Background and study aims Pancreatic ductal adenocarcinoma (PDAC) is a poor prognostic malignancy. Comprehensive genomic profiling (CGP) has improved outcomes in many cancers, but widespread uptake in PDAC remains elusive. This study investigated the feasibility of using endoscopic ultrasound with fine-needle biopsy (EUS-FNB) for CGP in advanced PDAC. Patients and methods (experimental design) A multicenter prospective cohort study was conducted to assess the feasibility of using DNA and RNA extracted from fresh frozen or archival formalin-fixed paraffin-embedded (FFPE) EUS-FNB for CGP on advanced PDAC using the TSO-500 gene panel testing. Results of the CGP were reviewed at a molecular tumor board (MTB) and subsequent treatment recommendations were forwarded to the referring clinicians. Results CGP was successful in 129 of 143 patients (90%) enrolled between May 2020 to September 2023. Fresh frozen EUS-FNB provided suitable genetic material for CGP in 123 of 133 patients (92%). Conversely, CGP was successful on FFPE biopsy blocks from only six of 16 patients (38%). Fifty-two of 143 patients (36%) had a potentially targetable mutation detected, and eight of these patients (6%) were treated with targeted therapy based on their EUS-FNB-derived molecular profile. Patients who received personalized therapy had a significant ( P < 0.0001) increase in survival versus standard or no therapy at 12 and 36 months. Median patient survival on standard therapy was 9.47 months versus > 18 months for personalized therapy. Conclusions This real-world study confirms the feasibility and utility of CGP using EUS-FNB in advanced PDAC. It illustrates the importance of timely access to personalized therapy informed by CGP, which can impact the treatment pathway and improve survival outcomes.

Borderline-resectable pancreas cancer(BRPC) is defined by extent of peri-pancreatic vascular involvement. BRPC patients have been demonstrated to have improved survival outcomes when treated with neo-adjuvant systemic chemotherapy(NAC). Pre-operative anatomical interpretation to define those likely to benefit from NAC is a crucial step in ensuring patients undergo optimal treatments. A prospectively maintained surgical database was reviewed between 1/1/2020 and 31/12/2023. Patients with incomplete data were excluded. We reviewed pre-operative radiological(CT) and endoscopic ultrasound(EUS) reports to compare with intra-operative findings and post-operative histology. 19 patients underwent combined Whipple/Total Pancreatectomy and vascular(SMV/PV) resection: 8 underwent NAC, 1 was deemed physiologically inappropriate for NAC and 10 were intra-operatively diagnosed with vascular involvement. Of 8 patients undergoing NAC, pre-operative radiology described vessel abutment/contact in 100% and deformity in 63%; whereas, EUS identified vessel involvement in 63%. Histological vein involvement was confirmed in 7/8. The patient deemed physiologically inappropriate for NAC was reported as having vessel contact at CT and contour deformity on EUS; however, post-operative histology reported no venous involvement. All 10 operatively diagnosed patients were assessed as having no vessel involvement at pre-operative radiology/EUS; histology confirmed venous involvement in only 1. Pre-operative anatomical interpretation and staging of BRPC remains crucial but challenging. In this subset of patients undergoing combined pancreatic/vascular resection, the optimum sensitivity/specificity was defined by pre-operative radiological assessment. Intra-operative diagnoses of vessel involvement were more likely due to inflammation/desmoplastic change. A multi-modal approach may improve accuracy of pre-operative assessment of vascular involvement.

PURPOSE Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS). METHODS A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL). RESULTS INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports. CONCLUSION Regorafenib improves survival compared with placebo in refractory AGOC.

