Targeted Agent And Profiling Utilization Registry Research Articles

Abstract CT135: Cetuximab (C) in patients (Pts) with breast cancer (BC) and non-small cell lung cancer (NSCLC) without reported KRAS, NRAS, BRAF mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Abstract Background: The TAPUR Study is a phase II multi-basket study that evaluates the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations known to be drug targets. Results in two cohorts of BC and NSCLC pts each without reported KRAS, NRAS, BRAF mutationstreated with C are reported. Methods: Simon’s optimal two stage design was used to test the null hypothesis of 15% response rate versus the alternative of 35%. Power and alpha were set at 85% and 10%, respectively. Response was assessed per RECIST v1.1. This design requires 10 pts in stage 1 and if <2 pts have objective response (OR) or stable disease (SD) at 16 weeks (wks), the cohort is closed. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Genomic testing was performed using commercially available tests selected by clinical sites. Treatment was determined according to protocol matching rules based on genomic inclusion criteria. Results: Ten pts were enrolled in the BC cohort from June 2016 to May 2018. Ten pts were enrolled in the NSCLC cohort from January 2017 to May 2018. Pts received C at an initial intravenous infusion of 400 mg/m2 over 120 minutes and subsequent weekly infusions of 250 mg/m2 over 60 minutes. All pts are included in the data analysis for demographics, safety, PFS and OS (Table 1). No ORs or SD at 16 wks were observed in either cohort and both were therefore closed. Grades 3-4 adverse events (AEs) at least possibly related to drug are required to be reported. A single grade 3 AE of hypomagnesemia was reported in the NSCLC cohort as possibly related to C. Conclusions: Results from these cohorts suggest monotherapy with C does not have clinical activity in BC or NSCLC pts without reported KRAS, NRAS, BRAF mutations. Other treatments should be considered for these pts, including treatments offered in clinical trials. Table 1:Baseline demographics, clinical characteristics and outcomes by cohortCetuximab targeting tumors without reported KRAS, NRAS, BRAF mutationsTumor TypeBC (N=10)NSCLC (N=10)Median age, yrs (range)59 (45, 65)60 (55, 82)Male, %060ECOG Performance Status, %01260301010900Median PFS, wks (90% CI)6.7 (4.0, 7.9)8.0 (7.6, 8.4)Median OS, wks (90% CI)11.0 (4.9, 30.1)19.6 (8.6, 25.6)Drug-related AEs, grades 3-4 (% of pts)010 Citation Format: Julie Fisher, Elizabeth Garrett-Mayer, Susan Halabi, Pam K. Mangat, Ricardo H. Alvarez, Timothy L. Cannon, Pamela Crilley, Theodore Pollock, Tareq Al Baghdadi, Jared A. Cotta, Andrew L. Rygiel, Kaitlyn R. Antonelli, Samiha Islam, Suanna S. Bruinooge, Richard L. Schilsky. Cetuximab (C) in patients (Pts) with breast cancer (BC) and non-small cell lung cancer (NSCLC) without reported KRAS, NRAS, BRAF mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT135.

Use, attitudes, and perceptions of tumor genomic testing: Survey of TAPUR physicians.

6531 Background: This survey of Targeted Agent and Profiling Utilization Registry (TAPUR) Study physicians examined use, attitudes, and perception of tumor genomic testing (TGT), defined as any DNA test performed on tumor specimen/plasma. TAPUR is a multibasket study of marketed agents targeting tumor genomics. Methods: 333 physicians at 54 TAPUR sites were surveyed (2016-2017). Survey domains included use of TGT, barriers to ordering TGT, and genomic confidence. Surveys included 3 scenarios for TGT ordering 1) pretreated advanced cancer patients (pts) without options, 2) newly diagnosed, untreated, metastatic pts and 3) early stage/potentially curable pts with standard options. Data were analyzed with descriptive statistics. Results: 112 physicians responded (33%). The table displays demographics and genomic confidence. Respondents reported a median of 25% of their pts had TGT in past 12 months for trials/routine care (range 0-85%). Barriers to testing included access to tumor specimen (86%), insurance coverage (67%), concerns that results will not be actionable (55%), and test issues (wait time, unsure which test/lab to use, test accuracy) (54%). TGT was ordered most often for scenario 1 (96%) and 2 pts (70%). Few respondents (32%) would order testing in scenario 3. Of those who reported testing for scenarios 1 & 2, most told pts that results could inform treatment/prognosis/trials (97%) or may be uninformative (84%). In all scenarios, pt expectations of TGT results were discussed prior to testing. A minority reported frequently telling pts in advance that results could inform heritable cancer susceptibility (37%). Conclusions: Confidence in using TGT was high. TGT was performed most for pts with advanced cancer and few options. Availability of specimens was largest barrier reported, indicating the importance of blood-based tests. Few respondents discussed implications of germline findings in advance, despite growing evidence of germline findings in somatic testing. [Table: see text]

Pembrolizumab (P) in patients (pts) with metastatic breast cancer (MBC) with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

