2017.

“Phenotype to Genotype” trial:

The “Exceptional Responders” study

Rarely, a patient has all tumor disappear, or has a long-term response to a drug that doesn’t usually cause such responses to happen. In the Exceptional Responders study, investigators will study the molecular characteristics of tumors of patients who had an exceptional response to a cancer therapy. In doing this, they hope to discover molecular features in the tumors that may predict benefit to a particular drug or type of drug. Where possible, non-tumor specimens from the patients will also be examined, as these help in determining which mutations are present only in the tumor, rather than in normal cells/tissue.

The Exceptional Responders Initiative is a pilot study to determine if information can be obtained from archived samples that will enable hypotheses to be made about the reasons for exceptional responses to cancer treatment.

The molecular information will be placed into a large database, along with clinical information, and shared with other approved researchers so that they can help determine why the patient(s) had such an exceptional response, and if this knowledge can be applied to other cancer patients. (Information will be de-identified.)

The Exceptional Responders study will be led by NCI Division of Cancer Treatment and Diagnosis and Center for Cancer Genomics, with genetic sequencing performed at Baylor. The NCI will collect up to 300 samples to successfully analyze 100 cases.

Clinical providers and investigators are invited to send NCI information on patients they believe may be “exceptional responders” by following the instructions below (NCI will provide reimbursement for each accepted case):

How to inform NCI of cases you believe are Exceptional Responders

Definition of “Exceptional Responder”:

In a setting where the patient has:

  1. a complete response to a drug(s) where complete response is seen in < 10% of patients receiving similar treatment
  2. a partial response of at least 6 months duration where such a response is seen in < 10% of patients receiving similar treatment
  3. a complete or partial response that lasts longer than 3 times the median response duration in the literature for the treatment

The response can be to an experimental systemic therapy or to a standard systemic therapy, in a trial setting or in a clinical setting.

Providers or investigators who know of a potential “Exceptional Responder” can propose cases by sending an email

In this email, please:

  1. Provide a short description of the case, without patient identifiers. The description should include the patient’s disease, length of response, and treatment (treatment associated with the exceptional response and prior treatment). No Personal Health information should be included in the description.
  2. Note whether tissue is available from the time before the exceptional response occurred. (This is required.). Additional information on the type of tissue (Fresh frozen or formalin fixed paraffin embedded) is appreciated.
  3. Note whether informed consent was given to use tissue for research. (The study has a process to address cases without informed consent.)
  4. Note the patient’s vital status.
  5. Provide any additional information you wish.

Within one month, NCI will email you informing you whether the case appears eligible. If the case appears eligible, the site that treated the patient will be asked to provide clinical information, informed consent, tissue samples, and a pathology report. The site will also execute a material transfer agreement (MTA) with the biospecimen facility for the tissue transfer, and a contract with the CTSU for reimbursement for the provision of samples and data. In order to complete these steps, the site must have IRB approval for the study; the study does have approval from an NCI Central IRB (CIRB).

After the full clinical data are provided and, reviewed, if the case is approved at this stage, the site will be asked to send the tissue to the biospecimen resource (instructions will be given). Once the sequencing has been done, the proposer for the case is welcome to participate in the analysis of the data for their case. Results of the sequencing are being done in a research laboratory, not a clinical laboratory, so they cannot be given back to the provider or the patient.

We have also initiated a study of complementary and alternative medicine use, lifestyle changes and comorbid conditions and their medications in patients who are exceptional responders. These data will assist our analysis of why the patient may have responded exceptionally, as well as assist in understanding the prescribed and unprescribed medications that cancer patients take along with their cancer treatment.

You may also email if you have any questions about the Exceptional Responders study.

Other links to information about Precision Medicine: