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Studies linking genomic and phenomic data are subject to selection biases, including delayed entry or immortal time bias. Delayed entry can be problematic for time-to-event analyses, but utilization of appropriate statistical methods to account for delayed entry are underutilized. Delayed entry commonly occurs when genomic sequencing results are obtained after the start time for survival estimation. To evaluate the impact of left truncation on overall survival (OS) estimates, we explored outcomes in patients with de novo stage IV non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) from the AACR GENIE Biopharma Collaborative, who had genomic sequencing within a specified timeframe. We analyzed OS from diagnosis and from start of the most common first-line regimen, carboplatin/pemetrexed for NSCLC (N = 212 patients) and FOLFOX for CRC (N = 369 patients). We compared median OS using standard Kaplan-Meier methods to median OS using left truncation methods to account for delayed entry. All NSCLC and CRC patients underwent genomic sequencing after their diagnosis date. Among NSCLC patients on carboplatin/pemetrexed, 41% and among CRC patients on FOLFOX, 14% had sequencing determined after starting first-line regimen. The survfit function in R package survival was used, and the absolute differences and percent differences in median OS estimates were calculated. Failure to account for delayed entry leads to an overestimation of OS, regardless of cohort and start date. Adjusting survival outcomes using left truncation methods reduces the influence of some aspects of selection bias and results in better estimates of time to event outcomes. Analyses from these cohorts can provide meaningful insights about survival outcomes outside the clinical trial setting and may support trial design and reliable selection of control arms. As such, it is imperative that analytic methods to account for the inflated survival estimates are incorporated. EstimateCRC Stage IV (N = 658)NSCLC Stage IV (N = 722)Unadjusted Median (IQR) Overall Survival from Diagnosis (Years)3.2 (2.9, 3.4)2.3 (2.0, 2.5)Median (IQR) Overall Survival from Diagnosis in Years, Adjusting for Delayed Entry2.1 (1.9, 2.4)1.3 (1.1, 1.6)Difference in Medians (Years)1.11.0% Difference in Medians34%44%EstimateCRC Stage IV (N = 369)NSCLC Stage IV (N = 212)Unadjusted Median (IQR) Overall Survival from Most Common First-Line Regimen (Years)2.9 (2.6, 3.4)1.3 (1.0, 1.6)Median (IQR) Overall Survival from Most Common First-Line Regimen in Years, Adjusting for Delayed Entry2.1 (1.8, 2.5)0.9 (0.7, 1.2)Difference in Medians (Years)0.80.4% Difference in Medians28%31% Citation Format: Samantha Brown, Jessica A. Lavery, Eva M. Lepisto, Caroline McCarthy, Hira Rizvi, Celeste Yu, Kenneth L. Kehl, Shawn M. Sweeney, Julia E. Rudolph, Nikolaus Schultz, Ritika Kundra, Brooke Mastrogiacomo, Phillipe Bedard, Jeremy L. Warner, Gregory J. Riely, Deborah Schrag, Katherine S. Panageas, The AACR Project GENIE Consortium. Ignoring left truncation in overall survival within real-world genomic-phenomic data leads to inflated survival estimates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2620.

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

Background: Variants in homologous recombination (HR) genes other than BRCA1/2 may cause a BRCA-like phenotype triple negative breast cancer (TNBC), which includes the sensitivity to platinums and DNA repair inhibitors. Evaluation of HR proficiency may influence the clinical management of TNBC. Our aim was to evaluate germline and somatic HR gene variants in advanced TNBC patients (pts) and clinical outcome. Methods: Our cohort included advanced TNBC pts unselected for family history or age at diagnosis, enrolled in an institutional molecular screening program (NCT01505400). DNA from matched blood and FFPE tumor samples was assessed using a lab developed next generation sequencing Hereditary Cancer Panel (NGS-HCP) that includes all exons of 52 cancer predisposition genes, with 20 HR genes (Illumina MiSeq/NextSeq, germline coverage 100x, somatic coverage 500x). Medical records were reviewed for clinical outcome, pathology and prior germline BRCA1/2 testing results. All pts consented for research on banked samples and return of pathogenic germline variants was optional. Log rank test was used to determine time from surgery with curative intent to relapse (TTR) and overall survival from diagnosis to death (OS) differences based on presence of HR variants. Results: We included 32 pts who consented for return of pathogenic germline variants and had sufficient DNA for NGS-HCP analysis. Median age at diagnosis was 45 years (range 21-80). Initial stages at diagnosis were: I (12.5%), II (62.5%), III (19%) and IV (6%). Germline HR variants were detected in 17 pts (53%) with a median number of variants per patient of 1 (range 0-6). Five pts had likely pathogenic or pathogenic variants in HR genes: BRCA1 (2), BRCA2 (1) FANCC (1) and FANCC + BML (1). Another patient had a BRCA1 pathogenic variant previously detected by Multiplex Ligation-dependent Probe Amplification but was not detected by NGS-HCP. 26 variants of unknown significance (VUS) were identified in 13 HR genes, including FANCA (6), FANCF (3) and BRCA1 (3). Only one patient had a somatic HR variant in FANCA not found in the germline. 30 pts (94%) had somatic TP53 variants. Sporadic somatic BRCA1/2 variants were not seen. BRCA1/2 variants present in the tumor were equivalent to those detected in blood of BRCA1/2 carriers. Median (m) TTR was 17 months (range 1-119) and mOS was 49 months (range 8-123). Presence of likely pathogenic or pathogenic germline variants was not associated with TTR (p=0.78) and OS (p=0.23). Presence of germline VUS, likely pathogenic or pathogenic variants also did not correlate with TTR (p=0.72) and OS (p=0.47) Conclusions: In our cohort of pts with advanced TNBC, 12% had germline pathogenic variants in BRCA1/2, similar to the previously reported rate in early stage TNBC pts. Prevalence of likely pathogenic or pathogenic variants in non-BRCA HR genes was 6%. The presence of germline variants in HR genes was not associated with clinical outcome, however, the number of patients included was small and we had limited power to detect survival differences.Background: Variants in homologous recombination (HR) genes other than BRCA1/2 may cause a BRCA-like phenotype triple negative breast cancer (TNBC), which includes the sensitivity to platinums and DNA repair inhibitors. Evaluation of HR proficiency may influence the clinical management of TNBC. Our aim was to evaluate germline and somatic HR gene variants in advanced TNBC patients (pts) and clinical outcome. Methods: Our cohort included advanced TNBC pts unselected for family history or age at diagnosis, enrolled in an institutional molecular screening program (NCT01505400). DNA from matched blood and FFPE tumor samples was assessed using a lab developed next generation sequencing Hereditary Cancer Panel (NGS-HCP) that includes all exons of 52 cancer predisposition genes, with 20 HR genes (Illumina MiSeq/NextSeq, germline coverage 100x, somatic coverage 500x). Medical records were reviewed for clinical outcome, pathology and prior germline BRCA1/2 testing results. All pts consented for research on banked samples and return of pathogenic germline variants was optional. Log rank test was used to determine time from surgery with curative intent to relapse (TTR) and overall survival from diagnosis to death (OS) differences based on presence of HR variants. Results: We included 32 pts who consented for return of pathogenic germline variants and had sufficient DNA for NGS-HCP analysis. Median age at diagnosis was 45 years (range 21-80). Initial stages at diagnosis were: I (12.5%), II (62.5%), III (19%) and IV (6%). Germline HR variants were detected in 17 pts (53%) with a median number of variants per patient of 1 (range 0-6). Five pts had likely pathogenic or pathogenic variants in HR genes: BRCA1 (2), BRCA2 (1) FANCC (1) and FANCC + BML (1). Another patient had a BRCA1 pathogenic variant previously detected by Multiplex Ligation-dependent Probe Amplification but was not detected by NGS-HCP. 26 variants of unknown significance (VUS) were identified in 13 HR genes, including FANCA (6), FANCF (3) and BRCA1 (3). Only one patient had a somatic HR variant in FANCA not found in the germline. 30 pts (94%) had somatic TP53 variants. Sporadic somatic BRCA1/2 variants were not seen. BRCA1/2 variants present in the tumor were equivalent to those detected in blood of BRCA1/2 carriers. Median (m) TTR was 17 months (range 1-119) and mOS was 49 months (range 8-123). Presence of likely pathogenic or pathogenic germline variants was not associated with TTR (p=0.78) and OS (p=0.23). Presence of germline VUS, likely pathogenic or pathogenic variants also did not correlate with TTR (p=0.72) and OS (p=0.47) Conclusions: In our cohort of pts with advanced TNBC, 12% had germline pathogenic variants in BRCA1/2, similar to the previously reported rate in early stage TNBC pts. Prevalence of likely pathogenic or pathogenic variants in non-BRCA HR genes was 6%. The presence of germline variants in HR genes was not associated with clinical outcome, however, the number of patients included was small and we had limited power to detect survival differences. Citation Format: Stjepanovic N, Kim RH, Wilson M, Mandilaras V, Berman H, Amir E, Cescon D, Elser C, Randall Armel S, McCuaig J, Volenik A, Demsky R, Chow H, Misyura M, Wang L, Oza AM, Kamel-Reid S, Stockley T, Bedard PL. Clinical outcome of patients with advanced triple negative breast cancer with germline and somatic variants in homologous recombination gene [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-09-05.

