Gönen, Mithat

11059 Background: Payments from the drug industry to oncologists are common and influence physicians’ prescribing decisions. However, whether payments affect the likelihood that patients receive optimal cancer treatment has not been assessed. Methods: This was a population-based cohort study. We used fee-for-service Medicare claims to identify patients with incident cancer diagnosis (new cancer diagnosis code after >= 1 year with no cancer diagnosis codes) from 2014-2020. We used National Comprehensive Cancer Network (NCCN) Guidelines to identify treatment scenarios (e.g., metastatic melanoma, stage III colon adjuvant therapy) with variation in the clinical benefit among recommended treatment options. The patient cohort corresponding to each scenario was identified using claims. We used NCCN Guidelines to identify the “optimal” treatment for each scenario (defined as the designated “preferred” treatment, with NCCN Evidence Blocks scores used for tiebreaks) at each time point across the study period. The primary outcome was whether a patient received the treatment that was, as of their diagnosis date, the optimal treatment for their cancer (vs. any non-optimal treatment). The primary exposure[s] were whether a patient’s medical oncologist received personal (“general”) payments (source: linked Open Payments data) related to 1) optimal treatment or 2) any non-optimal treatment, during the year prior to the patient’s cancer diagnosis. We fit Poisson-family generalized estimating equations, with physician-level clustering and adjustment for scenario, year, and patient characteristics, to estimate the relative risk (RR) of optimal treatment. Results: There were 14 clinical scenarios comprising 15,835 patients. There were 3,429 (21.7%) patients whose oncologist received payment for the optimal treatment, 4,891 (30.9%) for non-optimal payments, and 1,993 (12.6%) to both payment types. Oncologist receipt of payment for optimal treatment was associated with a greater likelihood (RR=1.07, 95%CI:1.01-1.13), and payment for non-optimal treatment was associated with lower likelihood (RR= 0.94, 95%CI:0.89-0.98) of patients receiving optimal treatment. Associations became stronger as payment dollar value increased; for optimal payments ≥$10,000, RR=1.26 (95%CI:1.02-1.57), and for non-optimal payments ≥$10,000, RR=0.70 (95%CI: 0.49-1.00). An estimated 41.6% of unexposed patients received optimal treatment; versus 52.6%, 29.3%, and 33.8% among patients exposed to ≥$10,000 of payments for optimal treatment only, ≥$10,000 non-optimal payments only, and ≥$10,000 of both payment types, respectively. Conclusions: Industry payments related to the optimal cancer treatment were associated with increased use of the optimal treatment. However, payments related to non-optimal treatments were more common and were associated with decreased use of optimal treatment.

This report presents the American Society of Clinical Oncology’s (ASCO’s) evaluation of the adaptations in care delivery, research operations, and regulatory oversight made in response to the coronavirus pandemic and presents recommendations for moving forward as the pandemic recedes. ASCO organized its recommendations for clinical research around five goals to ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality. The specific goals are: (1) ensure that clinical research is accessible, affordable, and equitable; (2) design more pragmatic and efficient clinical trials; (3) minimize administrative and regulatory burdens on research sites; (4) recruit, retain, and support a well-trained clinical research workforce; and (5) promote appropriate oversight and review of clinical trial conduct and results. Similarly, ASCO also organized its recommendations regarding cancer care delivery around five goals: (1) promote and protect equitable access to high-quality cancer care; (2) support safe delivery of high-quality cancer care; (3) advance policies to ensure oncology providers have sufficient resources to provide high-quality patient care; (4) recognize and address threats to clinician, provider, and patient well-being; and (5) improve patient access to high-quality cancer care via telemedicine. ASCO will work at all levels to advance the recommendations made in this report.

