Esophageal cancer incidence is rising globally, with at least 500,000 new cases diagnosed annually. Management options for non-metastatic disease include primary resection, neoadjuvant or perioperative therapies, or definitive non-surgical treatment, with the choice being guided by tumor staging, histology, patient fitness, and available resources. However, even with the use of advanced diagnostic modalities, preoperative clinical staging is challenging with respect to accuracy of both tumor and nodal assessment. Early-stage esophageal cancer may be managed with local therapies, such as endoscopic mucosal resection or submucosal dissection, while for more advanced tumors managed with curative intent neoadjuvant oncologic therapy is commonly recommended. However, between these two groups lies an infrequent but important subgroup of patients, clinically staged cT2N0M0 esophageal cancer. Guidelines such as the NIH's National Cancer Institute recommends either surgery alone or neoadjuvant therapy followed by surgery for AJCC Stage I cancers, and add the option of definitive chemoradiation for Stage II disease. With cT2N0 disease straddling both AJCC classifications, management guidance is lacking. This guideline will provide an evidence-based recommendation from the International Society For Disease Of The Esophagus on the management of cT2N0 esophageal cancer, of all types. The recommendations are intended to support surgeons, oncologists, and patients in decisions about the best practice preoperative oncologic management of cT2N0M0 esophageal cancer.A Working Group within the International Society for Diseases of the Esophagus (ISDE) Guidelines Committee performed a systematic review of the literature. Results of the systematic review were presented to a panel of experts and these results informed the panel discussion about the guideline. This panel used Grading of Recommendations Assessment, Development, and Evaluation approach to deliberate and formulate recommendations.The panel agreed on a conditional recommendation for the use of neoadjuvant therapy followed by surgery over primary surgical resection (PSR) for adult patients with cT2N0M0 esophageal cancer.Preoperative clinical staging of esophageal cancer is uncertain, with deficiencies in all diagnostic modalities. However, when all modern staging techniques are utilized, the ISDE recommends neoadjuvant therapy followed by surgical resection as the favored treatment of cT2N0 esophageal cancer. Certain patient groups may still be offered PSR, particularly those unable to tolerate neoadjuvant therapies, or those patients with very low risk of lymph node metastasis as suggested by histological features, small tumor size, and other features.

654 Background: KRAS G12D is the most common KRAS mutation, occurring in ~40% of patients (pts) with PDAC. INCB161734, a novel, selective ON/OFF KRAS G12D small molecule inhibitor, is being evaluated in a phase 1 trial. Here we report results in pts with advanced/metastatic PDAC, including safety and efficacy of INCB161734 monotherapy, and preliminary safety results of combinations. Methods: This multi-center, first-in-human dose escalation/expansion study is enrolling adult pts with advanced/metastatic solid tumors and KRAS G12D mutation (NCT06179160). The study is evaluating INCB161734 monotherapy including a PDAC-specific expansion cohort and INCB161734 combination therapies, including with mFOLFIRINOX or GEMNabP in pts with PDAC and ≤1 prior treatment (tx) in the metastatic setting. The primary endpoint is safety. Secondary endpoints include pharmacokinetics and preliminary efficacy (per RECIST v1.1). Translational assessments include longitudinal ctDNA analyses. Results: As of August 1, 2025, 136 pts, including 83 with PDAC, had received INCB161734 monotherapy at daily doses of 200 mg to 1600 mg in escalation and at recommended doses for expansion (RDEs) of 600mg QD and 1200mg QD in expansion. Tx-related AEs (TRAEs) in ≥15% of pts were nausea (58%), diarrhea (51%), vomiting (46%), and fatigue (18%); mostly grade 1/2; 4 (3%) pts had serious TRAEs. No pt had a fatal TRAE or a TRAE leading to tx discontinuation. INCB161734 monotherapy efficacy and ctDNA analyses in PDAC at RDEs are summarized in the Table. INCB161734 dose escalation combined with chemotherapies has begun (starting dose 600 mg daily). Among pts with PDAC who received INCB161734 600 mg in combination with GemNabP (n=6) or mFOLFIRINOX (n=4), no dose limiting toxicities were observed, allowing further INCB161734 dose escalation with both chemotherapies. INCB161734 showed comparable steady state exposures as monotherapy or in combination with either chemotherapy. Further data from combination therapies will be presented. Conclusions: INCB161734 monotherapy has a manageable safety profile, with promising early clinical efficacy and evidence of molecular response in pts with advanced/metastatic PDAC harboring KRAS G12D mutation. Ongoing dose escalation of INCB161734 in combination with chemotherapy shows an encouraging safety profile. Clinical trial information: NCT06179160 . INCB161734 monotherapy outcomes at selected doses in pts with PDAC and ≥1 post-baseline scan. 600 mg Dailyn = 22 1200 mg Daily † n = 29 PR, n (%) 5 (23) 10 (34) Disease control*, n (%) 16 (73) 25 (86) Molecular response ‡ , % (n) 41 (7/17 § ) 72 (13/18 § ) Includes pts enrolled in escalation or expansion. *PR + stable disease; † total daily dose as QD or BID; ‡ ≥90% reduction in ctDNA G12D variant allele frequency; § Pts with detectable baseline G12D. PR, partial response.

