A phase II study of potentiation of pembrolizumab with binimetinib and bevacizumab in refractory microsatellite stable colorectal cancer.

PURPOSE: In this single-institution phase II investigator-initiated study we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite stable metastatic colorectal cancer (MSS mCRC). PATIENTS AND METHODS: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate in all patients combined (ORR, by RECIST v1.1). RESULTS: Fifty patients received study drug treatment; 54% were male with median age 55 years (range 31-79). The primary endpoint, ORR, was 12.0% (95% confidence interval [CI] 4.5-24.3%), which was not statistically different than the historical control data of 5% (p=0.038, exceeding pre-specified threshold of 0.025). The disease control rate was 70.0% (95% CI 55.4-82.1%), median progression-free survival 5.9 months (95% CI 4.2-8.7 months), and median overall survival 9.3 months (95% CI 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%). CONCLUSION: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared to historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.

Zolbetuximab plus chemotherapy for locally advanced unresectable or metastatic stomach or gastroesophageal junction cancers: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of two articles. The first article is about a clinical trial called SPOTLIGHT and it was published in the medical journal The Lancet in in April of 2023. The second article is about a clinical trial called GLOW and it was published in the medical journal Nature Medicine in July of 2023. WHAT ARE THE KEY TAKEAWAYS?: Until recently, chemotherapy was the first treatment given to people with stomach cancer or gastroesophageal junction (or GEJ) cancer that is locally advanced unresectable or metastatic. When cancer cells have high amounts of the protein CLDN18.2 but do not have high amounts of the protein HER2, the cancer is known as CLDN18.2-positive (or CLDN18.2+) and HER2-negative (or HER2-). New medicines to treat cancer are being developed. These medicines attach to proteins on cancer cells to help the body recognize and kill cancer cells.The clinical trials SPOTLIGHT and GLOW included participants with CLDN18.2+ and HER2- stomach or GEJ cancer that was locally advanced unresectable or metastatic. These trials looked at whether adding a medicine called zolbetuximab to chemotherapy as the first treatment for cancer helped people live longer before their tumors grew bigger or new tumors grew, after starting the trial. These studies also looked at whether adding zolbetuximab to chemotherapy helped people live longer after starting the trial. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: In SPOTLIGHT and GLOW, on average, participants assigned to zolbetuximab plus chemotherapy lived 1.4 to 1.9 months longer before their tumors grew bigger or new tumors grew, after starting the trial, than participants assigned to a placebo plus chemotherapy. On average, participants assigned to zolbetuximab plus chemotherapy also lived 2.2 to 2.7 months longer, after starting the trial, than participants assigned to a placebo plus chemotherapy. These results suggest that zolbetuximab plus chemotherapy could be a new first treatment for people with CLDN18.2+ and HER2- stomach or GEJ cancer that is locally advanced unresectable or metastatic.Clinical Trial Registration: NCT03504397 (SPOTLIGHT); NCT03653507 (GLOW).

The clinical trials SPOTLIGHT and GLOW showed that, on average, participants with stomach or GEJ cancer assigned to zolbetuximab plus chemotherapy lived 2.2 to 2.7 months longer than participants assigned to a placebo plus chemotherapy.

State-of-the-Art Advancements in Gastroesophageal Cancer Treatment: Harnessing Biomarkers for Precision Care.

Gastroesophageal cancers (GECs) represent a significant clinical challenge. For early resectable GEC, the integration of immune checkpoint inhibitors into the perioperative chemotherapy and chemoradiation treatment paradigms are being explored and showing promising results. Frontline management of metastatic GEC is exploring the role of targeted therapies beyond PD-1 inhibitors, including anti-human epidermal growth factor receptor 2 agents, Claudin 18.2 inhibitors, and FGFR2 inhibitors, which have shown considerable efficacy in recent trials. Looking ahead, ongoing trials and emerging technologies such as bispecific antibodies, antibody-drug conjugates, and adoptive cell therapies like chimeric antigen receptor T cells are expected to define the future of GEC management. These advancements signify a paradigm shift toward personalized and immunotherapy-based approaches, offering the potential for improved outcomes and reduced toxicity for patients with GEC.

Effect of Neoadjuvant Chemotherapy on Tumor-Infiltrating Lymphocytes in Resectable Gastric Cancer: Analysis from a Western Academic Center.