Abstract Background Safety is a central consideration when choosing between multiple medications with similar efficacy. We aimed to evaluate whether adverse event (AE) profiles of 3 such drugs in advanced prostate cancer could be distinguished based on published literature. Methods We assessed consistency in AE reporting, AE risk in placebo arms, and methodology used for risk estimates and quantification of statistical uncertainty in randomized placebo-controlled phase III trials of apalutamide, enzalutamide, and darolutamide in advanced prostate cancer. Results Seven included clinical trials enrolled a total of 9215 participants (range = 1051-1715 per trial) across 3 prostate cancer disease states. Within disease states, baseline patient characteristics appeared similar between trials. Of 54 distinct AE types in total, only 3 (fatigue, hypertension, and seizure) were reported by all 7 trials. Absolute risks of AEs in the placebo arms differed systematically and more than twofold between trials, which was associated with visit frequency and resulted in different degrees of uncertainty in AE profiles between trials. No trial used inferential methodology to quantify statistical uncertainty in AE risks, but 6 of 7 trials drew overall conclusions. Two trials concluded that there was no elevated AE risk because of the intervention, including the trial of darolutamide, which had the greatest statistical uncertainty. Conclusions Rigorous comparison of drug safety was precluded by heterogeneity in AE reporting, variation in AE risks in the placebo arms, and lack of inferential statistical methodology, underscoring considerable opportunities to improve how AE data are collected, analyzed, and interpreted in oncology trials.

507 Background: The 21-gene Recurrence Score (OncotypeDX Breast Cancer Assay) predicts outcome and benefit from chemotherapy (CT) in early stage ER+ BC treated with adjuvant endocrine therapy. We evaluated the association between Recurrence Score (RS), time to progression (TTP), and overall survival (OS) in patients with stage IV BC enrolled in TBCRC 013. Methods: TBCRC 013 is a registry study evaluating surgery of the primary tumor in pts presenting with Stage IV BC. From 7/09 - 4/12, 128 evaluable pts were enrolled in two cohorts (A: metastases (mets) with intact primary tumor (n=112); B: mets within 3 months of primary surgery (n=16)). This study includes 110 pts with pre-treatment primary tumor samples available for analysis. Clinical variables, TTP and OS were correlated with RS using long-rank, Kaplan-Meier and Cox regression. Results: Median pt age was 52yrs (21-79) and median tumor size 3.1cm (0.7-15). 82 (80%) were ER+, 83 (81%) Her2(-) and 51 (46%) had bone-only mets. Cohorts A and B did not differ. At a median follow-up of 26 mos (1-47), median TTP is 19 mos (95%CI16-25) and surgery is not associated with OS. 102 samples qualified for RS. 23 (23%) had low RS<18, 29 (28%) intermediate RS, 18-30; and 50 (49%) high RS≥31. Age, tumor size or site of 1stmets was not associated with RS. Risk groups were prognostic for TTP in ER+ pts and for 2 yr OS in ER+Her2- pts (Table). In Cox models continuous RS was also prognostic for TTP in ER+ pts (HR 3.5; for 50 point difference (PD) 95%CI 1.5-8.1, p=0.003) and for OS in ER+Her2- pts (HR 21.4, for 50 PD 95%CI 2.2-204.4, p=0.008). In MVA, adjusting for clinical variables, RS remained prognostic for TTP in ER+ pts (p=0.01). Further analysis of surgery in this trial is ongoing. Conclusions: The 21-gene RS is independently prognostic for TTP in ER+ Stage IV BC. RS is also prognostic for OS in ER+Her2- BC, suggesting that a high RS may be a surrogate for endocrine resistance and could be used to select pts with ER+ Stage IV BC for CT. A randomized trial to address this hypothesis is warranted. Clinical trial information: NCT00941759. [Table: see text]

