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For hepatocellular carcinoma, the IMbrave150 trial demonstrated that combination atezolizumab and bevacizumab had significantly better overall survival compared with sorafenib in patients with unresectable disease. However, as more immune checkpoint inhibitors are approved as first-line agents in gastrointestinal cancers, there have been few reports on whether sequential PD-1/PD-L1 blockade is beneficial in the treatment of these diseases. We present a patient with hepatocellular carcinoma who had disease progression on atezolizumab, a PD-L1 inhibitor, but subsequently had a remarkable response to pembrolizumab, a PD-1 inhibitor.

Supplemental Figure 1

Supplementary Figure Legend

Details of the Patients with HR-DDR Mutations.

Purpose:Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined.Patients and Methods:We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1–7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations.Results:The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%.Conclusions:The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation.

Revised supplemental figures and tables

Veliparib pharmacokinetics compared to historical control.

Written Description of the Supplementary Methods; and the Supplementary Figure/Table Legends

Visual Depiction of the therapy dosing, and pharmacokinetic (PK) sampling schedule for patients in the Phase I portion of the trial.

Veliparib dose levels

Veliparib pharmacokinetics

Purpose:Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response.Patients and Methods:Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level.Results:Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs.Conclusions:In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Background FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. Methods Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. Results Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. Conclusions SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell–mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.

The prevalence of homologous recombination–DNA damage response (HR-DDR) genetic alterations is of therapeutic interest in gastroesophageal cancers. This study is a comprehensive assessment of HR-DDR mutation prevalence across gastroesophageal adenocarcinomas and squamous cell carcinomas. Here we investigate the association of HR-DDR mutations with known predictors for immune-checkpoint inhibition [deficiency in mismatch-repair (dMMRP), tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1)]. We confirmed HR-DDR mutations are present in a subset of gastroesophageal adenocarcinomas (23%) and gastroesophageal squamous cell carcinomas (20%). Biomarker expression of dMMRP (18% vs. 1%) and TMB-high with a cutoff of ≥10 mt/MB (27% vs. 9%) was significantly more prevalent in the DDR-mutated cohort compared with the non-DDR-mutated cohort. Mean combined positive score for PD-L1 in the total adenocarcinoma cohort was significantly higher in the DDR-mutated cohort compared with the non–DDR-mutated cohort (10.1 vs. 5.8). We demonstrated that alterations in ARID1A, BRCA2, PTEN, and ATM are correlated with dMMRP, TMB-high, and increased PD-L1 expression in gastroesophageal adenocarcinomas. Our findings show that a subset of gastroesophageal tumors harbor HR-DDR mutations correlated with established immune biomarkers. By better understanding the relationship between HR-DDR mutations and immune biomarkers, we may be able to develop better immunotherapy combination strategies to target these tumors.

Purpose: Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined. Patients and Methods: We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1–7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations. Results: The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%. Conclusions: The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation.

TPS257 Background: Refractory microsatellite stable colorectal cancer (MSS CRC) is immunologically cold and single-agent anti-PD-1/PD-L1 drugs are ineffective; novel immune-based approaches are needed. Evorpacept (E, ALX148) is an engineered protein (high-affinity CD47-blocker fused to an inactive IgG Fc region), which blocks the CD47/SIRPα innate immune inhibitory phagocytosis checkpoint expressed on CRC and phagocytes, respectively. The Fc region of E does not bind to Fcγ receptors, thereby limiting hematologic toxicity, and is intended to be given in combination. In CT26 CRC syngeneic models, E ± anti-PD-1 monoclonal antibody decreases tumor growth, reduces myeloid immunosuppression, increases dendritic cell activation, and increases T cell activation (Kauder, 2018); E enhances the antibody-dependent cellular phagocytosis activity of cetuximab (C) in vitro (Kauder, 2018); and E + pembrolizumab (P) was well-tolerated in the first-in-human trial (Lakhani, 2021). Methods: AGICC-ALX148 21CRC01 (NCT05167409) is a phase 2, single-arm, multicenter, investigator-initiated trial of E (15 mg/kg weekly), C (400 mg/m2 then 250 mg/m2 weekly), and P (200 mg every 3 weeks) in 21-day cycles for patients with unresectable MSS/proficient mismatch repair CRC refractory to oxaliplatin, irinotecan, and a fluoropyrimidine, regardless of tumor sidedness and RAS/BRAF status. Additional key eligibility criteria include ECOG performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and end organ function, absence of prior checkpoint inhibitor use, and absence of significant autoimmune disease. Six patients will be enrolled in Stage 1 (safety run-in) and treated with ECP. The study will proceed to Stage 2 (dose expansion, N = 42, and all treated with ECP) if less than 33% of patients in Stage 1 experience a dose-limiting toxicity. Otherwise, additional patients will be enrolled in Stage 1 at lower dose level(s). The co-primary objectives are to determine 1) the recommended dose of E with CP, and 2) objective response rate by RECIST v1.1 (by one-sided exact test with α = 0.05, H0 p ≤ 3% [historical controls], HA p ≥ 15%; power is 87%). The study will close for futility if there are no responses (partial or complete) in the first 24 evaluable patients (by MinMax design with α = 0.025 [1-sided]; power is 87%). Secondary and exploratory aims include determination of progression-free survival, overall survival, safety, response assessment by iRECIST, and blood- and tumor-based immune modulation and baseline tumor expression (PD-L1, EGFR, and CD47) for association with tumor response. The study is open through the Academic GI Cancer Consortium and 5 patients have been enrolled at time of submission. Clinical trial information: NCT05167409 .