Tumor-infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles, as evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, as well as total TILs (CD4+, CD8+, Treg, B cells), within chemotherapy-treated tumors compared with chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic responses with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherapy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

Development of a platform method for rapid detection and characterization of domain-specific post-translational modifications in bispecific antibodies.

Charge heterogeneity is inherent to all therapeutic antibodies and arises from post-translational modifications (PTMs) and/or protein degradation events that may occur during manufacturing. Among therapeutic antibodies, the bispecific antibody (bsAb) containing two unique Fab arms directed against two different targets presents an additional layer of complexity to the charge profile. In the context of a bsAb, a single domain-specific PTM within one of the Fab domains may be sufficient to compromise target binding and could potentially impact the stability, safety, potency, and efficacy of the drug product. Therefore, characterization and routine monitoring of domain-specific modifications is critical to ensure the quality of therapeutic bispecific antibody products. We developed a Digestion-assisted imaged Capillary isoElectric focusing (DiCE) method to detect and quantitate domain-specific charge variants of therapeutic bispecific antibodies (bsAbs). The method involves enzymatic digestion using immunoglobulin G (IgG)-degrading enzyme of S. pyogenes (IdeS) to generate F(ab)2 and Fc fragments, followed by imaged capillary isoelectric focusing (icIEF) under reduced, denaturing conditions to separate the light chains (LCs) from the Fd domains. Our results suggest that DiCE is a highly sensitive method that is capable of quantitating domain-specific PTMs of a bsAb. In one case study, DiCE was used to quantitate unprocessed C-terminal lysine and site-specific glycation of Lys98 in the complementarity-determining region (CDR) of a bsAb that could not be accurately quantitated using conventional, platform-based charge variant analysis, such as intact icIEF. Quantitation of these PTMs by DiCE was comparable to results from peptide mapping, demonstrating that DiCE is a valuable orthogonal method for ensuring product quality. This method may also have potential applications for characterizing fusion proteins, antibody-drug conjugates, and co-formulated antibody cocktails.

Immune Landscape of Epstein-Barr Virus-Associated Gastric Cancer: Analysis From a Western Academic Institution.

INTRODUCTION: Epstein-Barr virus-associated gastric cancer (EBVaGC) may be a meaningful biomarker for potential benefit from immunotherapy. Further investigation is needed to characterize the immune landscape of EBVaGC. We assessed our institutional frequency of surgically treated EBVaGC and analyzed the immunologic biomarker profile and tumor-infiltrating lymphocyte (TIL) phenotypes of a series of EBVaGC compared to non-EBVaGC cases. METHODS: Available tissue samples from all patients with biopsy-confirmed gastric adenocarcinoma who underwent resection with curative intent from 2012 to 2020 at our institution were collected. In situ hybridization was used to assess EBV status; multiplex immunohistochemistry was performed to assess mismatch repair status, Programmed Death-Ligand 1 (PD-L1) expression, and phenotypic characterization of TILs. RESULTS: Sixty-eight samples were included in this study. EBVaGC was present in 3/68 (4%) patients. Among all patients, 27/68 (40%) had positive PD-L1 expression; two of three (67%) EBVaGC patients exhibited positive PD-L1 expression. Compared to non-EBVaGC, EBV-positive tumors showed 5-fold to 10-fold higher density of TILs in both tumor and stroma and substantially elevated CD8+ T cell to Tregulatory cell ratio. The memory subtypes of CD8+ and CD4+ T cells were upregulated in EBVaGC tumors and stromal tissue compared to non-EBVaGC. CONCLUSIONS: The incidence of surgically resected EBVaGC at our center was 4%. EBVaGC tumors harbor elevated levels of TILs, including memory subtypes, within both tumor and tumor-related stroma. Robust TIL presence and upregulated PD-L1 positivity in EBVaGC may portend promising responses to immunotherapy agents. Further investigation into routine EBV testing and TIL phenotype of patients with gastric cancer to predict response to immunotherapy may be warranted.

Immunotherapy in Esophagogastric Cancer: Treatment Landscape, Challenges, and New Directions.

