Jeeyun Lee

PURPOSE: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. PATIENTS AND METHODS: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. RESULTS: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. CONCLUSIONS: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

Background: Anti-PD-L1 and anti-CTLA-4 agents have demonstrated clinical activity in gastric and gastroesophageal junction cancer (GC/GEJC) tumors. However, response rates are low suggesting clinical benefit in only a subset of the population. This study prospectively evaluated the ability of a tumor-based interferon (IFN)-γ gene signature to identify a subset of GC/GEJC patients more likely to respond to checkpoint inhibitor therapy.Methods: Second and third-line patients were prescreened using archival formalin-fixed paraffin-embedded tissue to assess IFN-γ gene signature (comprising IFNy, CD274, LAG3, and CXCL9) status with a custom, targeted RNA sequencing assay using Ion AmpliSeq (Thermo Fisher Scientific) sequencing technologies. The cutoff for positive was established at the upper tertile of expression from an existing data set. Patients who were positive during prescreening were eligible to screen. Enrolled patients received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV every 4 weeks (Q4W) for 4 cycles, followed by durvalumab 10 mg/kg Q2W for ≤12 months. Disease assessments were performed every 8 weeks according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.Results: As of August 24, 2018, 176 patients were prescreened. In these patients, the IFN-γ gene signature assay had a 70% rate for providing actionable data; 37.5% of prescreened patients had high expression. The primary failure reason was insufficient tissue, resulting in insufficient nucleic acid. 19 patients were enrolled, with a median follow-up of 5.8 months. Drug-related adverse events (AEs) occurred in 8 patients (42%); 4 (21%) had grade 3/4 AEs (fatigue, elevated lipase, decreased appetite, and interstitial lung disease, the latter of which led to treatment discontinuation). There were no drug-related deaths. Objective response rate (ORR) was 15.8% (95% CI, 3.4%-39.6%), including 1 complete response and 2 partial responses; 1 patient had stable disease. Duration of response was 13.3 weeks (range, 8.1-16.3 w). Median progression-free survival (PFS) was 1.8 months (95% CI, 1.6-1.9 mo), and median overall survival (OS) was 7 months (95% CI, 2.4-7.5 mo).Conclusions: Prospective screening of patients using a novel RNA-based IFN-γ gene expression signature was feasible for patient selection with predictable assay performance. Clinical activity of durvalumab + tremelimumab was increased, with a higher ORR in enrolled patients, compared with unselected populations receiving durvalumab and/or tremelimumab (presented at ASCO 2018); however, PFS and OS remained similar. Given the added complexity of patient preselection and lack of substantial improvement in clinical outcomes, these results, while encouraging, do not support further implementation of the IFN-γ gene signature for patient selection in this indication and treatment regimen.Citation Format: Geoffrey Ku, Jeeyun Lee, Heinz-Josef Lenz, Cheng Ean Chee, Takeshi Omori, Keun-Wook Lee, Yee Chao, Daniel Catenacci, Michael Gibson, Deirdre Cohen, Zev Wainberg, Philip Z. Brohawn, Peng He, Siddharth Sheth, Judson Englert, Ronan Kelly, Yung-Jue Bang. Safety and efficacy of durvalumab in combination with tremelimumab in patients with advanced gastric cancer with elevated tumor interferon-γ gene signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT057.