2501 Background: Despite anti-PD-1/PD-L1 therapy success, 60-70% of patients develop progression with limited options (ORR 6-8% to retreatment). Upregulation of inhibitory receptors LILRB1/2 and KIR3DL1 mediates immune escape in anti-PD-1/PD-L1-resistant tumors. IOS-1002, a novel LILRB1/2 and KIR3DL1 antagonist, restores anti-tumor immunity when combined with pembrolizumab. Methods: Open-label, multicenter, dose-escalation Phase 1a study (NCT05235308) evaluated IOS-1002 (300-1800mg, Q2W IV) plus pembrolizumab 400mg (Q6W IV) in advanced solid tumors progressing on prior anti-PD-1/PD-L1 therapy. Primary endpoints: safety, tolerability; secondary: ORR, DCR, duration of response (DOR). Comprehensive biomarker analysis included serial cytokine profiling, target receptor expression (LILRB1/2, KIR3DL1), and tumor immune score (TIS) by gene expression analysis. Responses were assessed by RECIST v1.1. Results: As of January 1st, 2026, 28 patients received combination treatment with 16 anti-PD-1/PD-L1-relapsed/refractory patients (median age 65, ECOG 0-1). 3 confirmed PRs (tumor reduction -35% to -58% from baseline) leading to an ORR of 20% (3/15 evaluable) were noted with a DCR of 54% at week 12 (7/13) and 40% at week 24 (4/10), respectively. Durable responses included: 1 metabolic CR (urothelial cancer), 1 pathological CR confirmed by repeat biopsy showing absence of viable tumor cells (cutanteous SqCC), and 1 cervical cancer patient achieving -29% tumor reduction with concomitant > 90% decline in CA-125 tumor marker. Median treatment DOR was 30+ weeks (range 12-46+); 8 patients remain on treatment. Biomarker analysis demonstrated strong predictive value for TIS and target receptor expression achieving 75% ORR (3/4) versus 0% in dual-low patients (0/5). Combined biomarker score significantly correlated with depth of response (R² = 0.72, p = 0.008) and progression-free survival (HR 0.31, 95% CI 0.11-0.88, p = 0.04). Safety profile was favorable with no increase in grade≥3 immune-related adverse events beyond pembrolizumab monotherapy. Conclusions: IOS-1002 plus pembrolizumab demonstrated clinically meaningful efficacy in pretreated anti-PD-1/PD-L1-relapsed/refractory patients. Biomarker-driven patient selection using dual-high TIS and target receptor expression enhanced ORR to 75% and strongly predicted response depth, durability, and survival benefit. The favorable safety profile with no incremental immune-related toxicity, coupled with durable responses and high disease control rates, provides compelling rationale for Phase 1b expansion in biomarker-selected PD-1/PD-L1-refractory solid tumors. Clinical trial information: NCT05235308 . Endpoint Result ORR (evaluable) 20% (3/15) DCR Week 12 54% (7/13) DCR Week 24 40% (4/10) Biomarker-selected ORR 75% (3/4) Ongoing treatment 8/16 (50%)