BACKGROUND:Panitumumab (pan) plus chemotherapy is a preferred first-line therapy for unresectable RAS and BRAF wild type metastatic colorectal cancer (mCRC). Older patients may not be suitable for combination regimens. We investigated 2 lower intensity pan-containing regimens. METHODS:Prospective, noncomparative, randomized (1:1) phase 2 study of pan alone (Arm A) or pan plus FU (Arm B). Previously untreated mCRC were ≥70 years; RAS/BRAF wild type. PRIMARY ENDPOINT:6-month progression-free survival (PFS). Secondary endpoints included: overall survival (OS), response rate (RR), feasibility of geriatric assessments and overall treatment utility (OTU)-a composite measure based on radiological response, clinical progress, toxicity and patient-reported treatment worth. Planned sample size was 40 patients per arm. RESULTS:36 patients (Arm A n = 19, Arm B n = 17) were randomized between June 2018 and June 2021. Median age was 79 and 80 years respectively. 6-month PFS 63% (95% CI 38%-80%) arm A 82% (95%CI 55%-94%) Arm B. Median OS 21 months Arm A (95%CI 13-31) 28 (95%CI 14-39) months Arm B. RR 47% and 65% Arms A and B respectively. Baseline comprehensive geriatric assessments were completed in >80% of patients. At week 16, OTU was categorized as good in 92% (Arm A) and 90% (Arm B). No unexpected adverse events were seen. CONCLUSIONS:Six-month PFS in both arms was consistent with that achieved with FU/bev, whilst the rate was numerically higher for Arm B. Baseline comprehensive geriatric assessments were feasible and OTU was high. Both treatment arms might be suitable in appropriately selected patients.

BACKGROUND:In Western countries, the current standard of care for resectable gastric cancer is perioperative chemotherapy. Preoperative chemoradiotherapy has been considered, but data are limited regarding this treatment as compared with perioperative chemotherapy alone. METHODS:We conducted an international, phase 3 trial in which patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive preoperative chemoradiotherapy plus perioperative chemotherapy or perioperative chemotherapy alone (control). In both groups, patients received either epirubicin, cisplatin, and fluorouracil or fluorouracil, leucovorin, oxaliplatin, and docetaxel both before and after surgery; the preoperative-chemoradiotherapy group also received chemoradiotherapy (45 Gy in 25 fractions of radiation, plus fluorouracil infusion). The primary end point was overall survival, and secondary end points included progression-free survival, pathological complete response, toxic effects, and quality of life. RESULTS:A total of 574 patients underwent randomization at 70 sites in Australasia, Canada, and Europe: 286 to the preoperative-chemoradiotherapy group and 288 to the perioperative-chemotherapy group. A higher percentage of patients in the preoperative-chemoradiotherapy group than in the perioperative-chemotherapy group had a pathological complete response (17% vs. 8%) and greater tumor downstaging after resection. At a median follow-up of 67 months, no significant between-group differences in overall survival or progression-free survival were noted. The median overall survival was 46 months with preoperative chemoradiotherapy and 49 months with perioperative chemotherapy (hazard ratio for death, 1.05; 95% confidence interval, 0.83 to 1.31), and the median progression-free survival was 31 months and 32 months, respectively. Treatment-related toxic effects were similar in the two groups. CONCLUSIONS:The addition of preoperative chemoradiotherapy to perioperative chemotherapy did not improve overall survival as compared with perioperative chemotherapy alone among patients with resectable gastric and gastroesophageal junction adenocarcinoma. (Funded by the National Health and Medical Research Council and others; TOPGEAR ClinicalTrials.gov number, NCT01924819.).

324 Background: TIGIT is a novel inhibitory immune checkpoint on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, e.g. PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. We report interim data from MORPHEUS-EC (NCT03281369) evaluating the combination of tira + atezo with CT in pts with untreated locally advanced unresectable or metastatic EC. Methods: Eligible pts (locally advanced unresectable, or metastatic EC with no prior systemic treatment; ECOG PS 0–1) were randomized to receive: cisplatin 80mg/m2 + 5-FU 800mg/m2/24 hours on Days 1–5 of each cycle (CT); atezo 1200mg + cisplatin + 5-FU (atezo + CT); or tira 600mg + atezo + cisplatin + 5-FU (tira + atezo + CT) in 21-day cycles. Primary endpoint: investigator (INV)-assessed objective response rate (ORR). Key secondary endpoints: INV-assessed progression-free survival (PFS), overall survival (OS), safety. Results: 152 pts were randomized to: CT (n=24; control); atezo + CT (n=65) or tira + atezo + CT (n=63). As of 14 Mar 2023, median follow-up was 8.7 months (mo) in the CT arm, 11.4 mo in the atezo + CT arm and 10.9 mo in the tira + atezo + CT arm. Pt characteristics were generally balanced between arms. ORR was 47.8% (CT) vs 53.8% (atezo + CT) vs 67.7% (tira + atezo + CT). Median PFS was 4.1 mo (CT) vs 6.8 mo (atezo + CT) vs 6.9 mo (tira + atezo + CT) (Table). ORR and PFS benefit was generally consistent across all pre-specified subgroups, including PD-L1 status. There was a numerical improvement in OS with tira + atezo + CT vs atezo + CT and CT alone (Table). Grade 3–5 adverse events (AEs) were 82.6% vs 83.1% vs 85.5% and treatment-related Grade 4/5 AEs were 4.3% vs 7.7% vs 14.5% for CT vs atezo + CT vs tira + atezo + CT. AEs leading to any tx discontinuation were 21.7%, 16.9% and 35.5%, respectively. Conclusions: Clinically meaningful improvements in INV-assessed ORR and PFS and a trend of improved OS were observed with tira + atezo + CT when compared with CT and atezo + CT. These results support the contribution of both tira and atezo in combination with CT. The safety profile was consistent with the known risks of the individual tx. Clinical trial information: NCT03281369 . [Table: see text]

