IMMU-40. IMMUNE PROFILING OF MATCHED PRIMARY AND RECURRENT GLIOBLASTOMA TUMORS IDENTIFIED CD64 AS A NEGATIVE PREDICTOR FOR SURVIVAL

BACKGROUND To target tumor-induced immune evasion mechanisms of glioblastoma for clinical research, we aimed at characterizing the immunological changes in patient-matched treatment-naïve and recurrent GBM samples. MATERIAL AND METHODS Proteins and total RNA were extracted from 15 patient-matched treatment-naïve (primary) and recurrent GBM fresh frozen tumor samples. The expression of genes involved in brain immune responses were compared using Nanostring panels encompassing Cancer and Neuroinflammation genes. Correlation analysis using log2-transformed patient-matched recurrent/primary expression ratio (log2(P/R)) and clinical outcome data (time to relapse and overall survival (OS)) was conducted. Proteomic was conducted to compare total protein expressions. Moreover, immunostaining was performed on a tissue microarray of matched tumor samples to visualize CD64+ cells, CD47+ tumor cells and microglia in order to assess quantitative transcriptome of these specific cell types using GeoMX technology. Functional assays are designed for deciphering phagocytosis induction by factors produced by primary and recurrent tumors. RESULTS Genes significantly differentially expressed between primary and recurrent tumors revealed “Antigen presentation” and “Microglia Pathogen Phagocytosis” as the most significant pathways enriched in recurrent tumors. Considering individual genes, a strong negative correlation (R2>0.4) between log2(R/P) and time to relapse and OS was found for 2 genes, FCGR1A (CD64) and CD47. We observed that only CD64 expression levels in recurrent samples also negatively correlated with OS. CD64 and CD47 proteins were quantified by proteomic analysis and log2 (R/P) of their levels also negatively correlated with time to relapse. Immunostaining revealed numerous CD64-positive cells in tumor biopsies resembling bushy or amoeboid microglia. CONCLUSION Upregulation of CD64 and CD47 expressions in recurrent GBM was identified as a negative predictor for time to relapse and OS. This suggests an important role of CD64 and CD47 and related inflammation dysregulation in tumor resistance and regrowth. Interfering with CD64-induced functions may represent a novel therapeutic option for GBM.

TCF-001 TRACK (Target Rare Cancer Knowledge): A national patient-centric precision oncology trial for rare cancers.

TPS3143 Background: Many rare cancers are understudied, and affected patients often have few if any standard treatment options and limited access to clinical trials. Comprehensive genomic profiling (CGP) is a robust tool to efficiently identify the genomic alterations of cancer and can be applied to study rare tumors. The promise of this technology is to simultaneously enhance our understanding of diverse rare tumors and find matched therapies to benefit the individual patient in real-time. The COVID19 pandemic has challenged the “trial-centric” clinical trial infrastructure. Novel “patient-centric” trials are needed, especially for rare cancers. TRACK is a decentralized, patient advocacy-initiated trial that aims to establish whether patients with rare tumors and cancer of unknown primary can benefit from matched molecular therapy as dictated by their CGP results. Methods: This is a national open label, non-randomized, multi-center (includes community and academic centers) pragmatic study in rare tumors (<6 cases per 100,000 persons per year) and cancer of unknown primary. All participants will have tumor tissue and blood analyzed by CGP (FoundationOneCDx and FoundationOneLiquidCDx). A Virtual Molecular Tumor Board (VMTB) will convene to identify targeted treatment recommendations for participants with genomic alterations. Overall, 400 participants will be enrolled to achieve the goal of 100 patients matched to genomically informed treatment, utilizing remote consenting to ensure study access regardless of geographic location. The primary feasibility endpoint is the percent of participants who receive a molecularly matched treatment after recommendation from the VMTB. The primary efficacy endpoint is the progression-free survival (PFS) among participants who received the molecularly matched treatment. Secondary endpoints include the percent of participants with genomic alterations, overall response rate, response duration, overall survival, clinical benefit rate (SD > 6 months; PR; CR), and high-grade toxicities (as available) of matched targeted therapy. Exploratory endpoints include matching rates; understanding genomic correlates of response; concordance rates between CGP from tissue and blood, time-to-treatment failure, and the impact of the cancer treatment from the patient perspective (via ESAS-FS, a validated patient-reported outcomes (PRO) instrument). All eligible and enrolled patients, regardless of whether receiving matched treatment or not, will be followed for a minimum of one year in a uniform way such that the treatment efficacy and outcomes can be assessed in standard formats. The study is open with six patients enrolled at time of submission. Clinical trial information: NCT04504604.