4034 Background: Combining immune checkpoint inhibitor (ICI) with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. This phase II trial investigated the efficacy and molecular mechanisms of ramucirumab plus pembrolizumab in refractory gastric cancer patients. Methods: We conducted a prospective phase II single-arm trial of ramucirumab plus pembrolizumab as salvage treatment in patients with metastatic GC who failed to respond to standard fluoropyrimidine plus platinum with or without programmed cell death protein 1 (PD-1) inhibitors. Eligible patients had programmed death-ligand 1 (PD-L1) combined positive score more than five. The primary objective was to objective response rate (ORR) and secondary end points included disease control rate, duration of response, progression-free survival and overall survival, and toxicity. Comprehensive molecular profiling, including Digital Spatial Profiling, and mass cytometry was performed on tumor samples and peripheral blood. Results: Twenty-six patients were enrolled in this study between June 2021 and May 2023. No patient attained complete response (CR), while 6 patients achieved confirmed partial response (PR), resulting in a response rate (RR) of 23.1% (95% CI, 4.06–34.4). The median PFS for all patients was 2.7 months (95% CI, 1.84 - 3.56 months), and median OS was 10.9 months (95% CI, 2.31 – 18.29). Grade ≥ 3 treatment-related adverse events occurred in 38.5 % of patients. Digital Spatial Profiling revealed distinct tumor microenvironment (TME) phenotypes between responders and non-responders. Responders had high CTL infiltration and vascular normalization in their tumor specimen after treatment which led to favorable treatment outcome. In support of this, spatial profiling revealed the shortest median distance between immune cells and vessels, suggesting enhanced transendothelial migration of immune cells. Nonresponders had significantly upregulated TGF-β pathway and low tumor vascularity. On-treatment analysis demonstrated a shift towards increased immune cell infiltration and decreased tumor cellularity. Mass cytometry of peripheral blood revealed lower proportions of myeloid-derived suppressor cells in responders. Conclusions: Ramucirumab+pembrolizumab showed modest clinical efficacy, with manageable toxicity and durable responses. Although limited to a small subset of patients, a few patients who had previously responded to ICI benefited from ramucirumab+pembrolizumab. Clinical trial information: NCT0005753 .

11542 Background: We conducted a single-center, prospective, phase II trial to evaluate the efficacy and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, in patients with recurrent or metastatic carcinosarcoma who progressed after prior chemotherapy. Carcinosarcoma, a malignant neoplasm composed of both epithelial and mesenchymal elements, is a rare and aggressive tumor categorized as high-grade cancer by NCCN guidelines. Given the potential for nivolumab to selectively target PD-L1 overexpressing tumor cells, this study aims to identify patients who would likely benefit and orphan malignancy components. Methods: In this single arm phase 2 trial (NCT05224999), eligible patients had histologically confirmed metastatic and/or recurrent carcinosarcoma, measurable disease, 1-3 prior chemotherapy, and adequate renal/hepatic/hematologic function. Treatment consisted of nivolumab 3 mg/kg every 2 weeks. We compared the genomic and transcriptomic properties in our carcinosarcoma tissue with those in TCGA sarcoma, TCGA carcinoma, and TCGA uterine carcinosarcoma. Results: Between July 2020 and Nov 2023, 28 patients enrolled and received trial treatment. Of the 28 patients evaluable, 4 (14.3%) achieved confirmed partial response, and 11 (39.3%) had stable disease, yielding and disease control rate of 53.6%. The median PFS was 2.6 months. The pre-specified primary endpoint was met with 6-months PFR of 30.8%. NGS analysis revealed that carcinosarcoma shares molecular features with both carcinoma and sarcoma, while also exhibiting unique genetic and transcriptional profiles. While some molecular characteristics were common across all three tumor types, carcinosarcoma also displayed unique genetic alterations and transcriptional patterns, underscoring its distinct molecular identity. When comparing our genomic data to TCGA datasets, we observed overlapping mutations. In carcinosarcoma, frequently altered genes included TP53 (sarcoma), ZFHX3 (carcinoma), CHD4 (sarcoma), IRS1 (sarcoma), ARID1A (both), ABL1 (sarcoma), MED12, and PIK3CA (carcinoma). These findings suggest potential shared molecular mechanisms and emphasize the unique genomic landscape of carcinosarcoma. Conclusions: Carcinosarcoma comprises features shared with carcinoma and sarcoma, along with distinct characteristics unique to this tumour type. These findings highlight the distinct molecular landscape of carcinosarcoma and pave the way for more precise, biomarker-driven therapeutic approaches. Furthermore, patients were stratified based on the degree of molecular similarity to carcinoma or sarcoma, enabling exploratory analyses to assess the potential relationship between these stratifications and drug response. Clinical trial information: NCT05224999 .