Long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological CR in 10-30% of patients (pts). Radiotherapy (RT) is immuno-stimulatory by enhancing tumour cell death, but also immunosuppressive stimulating PDL1 production and myeloid-derived suppressor cells. PDL1 inhibition may be required to enhance RT immuno-stimulatory effects. Hypothesis: In pts with resectable LARC, Avelumab given post LCCRT may enhance tumour response rates whilst reducing relapses. Phase II single arm trial. Pts had LCCRT (50.4Gy + 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID]/5.5 weeks). Post LCCRT pts received 4 cycles Avelumab (AV) (10mg/kg, q2 weeks), then resection 10-12 weeks post LCCRT. Fresh tumour biopsy/ctDNA sampling taken at pre LCCRT, pre AV and at surgery. Response by FDG PET and pelvic MRI. Inclusion Criteria: pts with MRI stage T3b-4/N1-2/M0 LARC , tumoural lower border <12cm from anal verge, measurable disease, ECOG 0-1, adequate organ function. Endpoints: (a) Primary; Complete pathological response rate (Target ≥ 35%) reported centrally, (b) Secondary; Imaging responses, Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression and ctDNA analysis, Distant relapse-free survival and the sites of relapse. 37 pts entered. Baseline TNM: T3b-d 75%, T4a-b 25%. 33 pts completed LCCRT, 31 pts (83%) had all 4 cycles of AV and 32 pts (86%) had surgery. ORR Pelvic MRI (N=33): 2 CR, 14 PR, 31 DCR. FDG PET: 10 CMR, 18 PMR.. 10 pts Grade 3 AEs, 3 pts with treatment-related G3 and no G4 AEs. No immune-related G3 AEs. Post-operative complications as expected. Pathological response (Modified Ryan Score) (N=32): Complete pathCR (18.7%), near CR (15.7%), in MSI-H (N=4), 50% and 25% resp. Median followup 3.1 yrs: 3 yr est. time to progression 82%, distant relapse free survival 80%, disease free survival 80%. The Ave-Rec phase II study has shown Avelumab post LCCRT is safe with significant imaging responses and complete/near-complete path response rate of 34.3% in pts with ESMO high risk rectal cancers. Parallel translational studies are ongoing. The addition of immune checkpoint inhibitors warrants further evaluation in LARC.