Background: Next-generation sequencing (NGS) has improved our understanding of breast cancer (BC) biology. Somatic TP53 mutations (TP53m) are present in 30% of BC, and are particularly common in triple negative (TN) tumors. Although multiple studies have indicated poor prognosis in BC patients (pts) with TP53m, there is still uncertainty regarding its correlation with clinical outcomes, which may be influenced by other molecular, histological and clinical factors. Our aim was to investigate the functional effect of TP53m in advanced BC pts and evaluate associations with clinical outcomes in different BC subtypes. Methods: Advanced BC pts enrolled in an institutional molecular screening program (NCT01505400) were evaluated. TP53m were assessed on archived FFPE tumor samples using NGS Illumina MiSeq TruSeq Amplicon Cancer Panel (500x depth of coverage; 10-15% variant detection threshold). Functional effect of TP53m was classified as gain of function (GOF), loss of function (LOF) and variants of unknown significance (VUS), as adapted from IARC TP53 database. Patients' medical records were reviewed for clinical data. TP53m functional effect class was correlated with BC subtypes using Fisher's exact test. TP53m were correlated with time from surgery with curative intent to distant relapse (TTR) and overall survival from diagnosis to death (OS) using Log-rank test. Impact of TP53m functional type on TTR and OS was determined by Cox proportional hazard model. Results: The study enrolled 220 pts from Oct 2012 - Nov 2015. Median age at diagnosis was 46 years (range 21-80). The cohort included 141 ER+/HER2- (64%), 25 HER2+ (11%) and 54 triple negative (TN) (25%) BC pts. Stage at diagnosis was: I (14%), II (33%), III (24%), IV (21%) and not documented in 8%. Median follow-up was 15 months (m) (range 1-41). Somatic TP53 variants were identified in 80 patients [36%; 23 ER+/HER2- (16%), 18 HER2+ (72%), 39 TN (72%)]. By TP53 functional class, there were 19 GOF (24%), 35 LOF (44%) and 26 VUS (32%). Histologic subtypes were not correlated with TP53m function (p = 0.09). TTR for 174 pts, who underwent surgery with curative intent at diagnosis, and OS (94 death events, 43%) are reported in Table 1. TTR and OS were shorter in TP53m compared to TP53 wild type (wt) in the overall cohort and the ER+/HER2- subgroup, but not the HER2+ and TN subgroups. TABLE 1: Log rank test resultsTP53mTP53wtP valueTotal cohortTTR (m)2054 In the ER+ subgroup TP53m was significant prognostic factor associated with poor outcome in univariate analysis and remained significant after adjusting for age, stage and grade at diagnosis, neoadjuvant chemotherapy and germline BRCA1/2 status, with HR for TTR 3.4 (95%CI: 1.9-6.0, p Conclusions: In advanced breast cancer, somatic TP53m status is prognostic for outcome in ER+/HER2- but not TNBC or HER2+ subtypes. TP53m functional class was not associated with any difference in survival outcomes. Citation Format: Stjepanovic N, Garg S, Berman H, Warr D, Amir E, Cescon D, Elser C, Wang L, Kamel-Reid S, Siu L, Bedard PL, Stockley T. Impact of TP53 functional mutation type on clinical outcomes of advanced breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-19.