85 Background: Rising rates of early-onset colorectal cancer (EOCRC) pose a dilemma for clinicians when deciding how to treat early-stage patients to maximize outcomes. While standard-of-care for Stage II colon cancer is largely surgical resection, evidence suggests that treatment selection may differ by patient age. We sought to determine whether rates of adjuvant chemotherapy administration differ between early and later-onset patients with Stage II CRC. Methods: Data were derived from the Flatiron National Database spanning 1/1/2003 to 8/1/2021. Patients 18 years or older with Stage II CRC were grouped into those aged 18-49 (EOCRC) and those aged 50 or older (LOCRC). Demographic characteristics, ECOG score, stage and site of tumor, and chemotherapy were included for all patients. Primary outcomes of interest included rates of adjuvant chemotherapy administration by age and ethnicity. Univariate and multivariable logistic regression models were used to evaluate relationships between chemotherapy administration, age groups, and ethnicity while adjusting for significant covariates. Results: Of 2133 patients with Stage II CRC, 1606 patients with complete data were included. A secondary analysis of 1065 patients with colon cancer was performed to address potential confounding factors related to neoadjuvant and/or adjuvant chemotherapy given in patients with stage II rectal cancer. Mean age of EOCRC patients was 45.0 years (range: 41.0-48.0) vs. 68.0 years (60.0-75.0) for LOCRC. Adjusting for ethnicity, gender, site, and ECOG score, multivariate analysis showed EOCRC patients received chemotherapy significantly more often than LOCRC patients for stage II CRC (adjusted odds ratio 1.85, 95% CI 1.32-2.60, p < 0.001). Similar findings were observed in the colon cancer only cohort (adjusted OR 2.02, 95% CI 1.31-3.09, p < 0.001). By ethnicity, non-Hispanic patients received chemotherapy at significantly lower rates than Hispanic patients in both cohorts (adjusted odds ratio 0.58, 95% CI 0.39-0.88, p = 0.009 and adjusted odds ratio 0.55, 95% CI 0.34-0.91, p = 0.018). In a subgroup analysis of Stage IIA patients, multivariate logistic regression adjusting for gender, ECOG, site, and ethnicity showed that patients with EOCRC were more likely to receive chemotherapy than patients with LOCRC (adjusted odds ratio 1.91, 95% CI 1.21-2.99, p = 0.005). Updated survival data will be presented. Conclusions: Adjuvant chemotherapy is given preferentially in Stage II EOCRC, even in Stage IIA disease, despite deviation from established guidelines. This may expose patients at low risk for recurrence to unnecessary toxicities and reveals potential provider bias in favor of younger patients in aggressively treating CRC, despite unclear evidence for any outcome benefit.

Purpose: Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Patients and Methods: Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Results: Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. Conclusions: In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

TPS365 Background: Despite standard treatment options (eg, CAPOX, capecitabine + oxaliplatin), 5-year survival with advanced/metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ) is poor and limited biomarkers exist to inform treatment selection. Claudin 18.2 (CLDN18.2), a targetable biomarker, is a tight junction protein that is normally confined to gastric mucosa of healthy tissue and is often retained in G/GEJ. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Phase 2 (FAST; Sahin, Ann Oncol. 2021) results showed prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in CLDN18.2+ advanced G/GEJ. Preliminary phase 2 (NCT03505320, ILUSTRO Cohort 2; Klempner, J Clin Oncol. 2021) results showed promising antitumor activity with combination zolbetuximab + mFOLFOX6 (5-fluorouracil, folinic acid, oxaliplatin) in CLDN18.2+ advanced G/GEJ. Methods: GLOW (NCT03653507) is enrolling ̃500 adults from global sites. Patients are required to have radiologically evaluable (RECIST v1.1) CLDN18.2+/HER2– locally advanced unresectable or metastatic G/GEJ. Prior chemotherapy for advanced/metastatic G/GEJ is not permitted. Patients will be randomized 1:1 to zolbetuximab + CAPOX or placebo + CAPOX. Randomization will be stratified by region (Asia vs non-Asia), number of metastatic sites (0 to 2 vs ≥3), and prior gastrectomy (yes vs no). Zolbetuximab will be administered at 800 mg/m2 IV on Cycle 1 Day 1 (loading dose), then at 600 mg/m2 IV every 3 weeks; 8 cycles of CAPOX will be administered. Central testing of tumor tissue will determine CLDN18.2 status; tumors will be considered CLDN18.2+ if ≥75% of tumor cells show moderate to strong membranous immunohistochemical staining. Primary endpoint: progression-free survival per independent review. Secondary endpoints: overall survival; objective response rate; duration of response; safety/tolerability, pharmacokinetics, and immunogenicity of zolbetuximab. As of September 22, 2021, 135 sites were open for screening and enrollment. Clinical trial information: NCT03653507.

