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Background: The NCI-MATCH precision medicine trial assigns patients (pts) with solid tumors, lymphoma, or multiple myeloma whose cancers have progressed on prior treatment to a targeted therapy based on genetic alterations identified in pre-treatment biopsies. Arm K2 (EAY131-K2) evaluated the pan-FGFR inhibitor erdafitinib (E) in pts with FGFR mutations or fusions. Patients and methods: Pts with bladder or urothelial cancers were excluded. Pts received E 8 mg PO daily (28-day cycle) until disease progression or unacceptable toxicity; dose reduction for toxicities was allowed; imaging was performed every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Results: A total of 35 pts were enrolled to this arm from 07/2018-07/2019; one was ineligible and one did not receive treatment. Nine distinct tumor histologies were represented, most common being pancreatobiliary (11), CNS (7) and gynecological tumors (5). 73% of pts were female, with median age of 59y (range 26-83y), 70% were Caucasian, and 61% of pts had received at least 3 prior therapies (range 0-22). Alterations in FGFR1, FGFR2 and FGFR3 were recorded in 6, 18, and 9 evaluable pts, respectively. 18 pt tumors had fusions and 15 had mutations in an FGFR gene. The confirmed ORR was 12% (90% CI 4%, 26%), with a median duration of response (DoR) of 7.3 months (mo), range 4.2-11.7 mo. Responses were seen in cholangiocarcinoma (2 pts), Brenner ovarian tumor and adenoid cystic carcinoma (1 pt each). Two (50%) of these 4 tumors harbored FGFR fusions and 2 FGFR mutations. 13 pts had stable disease (SD). Median PFS was 3.9 mo, and 6-mo PFS was 32.8% (90% CI 21.2%, 50.6%). Median OS was 11.0 mo. Of the 6 pts with intrahepatic cholangiocarcinoma, 2 had PR and 2 SD. The most frequent grade 3 treatment-related AEs were oral mucositis/pain (5 pts), paronychia, electrolyte disorders, and anemia/lymphopenia (2 pts each). There were no treatment-related grade 4-5 toxicities. Toxicities were reversible and manageable with E dose interruptions and/or dose reduction. Conclusions: In this pre-treated, mixed histology cohort with tumors harboring FGFR somatic alterations, E showed activity with durable responses and disease stabilizations outside of currently approved FDA indications, although the pre-specified criterion that the primary endpoint, ORR, be significantly greater than 16% was not reached. Toxicities were consistent with E safety profile. Responses were observed in tumors harboring FGFR fusions as well as in those with mutations of FGFR; further correlative analyses are planned. Citation Format: Alain C Mita, Zihan Wei, Ingrid A Mayer, Heather Cheng, Edith P Mitchell, John J Wright, Percy Ivy, Robert J Gray, Victoria Wang, Lisa M McShane, Larry V Rubinstein, David R Patton, Mickey Williams, Stanley R Hamilton, Barbara A Conley, Carlos L Arteaga, Lyndsay N Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty. Erdafitinib in patients with tumors harboring FGFR gene mutations or fusions: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K2 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA003.

Introduction: NCI-MATCH, developed by ECOG-ACRIN & NCI, is the largest precision medicine study for pts with refractory malignancy. Over 1100 clinical sites in the National Clinical Trials Network enrolled pts. The purpose of the study is to identify potentially beneficial targeted treatments across tumor types with similar molecular abnormalities. Methods: The NCI Central IRB approved NCI-MATCH. Pts with refractory/no treatment available solid tumors, lymphomas or myelomas had a fresh biopsy profiled by next generation sequencing (143 genes, > 4000 single nucleotide variants, indels, amplifications & targeted fusions). Pts are assigned by a defined algorithm to treatments with evidence of activity against tumors with the relevant molecular alteration. Pts are excluded if a treatment is FDA approved or known to be ineffective for their malignancy. After successfully sequencing fresh biopsies from 5540 pts, subprotocols with extremely rare variants lacked sufficient accrual. To address actionable variants with a prevalence of < 1.5%, we decided to accept clinical sequencing results from 30 commercial and academic laboratories vetted by NCI-MATCH to address relevant variants. These labs notify clinicians participating in NCI-MATCH if their pt’s tumor contains an actionable variant. Treatment continues until tumors became refractory, pt intolerance or withdrawal of consent. An objective response rate (ORR by RECIST) of > 16% among 31 eligible patients is considered a positive signal. Results: After screening 5540 pts, 37.6% had an actionable variant. After histology and treatment-specific exclusions, 17.8% were assigned and 69.5% enrolled on the assigned subprotocol. 