Lymphocyte antigen 6 complex locus G6D (LY6G6D) is a promising target in metastatic colorectal cancer (mCRC) due to its differentiated expression in tumor vs. normal tissues, and higher prevalence in microsatellite-stable CRC. Linclatamig (or BLYG8824A) is a humanized, IgG1, LY6G6D × CD3 T cell-engaging bispecific antibody (TCB), that binds to LY6G6D and CD3+ T cells, forming an immunologic synapse to facilitate T cell-mediated killing of LY6G6D+ cells. This study evaluated the safety, pharmacokinetics (PK), biomarkers, and anti-tumor activity of linclatamig in patients (pts) with LY6G6D+ mCRC. Pts aged ≥18 years with locally advanced or metastatic LY6G6D+ CRC refractory to established therapies, measurable disease by RECIST v1.1 and ECOG 0/1 were enrolled. Escalating doses of intravenous linclatamig were administered in 21-day cycles, beginning with a step-up dose on Cycle 1, Day 1 (C1D1), followed by a (higher) target dose on C1D8 and on D1 of every cycle (C2D1 onward). Pts (n=46) (prior therapy: median 4 lines; range 2-11) received linclatamig (median 3 cycles; range 1-37) at step-up doses 0.2-180 mg and target doses 0.6-1500 mg across 13 dose-escalation cohorts. The maximum tolerated dose was not reached. Dose-limiting toxicities included immune effector cell-associated neurotoxicity syndrome in 2 pts at 180 mg step-up dose, and respiratory distress in the context of CRS and tumor flare in 1 pt at 100 mg step-up dose. Most frequently reported adverse events (AEs) of any grade (Gr) and irrespective of causality were CRS (94%), anemia (48%), diarrhea (50%), fatigue (50%), dry skin (37%), and rash maculopapular (30%). Most frequent treatment-related Gr ≥3 toxicities were reduced lymphocyte count (13%), diarrhea (11%), and anemia (9%). CRS, mainly Gr 1/2, occurred at step-up C1D1 doses ≥5.4 mg and was mostly limited to C1. Skin-related AEs (74%) including alopecia were reported, consistent with LY6G6D expression in hair follicle bulbs. PK data indicated dose proportionality and faster-than-typical IgG1 clearance. Anti-tumor activity was limited, with 1 confirmed and 2 unconfirmed partial responses. Increased blood levels of IFNg, IL6, and T cell activation supported the mechanism of action. Tumor RNA of responders showed CD8B and activated NK cell enrichment, whereas tumors of pts with disease progression had more fibroblasts, TGFb, myeloid inflammation signatures, and KRAS signaling. This first-in-human study (NCT04468607) targeting LY6G6D in mCRC pts demonstrated a tolerable safety profile for linclatamig up to 1500 mg. Step-up dosing mitigated CRS severity, although skin toxicities indicated possible on-target/off-tumor effects. Limited anti-tumor activity of linclatamig was observed in pts with heavily pre-treated mCRC. Marwan Fakih, Jayesh Desai, Iosune Baraibar, Ignacio Melero, David Spigel, Eric Chen, Ben Markman, Arshdeep Pooni, Amy A. Lo, Rosanna S. Kwok, Stephanie Hilz, Zao Li, Pranay Dogra, Neha N. Shah, Andrew G. Polson, Douglas Leipold, Wei Zou, Mengsong Li, Luciana Molinero, Simon Heidegger, Victor Moreno. Phase 1 dose-escalation study of linclatamig, a LY6G6D×CD3 T cell-engaging bispecific antibody, in patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT157.