Introduction: A high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a poor prognostic indicator in several malignancies including breast cancer. It is unknown whether the prognosis associated with high NLR can be explained by other prognostic factors such as proliferation or estrogen receptor signalling. Here we explore the association between NLR and the 21-gene recurrence score (RS). Methods: The associations between RS, NLR, tumor size, histologic grade, and estrogen receptor (ER) and progesterone receptor (PgR) expression (assessed by immunohistochemistry) were explored in sequential women with early-stage, lymph node-negative (or with lymph node micrometastases), ER-positive and HER2-negative breast cancer treated at Princess Margaret Cancer Centre in Toronto, Canada and in whom results of the RS were available. NLR was measured prior to surgery. Patients with a documented history of pre-existing infectious/inflammatory condition were excluded. Associations were explored using simple linear regression and statistical significance was defined as p Results: A total of 130 women diagnosed between January 2006 and April 2015 were included in the analysis. Median age was 55 (range 32-79), 87% were lymph node negative and 13% had nodal micrometastases. The median NLR was 2.2 (range 0.9-9.1) and was collected at a median of 12 days prior to surgery (range 0-60). The median RS was 18 (range 0-41). There was no association between RS and NLR (R=-0.10, p=0.31), grade (R=0.13, p=0.15), age (R=-0.05, p=0.58) or tumor size (R=0.06, p=0.48). RS was negatively associated with the magnitude of expression of both ER (R=-0.22, p=0.01) and PgR (R=-0.44, p Conclusion: The poor outcomes associated with high NLR are unlikely explained by proliferation of estrogen receptor signalling. Citation Format: Srikanthan A, Bedard PL, Goldstein S, Templeton A, Amir E. Association between the neutrophil-to-lymphocyte ratio (NLR) and the 21-gene recurrence score. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-05.

Background: ONT 380 is a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects. Preclinical studies demonstrate synergism with trastuzumab (T) and chemotherapy, as well as activity in models of HER2+ CNS disease. Based on the potential for increased clinical activity of dual HER2 blockade in the context of a targeted cytotoxic agent, we evaluated the safety, tolerability, and anti-tumor activity of ONT-380 in combination with T-DM1 in patients (pts) with MBC with and without CNS metastases (mets). Methods: 3+3 dose escalation with MTD expansion cohorts in pts with/without CNS mets evaluating ONT-380 (300 or 350 mg PO BID) combined with T-DM1 3.6 mg/kg IV q 21 days. Prior treatment with T and taxane was required; prior lapatinib and asymptomatic brain mets (treated or untreated) were allowed. Assessments included safety, PK, and systemic (RECIST 1.1) and CNS (modified RECIST) tumor response, with brain MRI at baseline and q 6 wks in pts with CNS mets at baseline. DLT was defined as the occurrence of protocol-specified events during the 1st treatment cycle. Results: As of 01 June 2015, 51 pts have been enrolled and have received between 1 and 22 cycles, with safety data available for 43 pts (n=36 at 300 mg BID; n=7 at 350 mg BID). Pts had a median of 2 prior treatments for MBC, including T (n=43); pertuzumab (n=15) and lapatinib (n=7). The MTD for ONT-380 was 300 mg BID with 5/36 pts (14%) with DLT (Gr 3 AST/ALT [n=4]; Gr 2 vomiting/Gr1 diarrhea [n=1]) vs. 3/7 pts (43%) with DLT at 350 mg BID (Gr 3 vomiting [n=1]; Gr 3 hypersensitivity [n=1]; Gr 3 fatigue [n=1]). Overall, the majority of AEs have been Gr 1 or 2. The most common AEs, regardless of relationship, were nausea, fatigue, diarrhea, vomiting, thrombocytopenia, AST/ALT elevation, headache, decreased appetite, epistaxis, constipation, and hypokalemia. Gr 3 AST/ALT elevation has occurred in 7/43 pts (16%), with no events meeting Hy's law, and has been reversible with dose interruption and reduction except in 2 pts found to have progressive liver mets. No Gr 3 diarrhea has occurred at any dose. ONT-380 PK was dose proportional, and no drug-drug interaction was observed with T-DM1. In 33 of 43 pts with data available from at least one follow-up scan to evaluate response, best systemic response regardless of dose was 11 PR, 16 SD, and 6 PD, with clinical benefit rate (CBR= CR, PR, or SD >6 mos) of 19/33 (58%). The most common reason for treatment discontinuation was PD, with 3 pts coming off study for AEs (n=1 each of Gr 3 hypersensitivity, Gr 2 vomiting, Gr 3 AST/ALT). Eight pts to date have been evaluable for CNS response (untreated or progressive CNS mets with ≥1 follow-up MRI), with best CNS response of 1 CNS CR, 2 CNS PR, and 5 CNS SD, with a CNS CBR of 5/8 (63%). All pts with CNS response are still active. Conclusion: Treatment with ONT-380 300 mg BID and T-DM1 3.6 mg/kg has been tolerable. Early evidence of anti-tumor activity has been seen, including clinical benefit in patients with CNS mets. Updated results will be presented. Citation Format: Ferrario C, Hamilton E, Aucoin N, Falkson CI, Khan Q, Krop IE, Welch S, Bedard PL, Conlin A, Chaves J, Vo A, Walker L, Borges V. A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-20.