11 of the initial 30 subprotocols reached completion with adequate follow-up. Of the first 11 evaluable subprotocols, 3 addressing rare variants had a positive signal: Nivolumab in pts with loss of expression of MLH1 or MSH2 (ORR 36%), capivasertib in pts with AKT mutations (ORR 23%), and dabrafenib + trametinib in pts with BRAF V600 mutations (ORR 33%). These molecular variants were found in 2%, 1.2% and 1.9% respectively, of screened pts. Two other subprotcocols (afatinib in ERBB2 mutations and AZD4547 in FGFR abnormalities) showed responses in rare tumors or specific variant subsets, respectively. As of July 15, 2019, an additional 378 of 432 (88%) pts have been assigned to a treatment with a clinical sequencing assay; 83% of these pts enrolled to 1 of 24 subprotocols, allowing completion of an additional 9 of the original 30 subprotocols and complete accrual to 2 of 5 recently added subprotocols. Four of 35 subprotocols closed for lack of accrual, 10 continue accruing and 4 are planned. Conclusions: Platform precision medicine trials can identify potentially useful targeted treatments for diverse malignancies in pts with uncommon tumors & rare actionable variants, an unmet need. In a population of pts with refractory cancers, lymphomas and myelomas, 30-40% will have an actionable variant for targeted treatment (investigational or standard). Of the first 11 subprotocols with adequate follow-up, 3 (27%) showed a positive signal and an additional 2 showed responses in rare tumors or in a molecular subset, suggesting that the NCI-MATCH trial approach identifies useful targets for further exploration. Citation Format: Lyndsay N Harris, Robert J Gray, Barbara A Conley, Alice P Chen, Keith T Flaherty, Stanley R Hamilton, Paul M Williams, Chris Karlovich, David Patton, Shuli Li, Lisa M McShane, Larry V Rubinstein, Edith P Mitchell, James V Tricoli, Richard F Little, Carlos L Arteaga, Peter J O'Dwyer, NCI-MATCH team. National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH): A successful precision medicine signal-seeking trial in patients (pts) with rare variants and refractory malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A079. doi:10.1158/1535-7163.TARG-19-A079

Background: Over the last 30 years, adolescent and young adult (AYA, 15-39 years of age) patients (pts) with cancer have experienced smaller improvements in 5-year survival compared to younger and older pts. One reason is their historically lower rate of participation in clinical trials (~3% AYA vs. 10% in pts > 40 years of age in adult cancer centers). A histology-agnostic trial provides greater opportunity for the AYA population and may improve accrual. The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH; NCT0246506), a phase II precision medicine trial evaluating targeted therapy in adult pts (3 18 years old) based on molecular abnormalities in a tumor-agnostic fashion, has been open since 2015. Jointly developed and coordinated by NCI and ECOG-ACRIN and open through the NCI National Clinical Trials Network and the NCI Community Oncology Research Program at more than 1100 academic and community sites, this trial screened 6801 pts for 39 independently-accruing targeted treatment subprotocols. We reviewed the AYA data from the NCI-MATCH trial, which, due to eligibility criteria, does not include pts age 15-17. Materials and Methods: AYA pts age 18-39 with treatment-refractory malignancies (solid tumor, lymphoma, or myeloma) who were (a) eligible for a screening biopsy on the NCI-MATCH trial (screening cohort [SC]) or (b) had an actionable mutation previously identified through clinically indicated sequencing at a CLIA-approved and NCI-MATCH–accepted laboratory (outside assay cohort [OAC]) were eligible for MATCH AYA analysis. Results: Of the 6801 pts screened for NCI-MATCH, 373 were AYA pts age 18-39 (5.5%). Within the SC, 93.5% (300/321) of AYA pts were successfully biopsied, vs. 92.9% of those age 40+ (5240/5640); 35.7% of the SC AYA vs. 39.6% of the 40+ pts had a study-eligible actionable mutation, and 17% (51/300) of AYA pts vs. 17.8% (934/5240) of those 40+ were subsequently assigned to treatment. Of the 401 pts in the OAC, 30 (7.1%) were AYA; 24/30 (80.0%) of AYA OAC pts were assigned to treatment vs. 87.6% (332/379) of OAC pts age 40+. Screening enrollment data show that at Lead Academic Participating Sites (LAPS), a higher percentage of AYA pts were enrolled compared to pts age 40+ (32.8% [113/344] vs. 24.3% [1472/6047], respectively). In contrast, at NCORP sites, a higher percentage of 40+ pts was enrolled relative to AYA pts (43.8% [2647/6047] vs. 35.8% [123/344], respectively). Among the top histologies enrolled (aside from colon, breast, ovarian) were soft tissue sarcoma other than rhabdomyosarcoma, primary CNS tumors, and liver and hepatobiliary, cervical, and neuroendocrine cancers. Conclusions: There were no statistically significant differences between AYA and older (40+) pts in the number who underwent successful biopsies, the prevalence of tumor actionable mutations, or the number of pts assigned to or who received study treatment. AYA pts were more likely to have been enrolled at a LAPS than a NCORP site, consistent with the AYA population being referred to LAPS upon progression from first-line treatment. Enrollment of the AYA in adult cancer centers in the NCI-MATCH trial was higher than the historical 3%: 5.5% in the SC and 7.1% in the OAC. As more tissue-agnostic studies become available in nationwide trials, AYA participation in clinical trials may increase. Citation Format: Alice P Chen, Shuli Li, Brent Coffey, James V Tricoli, Stanley R Hamilton, Mickey P Williams, Edith P Mitchell, David Patton, Robert J Gray, Lisa M McShane, Lawrence V Rubinstein, Carlos L Arteaga, Peter J O'Dwyer, Lyndsay N Harris, Barbara A Conley, Keith T Flaherty. Adolescent and young adult (AYA) cohort of the NCI MATCH clinical trial (EAY131) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A089. doi:10.1158/1535-7163.TARG-19-A089

Purpose: NCI-Molecular Analysis for Therapy Choice (NCI-MATCH/EAY131), by ECOG-ACRIN (EA) and NCI, is the first national signal-finding trial to incorporate centralized NGS testing to direct patients (pts) to molecularly targeted parallel phase 2 treatment arms. We report status of accrual from opening on 08/12/15 thru 07/16/17 and future plans. Methods: Eligible pts have advanced/refractory solid tumors, lymphoma, or myeloma. Drug treatments and molecular targets require stringent levels of evidence (LOE). Each arm (N-35) has a phase 2 dose, a molecular abnormality believed to predict response, and evidence of clinical activity. Pts must have enrolled by 05/22/17 with intent to submit fresh tissue or recent clinical biopsy. Tumor cores are shipped to the EA Central Biorepository & Pathology Facility at MD Anderson Cancer Center for evaluation of histopathology and % tumor; PTEN, MLH1, and MSH2 IHC; and RNA/DNA extraction. NGS is performed in one of 4 CLIA-accredited laboratories using the NCI-MATCH adapted Oncomine™ panel (Version 1.0; 143 genes with >4000 reported variants including SNVs, indels, amplifications, and gene fusions). When an actionable mutation of interest (aMOI) or relevant IHC result is identified, the pt is assigned to treatment by a custom-designed informatics system (MATCHbox). If >1 aMOI present, the pt is assigned by the variant with the highest LOE. Results: As of 07/16/17, 5963 tumors were screened for 30 treatment arms. The assay success rate is 93%; median turnaround is 15 days (from sample receipt to return of results). 38.2% of pts have common cancers: colorectum (15.4%), breast (12.8%), lung (7.4%), and prostate (2.6%); 61.8% have less common tumors. The current overall match rate to aMOI’s is 18% (95% CI 17%, 19%); aMOI prevalence rates range from 3.47% to zero. The match rate also varies across tumor types: 30% in bladder/urinary tract, uterine, and head/neck cancer. 998 pts have been assigned to Rx; 69% have enrolled. Of 30 arms, 8 have enrolled ≥ 35 pts; some arms with higher prevalence rates have been expanded to N=70 to accommodate pts with matching aMOIs. Arms with less frequent aMOIs will not complete accrual within the 6,000-pt central screening goal, leading to identification of pts for screening based on approved high-volume NGS labs’ assay results, verified centrally. Conclusions: NCI-MATCH screened ~6000 pts at a rate that far exceeded expectations, and with acceptable toxicity; NGS was successful in 93%, well above the industry average of ~80%. The pace of enrollment, along with the trial’s availability at 1100+ sites, reflects the broad interest in the promise of genomics and the ability of such a trial to deliver on that promise. Lower accrual to "rare variant" arms led to use of high-volume NGS laboratories to complete the study. Follow-up will determine whether matching drugs to molecular targets results in meaningful response rates and improved patient outcome. Citation Format: Lyndsay Harris, Alice Chen, Peter O'Dwyer, Keith Flaherty, Stanley Hamilton, Lisa McShane, Robert Gray, Shuli Li, Edith Mitchell, Diane Dragaud, Mickey Williams, Jeffrey Sklar, A. John Iafrate, David Patton, Richard F. Little, James Zweibel, Jeffrey Abrams, James Doroshow, Barbara Conley. Update on the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH/EAY131) precision medicine trial [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B080.