4010 Background: Targeting tumor-infiltrating Tregs presents a promising strategy to overcome resistance to immunotherapy in cancer treatment. LM-108 is a novel Fc-optimized anti-CCR8 monoclonal antibody designed to selectively deplete tumor-infiltrating Tregs while sparing peripheral Tregs. This pooled analysis of two phase 1/2 trials assesses the efficacy and safety of LM-108 in combination with anti-PD-1 therapy in patients with pancreatic cancer. Methods: Eligible patients (pts) with pancreatic cancer who had progressed on or after at least one prior line of systemic therapy were included. Treatment regimens included LM-108 at doses of 3 mg/kg Q3W, 3 mg/kg Q2W, 10 mg/kg Q3W, or 10 mg/kg Q2W, in combination with pembrolizumab (400 mg Q6W) or toripalimab (240 mg Q3W). The primary endpoint was ORR. Secondary endpoints were DCR, PFS, OS, DoR, safety, and biomarkers analysis. Data cutoff: December 2, 2024. Results: A total of 80 pts (median age: 63 years; 58.8% male) from China and Australia were treated. Of these, 48 pts had progressed on or after 1 prior line of therapy, and 32 pts had ≥2 lines. Eighteen pts (22.5%) had prior anti-PD-1 therapy, and 52 pts (65.0%) had liver metastases at baseline. TRAEs were reported in 76 pts (95.0%). Common TRAEs (≥25%) included increased AST, increased ALT, anemia, rash, pyrexia, decreased platelet count and increased conjugated bilirubin. Grade ≥3 TRAEs occurred in 42 pts (52.5%), the most common events (≥5%) were lipase elevation (7.5%), increased ALT (6.3%), increased AST (5.0%), immune-mediated enterocolitis (5.0%), hypokalemia (5.0%), and rash (5.0%). Median follow-up was 10.48 months (95% CI 7.20-12.65). Among 74 efficacy-evaluable pts, ORR was 20.3% (95% CI 11.8-31.2%) and DCR was 62.2% (95% CI 50.1-73.2%). Median DoR was 5.49 months (95% CI 3.02-8.87), PFS was 3.12 months (95% CI 1.61-4.86), and OS was 10.02 months (95% CI 6.41-13.11). Among 45 pts who had progressed on or after one prior line of therapy, ORR was 24.4% (95% CI 12.9-39.5%) and DCR was 71.1% (95% CI 55.7-83.6%), with a median DoR of 6.93 months (95% CI 3.02-NA), PFS of 4.86 months (95% CI 2.79-6.90), and OS not reached. The 12-month OS rate was 51.6% (95% CI 31.4-68.5%). Among these, 9 pts with high CCR8 expression (7 with baseline liver metastases) showed ORR of 33.3% (95% CI 7.5-70.1%) and DCR of 77.8% (95% CI 40.0-97.2%). Median PFS was 6.90 months (95% CI 1.22-NA), and OS was 9.15 months (95% CI 3.61-NA). Conclusions: LM-108 in combination with anti-PD-1 therapy demonstrated encouraging antitumor activity and a manageable safety profile in patients with pancreatic cancer who had progressed on or after prior systemic therapies. These findings support further investigation of LM-108 in combination with anti-PD-1 therapy as a potential treatment option for pancreatic cancer. Clinical trial information: NCT05199753 ; NCT05518045 .

