CMS classification and tumor mutation status are associated with differential outcomes for rectal cancer patients, with some groups having a large likelihood of developing metastatic disease. Further work on optimizing and personalizing treatments for these high-risk populations is necessary.

BACKGROUND:Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS:MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS:As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS:The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

Patients diagnosed with (B)RPC proceeding with CRT have different odds of proceeding to surgery based on their response to CRT and extent of vessel involvement. Post-CRT CA19-9 can help predict which patients may proceed to resection. Future investigations will develop nomograms for estimating odds of proceeding to surgery in larger datasets to help aid in patient counseling and multidisciplinary discussion.

The monoclonal antibody (mAb) trastuzumab plus chemotherapy has been 1st-line standard of care in HER2+ metastatic GEA for a decade. M is an investigational (in GEA) anti-HER2 mAb engineered to confer enhanced Fc dependent antitumor activity across all Fc region gamma receptor genotypes. M may potentiate innate immunity (i.e. antibody-dependent cellular cytotoxicity) and adaptive immunity (i.e. anti-HER2–directed T-cell responsiveness). R, an investigational humanized IgG4 mAb, binds to PD-1 and blocks its interaction with PD-L1/2. MAHOGANY is a 2-cohort study in unresectable metastatic/locally advanced GEA. Cohort A (100 pt single arm) will determine safety/efficacy of Q3W M 15 mg/kg plus R 375 mg in HER2 3+, PD-L1+ (CPS ≥1) and non–microsatellite instability high pts. Primary endpoint of Cohort A is centrally-reviewed overall response rate (ORR); Investigator-assessed ORR is supportive. As of 16 April 2021, 43 pts were enrolled, with median exposure of 4.2 months and median duration of follow-up of 4.6 months. Safety data are available on 43; efficacy data are available on 43 with baseline scan for response assessment by the investigators. Of these 43, 37 have reached first tumor reassessment, with 1 confirmed complete response, 11 confirmed partial responses, 1 unconfirmed complete response, 11 unconfirmed partial responses, 7 stable disease, and 6 progressive disease (5 PD at first scan, 1 clinical PD). Tumor shrinkage was seen in 30/35 pts (85.7%) with at least 1 post-baseline target lesion measurement. The most common treatment-related adverse events were infusion related reaction (8/43, 18.6%), diarrhea and fatigue (6/43, 14% each). Grade 3 treatment-related events were singularly reported with no ≥ Grade 3 infusion related reaction or diarrhea. Regarding immune-related events, 1 pt discontinued due to renal dysfunction possibly related to M+R, 4 had hypothyroidism and 1 had immune-related renal dysfunction. This first report of MAHOGANY Cohort A of M plus R suggests the combination is well tolerated. The updated efficacy data including centrally-reviewed scans will be available at presentation.

This study provides evidence that although PBT appears to have a superior safety profile in regard to acute anorexia, patients treated with PBT have higher odds of acute RD; these effects persist even after controlling for relevant confounding factors. PBT may result in fewer GI toxicities at the cost of greater skin toxicity.

Our retrospective review of patients with unresectable HCC treated with definitive RT provides evidence that viral etiologies of HCC may fare better in OS and PFS when compared to non-viral etiologies. The etiology of HCC development for virally vs non-virally mediated tumors may have implications for treatment and response in the setting of radiation therapy.

Patients diagnosed with (B)RPC have many therapeutic options; this study suggests a benefit to CAPE-based concurrent chemotherapy when treating patients with SCCRT, even after controlling for significant confounding by greater use of neoadjuvant FOLFIRINOX with CAPE-based concurrent chemotherapy. SCCRT may be more effective with concurrent capecitabine instead of concurrent gemcitabine for (B)RPC.

