1. A phase II precision medicine cancer trial
NCI-Molecular Analysis for Therapy Choice (NCI-MATCH / EAY131) Overview
A phase II precision medicine cancer trial
Co-developed by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute
Version Date: 10/13/2017

2. On Behalf of the NCI-MATCH Study Leadership
Keith T. Flaherty1, Alice P. Chen2, Peter J. O'Dwyer3, Barbara A. Conley2, Lyndsay N. Harris2, James V. Tricoli2, Stanley R. Hamilton4, Mickey Williams5, Robert J. Gray6, Shuli Li6, Lisa M. McShane6, Lawrence V. Rubinstein2, Susanna I. Lee1, Constantine A. Gatsonis7, Lalitha K. Shankar8, Paolo F. Caimi9, Shaji Kumar10, Edith P. Mitchell11, James A. Zwiebel2, A. John Iafrate1, Jeffrey Sklar12, Carlos L. Arteaga13
1Massachusetts General Hospital, Boston, MA; 2National Cancer Institute (NCI), Division of Cancer Treatment and Diagnosis, Bethesda, MD; 3University of Pennsylvania, Philadelphia, PA; 4MD Anderson Cancer Center, Houston, TX; 5 NCI Frederick National Laboratory for Cancer Research, Frederick, MD; 6Dana-Farber Cancer Institute, Boston, MA; 7Brown University, Providence, RI; 8NCI Cancer Imaging Program, Rockville, MD; 9Case Western Reserve University, Cleveland, OH; 10Mayo Clinic, Rochester, MN; 11Thomas Jefferson University, Philadelphia, PA; 12Yale University, New Haven, CT; 13Vanderbilt University, Nashville, TN

3. Central screening cohort New process to identify patients
Contents
Trial introduction
Brief history
Central screening cohort
New process to identify patients
Important details
Future plans

4. Precision Medicine
BRAFV600E melanoma responds to BRAF inhibitors or BRAF inhibitors combined with MEK inhibitors; but colorectal cancers with the same mutations appear not to respond
Various tumors with NTRK fusions appear to respond to NTRK inhibitors (ASCO 2017)
We need to know more about which tumors will respond to agents targeted to “driver” mutations
Most driver mutations are relatively rare

5. What is NCI-MATCH?

6. NCI-MATCH Eligibility Overview
Adults ≥ 18 years of age
Solid tumor, lymphoma, or myeloma
Progressed following at least one line of standard systemic therapy
OR type of cancer for which no therapy exists that has been shown to prolong overall survival
Patients who cannot receive other standard therapy due to medical issues may be eligible
Rare diseases for which there is no standard therapy

7. NCI-MATCH Objective
To determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of the cancer type
A signal-finding trial
Treatments that show promise can advance to larger, more definitive trials

8. Levels of Evidence for Target Selection in NCI-MATCH
Level 1: Gene variant credentialed for selection of an approved drug
Level 2: Variant is eligibility criterion for an ongoing clinical trial for that drug OR variant identified in an N of one response
Level 3: Preclinical inferential data
Models with variant respond; without variant do not
Gain of function mutation demonstrated in preclinical model
Loss of function (tumor suppressor genes or pathway inhibitor e.g. NF1); stop codon or demonstrated loss of function in preclinical model

9. Levels of Evidence for Drugs in NCI-MATCH
Level 1: FDA-approved for any indication for that target
Level 2: Agent met a clinical endpoint (objective response, PFS, or OS) with evidence of target inhibition
Level 3: Agent demonstrated evidence of clinical activity with evidence of target inhibition at some level

10. NCI-MATCH’s ~1100 Trial Locations Nationwide
In every state, the District of Columbia, and Puerto Rico

11. Central screening cohort New process to identify patients
Contents
Trial introduction
Brief history
Central screening cohort
New process to identify patients
Important details
Future plans

12. Brief History of NCI-MATCH
Opened on August 12, 2015, with 10 treatment arms and a goal to have 3000 patients submit tumor samples for central testing
795 patients were screened in the first three months
Reached >100/week by the end of this period
Far surpassed the original estimate of 50 screens/month
Paused enrollment of new patients in November 2015, for a planned interim analysis
This resulted in a more accurate estimation of the prevalence rates for the targeted mutations

