Abstract: 3506 Background: The NCI-MATCH (EAY131) is a platform trial that enrolls patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on matching genomic alterations of interest (NCT02465060). Arm Z1F evaluated copanlisib, a highly selective, pan-Class 1 PI3K inhibitor with predominant activity against both the δ and α isoforms in pts with PIK3CA mutations. Methods: Pts received copanlisib (60 mg IV) on days 1, 8, and 15 in 28-day cycles until progression/toxicity. Tumor assessment was every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints were PFS, 6-month PFS, and predictive biomarkers. Pts with KRAS mutations, HER2+ve breast cancers, lymphomas were excluded. Results: 35 pts were enrolled (from 8/2/18 to 12/27/18), of which, 28 pts were available for analysis (7 patients, not eligible or did not start therapy). Multiple histologies were enrolled with gynecologic (n = 7), gastrointestinal (n = 6), and genitourinary (n = 5) the most common tumors. Median age 61 (range 42-78). 75% of pts had ≥ 3 lines of prior therapy. 54% of PIK3CA mutations were located in the helical domain, 32% in kinase domain and 14% in other domains. Twenty-six pts had co-occurring gene alterations (median 3; range 1-9), with 9 patients having 4 or more gene alterations. The ORR was 11% (3/28, 90% CI: 3%-25%). Partial responses were seen in uterine cancer, clear cell carcinoma of anterior abdominal wall, and liposarcoma. 6 pts had 〉 6 months of stable disease and clinical benefit rate was 32% (9/28). Two pts are still on treatment. The most common reason for protocol discontinuation was disease progression (n = 18, 69%). Thirty pts were included for toxicity analysis. Ten pts (33%) had grade 1 or 2 toxicities, 16 pts (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 11), hypertension (n = 10), diarrhea (n = 10), and nausea (n = 9). Total of 5 deaths were reported, none related to treatment. Conclusions: Copanlisib showed meaningful clinical activity across various tumors with PIK3CA mutation in the late-line refractory setting. Further study either alone or in combinations in select tumors is warranted. G3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Clinical trial information: NCT02465060 .

Abstract: National Cancer Institute–Molecular Analysis for Therapy Choice is a multicohort trial that assigns patients with advanced cancers to targeted therapies on the basis of central tumor genomic testing. Arm B evaluated afatinib, an ErbB family tyrosine kinase inhibitor, in patients with ERBB2-activating mutations. METHODS Eligible patients had selected ERBB2 single-nucleotide variants or insertions/deletions detected by the National Cancer Institute–Molecular Analysis for Therapy Choice next-generation sequencing assay. Patients had performance status ≤ 1, left ventricular ejection fraction 〉 50%, grade ≤ 1 diarrhea, and no prior human epidermal growth factor receptor 2 (HER2) therapy. Patients received afatinib 40 mg once daily in 28-day cycles. The primary end point was objective response rate (ORR). Secondary end points were 6-month progression-free survival, overall survival, toxicity, and molecular correlates. RESULTS A total of 59 patients were assigned and 40 were enrolled. The median age was 62 years, 78% were female, 68% had performance status = 1, and 58% had received 〉 3 prior therapies. The confirmed ORR was 2.7% (n = 1 of 37; 90% CI, 0.14 to 12.2), and 6-month progression-free survival was 12.0% (90% CI, 5.6 to 25.8). A confirmed partial response occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed partial responses were observed (low-grade serous gynecological tract and estrogen receptor–positive/HER2-negative immunohistochemistry breast ductal carcinoma). Of 12 patients with breast cancer, 1 additional patient with lobular carcinoma (estrogen receptor–positive/HER2 fluorescent in situ hybridization) had a 51% reduction in target lesions but progressed because of a new lesion at cycle 6. The most common ( 〉 20%) treatment-related adverse events were diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%), dehydration (27%), vomiting (27%), nausea (27%), anemia (27%), and anorexia (22%). Four patients (11%) discontinued because of adverse events. CONCLUSION Although afatinib did not meet the prespecified threshold for antitumor activity in this heavily pretreated cohort, the response in a rare tumor type is notable. The safety profile of afatinib was consistent with prior studies.