TPS376 Background: Human epidermal growth factor receptor 2 ( HER2) gene amplification or protein overexpression (HER2+) occurs in many gastrointestinal (GI) cancers; thus, there is interest in evaluating HER2-targeted therapies in these tumor types. Tucatinib (TUC) is a highly selective HER2-directed tyrosine kinase inhibitor with minimal EGFR inhibition, approved in multiple regions for HER2+ metastatic breast cancer. In patient-derived xenograft models of HER2+ tumors (including esophageal, gastric, and colorectal cancers), TUC + trastuzumab showed superior anti-tumor activity compared with either agent alone (Kulukian 2020). In the MOUNTAINEER study, TUC + trastuzumab in HER2+ metastatic colorectal cancer (CRC) resulted in an objective response rate of 52% and a median duration of response of 10.4 months (interim results, Strickler 2019). The SGNTUC-024 study (NCT04430738) will evaluate TUC + trastuzumab with and without oxaliplatin-based chemotherapy or pembrolizumab in patients with unresectable or metastatic GI cancers. Methods: SGNTUC-024 is an open-label, dose escalation and expansion phase 1b/2 trial. Phase 1b assesses the safety and tolerability of TUC + trastuzumab + either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) with or without pembrolizumab. One chemotherapy-free cohort is planned (TUC + trastuzumab + pembrolizumab). The initial phase 1b cohort enrolled patients with gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinomas; cholangiocarcinoma; gallbladder carcinoma; and CRC to receive TUC (150 mg oral [PO] twice daily [BID]) + trastuzumab + FOLFOX. Subsequent phase 1b cohorts will receive TUC (300 mg PO BID) + trastuzumab + either FOLFOX or CAPOX. Once the recommended dose for use with oxaliplatin is identified, cohorts enrolling patients with gastric, esophageal, and GEJ adenocarcinomas will open with patients receiving TUC (300 mg PO BID) + trastuzumab + pembrolizumab with or without either FOLFOX or CAPOX. Phase 2 will expand the assessment of safety and efficacy and enroll 2 cohorts: patients with gastric, esophageal, and GEJ adenocarcinomas (to receive TUC + trastuzumab + pembrolizumab + either FOLFOX or CAPOX, Cohort A) and patients with CRC (to receive TUC + trastuzumab + FOLFOX, Cohort B). Safety and efficacy will be summarized with descriptive statistics. Patients that receive chemotherapy must be eligible for an oxaliplatin-based regimen as standard of care. Patients with irradiated or resected central nervous system (CNS) lesions may enroll, and patients with known active CNS lesions may be eligible for phase 2. The phase 1b portion of the trial is currently enrolling. Clinical trial information: NCT04430738.

118 Background: To date, immune-checkpoint inhibition for microsatellite stable (MSS) mCRC has been ineffective, though targeted therapy combination strategies may be promising. This phase II, investigator-initiated trial (NCT03475004) was designed to evaluate the efficacy and safety of the three-drug combination of pembrolizumab (pembro), binimetinib, and bevacizumab in patients with advanced, MSS treatment-refractory colorectal cancer. Methods: Patients with mCRC locally determined to be MSS and whom have progressed on two prior lines of therapy were enrolled. Treatment consists of pembro (200 mg every 3 weeks), binimetinib (45 mg BID) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint is PFS using RECIST v1.1 by investigator review. Additional endpoints include objective response rate, disease control rate at time of first re-staging (2 mo), duration of response, and safety and tolerability. Results: 50 patients have been enrolled (accrual is completed). 53% of patients are male and the mean age is 53.6 (range 31-79). The mean number of prior therapies is 5.3. At the time of preliminary data review, 39 patients are evaluable for response data. The median PFS was 5.8 mo (95% CI 4.2 to 8.9). The objective response rate was 13% with 5 partial responses. 24 patients (62%) had stable disease and 10 (26%) had progressive disease as the best response. The disease control rate at the time of first re-staging was 74%. Median duration of response was 6.5 mo. 19 (40%) patients experienced serious adverse events; the most common grade ≥3 adverse events included transaminase elevation (15%), diarrhea (11%), acneiform rash (9%), hypertension (9%), and anemia (9%). Conclusions: Preliminary results from this phase II study indicate that this regimen of pembrolizumab, binimetinib, and bevacizumab has promising activity and acceptable tolerability in this heavily pre-treated population of patients with MSS metastatic colorectal cancer. Final results will be presented as well as ongoing correlative studies. Clinical trial information: NCT03475004.