13. Brief History of NCI-MATCH (cont’d)
Resumed enrollment of new patients in May 2016, with 24 treatment arms and more laboratory capacity to handle rapid pace of enrollment
Increased central screening goal to 6000 patients in late 2016
Added myeloma patients in late 2016
Expanded to 30 treatment arms in March 2017
Completed central screening of ~6000 patients in July 2017, nearly two years ahead of schedule

14. Central screening cohort New process to identify patients Future plans
Contents
Trial introduction
Brief history
Central screening cohort
New process to identify patients
Future plans

15. NCI-MATCH Central Screening Summary
# Registered for Screening
# With Samples
Submitted
# With Testing Complete
# Assigned
to Rx
# Enrolled
on Rx
6397
5962
5559
992
689
as of 09/17/2017

16. Estimated Central Screening Rates in NCI-MATCH
Cases with samples/# enrolled
93%
Assay successful/# with samples
94%
Assigned to Rx/Assay successful
19%
Enrolled on Rx/Assigned
70%
as of 09/17/2017

17. NCI-MATCH Wait Times for the ~6000 Tested Patients
Processing Step
Median
Calendar Days
Tumor sample submission from sites to EA central lab at MD Anderson Cancer Center 7
Completion of tumor testing by lab network and return of results to site 16
Further eligibility evaluation for patients assigned to a treatment arm 14
as of 09/17/2017

18. NCI-MATCH Screening Accrual as of 09/17/2017
Screened
% of Total
Less Common Cancers
3476
62.5%
Common Cancers*
2083
37.5%
Total
5559
Far exceeded the goal of 25%
Common cancers screened:
Colorectal 15.3%, Breast 12.4%, NSCLC 7.3%, Prostate 2.5%

19. NCI-MATCH Less Common Cancers as of 09/17/2017
Disease Site
Screened
% of Total Screened
(N=4694)
Assigned
to Rx
% of Screened
Ovarian
530
9.5 75
14.2
Uterine
345
6.2 90
26.1
Pancreas
341
6.1 21
Cholangiocarcinoma
154
2.8 40
26.0
Liver and Hepatobiliary other than Cholangio.
104
1.9 20
19.2
Sarcoma
255
4.6 31
12.2
Head and Neck
215
3.9 47
21.9
Neuroendocrine
186
3.3 26
14.0
Gastroesophageal
177
3.2 49
27.7
Central Nervous System 94
1.7 35
37.2
Bladder/Urinary Tract
1.6 32
35.6
Cervical 88 25
28.4
Small Cell Lung 80
1.4 4
5.0
Melanoma 77
27.3
Kidney 68
1.2 10
14.7
Anal 46
0.8 11
23.9
Mesothelioma 9
19.6
Lymphoma
0.7 2
Myeloma --
Other
540
9.7
100
18.5
Less Common Cancers
3476
62.5
648
18.6

20. NCI-MATCH Central Screening
What is the biggest change that occurred once the trial reached its 6000-patient central screening goal?
Patients do not need a new biopsy to determine eligibility for the trial because the trial laboratory network no longer collects and tests specimens centrally
NCI ended reimbursement for these procedures

21. NCI-MATCH Central Screening
40% of the treatment arms (12/30) reached the accrual needed for the primary outcome analysis
Some arms targeting more common gene variants were expanded to accommodate the higher numbers of patients with matches
Several arms did not complete accrual within the ~ patients given the low frequency of some of the gene variants
Final complete data is pending publication

22. NCI-MATCH Important Discovery
In the ~6000 patients tested, the tumor gene variants we are studying occurred less frequently than expected in this study population, ranging from 3.47 percent to zero

23. NCI-MATCH Major Change
How did the discovery that gene abnormalities are rarer than expected change the study?
It shed light on the fact that in order to fill the ‘rare variant’ arms, we need to look at tens of thousands of patients
It required setting a new goal for the trial:
Broaden the base of screened patients to complete those arms that target rare tumor gene abnormalities
Rare Variant: Estimated frequency rate of ≤ 1.5% in central screening cohort

24. NCI-MATCH 19 ‘Rare Variant’ Treatment Arms, By Gene Abnormality Prevalence Rate of ≤ 1.5%
Z1C
CDK4 or CDK6
1.36 S2
GNAQ/GNA11
0.16 M
TSC1 or TSC2
1.11 E
EGFR T790M
0.11
Z1B
CCND1/2/3
0.84 V
cKIT R
BRAF fusions
0.80 L
mTOR
0.31 Y
AKT
0.77 G
ROS1
0.05 H
BRAF V600 E/K
0.69 F
ALK
0.03 U
NF2 loss
Z1E
NTRK
0.10 C2
MET exon 14 sk
0.61 A
EGFR activating C1
MET amplif.
0.51 X
DDR2
0.00 T
SMO/PTCH1
0.42

25. NCI-MATCH Accrual Per Arm is Posted Publicly
ecog-acrin.org/trials/nci-match-eay131

26. Central screening cohort New process to identify patients
Contents
Trial introduction
Brief history
Central screening cohort
New process to identify patients
Important details
Future plans

27. New Process for Identifying NCI-MATCH Patients
Effective May 11, 2017 (Addendum #10):
Began a process of finding potentially eligible patients through routine genomic testing done by designated commercial and academic labs that have the capacity to test large numbers of patients
Now, the only pathway for new patients to enroll is through routine testing by a designated lab
Applies to patients at ~1100 participating trial sites
Labs seeking matches to the 19 ‘rare’ variant arms

28. Commercial Labs Collaborating with NCI-MATCH
Caris Life Sciences® and Foundation Medicine, Inc.
Will send a written referral or letter to physicians at any of the ~1100 participating sites
Notifying them that the genomic test they ordered to guide clinical care for their cancer patient has found a gene mutation that could make the patient eligible for one of the treatment arms

29. Selection Criteria for NCI-MATCH Designated Labs
Trial leaders vetted labs for their capabilities to:
Test a high volume of patients
Identify rare variant subsets using a comprehensive and highly-validated assay that considers the specific inclusion and exclusion criteria for each treatment arm
Provide results in a format that can be uploaded into MATCHbox, the trial’s informatics system that generates treatment arm assignments for patients

30. How Patients Move Thru the Trial Process
Physician orders routine test to guide patient’s clinical care (test is not specifically for NCI-MATCH)
Lab runs its standard test and sends results to physician
Lab flags case because patient has tumor gene abnormality and disease characteristics that possibly qualify them for the trial
Lab sends written referral or letter to physician
Physician considers referral
Physician informs patient of possible trial match that must be confirmed by enrolling in NCI-MATCH for screening (Step 0)
Patient decides to pursue and consents to screening (Step 0); physician completes eligibility checklist to confirm they are a candidate for screening
Cont’d next slide

31. How Patients Move Thru the Trial Process (cont’d)
8. Physician enrolls patient to Step 0 with required lab referral
Trial team completes Step 0 and informs physician whether patient will or will not be assigned to a treatment arm
Patient receives assignment, understanding their physician must evaluate them for treatment arm eligibility before they can enroll
Patient decides to pursue and consents to treatment (Step 1); physician evaluates patient for the arm, and enrolls if eligible
Once enrolled, patient will be treated for as long as their tumor shrinks or remains stable

32. Central screening cohort New process to identify patients
Contents
Trial introduction
Brief history
Central screening cohort
New process to identify patients
Important details
Future plans

33. More Details About Testing
Physicians do not order tests specifically for NCI-MATCH
This is standard testing done outside of the trial and prior to any involvement in the study
The patient does not need a fresh biopsy for this trial
The labs are collaborating to help identify patients with rare tumor gene abnormalities
Because these tests are performed as part of routine care planning, the NCI does not reimburse for them

34. More Details About the Lab Referral
Due to the specific inclusion and exclusion criteria for each treatment arm in NCI-MATCH:
The information in the standard testing report is not sufficient to determine trial eligibility, regardless of its content
Physicians must have the written lab referral to consider the trial as an option for their patient
The lab will send the written referral or letter to a physician separate from the standard report

35. Questions About Commercial Lab Referrals
Physicians should contact the designated lab with any questions on the referrals they receive
Physicians may also reach out to the lab about the potential availability for a particular patient

36. Academic Labs Collaborating with NCI-MATCH
Two clinical laboratories are designated to test their own patients using their institutional gene profiling assays done in the setting of clinical care
The University of Texas MD Anderson Cancer Center
Memorial Sloan Kettering Cancer Center
These labs also do not specifically test for NCI-MATCH
Again, the NCI does not reimburse for testing