Oncology has undergone major changes in systemic treatment options, from chemotherapy to antiangiogenic agents to tyrosine-kinase inhibitors to immunotherapy. Historically, a therapeutic agent is tested in separate trials as monotherapy or combined with investigational or approved agents/modalities, to determine antitumor activity in each histology based on the premise that each histology responds differently to the same treatment. This paradigm is time consuming and may or may not make use of molecular characterization to test each agent in each histology. However, with the expansion of biologic understanding and development of various biomarkers, e.g., estrogen receptor and Her 2 amplification, we move beyond the basic paradigm of general histology to one in which treatment is based upon molecular characteristics of the tumor. Examples of recent discoveries from this more modern paradigm are (1) multiple histologies sharing a common molecular profile and (2) a subset within a single histology having a given molecular characteristic. Various agents have been tested singularly in terms of molecular aberrations and histology, e.g., ALK inhibitors and NSCLC. However, with the rapid increase in the number of targeted agents in development, more facile and efficient clinical trial designs are needed. The National Cancer Institute (NCI) and ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) collaborated in designing the Molecular Analysis for Therapy Choice trial (NCI-MATCH or EAY131), the first large-scale signal-finding precision medicine oncology trial in the United States to incorporate centralized NGS testing to direct patients to parallel (nonrandomized) phase II treatment arms under a master protocol. The trial is being conducted by the NCI National Clinical Trials Network (NCTN), with ECOG-ACRIN leading the trial. More than 100 investigators from across the NCTN adult cancer-oriented member groups (Alliance for Clinical Trials in Oncology, ECOG-ACRIN, NRG Oncology, and SWOG) have worked collaboratively to design and lead what is currently 30 treatment arms (subprotocols), with more arms in development. Wide-scale NCTN investigator involvement ensures use of the latest knowledge to define the actionable mutations required for eligibility and to make evidence-based selections of experimental agents. In NCI-MATCH, patients are assigned treatment based on the genomic alterations found in their tumors through genomic sequencing and other tests at the time of initial enrollment for screening. Unlike other phase II trials, each arm is open to advanced solid tumors, lymphomas, or myeloma that share a set of molecular aberrations, not restricted to a single histology. This strategy accommodates and encourages enrollment of rare tumors for which there are often no standard treatments and limited clinical trial options. NCI-MATCH has 10-30 concurrent treatment arms available to patients at any given time, testing both investigational agents and FDA-approved drugs for new indications. Most treatment arms have an enrollment goal of 35 patients, with some arms that address tumor gene variants of higher prevalence expanded to 70 patients. Together, the NCTN and NCI Community Oncology Research Program provide infrastructure for many clinical sites (>1100) to participate, providing ready access to physicians and patients; screening enrollment has occurred in all 50 states in the U.S, the District of Columbia, and Puerto Rico. A specific assay was developed for the trial (the MATCH assay), and a laboratory network was organized to rapidly process the tissue and efficiently interrogate for mutations. NCI and ECOG-ACRIN statisticians developed the analysis plan and are currently maintaining data that are closely monitored by safety experts for any adverse event signals. Lastly, a bioinformatics system (MATCHbox) was developed to coordinate molecular data collection and support rule-based decision-making based on those data. Because genomics in oncology is rapidly expanding and evolving, NCI-MATCH required flexibility to accommodate brisker screening accrual than anticipated, and adaptation to constantly emerging information about new drugs and new molecular alterations. The goal to sequence the tumors of 6,000 patients with NCI funding was achieved two years ahead of schedule, but that cohort was not sufficient to fill all the arms—in particular, those aimed at the most rarely occurring tumor gene aberrations. Currently, the goal for the trial is to complete the open treatment arms by allowing for designated commercial and academic laboratories to notify ordering physicians when genomic tests they ordered to guide clinical care indicate a potential eligibility to a NCI-MATCH arm with a rare variant and allow for enrollment to the relevant treatment subprotocol if the patient meets all subprotocol eligibility criteria. The tissue confirmation of the molecular abnormality on the MATCH assay by the central laboratories will be accomplished after subprotocol enrollment so that patient treatment will not be delayed for confirmation. A demonstration project is now under way to test the applicability of this approach and potentially develop common standards for future use. With tumor sequencing becoming a more and more common practice in oncology, this may allow patients with mutations of low prevalence to have investigational treatment options. NCI-MATCH is expanding its panel and definition of actionable mutations to allow greater flexibility to incorporate in real time new mutations supported with adequate levels of evidence. The valuable genomic and clinical outcome data collected in the trial will permit evaluation of efficacy of targeting certain actionable mutations with a specific agent. In addition, biospecimens are being collected to build a rich resource for conducting auxiliary biology studies that may answer questions about prevalence of mutations in the metastatic setting, prevalence of mutations in rare histologies, and resistance mechanisms of various targeted therapy. At this meeting, two abstracts will provide an overall trial update and present information about the prevalence of mismatch repair deficiency (dMMR) in the centrally screened population. Citation Format: Alice P. Chen, Peter J. O'Dwyer, Lyndsay Harris, Barbara A. Conley, Stanley R. Hamilton, Mickey Williams, Robert J. Gray, Shuli Li, Lisa M. McShane, Lawrence V. Rubinstein, Susanna I. Lee, Shaji Kumar, Edith P. Mitchell, James A. Zwiebel, Constantine A. Gatsonis, Lalitha K. Shankar, Paolo F. Caimi, Carlos L. Arteaga, A John Iafrate, Jeffrey Sklar, Richard F. Little, Keith T. Flaherty. NCI-MATCH: A new paradigm in the era of genomic oncology [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr PL03-01.