MicroAbstract: Australian subset of the multicentric PACIFIC-R study (NCT03798535) in patients with unresectable, stage III non-small cell lung cancer without progression following chemoradiotherapy, found a median progression-free survival of 22.4 months (95% confidence interval, 17.5 to 30.8) confirming clinical benefit of durvalumab consolidation post-chemoradiotherapy in the real-world setting. Introduction: The Phase 3 PACIFIC trial established post-chemoradiotherapy (CRT) durvalumab consolidation as standard treatment for patients with unresectable, stage III non-small cell lung cancer (NSCLC). We present the results from the Australian subset of the multicentric PACIFIC-R study (NCT03798535) assessing the effectiveness of durvalumab in the real-world setting. Patients and Methods: Patients with unresectable, stage III NSCLC without progression following CRT, receiving at least 1 dose of durvalumab (10 mg/kg intravenously, every 2 weeks) through an early access program (EAP) between September 2017 and December 2019, were enrolled. Primary endpoints, progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan–Meier method. Results: As of February 7, 2022, 165 patients (median age: 67.0 years) with a median follow-up of 34.7 months were enrolled. Most received last radiation ≥42 days before durvalumab initiation (126, 79.2%) at a dose of 54 to 60 Gy (141, 88.7%). Median PFS was 22.4 months (95% confidence interval [CI], 17.5 to 30.8). The 3-year PFS and OS rates were 38.9% (95% CI, 31.0 to 46.7) and 59.1% (95% CI, 51.2 to 66.2). Pneumonitis was the most frequent adverse events of special interest (27, 16.4%); which led to treatment discontinuation in 19 (11.5%) patients. Conclusion: The real-world results from the Australian PACIFIC-R subset confirm translation of the clinical benefit of post-CRT durvalumab consolidation in the pivotal PACIFIC trial to the real-world setting, showing favorable survival outcomes, irrespective of delays in durvalumab initiation post-radiation.

Divarasib (GDC-6036), an oral, highly potent, and selective next-generation KRAS G12C inhibitor (KRAS G12Ci), has shown encouraging clinical activity and tolerability as a single agent in patients with KRAS G12C-positive NSCLC. In pre-clinical models, SHP2 inhibition increases KRAS-GDP occupancy and enhances the antitumor activity of KRAS G12C inhibitors. Here, we report clinical safety and activity of combination divarasib and migoprotafib (GDC-1971; SHP2 inhibitor) in patients with NSCLC. As part of an ongoing phase I study (NCT04449874), patients received divarasib 200 mg or 400 mg daily in combination with oral migoprotafib 20, 40, or 60 mg daily, until intolerable toxicity or disease progression. Safety (NCI-CTCAE v5), pharmacokinetics, and preliminary antitumor activity (RECIST v1.1) were assessed. Circulating tumor DNA (ctDNA) analyses were performed at Cycle 1 Day 1 and Cycle 3 Day 1. As of April 1, 2024, a total of 74 patients with NSCLC received combination divarasib and migoprotafib; 48 patients had no prior KRAS G12Ci exposure. Median lines of prior systemic therapy was 2 (range 0-7) and median time on study treatment was 7.2 months (range 0.3-26.0). Overall, 70 (94.6%) patients experienced at least one treatment-related adverse event (TRAE); the most common TRAEs (≥15%) were diarrhea, nausea, vomiting, peripheral edema, increased blood creatine phosphokinase, fatigue, increased amylase, increased aspartate aminotransferase and increased alanine aminotransferase. Grade 3-4 TRAEs occurred in 32 (43.2%) patients, including diarrhea in 11 (14.9%) patients, increased ALT in 4 (5.4%) patients, and pneumonitis, thrombocytopenia, and neutropenia in 3 (4.1%) patients each. There were no Grade 5 TRAEs. TRAEs led to divarasib dose reduction in 23 (31.1%) patients and migoprotafib dose reduction in 32 (43.2%) patients. Divarasib discontinuation due to TRAEs occurred in 2 (2.7%) patients; migoprotafib discontinuations due to TRAEs occurred in 5 (6.8%) patients. The pharmacokinetic profiles of both divarasib and migoprotafib in combination were similar to their respective single-agent profiles. Among the 48 patients who had no prior KRAS G12Ci exposure (all of whom had measurable disease at baseline), the confirmed ORR was 43.8% and the median PFS was 15.2 months (CI 95% 8.4-not estimated). A decline in ctDNA level was observed at Cycle 3 Day 1 upon divarasib plus migoprotafib treatment, similar to single-agent divarasib treatment. Updated data will be presented for patients both with and without prior KRAS G12Ci exposure. Divarasib in combination with migoprotafib demonstrated an acceptable safety profile and preliminary clinical activity in patients with KRAS G12C-positive NSCLC. Jia Luo, Adrian Sacher, Armando Santoro, Luis Paz-Ares, Sanjeev Deva, Hans Prennen, Maria de Miguel, Rafal Dziadziuszko, Scott A. Laurie, Manish R. Patel, Elena Garralda, Gianluca Del Conte, Loes Latten Jansen, Jayesh Desai, Rita De Cassia Costamilan, Patricia LoRusso, Ben Markman, Salvatore Siena, Pierre Freres, Marloes Van Dongen, Eugenio Fernandez, Andres Cervantes, Josiane Mourão Dias, Sergio Azevedo, Kathryn Arbour, Ruth Perets, Se Hyun Kim, Rasha Cosman, Victor Moreno, Matthew G. Krebs, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Zhen Shi, Kenneth K. Yau, Julie Chang, Stephanie Royer-Joo, Tomi Jun, Neekesh V. Dharia, Jennifer L. Schutzman, Myung-Ju Ahn. Divarasib plus migoprotafib combination treatment in patients with KRAS G12C-positive non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT022.

Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient’s gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB ( n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies ( n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain–response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type.

2504 Background: Targeting tumor-infiltrating regulatory T cells (Tregs) is a potential approach to overcome immunotherapy resistance in the treatment of cancers. LM-108 is a novel Fc-optimized, anti-CCR8 monoclonal antibody that selectively depletes tumor-infiltrating Tregs. Here we report a pooled analysis of results from 3 phase 1/2 studies (NCT05199753; NCT05255484; NCT05518045) to evaluate the efficacy and safety of LM-108 in combination with anti-PD-1 therapy in patients with gastric cancer. Methods: Eligible patients with gastric cancer treated with LM-108 in combination with an anti-PD-1 antibody were included in the analysis. Patients received intravenous LM-108 at dose levels of 3 mg/kg Q2W, 6 mg/kg Q3W, or 10 mg/kg Q3W plus an anti-PD-1 antibody (intravenous pembrolizumab 200 mg Q3W or 400 mg Q6W or toripalimab 240 mg Q3W). The primary endpoint was investigator-assessed ORR per RECIST v1.1. The secondary endpoints included safety, other efficacy outcomes, and biomarkers analysis. Data cutoff date for the pooled analysis was December 25, 2023. Results: Forty-eight patients with gastric cancer (median age: 60.5 years; male: 72.9%) from China, USA, and Australia were treated ≥ 1 dose of LM-108 in combination with pembrolizumab or toripalimab. Most (n = 47, 97.9%) patients had received at least 1 prior anticancer treatment, and 43 (89.6%) had received prior anti-PD-1 therapy. Treatment-related adverse events (TRAEs) occurred in 39 (81.3%) patients, in which the most common events (≥15%) were alanine transaminase increased (25.0%), aspartate transaminase increased (22.9%), white blood cell decreased (22.9%), anemia (16.7%). Grade ≥ 3 TRAEs occurred in 18 (37.5%) patients, the most common events (≥ 4%) were anemia (8.3%), lipase increased (4.2%), rash (4.2%), and lymphocyte count decreased (4.2%). Among 36 efficacy-evaluable patients across all regimens, ORR was 36.1% (95% CI 20.8%–53.8%) and DCR was 72.2% (95% CI 54.8%–85.8%). The median PFS was 6.53 months (95% CI 2.96–NA). Among 11 patients whose disease had progressed on first-line treatment, ORR was 63.6% (95% CI 30.8%–89.1%) and DCR was 81.8% (95% CI 48.2%–97.7%). Of the 11 patients who progressed on first-line treatment, 8 had high CCR8 expression. Among these 8 patients, ORR was 87.5% and DCR was 100%, with 1 CR, 6 PR, and 1 SD observed. Conclusions: LM-108 in combination with an anti-PD-1 antibody showed promising antitumor activity in patients with gastric cancer that was resistance to anti-PD-1 therapy. The combination therapy was well tolerated. These results support further evaluation of LM-108 in CCR8 positive gastric cancer. Clinical trial information: NCT05199753 ; NCT05255484 ; NCT05518045 .