Abstract: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 ( NF1[S1] or GNA11/Q [S2] ) altered tumors. METHODS Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss. RESULTS Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common. CONCLUSION Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Abstract: Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for NRAS-mutated cancers. Patients and Methods: Patients enrolled in the NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next-generation sequencing. Patients with NRAS-mutated tumors, except melanoma, were enrolled in subprotocol Z1A, a single-arm study evaluating binimetinib 45 mg twice daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A post hoc analysis examined the association of NRAS mutation type with outcome. Results: In total, 47 eligible patients with a refractory solid tumor harboring a codon 12, 13, or 61 NRAS mutation were treated. Observed toxicity was moderate, and 30% of patients discontinued treatment because of binimetinib-associated toxicity. The ORR was 2.1% (1/47 patients). A patient with malignant ameloblastoma harboring a codon 61 NRAS mutation achieved a durable partial response (PR). A patient with NRAS codon 61–mutated colorectal cancer had an unconfirmed PR, and two other patients with NRAS codon 61–mutated colorectal had stable disease for at least 12 months. In an exploratory analysis, patients with colorectal cancer bearing a NRAS codon 61 mutation (n = 8) had a significantly longer OS (P = 0.03) and PFS (P = 0.007) than those with codon 12 or 13 mutations (n = 16). Conclusions: Single-agent binimetinib did not show promising efficacy in NRAS-mutated cancers. The observation of increased OS and PFS in patients with codon 61 NRAS-mutated colorectal cancer merits further investigation.

Abstract: 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 & gt;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 & gt;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: & lt;10% in pancreatic & SCLC; & gt;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.

Abstract: 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.

Abstract: The NCI MATCH is an efficacy signal-finding trial to identify molecular alterations that can be matched to targeted treatments in tumor biopsies from patients (pts) with refractory solid tumors or lymphomas.br / & gt;METHODS: An Ion Torrent Oncomine panel sequencing assay and a binary PTEN immunohistochemistry assay were employed. NCI-MATCH opened in August 2015. A protocol-directed pause in screening for interim analysis occurred in November 2015 with goals to assess tumor biopsy feasibility and quality, performance of the CLIA-accredited laboratories, any unanticipated concerns with the study, the match rate for the first activated 10 arms and for planned arms, the spectrum of molecular abnormalities identified, histologic tumor types and demographics. RESULTS: Between 8-12-15 and 11-11-15, 795 pts enrolled for screening and 739 biopsies were submitted. Biopsies were submitted from community (2/3) and academic (1/3) sites. Sequencing was completed on 645 of these specimens (87%). Median turn around time was 27 days but increased from 14 days in the first month to 36 days in the last month, correlating with marked increase in weekly accrual. The highest toxicity (Grade 3) possibly related to biopsy was & lt; 1%. The most frequent tumor types sequenced were colorectal (13%), breast (13%), ovarian (11%), non-small cell lung (7.4%), endometrial (7%), pancreatic (5%), head/neck (5%) esophageal/gastric (4%), cholangiocarcinoma and neuroendocrine (3% each), and small cell lung, prostate, bladder, and unknown primary ( & lt;3% each). Fifty-six patients (9%) had actionable mutations of interest (aMOIs); of these, 33 pts (5.1%, 95%CI 3.5, 7.1%) met molecular eligibility for assignment to one of 10 treatment arms. The most common genetic mutations, amplifications or translocations were: PercentMutation/amplification/translocation52TP5319KRAS12PIK3CA10APC, CDH14-5CDKN2A3-4CCND13BRAF, PTEN, ESR1, CTNNB1, ERBB2, CCNE12.5EGFR, FBXW7,FGFR 1/2/3, MDM22KIT, BRCA 1/2, IDH 1/2, NF1, RB1 CONCLUSIONS: Accrual was brisk and biopsies were feasible and safe with adequate tumor yield and results. The match rate was lower than predicted for the first 10 treatment arms. Accrual of less common tumor histologic types exceeded expectations. Results from the interim analysis will inform the types of treatment and predicted match rate for additional MATCH arms. NCI-MATCH will re-open with increased capacity and additional treatment arms with a match rate goal of at least 20%. Citation Format: Barbara A. Conley, Robert Gray, Alice Chen, Peter O’Dwyer, Carlos Arteaga, Brent Coffey, David Patton, Shuli Li, Lisa M. McShane, Larry Rubinstein, Robert Comis, Jeffrey Abrams, Paul M. Williams, Chih-Jian Lih, Stanley Hamilton, Edith Mitchell, James Zwiebel, Keith Flaherty, NCI MATCH team. NCI-molecular analysis for therapy choice (NCI-MATCH) clinical trial: interim analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT101.

Abstract: 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 ( & gt;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.