Background: PreC study supported ColonAiQ Ò (a blood-based assay targeting circulating tumor DNA methylation) as a robust noninvasive option for colorectal cancer (CRC) and advanced adenoma (AA) screening to efficiently stratify individuals with a higher risk based on the first year's real-world data reported in 2022 World Congress on Gastrointestinal Cancer (LBA SO-23).Here, the update CRC screening outcome was reported.Methods: 105,285 participants living in the local community, aging from 40 to 80, were recruited from Jan 2021 to Dec 2022.ColonAiQ Ò test was used as the primary screening method for all participants and a follow-up colonoscopy was recommended after a positive primary test.Numbers of positive ColonAiQ Ò test, colonoscopy compliance rate and positive predictive values (PPV) for AA and/or CRC were determined.Results: Overall, a total of 6,759 participants (6.42%) were tested positive via ColonAiQ Ò test.In the positive test population, 3,282 (48.56%) participants performed colonoscopy with pathological confirmation.Overall, there were 1,773 (54.02%) participants confirmed with colonoscopy findings, including 63 (1.92%) CRC, 441 (13.44%)AA, 754 (22.97%) non-advanced adenoma, 327 (9.96%) polyps, and 188 (5.73%) non-neoplastic GI disorders.Particularly, early colorectal neoplasm diagnosis rate reached 90.28%.Therefore, The predictive value (PPV) was 1.92% for CRC and 36.41% for adenoma (13.44% for AA). Conclusions:The 2-year real world study confirms the initial findings that population compliance rate of colonoscopy is obviously higher than the average rate in Cancer Screening Program in Urban China (48.56%VS 17.25%).ColonAiQ Ò test could help to identify the asymptomatic patients with neoplasm who need endoscopic resection or surgery excision.These results warrant the cost-effectiveness of the two-step screening pattern in community populations from the ongoing PreC study.Clinical trial identification: NCT05336539.

BACKGROUND:Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved for the treatment of various solid tumors. In gastric cancer, genes commonly harbor mutations in the homologous recombination DNA repair pathway, potentially increasing sensitivity to PARPi. Pamiparib (BGB-290) is a small molecule inhibitor of PARP1 and PARP2. METHODS:The PARALLEL-303 study (NCT03427814) investigated the efficacy and safety of pamiparib 60 mg orally (PO) twice daily (BID) versus placebo PO BID as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer that responded to platinum-based first-line chemotherapy. The primary endpoint of this double-blind, randomized, global phase 2 study was progression-free survival (PFS) (RECIST version 1.1; per investigator assessment). Secondary endpoints included overall survival (OS) and safety. RESULTS:In total, 136 patients were randomized 1:1 to receive pamiparib (n = 71) or placebo (n = 65). Median PFS was numerically longer with pamiparib versus placebo but did not reach statistical significance (3.7 months [95% confidence interval (CI): 1.9, 5.3] vs. 2.1 months [95% CI: 1.9, 3.8]; hazard ratio 0.8 [95% CI: 0.5, 1.2]; p = 0.1428). Median OS was 10.2 months (95% CI: 8.7, 16.3) in the pamiparib arm versus 12.0 months (95% CI: 8.2, not estimable) in the placebo arm. Overall, 8 patients (11.3%) in the pamiparib arm and 2 patients (3.1%) in the placebo arm experienced ≥1 TEAE leading to treatment discontinuation. CONCLUSIONS:Maintenance pamiparib did not meet statistical significance for superiority versus placebo for PFS, but was well tolerated with few treatment discontinuations; no unexpected safety signals were identified.

LBA294 Background: AGOC has limited options after second-line therapy. Regorafenib (Rego), an oral multi-targeted tyrosine kinase inhibitor (TKI) targeting angiogenic, stromal and oncogenic receptor TKs, prolonged progression free survival (PFS) versus placebo (PBO) across all regions/subgroups in the INTEGRATE phase 2 randomised trial (JCO 2016 43(23):2728-2735). INTEGRATE IIa was designed to examine if Rego improves overall survival (OS). Methods: Double-blind placebo-controlled phase 3 trial comparing Rego + best supportive care (BSC) vs PBO + BSC using 2:1 randomisation, stratified by tumour location (GO junction vs gastric), geographic region (Asia vs rest of world), prior VEGF inhibitors (Y/N). Eligibility criteria: histologically/cytologically confirmed AGOC, evaluable metastatic/locally advanced disease, failure/intolerance of ≥ 2 prior lines of therapy with a platinum agent + fluoropyrimidine. Primary objective: OS in the whole study population. OS among Asian sub-population is a key secondary objective. Target of at least 221 events from 250 patients provides 80% power to detect an OS hazard ratio (HR) of 0.67. Pooled OS analysis incorporating INTEGRATE phase 2 data is also planned. Secondary endpoints include PFS, objective response rate, safety and quality of life. Results: 251 patients enrolled (Oct16 - Sep21) from 5 countries:157 from Asia (Korea, Taiwan, Japan);169 Rego and 82 PBO. After 238 events, median OS (in months) for Rego vs PBO was 4.5 vs 4.0 (HR 0.70 [95%CI: 0.53 to 0.92]; p = 0.011) in the whole study population, with a 12 mo survival of 19% vs 6%. Median PFS was 1.8 v 1.6 (HR = 0.52; [95%CI: 0.40-0.69]; p = < .0001). After pre-planned adjustment for multiplicity, there were no statistically significant differences across regions (Asia versus non-Asia) or other pre-specified subgroups. Pooled analysis median OS was 5.0 v 4.1 (HR 0.69 [95% CI:0.56 to 0.87]; p = 0.001). Rego toxicity was similar to previously reported. Conclusions: Rego improves survival compared with PBO in advanced refractory AGOC, offering a new treatment option. This result creates a therapeutic platform for combination studies. INTEGRATE IIb is an ongoing international randomised Phase 3 trial in pre-treated patients with AGOC comparing Rego + nivolumab to standard chemotherapy (NCT0487936). Clinical trial information: NCT02773524 .