Introduction: NCI-MATCH (EAY131), a national signal-finding trial, assigns targeted treatments to patients (pts) with relapsed/refractory solid tumors, lymphomas and myelomas based on molecular abnormalities in tumors. We screened 4901 pts for dMMR, an eligibility criterion. Methods: Immunohistochemical expression (IHC) of MLH1 and MSH2 was performed at the CLIA-accredited MD Anderson Clinical IHC Laboratory. Loss of nuclear expression of MLH1 or MSH2 predicted microsatellite instability resulting from sporadic alterations or germline mutations. Assays were validated for FFPE tissue and used under an FDA abbreviated investigational device exemption. IHC was performed on 4 μm deparaffinized and rehydrated FFPE tissue sections. Antigen retrieval was performed at 100°C for 20 minutes with Tris-EDTA buffer solution, pH 6.0 & blocking of endogenous peroxidase with 3% peroxide for 5 minutes. Primary MLH1 antibody (Cell MarqueTM, clone G168-728) at 1:300 dilution and primary MSH2 antibody (Calbiochem®, clone FE11) at 1:100 dilution were applied. Primary antibody detection used a commercial polymer system (Bond Polymer Refine Detection, Leica) with stain development using incubation with DAB and DAB Enhancer (Leica). Loss of nuclear expression (required for dMMR eligibility): Complete loss of nuclear expression by tumor cells and retention of staining in non-neoplastic cells (internal control). Intact nuclear expression: Nuclear expression of any intensity within tumor cells. Cannot be determined: Insufficient specimen, technically inadequate IHC assay, or cytoplasmic staining without definite nuclear staining. Results: 4901 pts had MLH1/MSH2 IHC assay, of whom 37 had both MLH1 and MSH2 indeterminate. Of 4864 cases with valid MLH1/MSH2 results, 2% had dMMR (Table–histologies combined to fit allowed space). The most frequent dMMR was in the few thyroid/parathyroid tumors, followed by various gynecologic tumors. Conclusion: 2% of 4864 cases with valid MLH1/MSH2 results in NCI-MATCH had dMMR by IHC; prevalence varied across histologies. Many tumors lacking expression of MLH1 or MSH2 are not prominently associated with Lynch syndrome or frequent somatic dMMR. The NCI-MATCH screen for dMMR adds to information on the potential benefit of screening advanced/refractory tumor types for this abnormality as a standard practice for determining eligibility for PD-1 inhibitors. Pecent tumor categories lacking MLH1/MSH2 expressionHistologyLoss of nuclear MLH1 expressionLoss of nuclear MSH2 expression# screenedPercent of screenedGastrointestinal cancer29413252.5%Gynecological cancer28330110.3%Brain cancer02523.8%Sarcoma (various)601065.7%Thyroid/Parathyroid02366.7%Prostate071225.7%Breast715661.4%Neuroendocrine231922.6%Other303260.9% Citation Format: Barbara A. Conley, Stanley R. Hamilton, Shuli Li, Robert J. Gray, David R. Patton, Peter J. O'Dwyer, Robert L. Comis, Jeffrey S. Abrams, Nilofer S. Azad, Michael J. Overman, Jonathan D. Schoenfeld, Paul M. Williams, James V. Tricoli, Elad Sharon, Howard Streicher, Lyndsay N. Harris, Alice P. Chen, Keith T. Flaherty. Prevalence of mismatch repair deficiency (dMMR) in the NCI Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) population [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A053.