TPS275 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in US. The majority of US patients (pts) receive first-line therapy (Rx) with FOLFOX [Folinic acid (FA), 5-fluorouracil (5-FU) and oxaliplatin (Ox)] + a biologic, making FOLFIRI [FA+ 5-FU+ irinotecan (Iri)] + bevacizumab (Bev) a common second-line Rx. This regimen has a median progression-free survival (PFS) of approximately 6 months (mo) and overall survival (OS) of 12 mo. Further gains are desperately needed. Trifluridine/tipiracil (FTD/TPI) is an oral combination Rx of a thymidine-based nucleoside analogue, FTD, and a phosphorylase inhibitor, TPI. FTD/TPI has a distinct mechanism of action from 5-FU and in preclinical models can overcome 5-FU resistance via DNA incorporation, base excision repair pathway and glycosylation responses to DNA damage. Further, there is an additive effect in combination with Iri. FTD/TPI was FDA approved for use in refractory metastatic CRC (mCRC) based on phase III RECOURSE trial. Phase I data showed combination of FTD/TPI, Iri and Bev to be safe, and an efficacy signal was seen in dose-expansion cohort (NCT01916447). A 12.5% response rate, 83.4 % disease control rate and PFS of 7.9 mo was achieved. As this study largely assessed refractory pts, one might expect a greater efficacy in Iri naïve pts. To test this hypothesis, we are conducting a multi-center phase II study of FTD/TPI, Iri and Bev as second-line Rx in mCRC pts. Methods: Eligible pts have mCRC and received first-line Ox based Rx. Rx to be given in 28-day cycles: Iri (180 mg/m2) and Bev (5 mg/kg) on D1 & 15, and FTD/TPI (25 mg/m2) twice daily on D2-6 & 16-20. Response assessment via CT/MRI to be done q8 wks (RECIST 1.1). Rx to continue until disease progression or unacceptable toxicity. The primary objective is to estimate PFS. Secondary objectives include ORR, OS, and safety. Final analysis to be done either 12 mo after enrollment of the final pt or once all pts have progression, whichever occurs earlier. A total of 40 pts to be accrued, and enrollment to start in January 2020. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Taiho Oncology, Inc.

Liposomal irinotecan + 5-FU/LV is approved for treating patients with mPDAC following progression with gemcitabine-based therapy. Liposomal irinotecan + 5-FU/LV + OX (NALIRIFOX) is being investigated 1L in a phase I/II study of patients with locally advanced/mPDAC. Serum CA 19-9 levels are typically elevated in such patients and post-treatment decreases are associated with prolonged survival. We report exploratory survival analyses from the phase I/II study for subgroups defined by post-treatment changes in CA 19-9 levels. Following dose exploration, the regimen of liposomal irinotecan 50 mg/m2 (free base), OX 60 mg/m2, 5-FU 2400 mg/m2 and LV 400 mg/m2, on days 1 and 15 of 28-day cycles, was selected for dose expansion and 25 more patients were enrolled. In total, 32 patients received the selected (maximum tolerable) dose. Tumors (RECIST v1.1) and serum CA 19-9 were assessed at screening, every 8 weeks and at end of treatment (EoT); tumor assessments continued after EoT. Progression-free and overall survival (PFS and OS) were compared across subgroups defined by best change within the first 16 weeks (data cut-off 26 Feb 2020). In total, 30/32 patients had a baseline CA 19-9 measurement (median 315.5 U/mL, range 2–127115) of whom 22 had measurements by week 16 (analysis set) with median best change –49.4% (range –100%, +376%). Survival data (Table) were similar for patients with above-normal (≥ 37 U/mL) baseline CA 19-9 levels (n = 17; median best change –35.9% [range –100%, +278%]).Table: 1529PPFSPP 50/60 N = 32All n = 22Analysis set, best CA 19-9 change≥ 20% decrease≥ 50% decreaseYes n = 14No n = 8Yes n = 11No n = 11Progressed/died,a n (%)17 (53.1)12 (54.5)6 (42.9)6 (75.0)4 (36.4)8 (72.7)Median, mo (95% CI)9.2 (7.69, 11.96)9.6 (7.59, 32.30)32.3 (7.95, 32.30)7.6 (1.48, 9.56)11.2 (7.95, NE)7.6 (1.48, 32.30)HR (95% CI)--0.13 (0.04, 0.50)0.33 (0.09, 1.12)OSDied, n (%)20 (62.5)14 (63.6)7 (50.0)7 (87.5)6 (54.6)8 (72.7)Median, mo (95% CI)12.6 (8.74, 18.69)12.7 (8.74, 22.54)22.5 (12.39, NE)8.2 (2.50, 18.69)22.5 (11.60, 22.54)9.2 (4.83, NE)HR (95% CI)-0.24 (0.08, 0.75)0.55 (0.19, 1.60)a Patients who progressed/died after new therapy or >16 wks after last non-PD assessment were censored. Open table in a new tab a Patients who progressed/died after new therapy or >16 wks after last non-PD assessment were censored. 1L NALIRIFOX reduced CA 19-9 levels in patients with locally advanced/mPDAC. Median OS and PFS were numerically higher in patients with a ≥20% decrease within the first 16 weeks. CA 19-9 is a potential biomarker of post-NALIRIFOX outcomes.

Liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) is approved for adults with metastatic pancreatic ductal adenocarcinoma following progression with gemcitabine-based therapy. We report results from an open-label phase I/II study (NCT02551991) of adults with untreated, unresectable, locally advanced/metastatic PDAC receiving liposomal irinotecan + 5-FU/LV + oxaliplatin (NALIRIFOX). Eligible patients were adults with ECOG performance status (PS) ≤ 1 and adequate organ function who received NALIRIFOX (liposomal irinotecan 50 mg/m2 (free base), 5-FU 2400 mg/m2, LV 400 mg/m2, oxaliplatin 60 mg/m2) on days 1 and 15 of each 28-day cycle. The primary endpoint was safety; secondary endpoints included progression-free survival (PFS), overall survival (OS), best overall response, overall response rate (ORR), disease control rate at 16 weeks (DCR16) and duration of response (DoR). RECIST v1.1 was assessed at screening, every 8 weeks and at treatment end. Overall, 32 patients were included (median [range] age 58.0 [39–76] years; 43.8% men; 87.5% metastatic disease; 56.3% ECOG PS 1). In total, 22 patients experienced grade ≥ 3 treatment-emergent adverse events (TEAEs): neutropenia (31.3%), febrile neutropenia (12.5%), hypokalemia (12.5%), diarrhea (9.4%), nausea (9.4%) and decreased neutrophil count (9.4%). Serious TEAEs were reported in 17 patients: nausea (9.4%) and febrile neutropenia (9.4%). TEAEs led to 3 deaths (none treatment-related), to dose adjustment in 26 and discontinuation in 8 patients. Median (95% CI) PFS and OS were 9.2 (7.69–11.96) months and 12.6 (8.74–18.69) months, respectively. One patient, with locally advanced disease, had complete response, 10 partial response, and 15 stable disease. ORR (95% CI) was 34.4 (18.6–53.2) %, DCR16 was 71.9 (53.3–86.3) % and median (95% CI) DoR was 9.4 (3.52, NE) months. First-line NALIRIFOX raised no new safety signals in patients with locally advanced/metastatic PDAC; anti-tumour activity was promising. The randomized phase III NAPOLI-3 study (NCT04083235) will compare NALIRIFOX with gemcitabine + nab-paclitaxel.

Anti-EGFR therapy has the potential to increase antitumor immune responses. Therapeutic strategies targeting EGFR and immune checkpoints may benefit patients (pts) with mCRC. We conducted a phase Ib/II clinical trial of cetuximab with pembrolizumab in RAS wild-type (RASwt) mCRC; the primary efficacy results of the trial have been reported (Fountzilas et al ESMO GI 2020). Herein, we present correlative tissue analysis. Tumor biopsies were obtained baseline (pre-Tx) and after 12 weeks (post-Tx); multiplex immunohistochemistry for PD-L1, T-cell exhaustion (TIM3, CTLA4, LAG3) and activation (OX40) markers was performed. T-cells were characterized as partially activated-1 (OX40+/PD-L1-, 1/3 exhaustion markers+); partially activated-2 (OX40+/PD-L1-, 2/3 exhaustion markers+); partially activated-3 (OX40+/PD-L1-, 3/3 exhaustion markers+); exhausted-1 (OX40-/PD-L1-, 1/3 exhaustion markers+); exhausted-2 (OX40-/PD-L1-, 2/3 exhaustion markers+); and exhausted-3 (OX40-/PD-L1-, 3/3 exhaustion markers+). Forty-two pts were enrolled; 14 with matched pre-Tx and post-Tx biopsies, 24 with pre-Tx only. PD-L1 expression was higher in pre-Tx metastasis (M) vs. primary tumor (PT) in both tumor and stromal cells within the microenvironment (TME). The no. of activated T-cells was higher pre-Tx in PT compared to M. The no. of exhausted-2 T-cells in pre-Tx was higher in M vs. PT. The no. of activated T-cells and partially activated-1 T-cells was higher in post-Tx vs. pre-Tx M. There was no change in the no. of exhausted T-cells on post-Tx. PD-L1 decreased on tumor cells and increased in the TME on post-Tx. Temporospatial heterogeneity in the immune landscape of the TME was evident in RASwt mCRC. With the limitation of small sample size, we observed increased PD-L1 expression and exhausted T-cells and decreased activated T-cells in M compared to PT. There was an increase in activated T-cells post-Tx, but the no. of exhausted T-cells was similar, potentially explaining the lack of additive benefit from pembrolizumab. Evaluating the PT in mCRC might not be reflective of immunosuppression in M. Combinations with mAb targeting other T-cell exhaustion pathways may be necessary to improve the antitumor efficacy of the EGFR-based regimens.

