Testing targeted therapy based on genetic mutation: MATCH trial

JohnSmith · June 2015

The U.S. federal government is launching a very different kind of cancer study that will assign patients drugs based on what genes drive their tumors rather than the type of cancer. (I thought this was already happening!)

The National Cancer Institute (NCI) announced today at the annual ASCO conference that they are now enrolling patients for the MATCH trial ("Molecular Analysis for Therapy Choice").
This cancer study that will assign drugs based on what genes drive their tumors, rather than the type. 3,000 patients will have their tumor genes sequenced to see what mutations or pathways fuel their disease.
Those eligible for the study will be adults with tumors that worsened or spread despite at least one standard treatment.
The trial is based on the growing realization that many cancers share the same gene mutations or pathways to grow. So a drug that targets one of these for a specific cancer, such as breast, may work against other types, such as lung, and vice versa.

Here's the link to the NCI website that describes the trial details.

Here's a couple media articles announcing the news.
Testing targeted therapy based on genetic mutation

NCI-MATCH trial will link targeted cancer drugs to gene abnormalities

MusicLover · June 2015

Thank you once again for the post but if you read the first and last (third) link that you posted this is only for rare cancers currently and does not include breast cancer at this time. This still is a good post and hopefully be very successful and then become available to the common cancers like breast cancer, I think that is what they are saying, correct?

(I thought it was happening already also, what is genomic testing for then? So confusing.)

JohnSmith · June 2015

It's a bit tricky to read since enrollment involves multiple arms over the course of months/years.

From what I understand, the study aims at enrolling 25% with rare cancers. The other 75% would be common cancers.

Here's a bit more from the actual trial page: "A goal for NCI-MATCH is for at least 25 percent of the approximately 1,000 patients enrolled in the trial to have rare cancers. Rare cancers cancers can include cancers at sites in the body where cancer rarely occurs, such as the eye, ureter, and pituitary gland, as well as cancers that are classified as rare because the primary location of the tumor could not be determined at the time of diagnosis. Common cancers are non-small-cell lung, breast, colorectal, and prostate cancers."

For those that are visual, here's a simple explanation of the trial: NCI-MATCH Clinical Trial Infographic

MusicLover · June 2015

Thank you again.

JohnSmith · June 2015

They actually announced three trials at ASCO today.

This news article describes the trials quite clearly: Cancer trials aim to shore up 'precision medicine's' base of evidence

-> Precision, personalized or individualized medicine: By any name, it's going to take big clinical trials
-> Cancer patients with few options left will get a crack at more targeted treatments
-> In one trial, cancer medicines will come from drug companies, averting insurance hassles many patients face

cp418 · June 2015

http://medicalxpress.com/news/2015-06-cancer-preci...

more on the same article

JohnSmith · October 2016

An update on the NCI-MATCH Clinical Trial.
Volunteers are needed for this nationwide trial. The trial will examine tumor biopsy specimens from as many as 5,000 patients. It is expected that ~10% will have actionable mutations, so ~500 patients will be enrolled into the following Trial Arms below.
Here's the list of actionable Mutations and matching Drugs (as of Sept 2016)

Arm ----- Target ------------ Drug(s)

A -------- EGFR mut ----------- Afatinib
B -------- HER2 mut ----------- Afatinib
C1 ------- MET amp ----------- Crizotinib
C2 ------- MET ex 14 sk ------- Crizotinib
E -------- EGFR T790M -------- AZD9291
F -------- ALK transloc --------- Crizotinib
G -------- ROS1 transloc ------- Crizotinib
H -------- BRAF V600 --------- Dabrafenib+trametinib
I --------- PIK3CA mut -------- Taselisib (Roche / Genetech's second generation PI3K inhibitor)
N -------- PTEN mut --------- GSK2636771
P -------- PTEN loss --------- GSK2636771
Q -------- HER 2 amp -------- Ado-trastuzumab emtansine
R -------- BRAF nonV600 ----- Trametinib
S1 ------- NF1 mut ------------ Trametinib
S2 ------- GNAQ/GNA11 ------ Trametinib
T -------- SMO/PTCH1 -------- Vismodegib
U -------- NF2 loss ----------- Defactinib
V -------- cKIT mut ----------- Sunitinib
W -------- FGFR1/2/3 -------- AZD 4547
X -------- DDR2 mut ---------- Dasatinib
Y -------- AKT1 mut ---------- AZD 5363
Z1A ------ NRAS mut -------- Binimetinib
Z1B ------ CCND1,2,3 amp ---- Palbociclib (Ibrance)
Z1D ------ dMMR -------------- Nivolumab (Opdivo, an Immunotherapy drug)

JohnSmith · February 2017

January 2017 Update:

http://www.ajmc.com/journals/evidence-based-oncology/2017/january-2017/innovative-approach-to-precision-trial-design-nci-match-and-beat-aml-/P-2

Keith Flaherty, MD, provided an update on the NCI-MATCH trial. Flaherty, director of the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital and associate professor of medicine at Harvard Medical Center, also chairs ECOG-ACRIN, which is collaborating with NCI on this trial. He was very excited to share with the audience that the trial was expected to hit it's 6000 patient enrollment target in the next 6 months.

"We are currently enrolling 120 to 150 patients being each week," Flaherty said. "The objective of this phase 2 precision-med trial is to match genetic abnormalities of tumors with a suitable targeted drug, regardless of cancer type," he explained. "It's a signal-finding trial, meaning promising treatments can be expanded to a more definitive trial in the future."

Eligibility criteria for enrollment in NCI-MATCH include adults over 18 years, those who lack or have exhausted standard treatment, patients who have developed either solid or liquid tumors, patients with a good ECOG performance status and adequate organ function, and patients who can tolerate being off treatment for 6 weeks. Flaherty listed the following criteria for source material for genetic and immunohistochemistry analysis:

The trial mandates a fresh tumor biopsy to identify gene abnormalities
Patients can be screened with local next-generation sequencing, but results have to be confirmed on an NCI-MATCH assay
Biopsy and sequencing on progression for responders
Planned assays for research purposes:
- Whole-exome DNA sequencing
- RNA analysis by whole transcriptome analysis
- microRNA assay

The following Levels-of-Evidence strategy is being implemented by NCI-MATCH:
Level 1: gene variant credentialed for selection of an approved drug
Level 2a: variant eligible for an ongoing clinical trial
Level 2b: variant identified in an N of 1 response Level 3: preclinical inferential data

Levels of Evidence for drugs in NCI-MATCH include:
Level 1: FDA-approved for any indication for that target
Level 2: agent met a clinical endpoint, with evidence of target inhibition
Level 3: agent demonstrated evidence of clinical activity, with evidence of target inhibition at some level

Among the 6000 patients that will be the final enrollment, 929 treatment enrollments are anticipated across 24 gene abnormalities that are currently being evaluated as part of this trial. The primary trial endpoint is overall response rate, with secondary endpoints of PFS, time to progression, toxicity, and biomarker expression.

Flaherty explained that the trial demands 4 core biopsies at initial entry, which are shipped to the central lab at MD Anderson. H&E sections are assayed by a pathologist for tumor type, content, percent necrosis, and inflammation, and scanned into a high-resolution image database. RNA and DNA are then extracted and distributed to a network of laboratories.

Currently, immunohistochemistry analysis is being conducted for PTEN, MLH1, MSH2, and Rb. "We have also added mismatch repair genes and are evaluating PD-1 expression," he added. The trial has incorporated a customized Oncomine assay, which has been developed by Thermo Fischer. The panel includes 143 genes, 2530 amplicons in the DNA panel, and 207 amplicons in the RNA panel. Flaherty provided a very uplifting picture on patient wait times:

Sample submission from sites to central lab at MD Anderson: 7 days
Completion of tumor testing by lab network and return of results to site: 15 days
Secondary screening for patients assigned to a treatment arm: 14 days.

"As of November 27, we have 3149 patients with tumor samples, of whom 2589 have received their test results; 468 had a genetic abnormality matching an available treatment," Flaherty told the audience, "and 22% of currently enrolled patients have a gene abnormality that matches one being studied in the trial." Although the trial currently has 24 arms, this number is expected to increase. - See more at: http://www.ajmc.com/journals/evidence-based-oncolo...

Rseman · March 2017

I have the PIK3CA mutation and there is a waiting list to get on Genetech's clinical trial. I was ineligible for MATCH because I have a pacemaker but had the testing done anyway. I hope a spot opens up for me. My last treatment failed and I haven't been on effective treatment since before Jan 24. Something has to give

Testing targeted therapy based on genetic mutation: MATCH trial

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