Profiling of circulating tumor DNA and tumor tissue for treatment selection in patients with advanced and refractory carcinoma: a prospective, two-stage phase II Individualized Cancer Treatment trial

Background: Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma. Patients and methods: A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm. Results: Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8–71.0] compared with 81.5 days (IQR 68.5–117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6–0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option. Conclusions: Our study employed a histotype–agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes. EU Clinical Trials Registry ( https://www.clinicaltrialsregister.eu ): EudraCT: 2014-005341-44

Identification of Lenalidomide Sensitivity and Resistance Mechanisms in Non-Del(5q) Myelodysplastic Syndromes

Whereas lenalidomide is an effective therapy for del(5q) MDS patients, a minority of non-del(5q) MDS patients achieve hematologic improvement with lenalidomide. We used computational biology modeling and digital drug simulation to examine genomic data from 56 non-del(5q) MDS patients treated with lenalidomide, and then matched treatment response with molecular pathways. The computer inferred genomic abnormalities associating with lenalidomide treatment response in non-del(5q) MDS to include trisomy 8, del(20q), or RUNX1 loss of function mutations. Genomic abnormalities associating with lenalidomide resistance in non-del(5q) MDS patients included mutations in SF3B1, TET2, WNT3A amplification, MCL1 amplification, and/or PSEN2 amplification. These results may inform protocols for determining appropriateness of lenalidomide in non-del(5q) MDS.

Mutational landscape of endometrial cancer identified by prospective clinical sequencing in a nationwide cancer network.

e17123 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that have the potential to be targeted therapeutically. We present an analysis of comprehensive genomic profiling (CGP) of a large series of endometrial cancer (EC) patients assayed in a nationwide cancer network. Methods: 278 Pts with advanced EC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue or for 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 05-2018. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. The treatment histories for these patients were obtained with IRB-approved retrospective review. Results: Median age was 59 years (range, 37-85), 58% were Caucasian. GA were identified in 97% (271/278) of EC, of which 218 (80%) had a clinically relevant genomic alteration (CRGA). PI3K/AKT/mTOR pathway ( PIK3CA, AKT1/2/3, PIK3R1, PTEN, MTOR, STK11, FBXW7) CRGA were most common, present in 63.8% of EC. CRGA in other targetable pathways were identified: 28.4% in MEK ( KRAS, NRAS, HRAS, BRAF, RAF1, GNAS, NF1, NF2) , 12.5% in HRD (BRCA1/2, ATM, PALB2, BRIP1 ) and 9.9% in ERBB ( ERBB2, ERBB3, ERBB4, EGFR). 26 patients are MSI-high 9.5% (26/271) and 21 patients are TMB-high 7.7% (21/271). 29.8% (65/218) of EC patients were ordered a genomically-matched treatment, and 61 of these patients received the treatment. 69.2% (45/65) were agents that were FDA approved in a different tumor type, and 24.6% (16/65) through referral to a matched mechanism driven clinical trial. With access to the clinical trial TAPUR, the frequency of matched treatment through clinical trials increased over time from 2013 to 2018. The median PFS for non-clinical trial study patients was 9 weeks, and the median OS was 27 weeks. Conclusions: In a large series of Endometrial and Uterine cancer patients assayed with CGP, 27.9% (61/218) of pts received matched treatment, which was predominantly targeted therapy. The comprehensive sensitive and unbiased nature of CGP, coupled with a multidisciplinary molecular tumor board and staff dedicated to genomic interpretation, assisted in achieving a high frequency of patients’ participation in clinical trials and gene-directed treatment.

Mutational landscape of ovarian cancers (OC) identified by prospective clinical sequencing in a nationwide cancer network.

e17067 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that have the potential to be targeted therapeutically. We present an analysis of comprehensive genomic profiling (CGP) of a large series of OC assayed in a nationwide cancer network. Methods: 449 Pts with advanced OC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue or for 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 05-2018. Clinically relevant (CR) GA were defined as associated with targeted therapies or mechanism-driven clinical trials. Treatment histories for the 449 patients were obtained with IRB-approved retrospective review. Results: Median age was 56 years (range, 23-83), 71% were Caucasian. GA were identified in 94% (420/449) of OC, of which 283 (63%) had a clinically relevant genomic alteration (CRGA). 24.0% in HRD ( BRCA1/2, ATM, PALB2, BRIP1). CRGA in other potentially targetable pathways were identified: 48.0% MEK pathway ( KRAS, NRAS, HRAS, BRAF, RAF1, GNAS, NF1, NF2) CRGA, 33.5% PI3K/AKT/mTOR pathway ( PIK3CA, AKT1/2/3, PIK3R1, PTEN, MTOR, STK11, FBXW7), and 10.6% in ERBB ( ERBB2, ERBB3, ERBB4, EGFR). All OC tested were microsatellite stable and only one patient had a tumor mutational burden > 20 muts/Mb. 21% (59/283) of OC patients were ordered a genomically-matched treatment, 58% (37/64) were agents that were FDA approved in a different tumor type, and 17% (11/64) through referral to a matched mechanism driven clinical trial. With access to the clinical trial TAPUR, the frequency of matched treatment through clinical trials increased over time from 2013 to 2018. For the off label non-study population the median PFS was 19 weeks, and the median OS was 34 weeks. Conclusions: In a large series of OC assayed with CGP, 21% of pts received matched treatment, which was predominantly targeted therapy. The comprehensive sensitive and unbiased nature of CGP, coupled with a multidisciplinary molecular tumor board and staff dedicated to genomic interpretation, assisted in achieving a high frequency of patients’ participation in clinical trials and gene-directed treatment.