An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal–Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

Anti-EGFR monoclonal antibody (mAb) therapy can increase EGFR-specific T cells in peripheral blood (Trivedi et al Clin Cancer Res 2016). Thus, therapeutic strategies jointly targeting the EGFR-RAS-MAPK pathway as well as block critical immune checkpoints may be of benefit for patients with metastatic colorectal cancer (mCRC). We conducted a phase Ib/II study of cetuximab, a mAb targeting EGFR, with the anti-PD-1 mAb pembrolizumab in RAS wild-type (RAS-wt) mCRC; the results of the phase Ib part have been previously reported (Boland et al ASCO GI 2018). Here we present the primary efficacy results. Patients with RAS-wt mCRC with at least one prior systemic therapy in the advanced setting were treated in 3-week cycles with cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) and pembrolizumab (200 mg on day 1). Tumor biopsies were obtained at baseline and on-treatment (C4D1). The primary objectives were to estimate the objective response rate (ORR) by RECIST 1.1 and the 6-month progression-free survival (PFS). We utilized a single-stage version of the bivariate design of Sill et al., 2012. For ORR, H0=0.2 vs. H1=0.4 and 6-month PFS, H0=0.3 vs. H1=0.5, a=0.1, with 38 evaluable patients the study had ≥80% power to detect activity based on ORR alone, ≥80% power to detect activity based on 6-month PFS alone, and ≥97% power if the regimen is active on both endpoints. Forty-two RAS-wt patients were enrolled through October 2019. There were no new safety signals and the combination was well tolerated. Three patients had prior exposure to anti-EGFR therapy. 6-month PFS was 30% (CI: 19%-43%) and ORR was 5%. The median PFS and overall survival (OS) were 4.1 months (95% CI 3.9-6) and 14.9 months (95% CI 8.3-24), respectively. The disease control rate (DCR) was 73%. Thirty percent of patients had their CEA levels decrease >50% and 49% had a decrease in disease burden based on a decrease in the sum of target lesions. An increase in tumor-infiltrating cytotoxic lymphocytes (CTLs, CD3+CD8+) was observed (p=0.035). CTL infiltration was more pronounced in patients with CEA levels that had decreased by >50% vs. not (34% vs. 17%, respectively; p=ns) and those with any decrease in tumor burden vs. not (34% vs. 18%, respectively; p=ns). Although the primary efficacy endpoint was not achieved, cetuximab plus pembrolizumab had modest anti-tumor activity in patients with RAS-wt mCRC. Compared to historic controls of anti-EGFR monotherapy, the PFS results are similar, though OS appears longer. Increased intratumoral CTL infiltration was noted following therapy; this appeared most pronounced in patients who benefited from therapy. Tissue analyses were underpowered owing to the small sample size. Further correlative analysis of tumor and blood specimens is ongoing.