Abstract Abstract 851 Clinical studies have demonstrated that acute myeloid leukemia (AML) is heterogeneous with respect to presentation and to clinical outcome, and many studies have shown that cytogenetics can be used to improve prognostication. More recently, it has been shown that FLT3, NPM1, and CEBPA mutations can be used to further risk stratify AML patients. Although recent studies have identified novel, recurrent somatic mutations in AML in genes including TET2, ASXL1, IDH1, IDH2, and PHF6, their prognostic value has not yet been evaluated among patients treated on a large phase III clinical trial. Here we report full-length DNA resequencing of FLT3, NPM1, CEBPA, H/K/NRAS, KIT, WT1, TET2, ASXL1, IDH1/2, TP53, RUNX1, PTEN, and PHF6 in pre-treatment genomic DNA from 398 patients with de novo AML younger than 60 years of age enrolled in the ECOG E1900 protocol. We could identify a clonal alteration, defined as a somatic mutation or cytogenetic abnormality, in 91.2% of all patients; 42% had 1 somatic alteration, 36.4% had 2 alterations, 11.3% had 3 alterations and 1.5% had 4 or more somatic alterations. Mutational Analysis: We identified somatic mutations in FLT3 (37% total; 30% ITD, 7% TKD), NPM1 (14%), CEBPA (10%), TET2 (10%), NRAS (10%), WT1 (10%), KIT (9%), IDH2 (8%), IDH1 (6%), RUNX1 (6%), ASXL1 (4%), PHF6 (3%), KRAS (2.5%), TP53 (2%), and PTEN (1.5%) (Figure 1A). We then performed correlation analysis to determine the frequency of different mutational combinations in AML patients. In addition to previously identified mutational correlations (FLT3 and NPM1, KIT and core binding factor leukemia), we found that FLT3 and ASXL1 mutations were mutually exclusive in this large cohort (p =0.0008). In addition, we found that IDH1/IDH2 mutations were mutually exclusive of both TET2 (p=0.02), and WT1 (p=0.01) mutations consistent with overlapping roles in AML pathogenesis (Figure 1B). Integration of mutational data with response data and outcome: Mutations in ASXL1 (CR rate 33.3% versus 66.5% for ASXL1-WT patients; p= 0.009) were enriched in patients who did not respond to induction chemotherapy. We found that mutations in FLT3 (p=0.0005), ASXL1 (p=0.005; Figure 1C), and PHF6 (p=0.02) were associated with reduced OS. Notably, the adverse effects of ASXL1 and PHF6 mutations on outcome were restricted to patients treated with standard dose daunorubicin (p<0.01 for each mutational cohort); ASXL1 and PHF6 mutational status did not affect outcome in patients treated with high-dose daunorubicin, demonstrating that increased intensity induction chemotherapy can improve outcomes in genetically defined poor risk AML subsets. We also found that mutations in CEBPA (p= 0.04) and in IDH2 (p=0.003) were associated with improved OS; the favorable impact of IDH2 mutations on outcome was exclusive to patients with IDH2 R140Q mutations (Figure 1D). Within the subset of patients with cytogenetically defined intermediate risk AML, we found, as expected, that FLT3-ITD mutations were associated with reduced OS and CEBPA mutations were associated with improved OS. Importantly, we found that IDH2 R140Q mutations were associated with improved OS (p=0.003) in patients with intermediate risk AML regardless of FLT3 mutational status. In contrast, TET2 mutations (P=0.0002) and PHF6 (p<0.0001) were associated with reduced OS in intermediate risk, FLT3-WT, AML. Summary: These data provide important clinical implications of genetic alterations in AML and provides insight into the multistep pathogenesis of adult AML. We identified novel mutations that impact response to induction chemotherapy and predict overall outcome, including ASXL1, PHF6, TET2 and IDH2, suggesting these mutations can be used to improve AML risk stratification and therapeutic decisions in AML patients 18–60 years of age. Most importantly, we identify TET2, IDH1/2, and WT1 mutations as mutually exclusive somatic alterations that form a novel mutational complementation group that contributes to AML pathogenesis. Figure 1. A) Circos diagram depicting relative frequency and pairwise co-occurrence of mutations in de novo AML patients enrolled in the ECOG protocol E1900. B) Circos diagram showing mutational events in IDH1/2, TET2, and WT1 mutant AML patient. C) Overall survival in AML patients with and without ASXL1 mutations (p=0.005). D) Overall survival in AML patients with and without IDH2 R172 and R140 mutations (p=0.003). Figure 1. A) Circos diagram depicting relative frequency and pairwise co-occurrence of mutations in de novo AML patients enrolled in the ECOG protocol E1900. B) Circos diagram showing mutational events in IDH1/2, TET2, and WT1 mutant AML patient. C) Overall survival in AML patients with and without ASXL1 mutations (p=0.005). D) Overall survival in AML patients with and without IDH2 R172 and R140 mutations (p=0.003). Disclosures: No relevant conflicts of interest to declare.