Approximately one-quarter of patients with colorectal cancer have liver metastases (CLMs) at diagnosis. There is much debate regarding the optimal treatment of CLMs. Although many patients are diagnosed with CLMs initially (synchronous), many individuals develop hepatic metastases even after successful management of their primary tumor (metachronous). For this reason, much of our guidance for systemic and local therapies is centered on both preventing the development of liver metastases and eradicating existing CLMs. Surgical resection remains a mainstay of therapy; however, with the development of targeted biological agents and improvement of locoregional techniques for disease control including chemoembolization, thermal ablation, and arterial infusion chemotherapy, the management of CLMs is becoming more complex. This chapter focuses on the use of systemic chemotherapy and biologics in the management of CLMs.

3075 Background: OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-006, the active metabolite of OKI-179, inhibits HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs and has shown promising activity in preclinical models of solid tumors. We conducted a first-in-human dose escalation study of OKI-179 in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, ECOG ≤1, normal QTc, and disease refractory to or with no available standard therapy options were treated with OKI-179 with either intermittent dosing (once daily for 4 days on 3 days off) or continuous dosing (once daily). Dose escalation was conducted using a standard 3+3 design. Pharmacokinetic (PK) and pharmacodynamic (PD) testing was performed at various time points after dosing. Results: As of Feb 4, 2021, 26 patients (19 female, 7 male) were enrolled with mean age of 63 (range 41-83). Patients received a median of 5 (range 1-11) prior lines of therapy and most common tumor types included pancreatic (N = 5), breast (N = 4), lung (N = 4), and ovarian cancer (N = 4). Twenty patients were treated in intermittent dosing cohorts from 30-450 mg. One DLT (Grade 2 [G2] thrombocytopenia) occurred in the 450 mg cohort which was expanded to 6 patients without subsequent DLTs. Six patients were treated in 2 continuous dosing cohorts of 200 mg and 300 mg. Two of 3 patients in the 300 mg cohort had DLTs of G3-4 thrombocytopenia and no DLTs were observed in 3 patients treated at 200 mg PO daily. The most common adverse events (AEs) were nausea (62%), fatigue (42%), anemia (39%), anorexia (27%), and vomiting (23%). These AE’s were G1-2 except for G3 anemia (12%), G3 fatigue (12%), and G3 anorexia (4%). No other G4-5 treatment-related AEs occurred. Median time on study was 79 days and best response was stable disease (SD) in 10 of 24 patients evaluable for efficacy (42%). Prolonged SD was observed in patients with platinum-resistant serous ovarian cancer (446 days) and adenoid cystic nasopharyngeal carcinoma (256 days). OKI-006 achieved consistent exposure with Cmax > 2,000 ng/ml and AUC > 8,000 hr*ng/ml, well above the targeted exposure for efficacy based on pre-clinical studies in murine models. Tmax was 2 hours and T1/2 was 6-8 hours. OKI-179 treatment resulted in > 3X increased T cell histone H3K9 and H3K27 acetylation within circulating PBMCs at doses of 180 - 450 mg. Conclusions: OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT. It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses. The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing. Phase 2 studies are being designed, with a focus on combination with endocrine therapy in ER+ breast cancer and in NRAS-mutant melanoma. Clinical trial information: NCT03931681.

e14559 Background: While TMB is very dependent on methodology, tissue TMB-H (≥10 mutations/megabase) may predict benefit with ICIs. Pembrolizumab received tissue-agnostic approval for TMB-H unresectable cancers in 2020, but little is known about TMB as a predictive biomarker in mGI cancers. We hypothesized that tissue TMB will correlate with efficacy of ICIs in mGI cancers. Methods: A retrospective chart review identified patients with mGI cancers who received an anti-PD-(L)1 drug and had known TMB at a single academic center from 2012 to 2020. The association of TMB with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was analyzed using the Fisher’s exact and Log-rank tests. Survival curves were generated using the Kaplan-Meier method. Cox proportional hazard and logistic regression models were used to adjust for microsatellite status. Significance was prespecified at 0.05. Results: 83 patients were identified and included. The most common cancer types were colorectal adenocarcinoma (AC, n = 29), esophageal/gastric AC (n = 21) and SCC (n = 4), cholangiocarcinoma (n = 11), anal SCC (n = 7), and pancreas AC (n = 7). Average age was 61, average number of lines of prior systemic therapy for advanced disease was 1.3 (range 0-4), and 37% of patients were treated on a clinical study. All patients received an anti-PD-(L)1 drug; 6%, 2%, and 36% also received ipilimumab, cytotoxic chemotherapy, and other combinations, respectively. Among those with esophageal/gastric cancer, 76% had known PD-L1 CPS (84% ≥1, 63% ≥5, 42% ≥10). TMB was primarily determined by Foundation One CDx (87%). TMB ranged from 0 to 54; n = 22 (27%) were TMB-H (of these, n = 10 were microsatellite instability-high (MSI-H)), and n = 61 were TMB-L ( < 10 mutations/megabase; of these, n = 2 were MSI-H). The prevalence of TMB-H and microsatellite stable (MSS) was 14.4%. TMB-L, compared to TMB-H, was associated with inferior ORR (3.5% vs 55.6%; odds ratio (OR) 0.045; p < 0.001) and PFS (median 12.7 vs 29.3 weeks; hazard ratio (HR) 2.70; p = 0.001), but not OS (HR 1.20; p = 0.60). In patients with MSS disease, TMB-L, compared to TMB-H, was associated with inferior ORR (OR 0.13; p = 0.04) but not PFS (HR 1.76; p = 0.07) or OS (HR 0.89; p = 0.79). In subgroup analyses, ORR was not significantly associated to tumor type in all or MSS patients. TMB as a continuous variable, in patients with MSS disease, was positively correlated with ORR (p = 0.02) and PFS (p = 0.04), but not OS (p = 0.59). Among all patients, PFS and OS data is immature (median follow-up 13 and 31 weeks). Conclusions: In a single center retrospective study of patients with mGI cancers treated with ICIs, TMB-H was associated with improved ORR and PFS compared to TMB-L. In patients with MSS disease, ORR remained significant. PFS and OS data are immature. TMB as a biomarker of efficacy with ICIs in mGI cancers warrants further study to guide clinical use.