Background MEK inhibition may overcome resistance to EGFR inhibition alone in patients (pts) with RAS wt mCRC. We evaluated the antitumor activity of T (MEK1/2 inhibitor) with Pmab (EGFR monoclonal antibody) in a phase II trial. Methods Pts with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior EGFR therapy were treated with T 1.5mg oral daily and Pmab 4.8mg/kg IV every 2 weeks. Primary endpoint was clinical benefit (CB; CR, PR or SD ≥ 24 weeks) by RECIST v1.1. A 2-stage minimax design (p0=0.20, p1=0.45, 1-sided alpha=0.05, power=0.85) required ≥4/13 patients with CB in stage I and ≥8/26 patients with CB by end of stage II. Response assessments were performed every 4 cycles (C). Adverse events (AEs) were assessed by CTCAE v4.03. Tumor biopsies were performed before C1 and during C2. Plasma circulating free DNA (cfDNA) collected before C1, C2, C3 and every 2 subsequent C and were profiled using the Oncomine Lung cfDNA assay. Results There were 13 pts enrolled from Nov2015 to Dec2018. Of 12 evaluable patients, best response was confirmed PR (n = 3), unconfirmed PR (n = 5), and SD (n = 4) (unconfirmed ORR 67%). Two patients achieved CB ≥ 24 weeks (2/10; 20%) and two patients are still on trial with PR not yet evaluable for CB. The most common treatment-related AE (trAE) was acneiform rash (85%) including 31% with grade 3. Other trAEs were diarrhea (62%), mucositis (46%), maculopapular rash (54%), and vomiting (31%). Dose modifications and interruptions of T occurred in 69% of patients and 54% of patients receiving Pmab had dose modifications. Median PFS is 4.4 months (95% CI 2.9-7.1). Of 3 pts with serial cfDNA profiling results available, none had KRAS, NRAS, or BRAF mutations detectable before treatment, and 1 patient demonstrated polyclonal KRAS, NRAS, and BRAF mutations at C5 before radiographic progression at C9. Conclusions The addition of T to Pmab leads to a high rate of tumor shrinkage in RAS/RAF wt mCRC. Median PFS is similar to Pmab alone in the ASPECCT trial, which may be due to a high incidence of skin toxicity with the combination that leads to dose interruption and/or reduction. Additional results from cfDNA and tumor biopsies will be presented. Clinical trial identification NCT02399943. Legal entity responsible for the study Philippe Bedard. Funding Conquer cancer foundation of ASCO career development (Dr P. Bedard), Canadian Cancer Research Society Institute innovation grant (Dr P. Bedard), and drug supply from GlaxoSmithKline and Novartis. Disclosure A.R.R. Albiruni: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): CASI Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Genentech/ Roche; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Adaptimmune. A. Spreafico: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Symphogen AstraZeneca / Medimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen Oncology/ Johnson & Johnson. A.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Genentech/ Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Medimmune. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/ MedImmune; Advisory / Consultancy: Morphosys; Advisory / Consultancy: Roche; Advisory / Consultancy: GeneSeeq; Advisory / Consultancy: Loxo; Advisory / Consultancy: Oncorus; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AbbVie. P. Bedard: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): SERVIER; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly. All other authors have declared no conflicts of interest.

Background The goal of phase I trials is to determine adverse event (AE) profiles of new therapies. Typically, AEs are captured by clinicians, yet patient reported outcome (PRO) tools collect AEs which may be under reported. Our single center, prospective study aimed to validate PRO-CTCAE in phase I clinical trial patients (pts). Methods Pts eligible for phase I trials at Princess Margaret Cancer Centre were evaluated using tablet based, PRO-CTCAE with the full item library (n = 80) in addition to standard, matched clinician reported CTCAE grading of AEs at baseline (BL), mid cycle 1 (C1) and 2 (C2). Overall (BL + C1 + C2) totals were also assessed. Characteristics (age, gender, tumor group, ECOG, education), best response (using RECIST v1.1), and treatment information were collected. Comparative (kappa) statistics were used to assess agreement of patient and clinician reported AEs. Results Of 292 pts approached (05/2017 to 01/2019), 265 (91%) were consented and 243 (92%) were evaluable, with 552 surveys completed. Median age was 61 (range 18-82), 51% were female, and 79% were ECOG 1; with GI (31.7%), head and neck (13.2%), and breast (10.7%) as frequent tumor types. Pts were commonly treated with immune (66%) and/or targeted (21%), mono (35%) or combination (61%) therapy. PRO-CTCAE completion rates were high (98.7%), with fatigue (75%), pain (68%), and anxiety (54%) as often reported overall patient AEs. Common physician reported AEs were fatigue (41%), pain (39%) and insomnia (18%). Overall patient-clinician agreement (kappa), was poor for fatigue (0.12) and anxiety (0.08), and fair for pain (0.28). Clinician reported insomnia (0.2) was fair. Highest patient-clinician agreement was seen for dyspnea at BL (0.54), and edema (0.55) and rash (0.49) at C2. Despite patient reporting, clinicians did not report select AEs (palpitations, hiccups, vaginal dryness), and had poor overall agreement for cognitive (0-0.03), urinary (0.02-0.05), and mood (0.05-0.08) symptoms. Conclusions Completion of PRO-CTCAE was high in phase I trial pts. Clinician reported AEs had poor to fair agreement compared with PRO-CTCAE, suggesting under-reporting in phase I trials. This information could inform a phase I PRO survey to complement clinician reported AEs. Analyses are ongoing. Legal entity responsible for the study Drug Development Department, Princess Margaret Cancer Centre. Funding Has not received any funding. Disclosure A.A. Razak: Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): CASI; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Amgen; Honoraria (self): Boehringer Ingelheim. A. Spreafico: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen Oncology/Johnson & Johnson. P. Bedard: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Servier; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly; Research grant / Funding (self): Pfizer. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Loxo; Advisory / Consultancy: Oncorus; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy: Morphosys; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: GeneSeeq; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Intensity Therapeutics; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Mirati. A.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GSK; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Karyopharm. All other authors have declared no conflicts of interest.