1014 Background: TAPUR is a phase II basket study evaluating the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. P is an immune checkpoint inhibitor and HTMB is an emerging predictive biomarker for checkpoint inhibitor therapy. Results in a cohort of MBC pts with HTMB treated with P are reported. Methods: Eligible pts had advanced cancer, no standard treatment options, ECOG PS 0-1, measurable disease and acceptable organ function. Genomic testing was performed using commercially available tests selected by sites. Pts matched to P had HTMB defined as ≥9 mutations/megabase (Muts/Mb) by a FoundationOne test (n=20) or approved by the TAPUR Molecular Tumor Board for other tests (n=8). A Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) (SD16+)), an additional 18 pts are enrolled. If ≥7 of 28 pts have DC, the drug is considered worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight female MBC pts were enrolled from October 2016 to July 2018. Pts received P at 2 mg/kg (n=8) or 200 mg (n=20) IV over 30 minutes, every 3 wks. HTMB ranged from 9 to 37 Muts/Mb. Demographics and outcomes are summarized in Table (N=28). No relationship was observed between #Muts/Mb and PFS or OS. Two grade 3 AEs (weight loss and hypoalbuminemia) and 1 grade 2 SAE (urinary tract infection) were reported as at least possibly related to P. Conclusions: P demonstrated anti-tumor activity in heavily pre-treated MBC pts with HTMB . Additional study of P is warranted in MBC pts with HTMB. Clinical trial information: NCT02693535. [Table: see text]

Palbociclib (P) in patients (pts) with non-small cell lung cancer (NSCLC) with CDKN2A alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

9041 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of NSCLC pts with CDKN2A loss or mutation treated with P are reported. Methods: Eligible pts had advanced NSCLC, no standard treatment options, measurable disease, ECOG PS 0-2 and adequate organ function. Genomic testing was performed using commercially available tests. Pts matched to P had NSCLC with CDKN2A loss or mutation and no RB mutations. A Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) (SD16+)), an additional 18 pts are enrolled. If ≥7 of 28 pts have DC, the drug is considered worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-nine pts were enrolled from January 2017 to June 2018; 1 pt was unevaluable for response but is included in safety analyses. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off. Demographics and outcomes are summarized in Table (N = 28). One PR and 6 SD16+ were observed for a DC rate of 29% (90% CI, 15% to 37%). 10 pts had at least one grade 3 or 4 AE or SAE at least possibly related to P with the most common being cytopenias. Other grade 3-4 AEs or SAEs at least possibly related to P included fatigue, anorexia, febrile neutropenia, myocardial infarction, sepsis, vomiting, and hypophosphatemia. Conclusions: Monotherapy with P demonstrated evidence of anti-tumor activity in heavily pre-treated NSCLC pts with CDKN2A loss or mutation . Additional study is warranted to confirm the efficacy of P in pts with NSCLC with CDKN2A loss or mutation. Clinical trial information: NCT02693535. [Table: see text]

Rationale and Design of the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

Case reports and small prospective trials suggest that administering targeted therapies to patients with advanced cancer and an identified genomic target may be associated with clinical benefit. The TAPUR Study, a phase II, prospective, non-randomized, multi-basket, pragmatic clinical trial aims to identify signals of drug activity when Food and Drug Administration (FDA) approved drugs are matched to pre-specified genomic targets in patients with advanced cancer, outside of approved indications. Patients eligible to participate in TAPUR are ages 12 years and older, with advanced, measurable or evaluable solid tumors, multiple myeloma or B cell non-Hodgkin lymphoma. Eligible participants are matched to any of the sixteen FDA approved study drugs based on protocol specified genomic inclusion and exclusion criteria. Genomic profiling from any Clinical Laboratory Improvement Amendments certified, College of American Pathologists accredited laboratory is acceptable. The treating physician selects the treatment from the available study therapies, or consults with the TAPUR Molecular Tumor Board. Participants are placed into multiple parallel cohorts defined by tumor type, genomic alteration and drug. The primary study endpoint within each cohort is objective response or stable disease of at least 16 weeks duration. Secondary endpoints include safety, progression-free survival and overall survival. More than 1000 participants have thus far been registered and more than 800 treated with a TAPUR study drug. Two study cohorts have permanently closed to enrollment due to lack of anti-tumor activity and 12 have expanded to the second stage of enrollment due to promising preliminary activity. The TAPUR Study will describe the efficacy and toxicity of the targeted drugs used outside of their approved indications when matched to a somatic genomic variant.

Palbociclib (P) in patients (Pts) with pancreatic cancer (PC) and gallbladder or bile duct cancer (GBC) with CDKN2A alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

2532Background: The TAPUR Study is a phase II multi‐basket study that evaluates the anti‐tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alteratio...

Clinical application of comprehensive next generation sequencing in the management of metastatic cancer in adults.

101 Background: Next generation sequencing (NGS) platforms are frequently utilized in the care of patients (pts) with metastatic cancer to identify tumor genomic alterations that may serve as therapeutic targets. Biomarker driven clinical trials, such as NCI-Molecular Analysis for Therapy Choice (MATCH) and Targeted Agent and Profiling Utilization Registry (TAPUR) have augmented clinicians’ ability use this strategy in clinical practice. Methods: From 2011-2015 over 500 adult pts with metastatic solid tumors of diverse lineage underwent biopsy for whole exome and transcriptome sequencing of tumor and matched normal sample through the Michigan Oncology Sequencing Center (Mi-Oncoseq). Genomic alterations identified were reviewed at Precision Medicine Tumor Board and tiered according to their clinical relevance. Alterations were also classified as being identifiable or not identifiable by a commercially available NGS assay such as Oncomine Focus or FoundationOne. Results: Genomic alterations identified by Mi-Oncoseq provided rationale for enrollment in a clinical trial in 72% (n = 360) of cases. The percentage of pts who did receive therapy informed by NGS results increased over time (5% in 2012 versus 11% in 2015). 11% of pts (n = 55) had a pathogenic germline variant (PGV) conferring increased cancer risk identified, none of which were known prior to study entry. Numerous pts had clinically relevant molecular alterations identified by Mi-Oncoseq that would not have been identifiable utilizing targeted NGS assays, including PGVs and activating/deleterious gene fusions. Conclusions: Comprehensive NGS, including DNA and RNA sequencing, readily identifies potentially actionable alterations in the vast majority of pts beyond what is observed with use of targeted NGS platforms. Observed modest increase in utilization of NGS results to direct subsequent therapy over time is due to clinician employment of this strategy earlier in the therapeutic algorithm, increased availability of biomarker driven clinical trials and changes in physician referral patterns. Comprehensive NGS identified many unanticipated PGVs of clinical importance for pts and their families. Clinical trial information: HUM00067928.

Going into BATTLE: umbrella and basket clinical trials to accelerate the study of biomarker-based therapies.

With the recognition that tumor molecular phenotypes may predict response to targeted therapies, a number of national multi-center umbrella and basket trials have been initiated in recent years. Umbrella trials enroll patients with a single tumor type, defined by primary anatomic site, and assign various treatments according to the molecular characterization of each case. Conversely, basket trials enroll patients with multiple tumor types, restricting eligibility according to biomarker status. Examples of both models abound, including the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis (I SPY) trials in breast cancer (1), Lung Master Protocol (Lung MAP) trial in advanced squamous lung cancer (2), Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) in surgically resected non-small cell lung cancer (NSCLC) (3), Lung Cancer Mutation Consortium (LCMC)-associated trials in advanced lung adenocarcinoma (4), the National Cancer Institute (NCI)-Molecular Analysis for Therapy Choice (NCI MATCH) Trial (5), and the Targeted Agent and Profiling Utilization Registry (TAPUR) (6), sponsored by the American Society of Clinical Oncology (ASCO) in previously treated advanced solid tumors.

ASCO study will provide molecularly targeted drugs to patients with advanced cancers

The American Society of Clinical Oncology (ASCO) recently announced its first-ever clinical trial aimed at providing patients with advanced cancer access to molecularly targeted cancer drugs. The study also will collect “real-world” data regarding clinical outcomes to learn about applications for these drugs outside the indications approved by the US Food and Drug Administration. Known as the Targeted Agent and Profiling Utilization Registry (TAPUR), the prospective, nonrandomized trial will involve major pharmaceutical companies that will contribute drugs free of charge. TAPUR will gather information regarding the antitumor activity and toxicity of commercially available targeted drugs for a range of cancer types, including any advanced solid tumor, multiple myeloma, or non-Hodgkin lymphoma with a genomic variation known to be a drug target—a broader patient population than is normally included in clinical trials. Oncologists often use therapies approved for a specific cancer indication to treat individuals with other types of advanced cancer, but they rarely learn from that experience to benefit other patients, says Peter Paul Yu, MD, a past president of ASCO. TAPUR aims to do just that by documenting the realworld experience of patients who receive these targeted drugs. ASCO will organize operations for the study, including coordinating all collaborators. Among them will be oversight committees, pharmaceutical companies, technology firms, and community-based study sites. The participants represent an innovative, inclusive approach to studying targeted cancer drugs, according to ASCO. TAPUR not only will reach the many patients with cancer who receive their care through community-based treatment centers, but it also will provide education and support to community oncologists to help them interpret complex genomic tests. As the study proceeds, an Institutional Review Board will review the study protocol and consent form. In addition, ASCO has established 3 oversight committees, each of which will include patient representatives, clinical oncologists, statisticians, and genomic specialists. Physicians will select a drug from available TAPUR study drugs that target the identified genomic variation in the patient's tumor. If a relevant drug target match is unavailable, a physician may consult the molecular tumor board and request a review of the clinical and genomic features of the patient's case. Patients will be monitored for side effects and outcomes, including tumor response, progression-free and overall survival, and duration of treatment. At least 13 drugs that target more than 15 unique genomic variants will be provided by pharmaceutical companies. The trial will be launched at the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, and the Carolinas Healthcare System, all of which run trials for the NCI and industry. Leaders hope to expand the study nationally.