e16276 Background: Appendiceal adenocarcinoma is relatively rare and often diagnosed incidentally during operations for acute appendicitis. It is commonly associated, either at time of initial presentation or upon recurrence, with peritoneal metastases. A typical treatment strategy for patients with peritoneal disease includes cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Extrapolating largely from literature in colorectal cancer, chemotherapy is frequently given before and/or after CRS/HIPEC though high-level evidence to support this is lacking. We sought to evaluate the effect of systemic chemotherapy on survival. Methods: Utilizing a database of CRS/HIPEC procedures at University of Colorado Hospital from 2008 to present we retrospectively reviewed cases of appendiceal adenocarcinoma. Data collected included staging, histologic grade, chemotherapy given, surgical outcomes, and time to disease recurrence. Patients without adequate information regarding treatment, or without at least 1 year of clinical follow-up, were excluded. Associations between administration of chemotherapy or histologic grade and 1-year DFS were analyzed using Fisher’s exact test, and logistic regression was used to assess whether 1-year DFS were different in chemotherapy-treated patients when adjusted for histologic grade. Results: In total, 117 cases reviewed indicated an appendiceal pathology. Of these, 54 cases in a total of 51 patients met the specified criteria for pathology and completeness and length of follow-up information. The average age was 58 years (range 26-81 years). Adenocarcinoma was graded as low in 15 (28%) cases, intermediate in 18 (33%) cases, and high in 21 (39%) cases. 23 (43%) patients received no chemotherapy while 31 (57%) received chemotherapy before and/or after surgery. In the overall population, there was no significant effect of chemotherapy on survival, with 1-year DFS demonstrated in 74.2% of patients receiving some chemotherapy and 70% in patients not receiving chemotherapy (p = 0.765). One-year DFS was achieved in 86% of low-grade cases, 61% of intermediate-grade cases, and 71% of high-grade cases, though this was also not statistically significant (p = 0.254). Furthermore, when 1-year DFS between chemotherapy and non-chemotherapy patients was adjusted for grade, there was again no significant interaction (odds ratio = 0.48, 95% C.I. (0.13-1.64), p = 0.763). Conclusions: In this small, single-institution experience of patients with peritoneal appendiceal adenocarcinoma, there was no significant effect of chemotherapy administration on 1-year DFS. These findings are likely affected by significant confounding with the small sample size and retrospective nature of the data. Further investigation on a larger scale is warranted.

64 Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.

4031 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .

Due to their ease of use, the direct oral anticoagulants (DOACs) are an attractive treatment option for cancer-associated venous thromboembolism (VTE) and have been readily adopted by many clinicians. A recent published study comparing a DOAC (edoxaban) to the current standard-of-care low molecular weight heparin dalteparin for the treatment of cancer-associated thrombosis showed that edoxaban was noninferior to dalteparin for recurrent VTE, but the risk of major bleeding was higher. We present three patients with high-risk gastrointestinal malignancies complicated by cancer-associated VTE with progression of thrombosis while treated with the oral direct Xa inhibitor rivaroxaban. Upon switching therapy to low molecular weight heparin, we found that these patients had clinical and radiologic improvement of VTE. More studies are needed to evaluate the efficacy of rivaroxaban in high-risk gastrointestinal-VTE. We suggest that in some patients, DOACs may not be sufficient for the treatment of VTEs related to high-risk gastrointestinal malignancies.