Mutational landscape of cervical cancer identified by prospective clinical sequencing in a nationwide cancer network.

e17022 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that have the potential to be targeted therapeutically. We present an analysis of comprehensive genomic profiling (CGP) of a large series of cervical cancer (CC) patients assayed in a nationwide cancer network. Methods: 118 Pts with advanced CC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue or for 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 05-2018. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. The treatment histories for these patients were obtained with IRB-approved retrospective review. Results: Median age was 47 years (range, 27-71), 69% were Caucasian. GA were identified in 88% (104/118) of CC, of which 87 (74%) had a clinically relevant genomic alteration (CRGA). PI3K/AKT/mTOR pathway ( PIK3CA, AKT1/2/3, PIK3R1, PTEN, MTOR, STK11, FBXW7) CRGA were most commonpresent in 73.5% (64/87) of CC. CRGA in other targetable pathways were identified: 24.1% (21/87) in MEK ( KRAS, NRAS, HRAS, BRAF, RAF1, GNAS, NF1, NF2), 9.1% (8/87) in HRD (BRCA1/2, ATM, PALB2, BRIP1) and 24.1% (21/87) in ERBB ( ERBB2, ERBB3, ERBB4, EGFR). One patient was MSI-high and one patient was TMB-high. 29.8% (26/87) of CC patients were ordered a genomically-matched treatment, and 24 pts received treatment; 61.5% (16/26) were agents that were FDA approved in a different tumor type, and 34.6% (9/26) through referral to a matched mechanism driven clinical trial. With access to the clinical trial TAPUR, the frequency of matched treatment through clinical trials increased over time from 2013 to 2018. The PFS for non study related patients was 7 weeks and OS was 19 weeks. Conclusions: In a large series of Cervical Cancer patients assayed with CGP, 27.5% (24/87) of pts received matched treatment, which was predominantly targeted therapy. The comprehensive sensitive and unbiased nature of CGP, coupled with a multidisciplinary molecular tumor board and staff dedicated to genomic interpretation, assisted in achieving a high frequency of patients’ participation in clinical trials and gene-directed treatment.

Managing Laggards: The Importance of a Deep Sales Bench

Sales leaders often use threats of punishment to manage poor performers (i.e., laggards), but little research has examined the effect of these threats. The current research addresses this gap by investigating an intervention termed the “bench program” with a field-based quasi experiment and a randomized lab experiment. In the field, the company under study told salespeople in treatment districts that a trainee would replace them at the end of the year if they failed to hit their quota and placed last in their district. Difference-in-differences analyses of matched treatment and control groups show that the bench program had an immediate and sustained impact on performance. Moreover, laggards improved their performance more than higher performers, and salespeople with larger advice networks improved their performance more than salespeople with smaller advice networks. A lab experiment compares the bench program with a program that had the same threat of firing but did not have replacements in sight. Performance in the bench program exceeded that in the firing condition, indicating that the vividness of a threat can increase its deterrent value.

Delivering Precision Oncology in a Community Cancer Program: Results From a Prospective Observational Study

Introduction Precision oncology (PO) is a growing treatment approach in the era of next-generation sequencing (NGS) and matched therapies. Effective delivery of PO in the community has not been extensively studied. Our program developed a virtual molecular tumor board (MTB) strategy to help guide PO care. Materials and Methods Over 18 months, eligible adult patients with advanced, incurable solid tumor malignancies were enrolled in a molecular profiling (MP) study using the Foundation Medicine NGS panel. Results were reviewed through a weekly, videoconferenced MTB conducted across our largely rural integrated health system. Recommendations from the MTB were used to identify actionable alterations (AAs). Feasibility of PO care delivery was assessed as the primary outcome. Secondary outcomes included the frequency of AAs, genomic matched treatments, genomic matched clinical trial enrollment, and clinical outcomes. Results A total of 120 participants with a variety of advanced tumor types were enrolled. Of these, 109 (90.8%) had successful MP. Treatment on the basis of an AA was recommended by the MTB in 58% of patients (63 of 109) who had a successful MP result. For those completing MP, treatments included enrollment in a genomic matched clinical trial (n = 16; 14.6%) and genomic matched treatment with a Food and Drug Administration–approved agent (n = 23; 21.1%). Response and survival data were similar regardless of the matched treatment option chosen. Conclusion A video-conferenced MTB-facilitated NGS testing and treatment delivery system was implemented in our integrated community oncology program. Continued use of this model aims to increase understanding of the impact of PO in this setting.