Contains: Table S1. RAS and BRAF Mutation Status Table S2. Objective Response Rate in Patients with Mutated RAS Table S3. Depth of Response and Early Tumor Response in Wild-type KRAS Exon 2 Patients Figure S1. Disposition of patients in the study and RAS ascertainment.

TPS3622 Background: Standard neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate of 10-30%: but 20-40% of patients (pts) are non-responders, 10-15% have local recurrence. Tumoural immune infiltrates are predictive of response. Preclinical studies show that radiotherapy (RT) via interferon signaling is immuno-stimulatory, enhancing local/distant tumour cell death. RT also stimulates PDL1 production and the immunosuppressive activity of myeloid derived suppressor cells. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab post LCCRT may enhance the pathological/imaging response rates whilst potentially reducing local/distant relapse rates. Methods: (1) Trial Design: Phase II single arm trial, across 6 Australian sites (2) Endpoints: (a) Primary; Pathological response rate post-LCCRT, as documented by central pathologist, (b) Secondary; MRI/FDG PET imaging responses at 8 weeks post LCCRT (pre-surgery). Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression (by multiplex immunohistochemistry and in-vitro functional assays) and ctDNA analysis at baseline and during treatment. Distant relapse-free survival and the documentation of sites of relapse. (3) Sample size: An increase in the proportion of pathological complete responses by > 25% (from 10% to 35%) will be considered clinically important. Power = 90%, α = 0.05, 41 pts are required– an additional 4 pts to allow for drop-out. Total sample size = 45pts. Treatment: All pts to receive standard LCCRT (50.4Gy RT plus 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID on RT days] over 5.5 weeks). Post LCCRT (prior to surgery), pts receive 4 cycles Avelumab (10mg/kg, q2 weeks). Surgical resection 10-12 weeks post LCCRT. Fresh tumour biopsy and ctDNA sampling pre LCCRT, pre Cycle 1 Avelumab and at surgery. Response by FDG PET and pelvic MRI pre surgery. Pts to be followed up for 2 years. Major Inclusion Criteria: Pts with LARC, MRI stage T3b-4/N1-2/M0, planned for LCCRT followed by curative resection, tumoural lower border within 12cm from the anal verge, measurable disease (RECIST1.1), ECOG 0-1, adequate organ function and no contraindications to Avelumab therapy. Current Enrolment: 11 of the planned 45 patients enrolled. Clinical trial information: NCT03299660.

Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. We correlated cetuximab plasma concentrations after 4 weeks of treatment with survival and toxicity. Plasma cetuximab concentration was associated with OS (HR 0.66, 95% CI: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea. The standard cetuximab dosing regimen may not be optimal for all patients.Background: Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity.Methods: The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m(2) intravenously followed by weekly maintenance of 250 mg/m(2), plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables.Results: Week 5 plasma cetuximab concentrations were available for 591 patients (78.8%). The median overall survival (OS) was 11.4 months and 7.8 months for patients in the highest (T3) and lowest tertiles (T1) respectively. On multivariable analysis, plasma cetuximab concentration was associated with OS (HR 0.66, 95% confidence interval [CI]: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea.Conclusion: The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS.

Background: KRAS G12D mutation subtype is present in over 40% of pancreatic ductal adenocarcinoma (PDAC), one of the leading global causes of cancer death. This retrospective cohort study aims to investigate whether detection of the KRAS G12D mutation subtype in PDAC patients is a determinant of prognosis across all stages of disease. Methods: We reviewed the medical records of 231 patients presenting with PDAC at a large tertiary hospital, and compared survival using the Kaplan Meier, log-rank test and Cox proportional hazards regression model. Results: KRAS G12D mutation subtype was not significantly associated with poorer survival compared across the whole population of PDAC patients (p = 0.107; HR 1.293 95% CI (0.946–1.767)). However, KRAS G12D patients who were resectable had a shorter median survival time of 356 days compared to all other genotypes (median survival 810 days) (p = 0.019; HR 1.991 95% CI (1.121–3.537)). Conclusions: KRAS G12D patients who were resectable at diagnosis had shorter survival compared to all other PDAC patients. These data suggest that KRAS G12D may be a clinically useful prognostic biomarker of PDAC.

PD-1 checkpoint inhibitors are active in microsatellite unstable (MSI) mCRC, which have an inflamed TME but are inactive in MSS-mCRC. The resistance of MSS mCRC is potentially related to the TME which excludes immune cells. The Modulate study tested 2 strategies designed to alter the TME in MSS mCRC, thereby enabling synergy with PD1 inhibitors.

3109 Background: A subset of gastric cancers exhibits platinum sensitivity and genomic instability that is characteristic of homologous recombination deficiency (HRD). Cells with HRD are sensitive to poly (ADP-ribose) polymerase (PARP) inhibition. PARP inhibitor maintenance therapy following platinum-based chemotherapy has been a successful treatment strategy in pts with ovarian cancer. Pamiparib is an orally administered selective PARP protein 1 and 2 (PARP1/2) inhibitor that has shown potent DNA-PARP trapping activity and crosses the blood brain barrier in preclinical studies. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib showed an acceptable safety profile and promising antitumor activity. PARALLEL 303 compared the efficacy and safety of pamiparib vs placebo as maintenance therapy in pts with inoperable locally advanced or metastatic gastric cancer that responded to platinum-based 1L chemotherapy. Methods: The primary endpoint of this double-blind, randomized, global phase 2 study (NCT03427814) was progression-free survival (PFS) as determined by the investigator per RECIST Version 1.1. Key secondary endpoints included time to subsequent treatment, objective response rate, duration of response, time to response, overall survival (OS) and safety. At the time of this analysis, OS data were immature due to the short duration of study. Data presented here will focus on PFS and safety. Results: 136 pts were randomized 1:1 to receive pamiparib 60 mg orally (PO) twice daily (BID) (n=71) or placebo PO BID (n=65) in 28-day cycles. The median PFS was longer with pamiparib vs placebo, but did not reach statistical significance (3.7 months; 95% CI, 1.94–5.26 vs 2.1 months; 95% CI, 1.87–3.75 months); hazard ratio 0.799 (95% CI, 0.534–1.193; P=0.1428). Treatment-emergent adverse events (TEAEs) of ≥ Grade 3 were experienced by 29 pts (40.8%) in the pamiparib arm, and 20 pts (30.8%) in the placebo arm. The most common TEAEs of ≥ Grade 3 were blood and lymphatic system disorders in the pamiparib arm, and gastrointestinal disorders in the placebo arm. TEAEs leading to treatment discontinuation were: 8 pts (11.3%) in the pamiparib arm and 2 pts (3.1%) in the placebo arm. TEAEs leading to death were: 2 pts (2.8%; 1 pneumonia, 1 unexplained) in the pamiparib arm, and 2 pts (3.1%; 1 hepatic rupture, 1 sepsis) in the placebo arm. Conclusions: Although pamiparib did not meet statistical significance for superiority vs placebo for its primary endpoint, it was generally well tolerated with few treatment discontinuations due to TEAEs. No new safety signals were identified with pamiparib, and its safety profile was consistent with that of other PARP inhibitors. Clinical trial information: NCT03427814.

BACKGROUND:Patients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers.METHODS:This multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB).RESULTS:The objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB.CONCLUSIONS:Ipilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.