Abstract Acute Lymphoblastic Leukemia (ALL) is the most common malignancy observed in the pediatric population. Recent genomic studies have made considerable strides in improving our understanding of the molecular pathogenesis of pediatric B-cell ALL. This includes the discovery of recurrent somatic alterations targeting B-cell transcription factors, mutations in epigenetic regulators, and oncogenic mutations which activate signaling effectors, including in Ph-like B-ALL. However, the molecular pathogenesis of adult B-cell ALL has been less well studied, and there is a need to identify novel therapeutic targets in adult B-ALL. We therefore performed detailed genomic profiling in adults with B-cell ALL. We performed targeted DNA/RNA capture and sequencing of 189 patients with B-cell ALL enrolled on the ECOG E2993 clinical trial. All samples were taken at the time of diagnosis before patients were treated with multi-agent chemotherapy and followed for clinical outcomes including overall survival and remission/relapse duration and kinetics. We used the FoundationOne® Heme assay for our genomics study. This platform allows us to identify short events (point substitutions, short insertions/deletions) copy number and fusion events present in DNA and/or RNA. Of the 203 samples profiled, 189 had sufficient quality genomic data with a median coverage of 435 on DNA sequencing and 7.85 million on target distinct reads per case on RNA sequencing. In all, we identified cancer-related mutations in 108 genes, 55 of these genes being mutated in more than one sample. We identified a median of 2.98 genomic alterations per sample (standard deviation of 1.78) in the target gene set, which included all genes known to be altered in B-ALL and in other hematologic malignancies. The most common genomic events were the BCR-ABL1 fusion (69 samples, 36.5%), followed by CDKN2A loss (57 samples, 30%), CDKN2B loss (35 samples, 18%), NRAS and KRAS point mutations (32 samples, 16.9%), and MLL fusion genes with a spectrum of partners (25 samples, 13.2%). Notably, we found that BCR-ABL1 fusion are mutually exclusive with both RAS mutations (p<10^-7) and MLL mutations (p<5*10^-4). We next investigated the spectrum and frequency of alterations observed in different classes of oncogenes/tumor suppressors. We identified mutations which result in activation of oncogenic signaling pathways in 130 cases or 68.7% of our cohort. This included known mutations/fusions, such as BCR-ABL, RAS-MAPK pathway mutations, and JAK-STAT pathway alterations, and included missense alleles, insertion/deletion events, and fusion genes targeting a spectrum of genes including ABL, PDGFRB, and CRLF2. In aggregate, 33.8% of the cohort had mutations which activate signaling exclusive of BCR-ABL, demonstrating the high prevalence of the Ph-like B-ALL subtype in adult B-ALL. We identified mutations affecting key transcription factors, including PAX5 and IKZF1, in 31.2% of our cohort including missense, nonsense and deletion events. To confirm our ability to detect small deletions of PAX5 and IKZF1, we performed array CGH of 50 cases and compared copy number calls using high-throughput sequencing and CGH. Of note, all deletions targeting PAX5 and IKZF1 identified by NGS were confirmed by CGH. We also identified mutations in epigenetic regulators in 30.6% of cases, including MLL fusions, mutations in the DNA methylation/hydroxymethylation the pathway (DNMT3A, TET1, TET2), and mutations targeted chromatin modulators. Detailed analyses of the mutational spectra and their relationship to clinical outcome will be presented at the meeting. Taken together, these data show we can use a clinically validated sequencing assay to identify known and novel somatic mutations in adult B-ALL, including sequence alterations, rearrangements and copy number aberrations. These data demonstrate the feasibility of combined DNA and RNA study to identify a complex landscape of fusions and short mutations with prognostic and therapeutic relevance, and inform the use of genomic profiling in B-ALL in the clinical context. Figure 1. Figure 1. Disclosures He: Foundation Medicine, Inc.: Employment, Equity Ownership. Brennan:Foundation Medicine, Inc.: Employment, Equity Ownership. Nahas:Foundation Medicine, Inc.: Employment, Equity Ownership. Balassubramanian:Foundation Medicine, Inc.: Employment, Equity Ownership. Otto:Foundation Medicine, Inc.: Employment, Equity Ownership. Lipson:Foundation Medicine, Inc.: Employment, Equity Ownership. Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Merck: Honoraria; Regeneron: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tobira Therapeutics: Other: Advisory board attendee. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Retrospective studies suggest that primary breast surgery is associated with improved overall survival (OS) in Stage IV breast cancer. TBCRC 013 is a multi-center prospective registry study evaluating the role of surgery for the primary tumor in Stage IV disease. Methods: From 7/09 - 4/12, 128 eligible pts from 14 sites were enrolled in two cohorts (A: Stage IV with intact primary tumor (n = 112); B: metastases (mets) within 3 months of primary surgery (n = 16)). Baseline patient and tumor characteristics, and surgery of the primary were correlated with 2yr overall survival (OS) using log rank, Kaplan Meier and Cox regression for all patients. Comparisons were also made between cohorts A and B and within cohort A stratified by response to systemic therapy. Responders included those with any response (partial,complete) or stable disease at distant sites. Results: Median pt age was 52yrs(21-79) and median primary tumor size 3.2cm(0.7-15). Phenotypes were ER+ 106 (83%), HER2neg 91(71%), and triple neg 10(8%). 60(47%) had bone-only mets. The only significant baseline difference between cohorts A and B was the presence of palpable nodes (A:62% vs B:0%, p&lt;0.001). There were no differences in age, tumor size, ECOG scores, ER or HER2 status, number or sites of mets between cohorts A and B. At a median follow-up of 25 mo (95%CI, 23-31), 2yr OS for all pts is 86% (80-92) and is superior in cohort B as compared to A, (100% vs 84%, p = 0.03). On multivariate analysis (MVA) including all pts, only surgery, ER and HER2 positivity were associated with improved OS (table). Among 112 pts with an intact primary (Arm A), 17(15%) were non-responsive (NR) to systemic therapy, 3(18%) of whom required palliative surgery at a median time of 10.4mos. 2yr OS among NR was 33% (15-69) as compared to 94% (88-99) in Arm A responders (R) (p&lt;0.001). ER positivity was the only baseline difference between NR (65%) and R (88%) within Arm A (p = 0.02). Among 94(85%) Arm A responders, 39(41%) had elective surgery (median 8.4 mos, 95%CI:6.9-10.3) and only 1 of the remaining 47(2%) required palliation. When limited to Arm A responders, elective surgery was not associated with improved 2yr OS (surgery vs not: 94% vs 92%, p = 0.5). Median time to progression following elective surgery was 12 mos (95%CI,8-19mos). When cohort B (n = 16) and cohort A surgery groups (n = 39) are combined, surgery of the primary tumor is associated with improved 2yr OS (96% vs 74%, p = 0.002). Conclusions: In this prospective registry study, patients diagnosed with mets within 3 months of primary breast surgery have an improved 2yr OS. When all pts having surgery (A + B) are examined, surgery is associated with improved OS on MVA, but when limited to Arm A responders, elective surgery does not improve OS. Given that the number of Arm A responders is small, results from the prospective randomized trial will be needed to address this question. These data also demonstrate that the need for surgical palliation of the primary tumor is uncommon in the modern era. Multivariate Analysis for OSN = 128HR Death (95%CI)pvalueSurgery0.28 (0.10-0.74)0.01ER positivity0.28 (0.10-0.72)0.01HER2 positivity0.21 (0.06-0.74)0.01MVA included: age, tumor size, ECOG, ER, PR, HER2, met sites, and surgery Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-09.

Abstract We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group trial, E1900. We identified CD25POS myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25POS patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25NEG cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITDPOS AML was restricted to CD25POS patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25POS status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25POS status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML.