Gastric Gastroesophageal Junction Research Articles

Abstract CT215: Frontline vaccination with the B-cell peptide compound HER-Vaxx (IMU-131), combined with standard-of-care chemotherapy induces high levels of HER2-specific antibodies mediating ADCC and intracellular phosphorylation inhibition resulting in overall survival benefit in patients with HER2+ metastatic or advanced gastric/GEJ adenocarcinoma - Final results from Phase II/HERIZON study

Abstract Background: HER2, a member of the epidermal growth factor receptor (EGFR) family, is overexpressed in approximately 30% of gastric cancers. HER-Vaxx is a B cell peptide-based anti-HER2 vaccine (IMU-131) comprising trastuzumab’s binding site. Here, we present the results of the randomized open-label, multicenter phase 2 HERIZON trial (NCT02795988), which compared HER-Vaxx plus chemotherapy to chemotherapy alone. The study aimed to evaluate clinical (primary endpoint) and antibody (secondary endpoint) responses in patients with HER2-overexpressing gastric/gastro-esophageal junction (GC) cancer naïve to anti HER2 therapy. Methods: Patients were randomized to chemotherapy alone (n=17) or HER-Vaxx (50µg, recommended phase 2 dose) plus chemotherapy (n=19). In the HER-Vaxx group, patients received the vaccine at days 0, 14, 35, and 77, then every 63 days until disease progression. Chemotherapy consisted of oxaliplatin plus capecitabine and was started at day 0, repeated every 21 days for a maximum of 6 cycles. The clinical responses were assessed by RECIST 1.1 criteria. FACS analysis of PBMCs for immunophenotyping was carried out, as well as in vitro phosphorylation inhibition assays of HER2 and the signaling pathway kinases Akt and MAPK, and mediation of ADCC to characterize the vaccine-induced IgG antibodies. Results: A 42% survival benefit for patients treated with HER-Vaxx plus chemotherapy [median overall survival: 13.9 months (7.5, 14.3)] compared to chemotherapy alone [mOS: 8.3 months (6.0, 9.6)] was shown, which translated into an OS HR of 0.580 (80% 2-sided CI: 0.362, 0.927). A highly significant HER2-specific IgG and IgG1 antibody response at all time points, particularly after 3 or more doses of HER-Vaxx were induced (P<0.001). The HER-Vaxx antibody response correlated well with mediating ADCC (IgG, P=0.003; IgG1, P=0.05) and the anti-tumor effect (IgG, P=0.001; IgG1, P=0.016). Moreover, the HER-Vaxx-induced IgG antibodies exhibited binding to the gastric cancer cell line N87, with capacity to inhibit HER2 signaling pathway kinases Akt and MAPK phosphorylation. It also demonstrated decreased levels of Foxp3+ Tregs (P=0.0013). Conclusions: The previously shown safety profile of HER-Vaxx, along with the improved clinical and antibody responses in HER2-overexpressing GC patients shown here, validate the proof of concept for a first-in-class B-cell immunotherapy based on HER2 B-cell peptides. Clinical trials evaluating further treatment with HER-Vaxx in HER2+ GC are ongoing. Citation Format: Joshua Tobias, Michael Kundi, Erika Garner-Spitzer, Christoph Zielinski, Marina Maglakelidze, Zoran Andric, Zoran Petrovic, Rajnish Nagarkar, Tanuj Chawla, Leslie Mi Ok Chong, Bonnie Nixon, Sharon Yavrom, Nicholas J. Ede, Ursula Wiedermann. Frontline vaccination with the B-cell peptide compound HER-Vaxx (IMU-131), combined with standard-of-care chemotherapy induces high levels of HER2-specific antibodies mediating ADCC and intracellular phosphorylation inhibition resulting in overall survival benefit in patients with HER2+ metastatic or advanced gastric/GEJ adenocarcinoma - Final results from Phase II/HERIZON study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT215.

Diversity of patients enrolled in SWOG gastrointestinal cancers therapeutic trials.

726 Background: Racial/ethnic minorities, elderly, and rural populations are underrepresented in clinical trials. Globally, gastrointestinal (GI) cancers represent more than a quarter of all cancers, and socioeconomic and lifestyle factors impact their incidence. Additionally, racial/ethnic disparities exist across GI tumor types, including early-onset colorectal cancer, and are associated with survival outcomes. Here we examine the proportion of women and minority participants with GI malignancies enrolled on SWOG Cancer Research Network therapeutic trials. Methods: We analyzed data on participants enrolled to SWOG phase I-III GI cancers treatment trials launched and completed between 2011-2021 according to sex, age (< 70 years vs ≥ 70 years), ethnicity (Hispanic vs not Hispanic), Race (Black vs Asian/Pacific Islander (PI) vs Native American vs White), insurance type (Medicaid or no insurance vs other), and residence types (classified as urban, large rural, small rural, and isolated small rural) using Rural-Urban Commuting Area (RUCA) codes based on zip codes. Participants reporting any category of Black, Asian/PI, Native American, or Hispanic were considered minority. Results: In total, n=1486 participants from 10 trials (S1005, S1115, S1201, S1310, S1313, S1406, S1505, S1513, S1613, S1815) conducted in 5 different GI cancers categories were enrolled, of whom 696 (46.8%) were women and 313 (21.1%) were minority. The five cancer types represented were biliary tract (34.0%), colorectal (10.8%), esophageal (4.8%), gastric/gastroesophageal junction (GEJ) (14.5%), and pancreatic (35.9%). Overall, 696 (46.8%) were female, 94 were Black (6.3%), 83 (5.6%) were Asian/PI, 5 (0.3%) were Native American, 132 were Hispanic (8.9%), 349 (23.5%) were ≥ 70 years, 1263 (85.0%) lived in an urban area, and 155 (10.4%) had Medicaid or no insurance. Minority participants were younger on average than non-minority participants (mean 58.7 vs 63.1, p<0.001), more likely to live in urban settings (92.7% vs. 82.9%, p<0.001) and have Medicaid or no insurance (26.5% vs. 6.1%, p<0.001). Over one-third (37.9%) of Hispanic, 22.3% of Black, and 13.3% Asian/PI participants vs 8.0% of White participants had Medicaid or no insurance. Women’s participation varied according to cancer type, ranging from 8.3% for esophageal to 56.2% for biliary tract, as did minority participation, ranging from 5.6% for esophageal to 36.6% for gastric/GEJ. Conclusions: Our findings suggest that racial/ethnic minorities, the elderly, and those residing in non-urban settings were less likely to enroll in SWOG GI cancers treatment trials than were whites, younger patients, and urban residents. Efforts are needed to enhance diverse enrollment, to break down barriers preventing minority participation, and to improve trial access to minimize disparities.

Zolbetuximab + CAPOX Improves Survival in Advanced Gastric/GEJ Cancer

Zolbetuximab + CAPOX Improves Survival in Advanced Gastric/GEJ Cancer

Abstract CT154: Combination of cinrebafusp alfa with ramucirumab and paclitaxel is well tolerated and elicits encouraging clinical activity in patients with HER2-positive gastric/gastroesophageal junction (GEJ) adenocarcinoma

Abstract Introduction: Cinrebafusp alfa is a first-in-class bispecific antibody-Anticalin® fusion protein that targets HER2 and the costimulatory receptor 4-1BB, leading to enhanced activation of T cells in the tumor, while avoiding liver toxicity. In a Phase 1 monotherapy study, cinrebafusp alfa was well tolerated and showed single agent activity in patients with HER2-positive malignancies. Based on pharmacokinetics (PK), pharmacodynamics and clinical efficacy data, a loading dose of 18mg/kg Q2W in cycle 1 followed by 8mg/kg Q2W in subsequent cycles as maintenance dose was chosen for the Phase 2 study. Methods: This Phase 2 study enrolled patients with metastatic gastric/gastroesophageal junction cancer and confirmed HER2-high status (IHC 3+ or IHC 2+ with HER2/neu gene amplification) who had received one or two prior lines of treatment. Patients received cinrebafusp alfa in combination with ramucirumab and paclitaxel. Primary endpoint was objective response rate (ORR), and key secondary endpoints included safety profile, PK, and immunogenicity. Summary of data: 5 patients were enrolled before enrollment ceased for reasons unrelated to safety or efficacy profile. As of the cut-off date (19-Dec-2022), 5 out of 5 patients achieved a partial response (PR) as best overall response with tumor lesion shrinkage ranging between 35% and 66%. Two of the PRs have been confirmed, one PR is unconfirmed, and 2 patients with currently unconfirmed PRs are continuing to receive treatment. In total, 2 of 5 patients discontinued treatment due to disease progression after 140 and 113 days (patient discontinued cinrebafusp alfa after 42 days but continued on ramucirumab and paclitaxel); 3 patients remain on treatment. Median duration of response was 3.8 months at time of data cut-off. The most frequent treatment emergent adverse events (TEAEs) included Grade 1/2 fatigue (4 patients) and Grade 1-3 diarrhea (4 patients). Infusion related reactions (Grade 2/3) were seen in 1 patient, leading eventually to discontinuation of cinrebafusp alfa. With regards to prior treatment history, all patients received trastuzumab and chemotherapy. 2 patients also received trastuzumab deruxtecan while 4 patients previously received anti-PD1 therapy. Conclusions: The combination of cinrebafusp alfa with ramucirumab and paclitaxel was safe and tolerated in the 5 patients treated. Preliminary activity of cinrebafusp alfa in combination with ramucirumab and paclitaxel demonstrated a high response rate indicating that the combination can elicit clinical responses in patients who have progressed on trastuzumab deruxtecan or checkpoint inhibitor regimens. Citation Format: Geoffrey Ku, Jeeyun Lee, Kayti Aviano, Tim Demuth, Laura-Carolin Hasenkamp, Shane A. Olwill. Combination of cinrebafusp alfa with ramucirumab and paclitaxel is well tolerated and elicits encouraging clinical activity in patients with HER2-positive gastric/gastroesophageal junction (GEJ) adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT154.

Real-world clinical outcomes of the combination of anti-PD-1 antibody, trastuzumab, and chemotherapy for HER2-positive gastric/gastroesophageal junction cancer.

Previous clinical trials indicated the addition of anti-PD-1 antibody remarkably improved the efficacy of trastuzumab and chemotherapy in patients with HER2-positive gastric/gastroesophageal junction (GEJ) cancer. However, no real-world experiences have been reported yet. We retrospectively analyzed 1212 patients with gastric/GEJ cancer treated at Nanjing Drum Tower Hospital between 2019 and 2022. Among 138 patients with HER2-positive gastric/GEJ cancer, 47 patients receiving at least two doses of the combination regimen with anti-PD-1 antibody, trastuzumab, and chemotherapy were recruited in the study population, and 38 out of 47 patients with measurable disease were included in the efficacy population. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were reported. In the study population, 37 (78.7%) received the study therapy as a first-line treatment. In the efficacy population, the ORR and DCR were 76.3% and 94.7%, respectively. The overall median PFS was 9.1months (95% confidence interval [CI] 6.3-11.9months). For the first-line treatment, the mPFS was 10months, and 7months for the second-line. Among 14 patients who failed the study treatment, three (21.4%) developed brain metastasis as the first failure site. No significant association was found between PFS and the expression of PD-L1. 22.2% of patients developed grade 3 treatment-related adverse events (TRAEs). No treatment-related grade ≥4 adverse events or deaths occurred. This real-world study validated the combination regimen's high efficacy and good tolerance in patients with HER2-positive gastric/GEJ cancer. An increased incidence of brain metastasis was observed in patients who failed this regimen.

Safety and Efficacy of Treatment with/without Ramucirumab in Advanced or Metastatic Cancer: A Meta-Analysis of 11 Global, Double-Blind, Phase 3 Randomized Controlled Trials.

Ramucirumab, as a vascular endothelial growth factor receptor-2 inhibitor, was first approved in 2014 for treated advanced or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. This study deeply analyzed the efficacy and safety of advanced or metastatic cancer treated with ramucirumab, which included 11 global, double-blind, phase 3 randomized controlled trials with a total of 7410 patients. Subgroup analysis based on different cancer types showed that standard regimens plus ramucirumab significantly increased progression-free survival and overall survival compared with placebo groups in patients with advanced non-small-cell lung cancer (NSCLC), hepatocellular carcinoma, gastric cancer, or GEJ adenocarcinoma. Although a higher proportion of patients achieved overall response and disease control than those treated with placebo, the overall response was not statistically significant between the two groups in advanced NSCLC. Grade 3 or worse treatment-emergent adverse events (TEAEs) that occurred in at least 5% of patients were neutropenia (30.5% in the ramucirumab group vs. 23.5% in the placebo group), leucopenia (14.8% vs. 9.2%), weight decreased (14.2% vs. 8.0%), myalgia (11.7% vs. 7.7%), fatigue (10.9% vs. 7.7%), hypertension (9.2% vs. 2.3%), and anaemia (6.2% vs. 7.7%). In the TEAEs of special interest, the ramucirumab group had a significantly higher incidence of bleeding (mainly grade 1-2 epistaxis and gastrointestinal bleeding), hypertension, proteinuria, liver injury/failure (grade 1-2), venous thromboembolism (grade 1-2), and gastrointestinal perforation (grade ≧3) than the control group.

1205MO Updated analysis of DESTINY-Gastric02: A phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable/metastatic gastric/gastroesophageal junction (GEJ) cancer who progressed on or after trastuzumab-containing regimen

Primary results of DESTINY-Gastric02 (NCT04014075; data cutoff [DCO] April 9, 2021), a single-arm, phase II trial of T-DXd in Western pts with HER2+ gastric/GEJ cancer, demonstrated a confirmed objective response rate (cORR) of 38.0% (95% CI, 27.3-49.6), and safety consistent with the established T-DXd safety profile. We report OS and updated efficacy and safety. Pts with centrally confirmed HER2+ (IHC3+ or IHC2+/ISH+ biopsy after progression on trastuzumab-based therapy) unresectable/metastatic gastric/GEJ cancer who progressed on or after 1L therapy received T-DXd 6.4 mg/kg Q3W. The primary endpoint was cORR per RECIST v1.1 by independent central review (ICR). Progression-free survival (PFS) by ICR, duration of response (DOR) by ICR, OS, and patient-reported outcomes based on the European Organization for Research and Treatment of Cancer 5-dimension 5-levels (EQ-5D-5L) quality-of-life (QoL) and Functional Assessment of Cancer Therapy-Gastric (FACT-GA) questionnaires were secondary endpoints. At DCO (November 8, 2021), 79 pts from the US/EU had received T-DXd. 76 pts (96.2%) had received 1 prior line of therapy and 3 (3.8%) had received 2 lines. With a median duration of follow up of 10.2 mo, 10 pts (12.7%) remained on treatment. Median OS was 12.1 mo (95% CI, 9.4-15.4); landmark 12-mo OS rate was 50.6%. cORR was 41.8% (33/79; 4 complete and 29 partial responses). Median DOR was 8.1 mo (95% CI, 5.9-NE). Median PFS was 5.6 mo (95% CI, 4.2-8.3). All pts experienced ≥1 treatment-emergent adverse event (TEAE); 55.7% experienced grade ≥3 TEAEs. The most common TEAEs were nausea (67.1%), vomiting (44.3%) and fatigue (57.0%). Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 pts (10.1%); 6 (7.6%) had grade 1-2 and 2 (2.5%) had grade 5. At DCO (April 9, 2021), QoL assessed by EQ-5D-5L and FACT-GA had been maintained over the treatment course. T-DXd continues to demonstrate substantial clinical benefit and a tolerable safety profile in 2L+ Western pts with HER2+ unresectable/metastatic gastric/GEJ cancer.

Abstract 327: Antitumor efficacy of trastuzumab deruxtecan in combination with adavosertib in HER2-expressing Cyclin E amplified gastroesophageal cancers

Abstract Purpose: Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved for patients with HER2-positive gastric/gastroesophageal junction (GEJ) cancers. Amplification of CCNE1, which encodes cyclin E, has been proposed as a mechanism of resistance to HER2-targeted therapies. The Wee1 kinase inhibitor adavosertib (AZD1775) has demonstrated enhanced antitumor activity in the setting of cyclin E overexpression. We investigated the efficacy of T-DXd in combination with adavosertib in HER2-expressing cancers with and without co-amplification of CCNE1. Methods: Frequency of CCNE1 amplification was determined among patients with ERBB2 amplification in a clinical genomic database at the MD Anderson Cancer Center (MDACC) and within The Cancer Genome Atlas (TCGA). Sulforhodamine B assay, western blotting, and Annexin V staining were used to determine the effects of T-DXd and DXd in combination with adavosertib in vitro. Four HER2-expressing gastric/GEJ patient-derived xenograft (PDX) models with or without co-amplification of CCNE1 were tested with T-DXd in combination with adavosertib in vivo. Tumor volume and body weights were measured twice weekly and treatment responses were assessed by the relative treatment-to-control ratio, waterfall plots, and event-free survival (event defined as the day which tumors doubled in size from baseline). Results: Of 515 patients identified at MDACC with ERBB2 amplification, 60 (11.6%) had co-amplification of CCNE1. Of the 405 patients identified within the TCGA with ERBB2 amplification, 43 (10.6%) had co-amplification of CCNE1. Tumor types with the highest frequency of ERBB2/CCNE1 co-amplification were gastric/GEJ (38.1% MDACC, 31.0% TCGA), endometrial (25.0% MDACC, 29.6% TCGA), and ovarian (15.4% MDACC, 15.4% TCGA). Adavosertib was synergistic in combination with DXd in four cell lines with ERBB2 amplification, CCNE1 amplification, or ERBB2/CCNE1 co-amplification. Both DXd and T-DXd upregulated cyclin E and γH2AX protein expression at 24 and 96 hours, and the combination of DXd or T-DXd with adavosertib enhanced apoptosis. T-DXd induced durable tumor regression in two HER2 amplified and HER2 overexpressing gastroesophageal PDX cancer models with HER2 amplification/3+ overexpression and concomitant cyclin E amplification/expression. Adavosertib enhanced the antitumor activity of T-DXd in two HER2 low, cyclin E amplified gastroesophageal cancer PDX models (one with an ERBB2 G778A mutation). Conclusions: ERBB2 and CCNE1 are frequently co-amplified. Our findings provide supporting rationale for combining T-DXd with adavosertib in HER2-expressing cancers with CCNE1 co-amplification. Further study is needed to determine if therapeutic induction of cyclin E with DXd may sensitize to Wee1 kinase inhibition in patients without cyclin E amplification as well. Citation Format: Timothy P. DiPeri, Kurt W. Evans, Gabriela Raso, Yasmeen Q. Rizvi, Xiaofeng Zheng, Bryce Kirby, Kathleen Kong, Khandan Keyomarsi, Jaffer A. Ajani, Timothy A. Yap, Funda Meric-Bernstam. Antitumor efficacy of trastuzumab deruxtecan in combination with adavosertib in HER2-expressing Cyclin E amplified gastroesophageal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 327.

Evaluating Alternative Ramucirumab Doses as a Single Agent or with Paclitaxel in Second-Line Treatment of Locally Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma: Results from Two Randomized, Open-Label, Phase II Studies.

Simple SummaryRamucirumab is indicated at a dosage of 8 mg/kg every 2 weeks as monotherapy or in combination with paclitaxel for second-line advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. A post hoc analysis of the phase III trials REGARD and RAINBOW suggested a positive correlation between ramucirumab exposure and efficacy. Studies JVDB and JVCZ explored different ramucirumab dosing regimens as monotherapy and in combination with paclitaxel, respectively. Here we report results from these studies, in which JVDB evaluated the pharmacokinetics and safety of the currently registered dosing regimen for ramucirumab monotherapy and three exploratory dosing regimens, and JVCZ evaluated the efficacy and safety of a higher dosing regimen of ramucirumab in combination with paclitaxel in second-line gastric/GEJ adenocarcinoma. Overall, the safety profiles were similar between the registered dose and the exploratory dosing regimens. However, a lack of a dose/exposure-response relationship supports the standard dose of ramucirumab as second-line treatment for patients with advanced/metastatic gastric/GEJ adenocarcinoma.Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. For JVDB, randomized patients (N = 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks (Q2W) (registered dose), 12 mg/kg Q2W, 6 mg/kg weekly (QW), or 8 mg/kg on days 1 and 8 (D1D8) every 3 weeks (Q3W). The primary objectives were the safety and pharmacokinetics of ramucirumab monotherapy. For JVCZ, randomized patients (N = 245) received paclitaxel (80 mg/m2-D1D8D15) plus ramucirumab (8 mg/kg- or 12 mg/kg-Q2W). The primary objective was progression-free survival (PFS) of 12 mg/kg-Q2W arm versus placebo from RAINBOW using meta-analysis. Relative to the registered dose, exploratory dosing regimens (EDRs) led to higher ramucirumab serum concentrations in both studies. EDR safety profiles were consistent with previous studies. In JVDB, serious adverse events occurred more frequently in the 8 mg/kg-D1D8-Q3W arm versus the registered dose; 6 mg/kg-QW EDR had a higher incidence of bleeding/hemorrhage. In JVCZ, PFS was improved with the 12 mg/kg plus paclitaxel combination versus placebo in RAINBOW; however, no significant PFS improvement was observed between the 12 mg/kg and 8 mg/kg arms. The lack of a dose/exposure-response relationship in these studies supports the standard dose of ramucirumab 8 mg/kg-Q2W as monotherapy or in combination with paclitaxel as second-line treatment for advanced/metastatic gastric/GEJ adenocarcinoma.

Abstract P032: Berzosertib plus irinotecan in patients with TP53 mutant gastric/gastroesophageal junction adenocarcinoma: A phase II study

Abstract Background: Nearly 50% of patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma possess somatic TP53 mutations, with most mutations falling within exons 2 or 4-11. Though the presence of TP53 mutations has historically been considered a poor prognostic factor in advanced gastric/GEJ adenocarcinoma, cancer cells with mutations in TP53 tend to depend on ataxia telangiectasia and Rad3-related protein kinase (ATR) as a primary mediator of DNA damage repair (DDR). In preclinical studies, topoisomerase 1 inhibitors and ATR inhibitors demonstrate synergy in TP53 mutant gastrointestinal cancer cell lines. Based on the dearth of active later-line treatments in patients with advanced gastric/GEJ adenocarcinoma, we initiated a combinatorial study of the highly selective ATR inhibitor berzosertib (formerly VX-970/M6620) with irinotecan in this disease population. Methods: The study is a single arm phase II trial of berzosertib plus irinotecan in patients with advanced (progressive on at least one prior line of therapy) TP53 mutant (with mutations in exons 2 or 4-11) gastric/GEJ adenocarcinoma and is sponsored by the National Cancer Institute [NCT03641313]. The primary endpoint of the study is objective response rate (ORR) with key secondary endpoints of overall survival (OS), progression-free survival (PFS), duration of response (DOR) and measuring pharmacodynamic biomarkers of DNA damage induction (γ-H2AX, KAP1 p-Ser 824 and p-ATR) from on-treatment biopsies in select patients. Exploratory aims of the study are to assess ORR, OS, PFS and DOR in patients based upon the presence of other tumor DDR mutations (e.g. BRCA1, BRCA2, MRE11, RAD50, RAD51, NBN, ATM). The study utilizes a Simon's Optimal two-stage design to assess ORR. If 2 or more responses are not observed in the first 9 response-eligible patients on the study, it will close for futility. If the interim efficacy threshold is achieved, 14 more response-eligible patients will be enrolled for a total of 23. A safety lead-in is being utilized for the initial 6 patients as the RP2D of the experimental combination had not yet been fully defined from its preceding phase I study. Results: The initial 6 patients have been treated with irinotecan (180 mg/m2 D1,D15 every 28 days) and berzosertib (270 mg/m2 D1,D15 every 28 days). No dose limiting toxicities were observed during cycle 1 in these patients and thus this dose was established as a safe dose for the remainder of the study patients. Patients have experienced grade 3/4 adverse events in 7 instances (most have been hematologic with 1 case of grade 4 neutropenia and 1 case each of grade 3 anemia, neutropenia and thrombocytopenia). Of the initial 6 patients, 1 has demonstrated a partial response while 3 others have demonstrated stable disease on initial response assessment (by RECIST 1.1). Conclusion: Berzosertib plus irinotecan appears to be safe in patients with TP53 mutated gastric/GEJ adenocarcinoma. The interim efficacy analysis, along with pharmacodynamic assessments of DNA damage induction, remain pending. Citation Format: Satya Das, G. Dan Ayers, Jennifer Whisenant, Anwaar Saeed, Edward Kim, Vaia Florou, George Yacoub, Percy Ivy, Charles Kunos, Jordan Berlin. Berzosertib plus irinotecan in patients with TP53 mutant gastric/gastroesophageal junction adenocarcinoma: A phase II study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P032.

439 A phase 2 study of evorpacept (ALX148) in combination with pembrolizumab in patients with advanced head and neck squamous cell carcinoma (HNSCC); ASPEN-03

BackgroundBoth innate and adaptive immune responses are important components of anticancer immunity. CD47 is a marker of self that interacts with SIRPα on myeloid immune cells, inhibiting their function. CD47 is upregulated by tumors to evade immune responses and its expression is associated with poor prognosis. Evorpacept is a high affinity CD47-blocking fusion protein with an inactive Fc region designed to be safely combined with and to enhance the efficacy of standard anticancer therapeutics. Evorpacept used in combination with pembrolizumab has the potential to augment both innate and adaptive anti-tumor immune responses. As an antibody inhibiting PD-1/PD-L1 signaling in the T cell immune checkpoint, pembrolizumab has demonstrated anti-tumor efficacy through activation of tumor-infiltrating lymphocytes. Pembrolizumab as a single agent is a standard treatment option for patients with previously untreated recurrent or metastatic (R/M) HNSCC with PD-L1-positive (combined positive score [CPS] ≥1) tumors. The combination of evorpacept + pembrolizumab has shown preliminary efficacy and acceptable tolerability in initial results available from the cohort of patients with ≥2nd line advanced HNSCC in the ongoing Phase 1 ASPEN-01 study.1 PD-L1-unselected patients who had not received prior checkpoint inhibitor treatment were treated with evorpacept + pembrolizumab and experienced a 40% ORR and 4.6 months median PFS, comparing favorably with historical controls. Based on these encouraging results, the ASPEN-03 study will assess the efficacy and safety of evorpacept in combination with pembrolizumab in previously untreated patients with metastatic or unresectable recurrent PD-L1 positive HNSCC.MethodsASPEN-03 (figure 1) is an ongoing non-comparative, open-label, randomized Phase 2 global study of evorpacept + pembrolizumab or pembrolizumab alone in patients with metastatic or unresectable recurrent, PD-L1-positive (CPS ≥1) HNSCC who have not yet been treated for their advanced disease. After an initial safety lead-in cohort, ~105 patients will be randomized 2:1 to receive evorpacept + pembrolizumab or pembrolizumab alone. Minimization factors used to randomize patients include geography, CPS, and HPV (p16) status. Patients in the evorpacept + pembrolizumab treatment arm will receive evorpacept 45 mg/kg IV Q3W. All patients will receive pembrolizumab 200 mg IV Q3W (maximum of 35 cycles). The primary endpoint in this Simon two-stage trial design is objective response rate using RECIST v1.1. Key secondary endpoints include duration of response, progression-free survival, overall survival, and safety. Exploratory endpoints will characterize pharmacodynamic properties.Abstract 439 Figure 1ASPEN-03 study schemaAcknowledgementsWe would like to thank all the participating patients, their families, and site research teams.Trial RegistrationClinicalTrials.gov identifier, NCT04675294ReferencesKeun-Wook Lee, Hyun Cheol Chung, Won Seog Kim, et al. ALX148, a CD47 blocker, in combination with standard chemotherapy and antibody regimens in patients with gastric/gastroesophageal junction (GC) cancer and head and neck squamous cell carcinoma (HNSCC); ASPEN-01. Poster presented at: Society for Immunotherapy of Cancer Annual Meeting; November 2020.Ethics ApprovalThe study was approved by all participating institutions’ Ethics and/or Review Boards.

Quality of life with first-line pembrolizumab for PD-L1–positive advanced gastric/gastroesophageal junction adenocarcinoma: results from the randomised phase III KEYNOTE-062 study

BackgroundIn the randomised phase III KEYNOTE-062 study, pembrolizumab was non-inferior to chemotherapy for overall survival in patients with programmed death-ligand 1 (PD-L1)-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (GEJ) cancer. We present findings of prespecified health-related quality-of-life (HRQOL) analyses for pembrolizumab versus chemotherapy in this population.Materials and methodsHRQOL, a secondary endpoint, was measured in patients who received ≥1 dose of study treatment and completed ≥1 HRQOL questionnaire [European Organisation for the Research and Treatment of Cancer (EORTC) 30-question quality-of-life (QLQ-C30), EORTC 22-question quality-of-life gastric-cancer-specific module (QLQ-STO22)]. Least squares mean (LSM) change (baseline to week 18) in global health status/quality of life (GHS/QOL; EORTC QLQ-C30) and time to deterioration (TTD) in GHS/QOL, nausea/vomiting and appetite loss scores (EORTC QLQ-C30) and abdominal pain/discomfort scores (EORTC QLQ-STO22) were evaluated.ResultsThe HRQOL population comprised 495 patients with CPS ≥1 (pembrolizumab, 252; chemotherapy, 243). Compliance rates at week 18 were similar for pembrolizumab and chemotherapy (EORTC QLQ-C30, 87.9% and 81.9%; EORTC QLQ-STO22, 87.9% and 81.3%, respectively). There was no between-arm difference in LSM score change in GHS/QOL [−0.16; 95% confidence interval (CI) −5.01 to 4.69; P = 0.948]. The LSM score change for most subscales showed comparable worsening in both arms. TTD for GHS/QOL [hazard ratio (HR), 0.96; 95% CI, 0.67-1.38; P = 0.826], appetite loss (HR, 0.83; 95% CI, 0.58-1.20; P = 0.314) and pain (HR, 1.22; 95% CI, 0.78-1.91; P = 0.381) were similar between arms. Longer TTD was observed for pembrolizumab versus chemotherapy for nausea/vomiting (HR, 0.61; 95% CI, 0.44-0.85; P = 0.003).ConclusionsHRQOL was maintained with first-line treatment with pembrolizumab in patients with PD-L1–positive advanced gastric/GEJ cancer and was similar between pembrolizumab and chemotherapy in this population.

P-57 US real-world ramucirumab and immune checkpoint inhibitor treatment sequences in advanced gastric, gastroesophageal junction, or esophageal cancer

Ramucirumab plus paclitaxel (RAM+pac) and RAM monotherapy have demonstrated survival benefit in advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma following fluoropyrimidine/platinum. More recently, immune checkpoint inhibitors (ICIs) have been studied in various lines of therapy for gastric, GEJ, and esophageal cancers, resulting in new treatment sequences.

Nivolumab in gastric/gastroesophageal junction cancer: real-world data from UK Early Access to Medicines Scheme.

Aim: This study provides real-world insight into patient profile, clinical effectivenessand health-related quality of lifeamong patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma treated with nivolumab. Materials & methods: Data werecollected from medical records of patients with advanced GEJ adenocarcinoma treated with nivolumab in a UK Early Access to Medicines Schemeand from the patient-reported EuroQoL five dimensions questionnaire. Results: Evaluable patients (n=113; median age 62years) were predominantly male (76.1%), White (87.4%) andwith GEJ adenocarcinoma (61.9%). Median follow-up was 2.8months. The 6-month progression-free survivaland overall survival were 31.6and 56.7%, respectively. Mean EuroQoL five dimensions questionnaire index utility scores at baseline, 8, 16and 24weeks were 0.795, 0.831, 0.870and 0.793, respectively. Conclusion: Progression-free survival was consistent with trial results and health-related quality of life remained stable over time.

Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma

In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n= 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

Phase II study of perioperative toripalimab in combination with FLOT in patients with locally advanced resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma.

4050 Background: FLOT is the standard perioperative treatment for resectable gastric /gastroesophageal junction (GEJ) adenocarcinoma. However, patient’s outcome is still poor. Toripalimab, a humanized IgG4 monoclonal antibody against programmed cell death receptor-1 (PD-1), has shown remarkable clinical efficacy in various cancers. This trial evaluates the addition of Toripalimab to FLOT for resectable patients. Methods: This is a prospective, single-arm, investigator-initiated phase II trial. Patients with histologically confirmed, resectable, gastric and GEJ adenocarcinoma (≥cT2 or cN+) were enrolled to receive 4 pre-and post-operative cycles of toripalimab (240mg, q2w) plus FLOT (docetaxel 50 mg/m2; oxaliplatin 85 mg/m2; leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2w). The primary endpoint was pathological complete response rate (pCR). The secondary endpoints included major pathological (complete and nearly complete) response (MPR), and R0-resection rate, 3-year disease-free survival rate, overall survival, and adverse events. Results: In total, of 36 patients were enrolled from June 2019 through Dec 2020. Male, 66.7%; median age, 60y; cT3 8.3%, T4, 83.3%; cN+ 88.9%; GEJ 47%; MSI-H, 5.6%, Her-2neu-positive, 5.6%, EBER-positive, 5.6%). Two patients refused surgery, six patients have not yet completely neoadjuvant treatment. 100% of patients completed the 4 pre-cycle. Patients who had received gastrectomy after neoadjuvant treatment (n=28) were included in this analysis. 6 (21%) patients had operations involving a thoracic approach (oesophagogastrectomy with two field lymphadenectomy), 21 (75%) gastrectomy with D2 lymphadenectomy. 8 (29%) evaluable patients had Clavien-Dindo grade II post-operative complications and 2 (7%) grade IIIA complications; one patient had an anastomotic leakage that was treated endoscopically. There were no emergency re-operations. All 28 patients achieved R0-resection and were discharged home after a median of 12 days (range:7-63) in hospital. 7 （25%）patients achieved pCR (TRG1a) and 12 (42.9%) patients achieved major pathologic response (MPR, TRG1a/b). Treatment-related adverse events (TRAEs) to any drug were reported in 30 (94%) patients. Mostly TRAEs were grade 1-2, the grade 3 or 4 TRAEs included neutropenia (34%), neutropenia (25%), lymphopenia (3%), Alanine aminotransferase increased (3%), hypokalemia (3%) and anaemia (3%). Conclusions: Perioperative toripalimab in combination with FLOT showed promising efficacy with high pCR and MPR rate and well tolerated safety profile in patients with resectable gastric/GEJ adenocarcinoma. This combination regimen might present a new option for patients with locally advanced, resectable gastric/GEJ adenocarcinoma. Clinical trial information: NCT04354662.

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model.

Trifluridine/tipiracil (FTD/TPI) (a.k.a. TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Herein, in KRAS mutant murine colorectal cancer CT26 syngeneic models, we investigate whether combination therapy with DC101 (a surrogate ramucirumab antibody, rat antimouse vascular endothelial growth factor receptor (VEGFR)-2 monoclonal antibody (mAb)) improves FTD/TPI efficacy. Tumor growth inhibition (TGI) on day 15 was 38.0% and 30.6% upon DC101 monotherapy and FTD/TPI monotherapy respectively, and 60.3% upon combination therapy. Tumor volume was significantly lower (p < 0.001) upon combination treatment than upon FTD/TPI or DC101 monotherapy, indicating the additive effects of FTD/TPI and DC101. DNA-incorporated FTD levels on Day 8 were significantly higher in combination therapy with FTD/TPI (for 5 consecutive days) and DC101 (on alternate days for 7days) than in FTD/TPI monotherapy. Furthermore, vascular endothelial cell-specific marker CD31 was downregulated in DC101-treated tumors on day 8. These results indicate that combination therapy with FTD/TPI and DC101 is a promising treatment alternative regardless of KRAS mutations.

Efficacy of immune-checkpoint inhibitors in metastatic gastric or gastroesophageal junction adenocarcinoma by patient subgroups: A systematic review and meta-analysis.