4015 Background: 17 – 25% of mPDACs harbor DNA damage response (DDR) mutations, the presence of which can be predictive of a response to platinum and PARP inhibitor-based therapy. The PARP inhibitor, Vel is a potent sensitizing agent for, and has been safely combined with DNA-damaging chemotherapies. Methods: We initiated a Phase I/II trial of Vel + FOLFOX in pts with mPDAC. Pts received standard mFOLFOX6 except without the 5FU bolus, Q2 weeks. For the Phase I portion, a 3+3 dose escalation of Vel identified a recommended Phase II dose of 200mg orally BID, days 1-7, Q2 weeks. For the Phase II portion, we enrolled two cohorts: 1) Untreated pts; 2) Previously treated pts. Also, for Phase II, pts were pre-selected if they had either a pathogenic germline or somatic DDR mutation (e.g. BRCA1/2, PALB2, ATM), and/or a family history suggestive of a breast or ovarian cancer syndrome (labelled FH+). Objective response rate (ORR) was the primary objective of the Phase II cohorts; key secondary endpoints were median progression-free survival (PFS) and overall survival (OS). Results: Between 01-2011 and 12-2018, 64 pts received treatment, 31 in Phase I, and 15 untreated and 18 previously treated in Phase II. The combination was well tolerated, with the main Grade 3/4 AEs being myelosuppression (16%) and nausea/vomiting (6%). Of the 64 pts, 55% were male; median age was 64; 95% had an ECOG PS of 1; 78% were platinum-naïve; 69% were FH+; and 27% had a known DDR mutation. 57 pts were evaluable for response, and the ORR, PFS, and OS for the different pt subgroups are detailed below. The Phase II cohorts achieved the primary endpoint of an ORR ≥ 25%. Most notably, plat-naïve, FH+, and DDR mutation+ pts had an ORR of 58%. Conclusions: The combination of Vel + FOLFOX is safe, well tolerated, and shows promising efficacy particularly in plat-naïve pts who are FH+ and/or harbor DDR mutations. A randomized trial to assess the contribution of Vel to the regimen is warranted. Clinical trial information: NCT01489865. [Table: see text]

60 Background: DDR mutations are associated with higher neoantigen load and tumor infiltrating lymphocytes, and are a potential biomarker for immunotherapy. We investigated the association of DDR mutations in gastric (GC), esophageal (EC), and gastroesophageal junction (GEJ) cancers with MSI, PD-L1, and TMB, known predictors for immune checkpoint inhibitors. Methods: 20 DDR mutations were tested by Next-Generation Sequencing (NGS) with a 592-gene panel on a total of 1935 (709 EC; 831 GC; 355 GEJ) cancers. TMB was assessed by NGS, MSI by NGS or fragment analysis, and PD-L1 by IHC (22c3 for CPS or SP142). Results: GC had the highest DDR mutation rate compared to EC and GEJ (27% vs. 20%, p = 0.0005 and 17%, p = 0.0002, respectively). MSI-High (MSI-H) was significantly more common in the DDR mutated cohort (DDR-M) compared to non-mutated cancers (18% vs. 1%; p < 0.0001). TMB-High (≥ 10 mutations/megabase [mt/MB]) was higher in DDR-M (35% vs. 21%; p < 0.0001); in DDR-M cohort, GC had the highest TMB compared to DDR-M EC and GEJ (mean: 13.8 vs. 9.4 vs. 10 mt/MB, respectively; p < 0.0001). DDR mutations were more frequent in the PD-L1 combined positive score (CPS) ≥ 50 group than CPS 0 (42.9% vs. 24%; p = 0.037) and CPS 1-9 (42.9% vs. 20.6%; p = 0.005). ARID1A, ATRX, BRCA2, and PTEN were the most prevalent DDR mutations in MSI-H (87%, 31%, 25%, 24%, respectively); ARID1A, ATRX, BRCA2, and PTEN in TMB-High (47%, 7.7%, 6.7%, 6.8%) and ARID1A, BRCA2, RAD50, and WRN in PD-L1 high (CPS ≥ 10) (48.5% vs. 5.2% vs. 2.5% vs. 3.4%). Conclusions: MSI-H, TMB-high and high PD-L1 expression were significantly more prevalent in the DDR-M cohort compared to non-DDR-mutated cancers, most pronounced in GC. Alterations in ARID1A, ATRX, BRCA2, and PTEN were correlated with MSI-H and TMB-high while ARID1A, BRCA2, RAD50, and WRN were correlated with increased PD-L1 expression. Our findings may help identify patients for tailored immunotherapy approaches in future clinical trials.

376 Background: nab-Paclitaxel plus gemcitabine ( nab-P+G) and FOLFIRINOX (FFX) are among the most common first-line (1L) therapies for metastatic adenocarcinoma of the pancreas (mPC), yet there is no head-to-head trial comparing their efficacy and real-world data is limited. As new second-line (2L) therapies become available, it is important to understand the real-world effectiveness associated with different treatment sequences. Methods: This retrospective cohort study compared the efficacy and safety of 1L nab-P+G vs. FFX, overall and under specific treatment sequences. Medical records were reviewed by 215 physicians across the US who provided information for mPC patients who initiated 1L with nab-P+G or FFX between 04/01/2015-12/31/2015. The outcomes of interest were overall survival (OS) and tolerability. OS was evaluated using Kaplan-Meier curves, and compared between cohorts using Cox proportional hazards model adjusting for baseline characteristics. Results: Medical records were reviewed for 654 patients receiving nab-P+G (n = 337) or FFX (n = 317) as 1L therapy for mPC. Patients in the nab-P+G cohort were older, less likely to have ECOG ≤ 1 and had more comorbidities than patients in the FFX cohort. There was no statistically significant difference in OS (adjusted HR = 0.99, p = 0.96), with median OS (mOS) being 12.1 and 13.8 months for nab-P+G and FFX, respectively. Among the subgroup of patients with ECOG ≤ 1, mOS was 14.1 and 13.7 months, respectively (adjusted HR = 1.00, p = 0.99). Among patients with 1L nab-P+G and FFX, 36.1% and 41.3% received 2L therapy and experienced mOS of 16.3 and 16.6 months, respectively (HR = 1.04, p = 0.76). Among commonly observed adverse events (AEs) (≥ 5% of patients in both cohorts), the rates of diarrhea, fatigue, mucositis, nausea and vomiting were higher in the FFX than nab-P+G cohort (all p < 0.05). Conclusions: In a nationwide sample of mPC patients, real-world survival outcomes were similar between patients receiving 1L nab-P+G or FFX. both overall and among patients who went on to receive active 2L treatments. In addition, nab-P+G was associated with significantly lower rates of common AEs compared with FFX.

251 Background: Metastatic pancreatic cancer is a deadly disease, with a median survival that remains less than 12 months. However, more patients than ever before are surviving for more than 1 year, though it has been difficult to determine which patients have a better or worse prognosis. In the MPACT trial of gemcitabine + nab-paclitaxel vs gemcitabine alone, the neutrophil-to-lymphocyte ratio (NLR) prior to treatment was found to be a promising prognostic marker. However, the significance of NLR has not been confirmed. We examined our institutional experience with assessing the prognostic value of the NLR for patients with metastatic pancreatic cancer treated with standard chemotherapies. Methods: We performed an IRB approved retrospective chart review of patients with metastatic pancreatic adenocarcinoma. Patients were eligible if a routine blood count from which an NLR would be calculated was available prior to initiating any chemotherapy. 41 patients were identified who were treated with either FOLFOX (n = 9), FOLFIRINOX (n = 8) or gemcitabine + nab-paclitaxel (n = 24). Patients were stratified into two groups: NLR < 5 and NLR > 5. The median progression free survival and overall survival were determined, and statistical analyses performed to observe any correlation to NLR. Results: In this review, patients with an elevated NLR (NLR > 5) had an improved PFS and OS when compared with patients with a decreased NLR (NLR < 5). OS was 12.2 months in NLR > 5 and 11.0 months in NLR < 5. PFS was 4.7 months and 3.6 months, respectively. When comparing patients that were treated with 5-FU based regimens, the overall survival was similar with the NLR > 5 of 11.5 months and the NLR < 5 group of 11.0 months. However, those patients treated with gemcitabine and abraxane had more of a difference; patients with an NLR > 5 had an OS of 16.0 months and NLR < 5, the OS was 11.5 months. Conclusions: Our single institution experience suggests that NLR could be a marker for prognosis for metastatic pancreatic cancer. However, our data contradicts the results of the MPACT trial where an increased NLR was associated with a worsened overall survival. Therefore, additional confirmatory studies will need to be performed to find the true prognostic value of the NLR.

TPS219 Background: Prognosis for advanced HER2+ GEJ and G cancers remains poor, with median survival just beyond one year. Trastuzumab (T) in combination with chemotherapy is the initial treatment of choice, but therapeutic options targeting HER2 beyond T are poorly defined. M is an Fc-enhanced monoclonal antibody (Mab) to HER2 that recognizes with similar affinity the same epitope as T and whose Fc domain, compared to T, binds with increased affinity to the activating CD16A Fc-receptor (FcR) and decreased affinity to the inhibitory CD32B FcR. Preliminary data shows that M monotherapy has clinical activity against HER2+ tumors in GEJ and G cancer patients previously treated with T or other anti-HER2 agents. P is a Mab that blocks the interaction of the immune checkpoint molecule, PD-1, with its ligands, facilitating tumor cell elimination by releasing tumor-associated T cells from exhaustion. Monotherapy P has demonstrated remarkable and durable clinical activity in a Phase I study. Safety profiles of M and P are acceptable and non-overlapping. Methods: This study advances a chemotherapy free combination of M + P treatment for advanced HER2+ GEJ and G cancer patients. Enrolled patients will have relapsed/refractory HER2+ GEJ or G adenocarcinoma with measurable disease that has progressed on T plus first line chemotherapy. HER2+ (IHC 3+ or ISH+) will be confirmed by central review. Two dose levels of M (10mg/kg and 15mg/kg) and a fixed dose of P (200mg) will be evaluated for safety and tolerability. Patients will receive combination treatment once every 21 days for up to 24 months, until confirmed disease progression or intolerable toxicity. Dose expansion will enroll up to 60 patients, with 20 undergoing pre- and on-treatment biopsy. Response will be assessed every 6 weeks for the first 6 months and every 12 weeks thereafter per RECIST v1.1 and immune RECIST to account for response patterns observed with immunotherapies. Primary endpoint is ORR and duration of response, and secondary endpoints include PFS and OS. The study was initiated on January 2016 and is ongoing in North America and Asia. Clinical trial information: NCT02689284.

Genetic aberrations in PTEN, the negative regulator of phosphoinositide 3-kinase (PI3K) signaling, are common in prostate cancers (PCA) with high Gleason Scores and correlate with adverse outcome. Currently, PI3K inhibitors, as single agents and in combination, have entered Phase I and II clinical trials for metastatic castrate resistant PCA. Alpha-specific and pan-PI3K inhibitors cause hyperglycemia as an on-target side effect by blocking insulin-dependent PI3K signaling in the liver and muscle and patients develop hyperinsulinemia in response to hyperglycemia, and insulin treatment is often needed to manage drug-induced hyperglycemia. Using human and murine prostate cancer cell lines, we examined the effect of adding insulin to BKM120 treatment on PI3K pathway activation. Using human prostate cancer cell lines LNCaP and PC3 which both express insulin receptor (IR) and IGF-1 receptor (IGF-1R), we found downregulation of the PI3K pathway by BKM120 treatment and upregulation of the PI3K pathway by insulin treatment, as assessed by AKT phosphorylation. In both cell lines, the PI3K pathway is reactivated when insulin is added to BKM120 treatment. Using cells derived from PTEN-/-P53-/- murine PCA which express low levels of IR and IGF-1R, we found minimal activation of the PI3K pathway with insulin, either alone or in combination with BKM120. Conversely, using cells derived from Myc-overexpressing mice which express high levels of IR and IGF-1R, we found robust activation of the PI3K pathway with insulin treatment. More importantly, while BKM120 abolished PI3K activity in the Myc-overexpressing cells, the addition of insulin to BKM120 resulted in the reactivation of the PI3K pathway to the level of PI3K pathway activity without BKM120 treatment. Together these findings suggest that the use of insulin in combination with BKM120 abrogates the therapeutic effect of PI3K inhibition. In addition, they indicate that PCAs that have high levels of IR and/or IGF-1 expression are particularly sensitive to PI3K inhibitors as well as insulin reactivation of the PI3K pathway. Citation Format: Lily C. Wang, Sunnie S. Kim, David M. Nanus, Lewis C. Cantley. Utilizing insulin the treatment of prostate cancer with BKM120 abrogates the therapeutic effect of PI3K pathway inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A33.

4068 Background: Adaptive immune response can play an important role in restricting tumor growth, and the presence of tumor infiltrating lymphocytes (TIL) is associated with lower cancer stage and ...

Background The caudate nucleus might contribute to the psychopathological and cognitive deficits observed in schizotypal personality disorder (SPD), a schizophrenia spectrum disorder. Here we focused on female patients, because this group is underrepresented in studies of SPD and schizophrenia, and we might learn more about the caudate and clinical and cognitive impairments that are unique to female patients diagnosed with SPD. Methods Magnetic resonance imaging scans, obtained on a 1.5-T magnet with 1.5-mm contiguous slices, were used to measure the caudate in 32 neuroleptic-naive women with SPD and in 29 female normal comparison subjects. Subjects were group-matched for age, parental socioeconomic status, and intelligence quotient. Results We found significantly reduced left and right caudate relative volume (8.3%, 7.7%) in female SPD subjects compared with normal comparison subjects. In female SPD subjects, we found significant correlations between smaller total caudate relative volume and worse performance on the Wisconsin Card Sorting test (nonperseverative errors) and on the California Verbal Learning Test (verbal memory and learning), and significant correlations between smaller total caudate relative volume and both positive and negative symptoms on the Structured Interview for Schizotypy. Conclusions These findings demonstrate that, for female SPD subjects, smaller caudate volume is associated with poorer cognitive performance and more schizotypal symptomatology.

Science of Synthesis: Houben-Weyl Methods of Molecular Transformations is the entirely new edition of the acclaimed reference series Houben-Weyl, the standard synthetic chemistry resource since 1909. This new edition is published in English and will comprise 48 volumes published between the years 2000 and 2008. Science of Synthesis is a quality reference work developed by a highly esteemed editorial board to provide a comprehensive and critical selection of reliable organic and organometallic synthetic methods. This unique resource is designed to be the first point of reference when searching for a synthesis strategy. Features: * Contains the expertise of presently 400 leading chemists worldwide. * Critically evaluates the preparative applicability and significance of the synthetic methods. * Discusses relevant background information and provides detailed experimental procedures For full information on the Science of Synthesis series, visit the Science of Synthesis Homepage Series Editors: D. Bellus, S. V. Ley, R. Noyori, M. Regitz, E. Schaumann, I. Shinkai, E. J. Thomas, B. M. Trost, P. J. Reider