TPS464 Background: Neoadjuvant chemoradiation (CRT) followed by surgery is a standard approach for localized EGAC. Despite multimodality treatment, 5-year overall survival (OS) is less than 50%, with pathologic complete response (pCR) rates of 20%. Achievement of pCR is associated with an improved OS. We propose to use a novel combination of FTD/TPI and oxaliplatin as IC. We hypothesize that IC before CRT will increase the pCR rate in localized EGAC. Methods: This is an open-label, multicenter phase II trial. Patients (pts) with potentially resectable loco-regional EGAC are eligible. Pts. should have adequate organ function, ECOG performance status of 0 –1, age < 76 years, and endoscopic ultrasound-determined node-positive disease with any T-stage, or T3-T4a with any N stage. Pts. with T4b or M1 disease will be excluded. Pts. will receive three cycles of IC with FTD/TPI and oxaliplatin. Based on the maximum tolerated dose (MTD) observed in a phase I trial, FTD/TPI will be administered 35 mg/m² BID, days 1–5 every 14 days, with a fixed dose of oxaliplatin 85 mg/m² (day 1). Pts will then undergo concurrent CRT (standard radiation dose of 5040 cGY will be utilized) with weekly Carboplatin (AUC 2) and Paclitaxel (50 mg/m2) for 6 weeks followed by surgery. Our primary objective is to evaluate the pCR rate. The secondary objectives include evaluation of 2-year disease-free survival (DFS), 2-year OS, and assessment of toxicities of the IC. As a correlative endpoint, circulating tumor DNA level will be correlated with disease recurrence and metabolic response on PET CT. Assuming a historic pCR rate of 20% with standard CRT, 41 pts (enrollment of up to 45 pts accounting for non-evaluable pts) are needed to show a 15% increase in pCR with IC with 80% power at one-sided significance level of α = 0.1. In stage 1, n1= 22 evaluable pts will be enrolled. If there is 5 or more pCRs, an additional n2= 19 pts will be enrolled in stage 2. If 12 or more pCRs are observed in the total n = 41 evaluable pts, then the proposed treatment regimen will be considered promising for further study. We anticipate accrual over a 2-year period from 3 sites. Clinical trial information: NCT04097028.

Liposomal irinotecan + 5‑fluorouracil/leucovorin (5-FU/LV) is approved for adults with metastatic pancreatic ductal adenocarcinoma (PDAC) following progression with gemcitabine-based therapy. We report long-term follow-up results (data cut-off 26 Feb 2020) from an open-label phase 1/2 study (NCT02551991; EudraCT 2015-003086-28) of adults with previously untreated, unresectable, locally advanced/metastatic PDAC receiving liposomal irinotecan + 5-FU/LV + oxaliplatin (NALIRIFOX). Following dose exploration (Part 1A), the dose selected for expansion (Part 1B), based on dose-limiting toxicities and cumulative safety data, was liposomal irinotecan 50 mg/m2 (free base), 5-FU 2400 mg/m2, LV 400 mg/m2, oxaliplatin 60 mg/m2 on days 1 and 15 of each 28-day cycle. The analyses included patients receiving the selected dose (pooled population 50/60): 7 patients from Part 1A and 25 from Part 1B. Patients were aged ≥ 18 years with ECOG performance status score ≤ 1 and adequate organ function. The primary endpoint was safety and tolerability; secondary efficacy endpoints were progression-free survival (PFS; primary efficacy endpoint), overall survival (OS), best overall response, overall response rate (ORR), disease control rate at 16 weeks (DCR16) and duration of response (DoR); exploratory endpoints included tumour subtype. Disease was assessed (RECIST v1.1) at screening, end of treatment and every 8 weeks. Archival tumour samples were subtyped (Moffitt schema) using the PurISTSM RNAseq assay (GeneCentric Therapeutics, Inc). The PP 50/60 comprised 32 patients (median age 58.0 years [range 39-76]; 14 [43.8%] men; 28 [87.5%] with metastatic disease at diagnosis; 18 [56.3%] with ECOG performance status score 1; 1 receiving study treatment at data cut-off). In total, 22 of these patients had grade ≥ 3 treatment-related treatment-emergent adverse events (TEAEs); the most common were neutropaenia (31.3%), febrile neutropaenia (12.5%), hypokalaemia (12.5%), diarrhoea (9.4%), nausea (9.4%) and decreased neutrophil count (9.4%); vomiting occurred in 6.3% of patients, while fatigue and peripheral neuropathy were not reported. Serious TEAEs (SAEs) were reported in 17 patients; 10 of these patients had SAEs considered related to treatment, most commonly nausea (9.4%) and febrile neutropaenia (9.4%). TEAEs leading to death occurred in 3 patients (malignant gastrointestinal obstruction, upper gastrointestinal haemorrhage, disease progression); none were considered related to treatment. TEAEs led to dose adjustment in 26 patients and discontinuation (of oxaliplatin or all four study drugs) in 8. Median PFS (95% CI) was 9.2 months (7.69, 11.96) and median OS was 12.6 months (8.74, 18.69). Complete response was observed in 1 patient (with locally-advanced disease), partial response in 10, and stable disease in 15. ORR (95% CI) was 34.4% (18.6, 53.2), DCR16 was 71.9% (53.3, 86.3) and median DoR was 9.4 months (3.52, NE). Tumour subtype and response data were available for 9 patients in the PP 50/60 (classical, n=8, PFS range 7.7-17.8 months; basal-like, n=1, PFS 9.6 months). No new safety signals were observed with first-line NALIRIFOX in patients with locally advanced/metastatic PDAC, and anti-tumour activity was promising. The ongoing randomized phase 3 NAPOLI-3 study (NCT04083235; EudraCT 2018-003585-14) will compare NALIRIFOX with gemcitabine + nab-paclitaxel.