BackgroundEfficacy of immune checkpoint inhibitors (ICIs) in metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma is inconsistent. Whether the efficacy of ICIs is comparable across different subgroups remains unknown.MethodsWe identified randomized controlled trials (RCTs) that compared standard treatment for metastatic gastric/GEJ adenocarcinoma to ICIs. Hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) were extracted and pooled in a meta‐analysis. Prespecified subgroups were included as follows: age at randomization (</≤65 vs ≥/>65 years), gender (female vs male), ethnicity (Asians vs non‐Asians), performance‐status (0 vs 1), tumor location (gastric vs GEJ), and histological subtype (diffuse vs others). OS in patients with programmed death ligand (PD‐L1) positive and with microsatellite instability‐high (MSI‐H) were also extracted and pooled in a meta‐analysis.ResultsFive RCTs comprising 2,264 patients were analyzed. Compared to standard therapy, ICIs did not improve OS (HR = 0.86, 95% CI 0.71‐1.03, P = .10) and the effect of ICIs on OS was similar in all subgroups. Nonsignificantly greater effect sizes were seen in older patients (HR = 0.85 vs 0.88, P = .81), male (HR = 0.82 vs 0.99, P = .16), Asians (HR = 0.86 vs 0.96, P = .55), performance‐status 0 (HR = 0.84 vs 0.88, P = .81), GEJ tumors (HR = 0.78 vs 0.90, P = .37), and nondiffuse subtype (HR = 0.71 vs 0.79, P = .62). ICIs were associated with significantly improved OS in patients with MSI‐H (HR = 0.33, P = .001), but not in PD‐L1 positive disease (HR = 0.86, P = .06).ConclusionsCompared to standard treatment, ICIs in metastatic gastric/GEJ adenocarcinoma did not improve OS. None of the evaluated subgroups has shown increased magnitude of effect to ICIs, aside of the small group with MSI‐H tumors.

Abstract CT246: Consortium-IO: A safety and efficacy study of VE800 in combination with nivolumab in previously treated patients with select advanced metastatic cancers

Abstract Background: Gut microbiome composition affects response to PD-1 blockade; and recent proof of concept studies suggest that gut microbiome manipulation is effective in reversing resistance to PD-1 blockade. VE800 is an oral live biotherapeutic consisting of 11 distinct non-pathogenic, non-toxigenic, commensal bacterial strains manufactured in lyophilized form. VE800 induces CD8+ T cell infiltrate into tumors; and significantly enhances anti-tumor activity of PD-1 blockade preclinically in multiple tumor models in a CD103+ dendritic cell and major histocompatibility (MHC) class I dependent fashion (Tanoue et al., 2019). Retrospective analysis of cancer patient's (pt) samples also suggests that greater VE800 strain abundance is associated with improved response to PD-1 blockade. The objective of this phase I study is to evaluate the safety, tolerability, and clinical activity of VE800 administered orally in combination with nivolumab in pts with select cancers. Methods: CONSORTIUM-IO (NCT04208958) is an open-label, first-in-human study evaluating VE800 and nivolumab combination in pts with anti-PD-1/PD-L1 relapsed/refractory melanoma, anti-PD-1/PD-L1 naïve gastric/gastroesophageal junction (GEJ) adenocarcinoma and anti-PD-1/PD-L1 naïve microsatellite-stable (MSS) colorectal cancer. Following a 5-day course of oral vancomycin 125mg QID, VE800 will be administered daily along with nivolumab (480mg Q4W). A single dose level of VE800 will be evaluated. In the interests of maximizing safety, a Simon 2-stage design will be used for each disease cohort. Although no dose-limiting toxicities (DLT) are expected, the first 3 pts will be enrolled serially 1 week apart; and safety data of the first 6 pts will be reviewed prior to further accrual. Pts will continue to receive VE800/nivolumab combination until disease progression or unacceptable toxicity. Primary endpoints include safety, tolerability; and clinical activity by objective response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS); and metagenomic strain-level analysis of degree/duration of VE800 strain colonization. Exploratory endpoints include tumor and blood immunophenotyping, serum/stool metabolomics and global changes in fecal microbiome composition. CONSORTIUM-IO is currently actively enrolling pts. Citation Format: Diwakar Davar, Judy S. Wang, Michael Cecchini, Zev Wainberg, Martin Gutierrez, Anita Turk, Rose Szabady, Jason Norman, Bernat Olle, Bruce Roberts, Dmitri Bobilev. Consortium-IO: A safety and efficacy study of VE800 in combination with nivolumab in previously treated patients with select advanced metastatic cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT246.

O-12 KEYNOTE-061: Response to subsequent therapy following second-line pembrolizumab or paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma

Observations from the phase 2 KEYNOTE-059 study (NCT02335411) revealed that some patients with advanced gastric/gastroesophageal junction (GEJ) cancer, whose disease progressed on pembrolizumab, achieved durable responses after subsequent therapy with ramucirumab plus paclitaxel. This led us to explore outcomes on subsequent therapy following the randomized phase 3 KEYNOTE-061 study (NCT02370498), which investigated second-line pembrolizumab or paclitaxel for advanced gastric/GEJ cancer. We present overall survival (OS) in response to subsequent lines of therapy following recurrence or relapse on KEYNOTE-061 study treatment.