Background Limited data exist in the clonal dynamics of serial ctDNA as a predictive biomarker in advanced solid tumor pts receiving immune checkpoint blockade. Methods Pts with mixed solid tumors received single agent P (anti-PD-1) 200mg IV Q3wks in the investigator-initiated phase II INSPIRE trial (NCT02644369). ctDNA was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera™). Samples were considered ctDNA positive if≥2 of 16pt-specific targets met the qualifying confidence score threshold.Table: 113PTable: 113PEndpointORR N=72*CBR N=72*EndpointPFS N=73*OS N=73*SubgroupCR/PR N=15SD/PD N=57CR/PR/SD≥6 cycles N=22CR/PR/SD Results Of 94 pts are presented. Demographics: male 38%; median age=55 yrs (range 21–81); triple negative breast (19%), ovarian (19%) and head and neck (17%) cancers comprised the major malignancies. Median no. of P cycles=3 (range 1–35); follow up was 14m (range 0.6-35.4); RECIST responses: CR 3.2% (n=3), PR 14% (n=13), CBR (CR+PR+SD>6 cycles) 28% (n=26), RECIST/clinical PD (n=61/18; 65%/19%). Median PFS=2.5m and median OS=14m. In all 94 pts, ctDNAB correlated with PFS (adjusted HR 0.53, 95% CI 0.34-0.84, p=0.01) and OS (adjusted HR 0.47, 95% CI 0.28-0.8, p=0.01). Among 74 pts with both ctDNAB and ctDNAC3, the change (ΔctDNA) correlated with clinical efficacy parameters (Table). Conclusions Strong correlations exist between both ctDNAB and ΔctDNA with clinical outcome, suggesting both prognostic and predictive values in pts with mixed solid tumors. Clinical trial identification NCT02644369, December 31, 2015. Legal entity responsible for the study University Health Network, Toronto. Funding Merck, Netera, Terry Fox Research Institute, Princess Margaret Cancer Foundation. Disclosure S. Dashner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. A.R. Hansen: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Karyopharm. P. Bedard: Honoraria (institution), Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Oncothyreon. S. Lheureux: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Tesaro. A. Spreafico: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Oncology/Johnson & Johnson; Research grant / Funding (institution): Array Biopharma. A.A. Razak: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): CASI Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Adaptimmune. H. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. S. Shchegrova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. P.S. Ohashi: Honoraria (self), Advisory / Consultancy: Symphogen Inc; Honoraria (self), Advisory / Consultancy: Providence Therapeutics. M. Louie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. H. Sethi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. A. Aleshin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. L.L. Siu: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfiser; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Honoraria (self), Advisory / Consultancy: Morphosys; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self), Advisory / Consultancy: GeneSeeq; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: Oncorus; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boerhinger-Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Intensity Therapeutics; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Shattucks; Spouse / Financial dependant: Agios. S. Bratman: Research grant / Funding (self): Nektar Therapeutics; Licensing / Royalties, Co-inventor of a patent relating to circulating tumor DNA detection technology: Roche Molecular Diagnostics. T.J. Pugh: Honoraria (self): Merck; Honoraria (self): Prosigna; Honoraria (self): Chrysalis Medical Advisors; Advisory / Consultancy: DynaCare; Research grant / Funding (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background Currently cancer patients treated with immune checkpoint modulators (ICMs) have their health related quality of life (HRQOL) measured by general patient reported outcome (PRO) tools such as the EORTC QLQC30 or Functional Assessment of Cancer Therapy-General (FACT-G). No instrument has been developed specifically for patients treated with ICMs, which may lead to their HRQOL being evaluated inaccurately. The objective of this study was to develop a toxicity subscale PRO instrument for ICM treated patients that would contribute to the measurement of HRQOL. Methods Input was collected from a prior systematic review, patients and physicians. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed the development of an initial list of items that described ICM side effects (SEs) and their impacts upon HRQOL. Physician surveys and interviews informed subsequent item generation/reduction. Cognitive debriefing interviews were conducted with a new set of patients after they completed the toxicity subscale. Results Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. Following a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for ICM treated patients were surveyed with a list of 49 patient reported toxicity related unique SEs; and 11 physicians participated in follow up interviews. Informed by the data collected from the physicians, a second round of item reduction produced a list of 25 items that covered a wide range of SEs including but not limited to gastrointestinal, cutaneous, musculoskeletal, respiratory, constitutional, neurological and endocrine. This final list was piloted with 11 patients who confirmed that it was comprehensible and complete. Conclusions This 25 item list is the first HRQOL toxicity subscale developed with patient and clinician input for patients treated with ICMs. The subscale will be combined with the FACT-G to form the FACT-ICM and this PRO instrument will undergo further validity testing. Clinical trial identification NCT02651831. Legal entity responsible for the study Princess Margaret Cancer Centre. Funding University of Toronto, Strategic Innovation Grant. Disclosure A.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution): Roche-Genentech; Advisory / Consultancy, Research grant / Funding (institution): MedImmune; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb. P. Bedard: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Servier; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly. All other authors have declared no conflicts of interest.

Background High tissue-tumor mutation burden (tTMB) is a predictor of response to immunotherapy (IO). Tissue availability and tumor heterogeneity are barriers to tTMB use in clinical practice. Plasma-based blood TMB (bTMB) is a convenient alternative that strongly correlates with tTMB in non-small cell lung cancer. Whether this correlation holds true in other cancers is unknown. Here, we examined the correlation between bTMB and tTMB as well as the clinical utility of TMB as a predictive marker of response in a heterogeneous Phase I IO cohort. Methods Advanced cancer patients (pts) treated with mono- or combination IO therapy at the Princess Margaret phase I unit were enrolled. Pre-treatment plasma ctDNA and matched normal blood controls were collected via an institutional liquid biopsy program (LIBERATE, NCT03702309). Available archival tissue FFPE samples were analyzed. The GeneseeqPrime 425 gene panel was used to sequence both ctDNA and FFPE samples. Results From December 2017 to July 2018, 39 pts with 19 tumor types were accrued from 25 different trials, 87% of which involved a PD-1/PD-L1 inhibitor. The median age was 59y (21 – 77) and 52% were female. The most frequent cancers were colorectal, head and neck and breast, each with 5 cases. Thirty-one patients (79%) had detectable mutations in plasma ctDNA. The median bTMB was 5 (1 - 53) mut/Mb. Twenty-one pts had available FFPE samples. Of those, mutations were detected in 20 (95%) samples. The median tTMB was 6 (2 - 124) mut/Mb. Among the 16 pts with detectable mutations in both FFPE and plasma samples, a significant correlation between bTMB and tTMB was observed (r = +0.67; p Conclusions In a typical heterogeneous phase I IO cohort, bTMB was correlated with tTMB. In this small series, neither bTMB nor tTMB were associated with survival. However, 2/3 PRs had high bTMB. Further studies in larger cohorts are warranted. Legal entity responsible for the study Lillian Siu. Funding Princess Margaret Cancer Centre; BMO Chair in Precision Genomics; Geneseeq Technology Inc. Disclosure A. Wang: Full / Part-time employment: Geneseeq Technology Inc. J. Huang: Full / Part-time employment: Geneseeq Technology Inc. A. Spreafico: Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Oncorus; Travel / Accommodation / Expenses: Idera; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (self): Symphogen; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): Surface Oncology; Research grant / Funding (self): Jansseen Oncology; Research grant / Funding (self): Northern Biologics. A.R. Hansen: Advisory / Consultancy: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca/MedImmune; Honoraria (self): Pfizer; Research grant / Funding (institution): Karyopharm Therapeutics. A.A. Razak: Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): CASI Pharmaceuticals; Research grant / Funding (self): Novartis; Research grant / Funding (self): Deciphera; Research grant / Funding (self): Karyopharm Therapeutics; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Roche/Genentech; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Blueprint Medicines; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Adaptimmune. P. Bedard: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Servir; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly. H. Bao: Full / Part-time employment: Geneseeq Technology Inc. X. Wu: Leadership role, Full / Part-time employment: Geneseeq Technology Inc. T.J. Pugh: Advisory / Consultancy: DynaCare; Licensing / Royalties: Hybrid-capture sequencing for determining immune cell clonality; Licensing / Royalties: Combined hybrid-capture DNA sequencing for disease detection; Honoraria (self): Merck; Honoraria (self): Prosigna; Honoraria (self): Chrysalis Biomedical Advisors; Research grant / Funding (institution): Boehringer Ingelheim. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy: MorphoSys; Advisory / Consultancy, Research grant / Funding (institution): Symphony Evolution; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Loxo; Shareholder / Stockholder / Stock options, Spouse / Financial dependant, Immediate Family Member - Leadership and Stock/Owenership: Angios; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Astellas Pharma. All other authors have declared no conflicts of interest.

The goal of many ongoing precision medicine initiatives is to match patients to targeted treatment(s) based upon the identification of specific driver mutations in their tumors. Although large-scale research projects have elucidated the genomic landscape of breast cancer, they have not provided insight into the clinical utility of genomic testing. Institutional studies of small, targeted sequencing panel-based testing approaches involving patients with advanced, metastatic disease demonstrate that only a small proportion of patients ultimately receive genotype-matched treatment. The reasons for this low treatment matching rate include: institutional and/or geographic barriers to access to genotype-matched clinical trials; patient deterioration after testing results are reported; and the limited range of somatic mutations that are “druggable” with approved or investigational drug therapies. While there are promising signals of activity from early phase clinical trials with novel drug treatments targeting specific genomically defined subpopulations - including AKT1, ERBB2, ESR1 and PIK3CA mutations as well as FGFR1 amplification - and advances in circulating tumor DNA technology may allow for greater integration at the point of care, further evidence is needed before multi-gene testing can be recommended in routine clinical practice. Citation Format: Bedard P. CS1-2 Clinical utility of multi-gene testing in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr CS1-2.

To review our experience of caspofungin in the treatment of persistent candidemia in the neonatal intensive care unit. This was a retrospective chart review on 13 infants in whom caspofungin was added to conventional antifungals (amphotericin B and/or fluconazole or flucytosine) for the treatment of refractory candidemia. A total of 12 infants were preterm (gestational age, 24 to 28 weeks) and one was term; the median birth weight was 800 g (range, 530 to 5600 g). Candidemia (Candida albicans in five, C. parapsilosis in six, C. albicans and C. parapsilosis in one and C. tropicalis in one) persisted despite 6 to 30 days of conventional antifungal therapy. After the addition of caspofungin, sterilization of blood cultures was achieved in 11 infants at the median time of 3 days (range, 1 to 21 days). Adverse events included thrombophlebitis (one patient), hypokalemia (two patients) and elevation of liver enzymes (four patients). Three infants had a second episode of candidemia and seven patients died. Caspofungin may be an efficacious addition for treatment of candidemia refractory to conventional antifungal therapy. This drug should be further investigated in neonates.

OBJECTIVE: To identify infants at risk of death and abnormal neurodevelopmental outcome following extracorporeal membrane oxygenation (ECMO) in the neonatal period. METHODS: The medical records of 82 neonates treated with ECMO were reviewed to evaluate risk of death. All survivors were followed by neurologic examinations and tested using the Bayley Scales of Infant Development or McCarthy Scale of Children’s Abilities, and risk for abnormal neurodevelopmental outcome was assessed. RESULTS: The overall survival was 91% (75 of 82). The mean gestational age and birth weight of nonsurvivors were lower than those of survivors (37 ± 1 weeks vs 40 ± 0 weeks; 2734 ± 230 vs 3325 ± 69 gm, p < 0.05). Infants who were lost to follow-up (16%) did not differ from those with follow-up in demographic variables or clinical indicators of illness severity. Thirty-five of 63 infants (56%) with follow-up had normal neurodevelopmental outcome. Risk of abnormal outcome was higher in infants requiring assisted ventilation for ≥15 days (relative risk [RR] 5.5; 95% confidence interval [CI] 2.0 to 14.8), supplemental oxygenation for ≥22 days (RR 3.1; 95% CI 1.3 to 7.6), and black race (RR 8.9; 95% CI 1.3 to 62.9). None of the neuroimaging studies accurately predicted the neurodevelopmental outcome of these infants. CONCLUSION: We conclude that ECMO in critically ill infants is associated with good survival. The need for prolonged respiratory support may help in identifying infants at risk for abnormal neurodevelopmental outcome.

Congenital hepatic arteriovenous malformations are rare anomalies, which typically present in infancy with congestive heart failure, anemia, and hepatomegaly. Morbidity and mortality is high if the condition is not recognized and treated promptly. Hepatic arteriovenous malformation associated with persistent pulmonary hypertension of the newborn has been reported in two cases in the literature. We report a neonate who was referred for management of persistent pulmonary hypertension and was subsequently diagnosed with a large hepatic arteriovenous malformation. He underwent coil embolization following which pulmonary hypertension resolved.

Gastrointestinal cytomegalovirus infection is a common opportunistic infection in immunocompromised patients. It is a rare cause of enterocolitis in immunocompetent hosts. We present a case of severe cytomegalovirus enterocolitis causing intractable diarrhea in a previously healthy infant. The child was successfully treated with intravenous ganciclovir.

e20640Background: Non-Small Cell Lung Cancer (NSCLC) is a heterogenous disease with 44% of pts developing brain metastases (BMs). Molecular Profiling (MP) enables selection of patients for targeted...

5509Background: Rare gynaecologic cancers (R-GYN) represent over 50% of all gynaecologic malignancies. Conducting clinical trials in R-GYN is challenging due to the limited number of patients (pts)...

2500Background: Phosphatidylinositol-3-kinase (PI3K) and fibroblast growth factor receptor (FGFR) pathway dysregulation can co-occur in tumors. In this study (NCT01928459), safety, tolerability, and preliminary activity of the pan-FGFR (BGJ398) + α-specific PI3K (BYL719) inhibitors were evaluated and maximum tolerated dose (MTD) was established in pts w/ advanced solid tumors w/ PI3K catalytic subunit (PIK3CA) mutations ± FGFR alterations. Methods: Pts w/ solid tumors received once-daily (QD) BGJ on D1-D21 of each 28-D cycle (C) and BYL continuously during escalation (PIK3CA-mutant ± FGFR-altered) and expansion (arm 1, PIK3CA-mutant [n = 15]; arm 2, PIK3CA-mutant + FGFR-altered [n = 10]; arm 3, PIK3CA-mutant + FGFR-altered breast cancer [n = 10]). Results: Of 62 pts enrolled, 44% had ≥ 4 prior therapies. The MTD, 125 BGJ + 300 BYL, was determined based on 32 evaluable pts’ data during escalation. C1 dose-limiting toxicities (DLTs) occurred in 4 pts (table). During expansion, 24 pts in arms 1 (n = 12), 2 (...

e16058Background: Data suggest that large RPLN significantly increase the risk of VTE in pts with mGCT receiving first line platinum based chemotherapy (chemo). This multinational G3 study aims to ...