37. More About NCI-MATCH Eligibility Testing
A few treatment arms require patients to have additional testing to find certain gene abnormalities, beyond the NGS testing done by the designated lab
Example: immunohistochemistry (IHC) testing
If a patient needs additional testing for eligibility, the study team will notify the trial site to submit archived tissue to the central trial lab

38. Confirmation Testing Using the NCI-MATCH Assay
The patient’s matching tumor gene abnormality on the outside assay will be confirmed on the NCI-MATCH assay by the central trial lab
Using archived tissue
Patients do not need a fresh biopsy
Patient treatment will not be delayed for confirmation testing

39. Archival Tissue for Confirmation Testing
Preferably from the same sample that was tested by the designated lab
Trial site should submit archival tissue for confirmation after receipt of a formal treatment assignment
If the trial team requested archival tissue earlier to determine eligibility (e.g. IHC testing), that tissue will also be used for confirmation testing and sites will not need to submit additional tissue unless requested

40. NCI-MATCH Outside Assay Demonstration Project
Trial leaders are testing out this new approach in a demonstration project with the 19 rare variant arms and the four initial labs
The project is helping to study the feasibility of this approach and to determine the potential for it to become a model for use in other precision medicine trials

41. Central screening cohort New process to identify patients
Contents
Trial introduction
Brief history
Central screening cohort
New process to identify patients
Important details
Future plans

42. Plans to Expand NCI-MATCH to Additional Labs
An upcoming protocol addendum, if approved, will allow more laboratories to be designated for testing of their own patients, using their institutional assays
Massachusetts General Hospital
NCI Molecular Characterization (MoCha) Laboratory
Yale University Cancer Center

43. Plans to Expand NCI-MATCH to Add’l Labs (cont’d)
NCI is seeking letters of interest from CLIA-certified/ accredited labs that test tumor specimens from patients utilizing NGS assays
Federal Register Notice, Vol. 82, No Pgs
Posted: August 2, 2017
Deadline: January 31, 2018

44. NCI-MATCH Outcomes Reporting
Reporting of ORR (primary endpoint), PFS, TTP, OS, and toxicity on individual arms will occur once complete response and toxicity data are available for at least 31 patients per arm
If the ORR is ≥ 5/31 (16%), the agent will be worthy of further study as defined by the master protocol
35 patients need to be accrued per arm to obtain 31 for that arm (assuming a 10% ineligibility rate)
Need ~eight months of follow-up after accrual is complete
Secondary analyses will examine response by disease histology, individual variants, and other factors

45. NCI-MATCH Effect of Outside Testing on Analysis
Patients confirmed by the NCI-MATCH assay will be included in the primary outcome analysis
Patients without confirmation may continue treatment, but will not be included in the primary outcome analysis

46. Prevalence Rate in NCI-MATCH
NCI-MATCH New Treatment Arms in Development, for Possible Activation in Late 2017*
Mutation
Prevalence Rate in NCI-MATCH
Arm
Drug
PIK3CA
3.47%
Z1F
Follows arm I
copanlisib
PTEN loss by IHC
1.93%
Z1G
Follows arm P
PTEN mutation and expression by IHC
1.75%
Z1H
Follows arm N
FGFR amplification
1.86% K1
Follows arm W
erdafitinib
FGFR mutation or fusion
1.00% K2
TP53 mutation and MYC amplification
unavailable
Z1J
AZ1775
* Patient entry via designated labs

47. Prevalence Rate in NCI-MATCH
NCI-MATCH New Treatment Arms in Development, for Possible Activation in Spring 2018*
Mutation
Prevalence Rate in NCI-MATCH
Arm
Drug
AKT mutations
0.77%
Z1K
Follows arm Y
ipatasertib
Non-V600
BRAF mutations
0.80%
Z1L
Follows arm R
ulixertinib
(BVD-523)
* Patient entry via designated labs

48. NCI-MATCH Resources Main Webpages: ecog-acrin.org/nci-match-eay131
cancer.gov/nci-match
Protocol Documents: ctsu.org (password required)
Spanish: cancer.gov/espanol/nci-match
Inquiries:
NCI Contact Center:
CANCER and cancer.gov/contact