589 Background: Neuroendocrine carcinomas (NEC) are rare and aggressive cancers. There are no randomised trials to date to establish standard therapy for advanced G3 gastrointestinal (GI) NENs. Extrapolating from small cell lung cancer data, standard practice is to treat G3 GI-NENs with etoposide and carboplatin. Paclitaxel is also active in NECs however there is no data on the role of nab -paclitaxel. NABNEC (ANZCTR # 12616000958482) aimed to determine the activity, safety and tolerability of carboplatin and nab -paclitaxel in advanced G3 GI-NENs and to enhance our understanding of the biology and imaging characteristics of such NENs. Methods: NABNEC was designed as a randomised non-comparative phase II study, evaluating the activity of nab- paclitaxel in patients with advanced and/or metastatic non-resectable G3 GI-NENs. The statistical plan was that 46 evaluable patients in the experimental arm would give 80% power and 95% confidence to rule out a 30% RR in favour of a more interesting RR of 50% at 6 months. Protocol version 3.0 was amended and randomisation to the control arm was suspended after 12 patients. Primary endpoint was objective response rate (RR) by RECIST 1.1. Secondary endpoints were progression free survival, overall survival, adverse events by NCI-CTCAE V4.03 and quality of life (EORTC QLQC30, QLQ-GINET21 questionnaires). Translational research endpoints include blood and tissue biomarkers including circulating tumour cells profiling, mutation profile (whole exome sequencing) and DNA methylation profile correlated with clinical endpoints. Correlation of 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) to early response has also been evaluated. Results: 60 patients were accrued between Sep 2016 and Dec 2021 from 16 centres, resulting in 58 evaluable patients, 12 (control arm), 46 (experimental arm). 43 patients (75%) had tumours with Ki-67>55%; the remainder had Ki-67 between 20 and 55%. About 20% had pancreatic primaries; more than half had liver metastases. The NABNEC trial met its primary endpoint. RR was 53% (38-69%) in the experimental treatment arm compared to 42% (16-71%) in the control group. Progression free survival was not different between the 2 treatments. 24m overall survival was 25% in the experimental group compared to 17% in the control. Grade 3 toxicity was worse in the nab-paclitaxel arms (52% v 42%). Quality of life and tertiary outcomes are being analysed. Conclusions: The combination of carboplatin and nab-paclitaxel is an active regimen for G3 GI-NENs. Further evaluation in a Phase III study is warranted. Clinical trial information: ACTRN12616000958482.

Best response according to histological grade

Background We assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC). Methods This phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1–21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D. Results In phase 1a ( N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b ( N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a ( N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses. Conclusions Nofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC. Clinical trial registr ation Clinicaltrials.gov (NCT03475251).

CancerEarly View REPLY Reply to “Is there a role for combined anti–PD-1/CTLA-4 checkpoint blockade in the management of advanced biliary tract cancers?” Vaibhav Sahai MBBS, MS, Vaibhav Sahai MBBS, MS orcid.org/0000-0003-1892-1548 Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USASearch for more papers by this authorMark M. Zalupski MD, Mark M. Zalupski MD Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USASearch for more papers by this author Vaibhav Sahai MBBS, MS, Vaibhav Sahai MBBS, MS orcid.org/0000-0003-1892-1548 Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USASearch for more papers by this authorMark M. Zalupski MD, Mark M. Zalupski MD Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USASearch for more papers by this author First published: 24 January 2023 https://doi.org/10.1002/cncr.34659 See correspondence on pages 000–000, this issue. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Early ViewOnline Version of Record before inclusion in an issue RelatedInformation

BACKGROUND:Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement. METHOD:Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type. RESULTS:The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation. CONCLUSION:Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective. POLICY SUMMARY:Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities.

PDF file - 4775KB, Supplementary Figure 3. Reduction in Extracellular Signal-Regulated Kinase (ERK) Pathway Signaling by SAR245409 in Paired Tumor Biopsies.

PDF file - 89KB, Supplementary Table 3. Reduction in Phosphoinositide 3-kinase and Mammalian Target of Rapamycin Complex 1 (mTORC1)/mTORC2 Pathway Signaling in Paired Tumor Biopsies.

Supplementary Figure 1 from NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations