Citations

4147 Background: Retrospective studies of phosphorylated STAT3 (pSTAT3, a regulator of gene expression) in cancer-lineage cells have suggested it is a biomarker of poor prognosis. We analyzed data from 3 phase 3 RCTs (BRIGHTER [T1; NCT02178956], CO.23 [T2; NCT01830621], CanStem111P [T3; NCT02993731]) to evaluate the prognostic impact of pSTAT3 on OS in GI cancer patients (pts). Methods: pSTAT3 was evaluated in archival tumor tissue from pts with gastric or gastroesophageal junction adenocarcinoma (T1), colorectal cancer (T2), or pancreatic cancer (T3) who received standard of care in the control arms (CTL) of their respective trials. pSTAT3 positive (+) or negative (−) status was determined by detecting pSTAT3 in both tumor and tumor microenvironment (TME) cells in a laboratory-developed immunohistochemistry (IHC) assay (T1; T2), later developed into the investigational pSTAT3 IHC D3A7 assay (Agilent Technologies, Inc.) (T3). The positivity cutoff requires a sample have both a TME score of 2 and ≥5% of tumor cells staining positively for pSTAT3. Pre-analytical variables (eg, specimen collection, handling, and processing), tumor indication, and slight differences in the assays used for each study may contribute to relative differences in evaluable rates between studies. In an exploratory analysis, OS was compared in pSTAT3+ vs pSTAT3− pts via an unstratified log-rank test. Results: In each study, intent-to-treat pts with evaluable pSTAT3 results were considered pSTAT3-evaluable. This abstract includes pSTAT3-evaluable pts randomized to the CTL arms (T1: n/N=248/357, 69.5%; T2: n/N=110/144, 76.4%; T3: n/N=243/569, 42.7%). Baseline characteristics are presented in the table. Median (m) OS was shorter in pts with pSTAT3+ tumors across all studies (T1 hazard ratio [HR]=1.32 [95% confidence interval (CI): 1.00, 1.74]; T2 HR=2.40 [1.50, 3.83]; T3 HR=1.08 [0.77, 1.50]). Conclusions: In pSTAT3-evaluable populations from 3 RCTs across GI cancers, CTL pts with pSTAT3+ (vs pSTAT3−) tumors had shorter mOS. These results suggest that pSTAT3 positivity may be a biomarker of poor clinical outcome. Clinical trial information: NCT02178956; NCT01830621; NCT02993731. [Table: see text]

4130 Background: Circulating cell-free tumor DNA (ctDNA) genomic profiling is an emerging tool for pancreatic cancer. The impact of detected genomic alterations in tumor response to systemic treatments and outcomes is under investigation. Methods: Patients with advanced pancreatic cancer and ctDNA collected at time of initial diagnosis were retrospectively evaluated. Results of ctDNA analysis were correlated with patients’ demographics, systemic treatment response, progression-free survival (PFS) and overall survival (OS). Results: A total of 104 patients were included in the analysis. The mean age was 70.5 years (SD: 8.3), 50% were male, 37% with locally advanced disease and 63% with metastatic disease. Somatic alterations were detected in 84.6 % of the patients, no genetic alterations were detected in 15.4%, and were associated more with locally advanced pancreatic cancer as opposed to metastatic, p = 0.025. 60.6 % of the cohort had ≥ 2 genomic alterations detected. 28% were treated with FOLFIRINOX and 63% with gemcitabine plus nab-paclitaxel as first-line systemic treatment. Patients with any detectable genomic alterations when compared to patients with no detectable variant had worse median PFS (6.2 versus 15.3 months, p = 0.005) and patients with ≥ 2 detectable genomic alterations had worse median PFS (5.6 versus 11.0 months, p < 0.001) and worse median OS (11.5 versus 24.2 months, p = 0.001). KRAS was detected in 62.5% of the patients and was associated with PD to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (5.8 versus 13.0 months, p < 0.001) and worse median OS (11.5 versus 26.3 months, p = 0.002). TP53 was detected in 60% of patients and was associated with worse median PFS (5.9 versus 10.9 months, p = 0.02) and worse median OS (13.5 versus 24.2 months, p = 0.001). CCND2 was detected in 14% of the patients and was associated with worse median PFS (3.6 versus 8.2 months, p = 0.004). Conclusions: Our study showed that initial detection of ctDNA may identify different genomic alterations that help predict disease outcomes, confirmation of these findings in larger studies are warranted.

4128 Background: Pancreatic cancer (PC) is a challenging target for immunotherapy due to suppressive immune-microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of tumor-infiltrating lymphocytes (TILs). We hypothesized that the combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC were randomized 2:1 to the investigational treatment (Arm A) of pembrolizumab 200mg IV every 3 weeks concurrently with CRT (capecitabine 825 mg/m2 orally twice daily and radiation 50.4 Gy in 28 fractions over 28 days) or CRT only (Arm B) prior to surgical resection. The primary endpoints were treatment safety and density of TILs with the objective to estimate differences in TILs density between the investigational and the control arms. Immune cell densities were assessed using multiplexed immunofluorescence on resected tumor specimens. Densities of CD8+TILs were measured in 2-10 representative regions containing residual cancer per case and then averaged to obtain overall densities. The study was amended after enrollment of 37 patients to allow FOLFIRINOX prior to CRT, given changes in standard of care. Results: 37 patients were enrolled (24 Arm A and 13 Arm B). Post-neoadjuvant therapy, 13 patients had unresectable disease (9 on A and 4 on B), and 24 patients underwent surgery and were evaluable for the TILs primary endpoint (17 arm A and 7 arm B). The mean difference (A-B) in CD8+ cell density was 36 cells/mm2 (95% CI -85 to 157, stdev 130) (p 0.48). Additional analysis did not show significant differences in CD8+Ki67+ (activated cytotoxic T-cells), CD4+, and CD4+FOXP3+ (regulatory T cells), M1- or M2-like polarized macrophages, or granulocytes. The median recurrence free survival (RFS) was 18.2 months on Arm A and 14.1 on Arm B (p 0.41) and Overall Survival was 27.8 months on Arm A and 24.3 on Arm B (p 0.68) with a median follow up of 2.2 years. The most common grade 3 treatment-related toxicities were lymphopenia reported in 29% on Arm A and 31% on Arm B followed by diarrhea in 8% on Arm A attributed to CRT. There was only 1 DLT of increased ALT attributed to the combination on Arm A that resolved after holding the treatment and receiving steroids. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizumab is safe. Preliminary analysis shows that the addition of pembrolizumab to CRT has minimal effects on several immune cell populations including CD8+TILs in the PC microenvironment. The study is currently enrolling 25 more patients who receive FOLFIRINOX prior to randomization to CRT+/- Pembrolizumab, which will help to dissect the immune modulatory effect of chemotherapy followed by CRT. Clinical trial information: NCT02305186.

4118 Background: Germline variations in cancer susceptibility genes have important implications on treatment and family counseling in pancreatic cancer (PC). We report the prevalence and clinical outcomes of unselected PC patients with pathogenic germline variants (PGV) detected using a universal testing approach. Methods: We undertook a prospective multi-site study of germline sequencing using an >80 gene next-generation sequencing platform among 250 PC patients (not selected for age or family cancer history) between April 1, 2018 and March 31, 2020. Demographic, tumor characteristics and clinical outcomes were compared between PGV carriers and non-carriers. Results: Of 250 patients, the mean age was 65 years (SD 8.7), 56% were male, 83.6% were white and 65.6% had advanced disease (Stage III and IV). PGV were found in 15.2% (N=38) of patients, two patients had more than one PGV. Variants of uncertain significance were found in 44.4% (N=111). Family history of cancer (OR 2.36, 95% CI: 1.14-5.19, p=0.025) was associated with a higher risk of PGV. In a median follow up of 16.5 months, median overall survival was 16.8 months in PGV carriers compared with 16.5 months in non-carriers (HR 0.51, 95 %CI, 0.25-1.01, p=0.05). Higher levels of CA 19-9 and advanced stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, RAD51C. In 65% of HRR gene carrier’s systemic therapy with platinum was used. Conclusions: Universal multi-gene panel testing in pancreatic cancer reveals that 1 in 6 patients are carriers of PGV and is associated with improved survival. Multi-gene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling. Distribution of the 40 PGV by penetrance status.[Table: see text]

4079 Background: Cell-free circulating tumor DNA (ctDNA) holds significant promise and is being used for clinical decision making in multiple tumors. This study aimed to evaluate the prognostic value of pre-treatment ctDNA in metastatic biliary tract cancers (BTC) treated with platinum based first-line chemotherapy treatment. Methods: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis we considered the detected gene with highest variant allele frequency (VAF). Results of ctDNA analysis were correlated with patients’ demographics, progression-free survival (PFS) and overall survival (OS). Results: The median age of patients was 67 y/o (27-90). 54 (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma and six gallbladder cancer. 46 (68.6%) of the patients were treated with cisplatin plus gemcitabine, 14 (21%) patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations while 7 (10.4%) patients were treated on a clinical trial with gemcitabine and cisplatin plus additional targeted agents (CX4945 or PEGPH20). TP53, KRAS, APC, FGFR2 and IDH1 were the genes with highest frequency as dominant clone. The median dominant clone allele frequency (DCAF) was 3% (0-97%). DCAF >3% was associated with statistically significant worse PFS (median PFS: 4.05 vs. 7.70 months, p=0.046) and OS (median OS: 10.8 vs. 18.8 months, p=0.056). Each 1% increase in DCAF is associated with a hazard ratio of 26.21 in OS when adjusting for subtypes, age, treatment type, and CA19-9 [Table]. Conclusions: Patients with metastatic BTC with DCAF > 3% at diagnosis have worse PFS and OS compared to patients with low ctDNA when treated with upfront platinum-based chemotherapy.[Table: see text]

4009 Background: IDH1/2 genetic aberrations (GA) occur in 20% of IHCC cases and may be specifically targeted by IDH inhibitors. The genomic and immunologic profile of IHCC with IDH1/2 GA remains undefined. IDH1 mutations impair DNA damage repair (DDR), loss of heterozygosity (LOH) and may represent a biomarker for DDR in these patients. Methods: Comprehensive genomic profiling (CGP) was performed in 3,067 cases of advanced stage IHCC using a hybrid capture-based FDA-approved assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression in tumor cells (Dako 22C3) was measured by immunohistochemistry (IHC). Genomic LOH (gLOH) was assessed for samples meeting quality criteria. Densities of tumor associated immune cells and immune-checkpoint markers expressed in epithelial malignant cells and in the tumor microenvironment of 100 surgical samples from 96 patients were evaluated by IHC using digital image analysis of 14 markers (CD3, CD4, CD8, CD68, PD1,PD-L1, B7-H4, B7-H3, IDO1, ICOS, VISTA, OX40, TIM3, LAG3). Tissue microarrays were generated for multiplex immune panel analysis. A p value < 0.05 was considered statistically significant. Results: 426 (14%) of IHCC were IDH1+ and 125 (4%) were IDH2+ (Table) and were mutually exclusive. All IDH1 GA occurred at the R132 locus and included R132C (69%) and R132L/G/S/H/F (16%/7%/4%/3%/ < 1%) and 119Q ( < 1%) and IDH2 GA at R172 (94.4%) and R140 (6.6%). IDH1+ and IDH2+ IHCC had fewer co-occurring targetable GA than IDH1/2 wildtype (WT, IDHwt) cases including FGFR2 rearrangements (RE) (P <.0001), ERBB2 (P =.0009) and BRAF (P =.04). Median gLOH were not significantly different between IDH1+ IDH2+ IHCC vs. IDHwt IHCC (p = 0.37). Potential biomarkers of immune checkpoint inhibition (ICI) response including MSI High, TMB > 10 mut/Mb, and PD-L1 positivity were more frequent in IDHwt IHCC than IDH1+ IHCC. 29/96 (30%) surgical patients were positive for IDH1/2 mutation though mutational status did not confer a statistically significant difference in the 14 immune biomarker panel expression. Conclusions: CGP reveals significant differences in GA between IDH1+, IDH2+ and IDHwt IHCC consistent with IDH1 and IDH2 being driver oncogenes for IHCC. Immune biomarker expression and gLOH did not differ significantly between IDH mutated and WT cases.[Table: see text]

TPS3151 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved in combination with trastuzumab (Tras) and capecitabine (Cape) for HER2 overexpressed/amplified (HER2+) metastatic breast cancer (BC), based on a statistically significant and clinically meaningful PFS, OS, and ORR benefit over Tras and Cape. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. While various HER2-directed agents have been evaluated in HER2+ and HER2-mut tumors, there are no approved HER2 therapies outside of breast and gastric cancers. The SGNTUC-019 basket study is evaluating TUC combined with Tras in patients (pts) with HER2+ or HER2-mut locally-advanced unresectable or metastatic solid tumors. Methods: SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international phase 2 study. Eligible pts must have progressed on or after the last systemic therapy for advanced disease. Metastatic cervical cancer: must have received platinum-based chemotherapy ± bevacizumab; hormone receptor positive (HR+) HER2-mut BC: must have received a prior CDK4/6 inhibitor. Pts must be ≥18 years old, with ECOG PS ≤1, adequate hepatic, hematological, renal, coagulation, and cardiac function, and no prior HER2-directed therapy (except Tras for uterine serous carcinoma). For eligibility, HER2 alterations can be demonstrated by HER2+ in tumor tissue by prior IHC/ISH (IHC 3+/signal ratio ≥2.0 or gene copy number >6), or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts with HER2+ disease will be enrolled in cohorts for cervical, uterine, biliary tract, and urothelial cancers, non-squamous NSCLC, and other solid tumors (except GEC, BC, and CRC). Pts with HER2-mut disease will be enrolled in cohorts for non-squamous NSCLC, BC, and other solid tumors. Except for solid tumor and BC cohorts, 12 RECIST 1.1 evaluable pts will be enrolled in each cohort. If ≥2 responses are observed, the cohort will be expanded to a total of 30 pts. Other solid tumor and BC cohorts will enroll 30 pts in a single stage. If justified, additional HER2+ or HER2-mut disease-specific cohorts may be opened. Approximately 162-270 pts are planned. The primary objective is antitumor activity in each cohort, with confirmed ORR per investigator as primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints. Pts will receive TUC 300 mg orally twice daily and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. HR+ BC pts will also receive fulvestrant 500 mg IM every 4 weeks and C1 D15. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. TUC PK will be evaluated in all pts in Cycles 2-6. QoL is evaluated q2 cycle using EQ-5D-5L. Sites are open in the US; EU and Asia will be opened. Enrollment began in Dec 2020. Clinical trial information: NCT04579380.

Abstract The past decade has seen a rise in the availability of breakthrough therapeutic strategies for treatment of hepatocellular carcinoma (HCC). A tumor microenvironment in HCC is regulated by various immunotolerance mechanisms; therefore, therapeutic strategies aiming at disrupting tumor immune tolerance are becoming attractive curative options in HCC. Immune checkpoint inhibitors have demonstrated impressive effectiveness in HCC, including in sorafenib-unresponsive patients. Synergistic approaches with checkpoint inhibitors (anti-PD-1/PD-L1 and CTLA-4) and antiangiogenic drugs are burgeoning as first-line treatment therapeutic modalities in HCC.

Abstract 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.