Liposomal irinotecan + 5‑fluorouracil/leucovorin (5-FU/LV) is approved for adults with metastatic pancreatic ductal adenocarcinoma (PDAC) following progression with gemcitabine-based therapy. We report long-term follow-up results (data cut-off 26 Feb 2020) from an open-label phase 1/2 study (NCT02551991; EudraCT 2015-003086-28) of adults with previously untreated, unresectable, locally advanced/metastatic PDAC receiving liposomal irinotecan + 5-FU/LV + oxaliplatin (NALIRIFOX). Following dose exploration (Part 1A), the dose selected for expansion (Part 1B), based on dose-limiting toxicities and cumulative safety data, was liposomal irinotecan 50 mg/m2 (free base), 5-FU 2400 mg/m2, LV 400 mg/m2, oxaliplatin 60 mg/m2 on days 1 and 15 of each 28-day cycle. The analyses included patients receiving the selected dose (pooled population 50/60): 7 patients from Part 1A and 25 from Part 1B. Patients were aged ≥ 18 years with ECOG performance status score ≤ 1 and adequate organ function. The primary endpoint was safety and tolerability; secondary efficacy endpoints were progression-free survival (PFS; primary efficacy endpoint), overall survival (OS), best overall response, overall response rate (ORR), disease control rate at 16 weeks (DCR16) and duration of response (DoR); exploratory endpoints included tumour subtype. Disease was assessed (RECIST v1.1) at screening, end of treatment and every 8 weeks. Archival tumour samples were subtyped (Moffitt schema) using the PurISTSM RNAseq assay (GeneCentric Therapeutics, Inc). The PP 50/60 comprised 32 patients (median age 58.0 years [range 39-76]; 14 [43.8%] men; 28 [87.5%] with metastatic disease at diagnosis; 18 [56.3%] with ECOG performance status score 1; 1 receiving study treatment at data cut-off). In total, 22 of these patients had grade ≥ 3 treatment-related treatment-emergent adverse events (TEAEs); the most common were neutropaenia (31.3%), febrile neutropaenia (12.5%), hypokalaemia (12.5%), diarrhoea (9.4%), nausea (9.4%) and decreased neutrophil count (9.4%); vomiting occurred in 6.3% of patients, while fatigue and peripheral neuropathy were not reported. Serious TEAEs (SAEs) were reported in 17 patients; 10 of these patients had SAEs considered related to treatment, most commonly nausea (9.4%) and febrile neutropaenia (9.4%). TEAEs leading to death occurred in 3 patients (malignant gastrointestinal obstruction, upper gastrointestinal haemorrhage, disease progression); none were considered related to treatment. TEAEs led to dose adjustment in 26 patients and discontinuation (of oxaliplatin or all four study drugs) in 8. Median PFS (95% CI) was 9.2 months (7.69, 11.96) and median OS was 12.6 months (8.74, 18.69). Complete response was observed in 1 patient (with locally-advanced disease), partial response in 10, and stable disease in 15. ORR (95% CI) was 34.4% (18.6, 53.2), DCR16 was 71.9% (53.3, 86.3) and median DoR was 9.4 months (3.52, NE). Tumour subtype and response data were available for 9 patients in the PP 50/60 (classical, n=8, PFS range 7.7-17.8 months; basal-like, n=1, PFS 9.6 months). No new safety signals were observed with first-line NALIRIFOX in patients with locally advanced/metastatic PDAC, and anti-tumour activity was promising. The ongoing randomized phase 3 NAPOLI-3 study (NCT04083235; EudraCT 2018-003585-14) will compare NALIRIFOX with gemcitabine + nab-paclitaxel.

Liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) is approved for adults with metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. First-line (1L) liposomal irinotecan + 5-FU/LV + oxaliplatin (NALIRIFOX) is being investigated in a phase I/II trial of patients with locally advanced/mPDAC (NCT02551991). Serum CA 19-9 levels are typically elevated in patients with mPDAC and post-treatment reductions in CA 19-9 levels have been associated with prolonged survival. We report the results of an exploratory survival analysis from the phase I/II trial of 1L NALIRIFOX in mPDAC for subgroups defined by post-treatment changes in CA 19-9 level. Eligible patients were adults with ECOG performance status (PS) ≤ 1 and adequate organ function who received 1L NALIRIFOX (liposomal irinotecan 50 mg/m2 (free base), 5-FU 2400 mg/m2, LV 400 mg/m2, oxaliplatin 60 mg/m2) on days 1 and 15 of each 28-day cycle. Tumors (RECIST v1.1) and serum CA 19-9 were assessed at screening, every 8 weeks and at end of treatment. Progression-free (PFS) and overall survival (OS) were compared for subgroups defined by best change in CA 19-9 level over the first 16 weeks of treatment (≥ 20% and ≥ 50% decrease; data cut-off 26 Feb 2020). In total, 32 patients were eligible for the trial, of whom 30 had a baseline CA 19-9 measurement (median [range] 315.5 [2–127115] U/mL) and 22 had a repeat CA 19-9 measurement by Week 16 (analysis set). Overall, NALIRIFOX reduced CA 19-9 level: median (range) best change of –49.4 (–100, +376)%. Median OS and PFS were numerically higher in patients with a CA 19-9 decrease ≥ 20% by Week 16 (Table)Table: 193PAll N = 32Analysis set n = 22Analysis set, by best change in CA 19-9 by Week 16≥ 20% decrease≥ 50% decreaseYes n = 14No n = 8Yes n = 11No n = 11PFSProgressed/died,a n (%)17 (53.1)12 (54.5)6 (42.9)6 (75.0)4 (36.4)8 (72.7)Median (95% CI) months9.2 (7.69, 11.96)9.6 (7.59, 32.30)32.3 (7.95, 32.30)7.6 (1.48, 9.56)11.2 (7.95, NE)7.6 (1.48, 32.30)HR (95% CI)–0.13 (0.04, 0.50)0.33 (0.09, 1.12)OSDied, n (%)20 (62.5)14 (63.6)7 (50.0)7 (87.5)6 (54.6)8 (72.7)Median (95% CI) months12.6 (8.74, 18.69)12.7 (8.74, 22.54)22.5 (12.39, NE)8.2 (2.50, 18.69)22.5 (11.60, 22.54)9.2 (4.83, NE)HR (95% CI)–0.24 (0.08, 0.75)0.55 (0.19, 1.60)a Patients who progressed/died after new therapy or >16 weeks after last non-progressive disease assessment were censored. Open table in a new tab . a Patients who progressed/died after new therapy or >16 weeks after last non-progressive disease assessment were censored. 1L NALIRIFOX reduced CA 19-9 levels in patients with locally advanced/mPDAC. CA 19-9 is a potential biomarker of post-NALIRIFOX outcomes in these patients.

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]