Twenty-eight term neonates with severe perinatal asphyxia were referred to a tertiary neonatal intensive care unit (NICU). The morbidity of asphyxia included involvement of the pulmonary (n = 24 infants), central nervous system (n = 22), renal (n = 15), cardiac (n = 14), metabolic (n = 13) and hematologic (n = 10) systems. The majority of neonates had more than three organ systems involved. Twenty-four neonates survived the neonatal course and at NICU discharge all system effects other than the central nervous system had resolved. At 5 years (60 months), 14 children had a normal neurologic examination, 9 had spastic quadriplegia and one had hemiplegia. Nine children had a McCarthy General Cognitive Index (GCI) greater than or equal to 84, 3 had a GCI between 68 and 83 and 12 scored less than 67. Neonatal seizures, renal problems, microcephaly at 3 months, and post-neonatal seizures were associated with an abnormal neurologic outcome or a GCI less than 67. A neurologic examination during the first year of life may reveal whether children with birth asphyxia will be relatively normal at age 5 years or whether they will show considerable delay.

Abradable seals have been used in aero-engines and land-based gas turbines for more than three decades. They are applied to various sections of the engine in order to reduce gas leakage by optimizing the gap between rotating and stationary parts. This optimization represents a significant increase in efficiency and decrease in fuel consumption. Performance evaluation of any abradable seal includes measurement of its mechanical properties, abradability tests and (ultimately) tests in engines. The aim of this paper is to study the effect of temperature on the rub performance of abradable seals. A series of experiments has been carried out in order to evaluate a commercially available seal material at different operating conditions. The effect of operating temperature on contact force, abrasion scar appearance and blade wear is examined and analyzed. A microstructural analysis of the rub scar has also been performed.Copyright © 2008 by National Research Council of Canada

Background The NOTCH signaling pathway has been implicated in the tumorigenesis and resistance to anti-VEGF therapy, providing a rationale for the combination of RO, a gamma secretase inhibitor of NOTCH signaling, and Cd, a VEGFR-tyrosine multi-kinase inhibitor. Methods The primary objectives of this study were to assess safety, tolerability, and recommended phase II dose (RP2D) of combination therapy in patients (pts) with advanced solid tumors. Secondary objectives were to determine preliminary anti-tumor efficacy, as per RECIST v1.1 criteria, as well as pharmacokinetic (PK) and pharmacodynamic (PD) studies. A standard 3 + 3 design was used. Cycle 1 is 42 days (D), where RO is given orally once daily D1-3, 8-10, 15-17, 22-24, 29-31, 36-38 and Cd is given orally once daily D22-42. Cycles 2 + are 21 days, with RO given D1-3, 8-10, 15-17 and Cd given D1-21. Dose-limiting toxicity (DLT) was evaluated during cycle 1 (42 days). Results Twenty pts (median age of 54 [18-87]; ECOG 0-1) have been treated at 3 dose levels (DL): 7 pts at DL1 (RO = 10 mg; Cd =20 mg), 7 pts at DL2 (RO = 20 mg; Cd = 20 mg), and 6 pts at DL3 (RO = 20 mg; Cd = 30 mg). Primary tumors included: colorectal carcinoma (6), uterine sarcoma (4), renal cell carcinoma (3), and others (7). Pts received a median number of 3 cycles (range 1-20). The most common adverse events (AEs) of all grades possibly related to study drugs included (#pts): diarrhea (12), hypertension (HTN) (11), fatigue (11), and nausea (9). Grade 3+ AEs possibly related to study drugs included HTN, ALT and AST elevation, diarrhea, and hypophosphatemia. Two DLTs were observed: grade 4 HTN in DL1 which resolved after dose reduction and grade 4 AST elevation in DL2 which improved after discontinuing treatment. Of the 19 patients evaluable for response, the best response was stable disease (SD) in 12 pts and progressive disease in 7. Prolonged SD of ≥6 cycles was observed in 4 pts, including 1 pt with low grade endometrial stromal sarcoma on DL1 who remains on study after 20 cycles. Conclusions RO in combination with Cd is generally well tolerated at the DLs tested. The RP2D was defined as 20mg RO and 30mg Cd. PK data for RO and Cd, as well as PD data for circulating angiogenic factors will be presented. Disclosure All authors have declared no conflicts of interest.

Aim: Core needle biopsies (CNB) are used routinely to obtain metastatic tumor tissue for genotyping and to aid clinical decision-making. Fine needle biopsies (FNB) are a less invasive method to procure tumor cells. This ongoing study aims to compare the success and concordance of clinical genotyping using CNB and FNB of the same metastasis. Methods: Patients (pts) with advanced melanoma, breast, colorectal and gynecological cancers with no contraindication to biopsy were eligible. FNB were performed first (≤3 passes) followed by 3 CNB, using 25 and 18 gauge needles respectively. FNB underwent rapid onsite evaluation to ensure lesion sampling and both rinse and smear were used for profiling. CNB were formalin fixed and paraffin embedded. Following pathology review, tumor DNA was extracted and profiling was performed in a CLIA-certified laboratory using the Illumina MiSeq TruSeq panel (48 genes, 212 amplicons) or a customized solid tumor genotyping panel on the Sequenom MassArray (23 genes, 279 mutations). If available, genomic concordance between the archival specimen of the primary tumor and metastasis was assessed. Results: 35 pts (21 breast, 5 gynecological, 5 colorectal and 4 melanoma) were enrolled. 31 pts underwent a single biopsy, 3 pts were considered unsuitable and 1 pt had 2 biopsies separated by a line of systemic therapy. Liver was the most common biopsy site (15 pts [48%]). No biopsy related severe adverse events occurred. 26 biopsies have been reported, 5 CNB-FNB pairs had no tumor and another 4 CNB had no tumor with malignant cells seen on FNB only. There was no difference in DNA yield from CNB and FNB (mean 660ng vs 900ng, p=0.24). 29 mutations in 12 genes were identified from 22 biopsies (TP53 9, PIK3CA 5, APC 3, BRAF 2, ERBB2 2, KRAS 2, AKT1 1, ATM 1, CTNNB1 1, JAK2 1, KIT 1, NRAS 1). Two of the 20 pts with available primary tissue showed discordance with the biopsy of the metastasis (involving ATM and TP53 variants). Conclusions: Genotyping or targeted sequencing of FNB is feasible. CNB and FNB show high concordance for genotype. Few genotype differences were detected between the primary tumor and metastasis, although broader genomic testing may be required to identify clonal evolution. Disclosure: L.L. Siu: Research funding: Roche, Pfizer, Bristol-Myer Squibb, Boerhinger-Ingelheim. All other authors have declared no conflicts of interest.

The incidence and site of electroencephalogram (EEG) abnormalities and the efficacy of post-ECMO EEG as a predictor of neurodevelopmental outcome was evaluated in survivors of neonatal extracorporeal membrane oxygenation (ECMO). All survivors of neonatal ECMO with an EEG performed prior to their discharge were included if they had at least 12 months of follow-up. The neurodevelopmental outcome was reported as normal, suspect, and abnormal on the basis of neurological examination and the scores on Bayley Scales of Infant Development or McCarthy Scale of Children's Abilities. EEG abnormalities were noted in 31 (70%) of 44 infants. The distribution of EEG abnormalities was not significantly different for right and left hemispheres. The incidence of abnormal neurodevelopmental outcome was similar in infants with a normal or an abnormal EEG (3 of 13 vs. 7 of 31; p = 0.8). EEG abnormalities had no correlation with neurodevelopmental outcome. We conclude that the high incidence of EEG abnormalities and their lack of correlation with neurodevelopmental outcome would suggest that these abnormalities do not represent permanent brain injury and a single EEG performed after decannulation from ECMO is not helpful in identifying infants at risk of subsequent abnormal neurodevelopmental outcome.

Objective. To evaluate the effect of antenatal phenobarbital (PB) therapy on neurodevelopmental outcome at 36 months. Design. Prospective, randomized, controlled trial. Setting. Single-institution study. Subject and Interventions. Children born to women who participated in the study evaluating the effect of antenatal phenobarbital (PB) on neonatal intracranial hemorrhage were prospectively followed to 3 years of age. Outcome Measures. Physical growth, neurologic examinations, and developmental testing (McCarthy Scales of Children's Abilities). Comparisons between groups were made on all children and those born to multiple gestations. Results. Forty-one children born to women who received 10 mg/kg PB before delivery and 55 children in the control group were evaluated. Three children, all in the control group, had growth parameters (height, weight, and head circumference) below the fifth percentile. The McCarthy General Cognitive Index (standard, 100 ± 16) was 93 ± 20 in the PB group and 85 ± 18 in the control group. The subscores tended to be higher in the PB group than in the control group, with higher quantitative scores in the PB group (44 ± 11 vs 39 ± 8). Neurologic deficits were noted in 2 of 41 in the PB group and in 6 of 55 in the control group. Conclusions. Infants born to women who received antenatal PB therapy had similar neurodevelopmental outcomes as infants born to women who did not receive PB. No adverse effects of PB exposure were detected.

The objective of the investigation was to determine what effect intracranial pathology has on alterations of superior sagittal sinus blood flow, and to determine the role of color flow Doppler imaging of the superior sagittal sinus in the diagnosis of intracranial pathology in the neonate and infant. One hundred examinations were performed prospectively in 96 patients. The velocity was determined with an angle correction at 30-60 degrees and was obtained with and without gentle transducer compression. Superior sagittal sinus thrombosis was identified in two patients by the absence of flow. Multiple t-tests for independent measures showed no clinically significant differences between flow velocities with regard to intracranial hemorrhage, ventriculomegaly, extracorporeal membrane oxygenation therapy or prematurity. The authors conclude that color flow Doppler can accurately diagnose superior sagittal sinus thrombosis and may be used to screen high risk neonates such as those with thrombosis elsewhere or those treated with extracorporeal membrane oxygenation. No clinically significant associations were found between superior sagittal sinus flow velocity and any of the parameters evaluated in this study.

Background The notch signalling pathway has a critical role in regulating cellular differentiation, proliferation, and apoptosis. RO is a potent and selective gamma-secretase inhibitor with antitumor activity in animal models. Pre-clinical experiments indicate that the PI3K/AKT/mTOR pathway may mediate resistance to gamma secretase inhibitors, providing a rationale for combination therapy with RO and TEM. Methods A phase Ib dose-escalation study with a 3 + 3 design was conducted. Three dose levels (DLs) were planned. Objectives were to determine the recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the combination. Eligible pts received once daily oral RO on a 3 day on/4 day off schedule every week (QW), and intravenous QW TEM. Initial doses were 10 mg RO and 25 mg TEM. Cycles were every 21 days, except for cycle 1, which was 28 days. Treatment-related dose-limiting toxicities (DLTs) were evaluated during cycle 1. Results 17 pts (data cut-off 26-Apr-2012) have been treated on three DLs. Number of pts, DLTs and schedule are shown in Table 1. Demographics: M:F 6:11; median age: 60 yrs (range 28-84); ECOG 0/1:4/13. Pts received a median of 3 cycles (range 1-12). The most common adverse events (AEs) related to the study drug combination included: fatigue (82%; G3 6%), mucositis, (71%; G3 6%), neutropenia (59%; G3 12%), anemia (59%; G3 0%), and hypertriglyceridemia (59%, G3 0%).Two DLTs (G3 rash, G3 mucositis) were observed in the same patient in DL1 prompting dose expansion. No additional DLTs were observed. Of 15 patients evaluable for response, no objective responses were observed. 11 pts (73%) had stable disease (SD) as their best response; with 3 pts (sarcoma, neuroendocrine, non-small cell lung cancer) on therapy for ≥6 cycles. Conclusions RO can be safely combined with TEM. The RP2D was established as RO at 20 mg combined with 37.5 mg of TEM. PK and circulating angiogenic factors analyses will be presented. Dose Level RO Dose (mg) TEM Dose (mg) No. of pts treated No. of pts with DLT DLT 1 † 10 25 8 1 G3 rash, G3 mucositis 2 20 25 3 0 3 ∧ 20 37.5 6 0 † 2 pts were not evaluable for DLT ∧ DL3 (RP2D) was expanded to 6 pts Disclosure All authors have declared no conflicts of interest.