BACKGROUND: Cancers of the upper gastrointestinal tract represent a lethal disease entity comprising the esophagus, gastroesophageal junction, and stomach. The backbone of therapy in esophagogastric cancers has predominantly been chemotherapy-based. However, over the last decade, with the debut of immune checkpoint inhibitors, sophisticated molecular testing, and a more comprehensive understanding of the tumor microenvironment, immunotherapy has been incorporated into the treatment of localized and advanced esophagogastric cancers with promising results. PURPOSE: This study aimed to review the unique tumor microenvironment and role of immunotherapy in esophagogastric cancers. METHODS: We conducted a systematic review of clinical and translational research for immunotherapy in esophagogastric cancers. RESULTS: This article will explore the unique tumor microenvironment in gastroesophageal cancers, the role of immunotherapy in localized and advanced disease, challenges in management, and new therapeutic approaches in clinical trials. CONCLUSION: With further exploration into targeted therapy and immunotherapy, we anticipate the emergence of novel treatments that will improve survival and quality of life in patients with esophagogastric cancers.

Investigation of High Molecular Weight Size Variant Formation in Antibody-Drug Conjugates: Microbial Transglutaminase-Mediated Crosslinking.

Microbial transglutaminase (mTG) has become a powerful tool for manufacturing antibody-drug conjugates (ADCs). It enables site-specific conjugation by catalyzing formation of stable isopeptide bond between glutamine (Q) side chain and primary amine. However, the downstream impact of mTG-mediated conjugation on ADC product quality, especially on high molecular weight (HMW) size variant formation has not been studied in a systematic manner. This study investigates the mechanisms underlying the formation of HMW size variants in mTG-mediated ADCs using size exclusion chromatography (SEC) and liquid chromatography-mass spectrometry (LC-MS). Our findings revealed that the mTG-mediated glutamine and lysine (K) crosslinking is the primary source of the increased level of HMW size variants in the ADCs. In the study, two monoclonal antibodies (mAbs) with glutamine engineered for site-specific conjugation were used as model systems. Based on the LC-MS analysis, a single lysine (K56) in the heavy chain (HC) was identified as the major Q-K crosslinking site in one of the two mAbs. The HC C-terminal K was observed to crosslink to the target Q in both mAbs. Quantitative correlation was established between the percentage of HMW size variants determined by SEC and the percentage of crosslinked peptides quantified by MS peptide mapping. Importantly, it was demonstrated that the level of HMW size variants in the second ADC was substantially reduced by the complete removal of HC C-terminal K before conjugation. The current work demonstrates that crosslinking and other side reactions during mTG-mediated conjugation needs to be carefully monitored and controlled to ensure process consistency and high product quality of the final ADC drug product.

The Local Microbiome in Esophageal Cancer and Treatment Response: A Review of Emerging Data and Future Directions.

The incidence of esophageal cancer is increasing worldwide, with established risk factors explaining only a small fraction of cases. Currently, there are no established screening protocols in most countries, and treatment options are limited. The human microbiome has been implicated in carcinogenesis and the cancer treatment response. The advent of nucleic acid sequencing technologies has enabled more comprehensive, culture-independent bacterial identification. Across several tumor types, studies of tissue-specific microbiomes have shown associations between the overall microbiome composition, the relative abundance of specific bacteria, and tumorigenesis. Furthermore, in the era of cancer immunotherapy, several studies have demonstrated that the microbiome and specific bacteria may modify treatment responses and the risk of immune-related adverse events. DESIGN: peer-reviewed, published studies describing the role of local, gastrointestinal-specific microbiota or the role of the gut microbiome in treatment responses were reviewed. PubMed was searched from 1 September 2022 to 1 November 2022, using the following terms in combination: "microbiome", "tumor microbiome", "esophageal cancer", "cancer", "cancer treatment", and "immunotherapy". Original research articles were considered, and other reviews or editorials were discarded. In total, approximately 250 articles were considered. RESULTS: over 70 studies describing microbiome research in either gastrointestinal carcinogenesis or the systemic treatment response were identified and reviewed. CONCLUSIONS: a growing body of evidence supports the role of the esophageal microbiome in both esophageal tumorigenesis and the immune checkpoint inhibitor response. More well-designed, comprehensive studies are required to collect the appropriate clinical, microbial, and immunophenotype data that are needed to clarify the precise role of the microbiome in esophageal carcinogenesis and treatment.

Esophageal and Esophagogastric Junction Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors.

(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11-447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.

Response to PD-1 inhibitor after progression on PD-L1 inhibitor in advanced HCC.

For hepatocellular carcinoma, the IMbrave150 trial demonstrated that combination atezolizumab and bevacizumab had significantly better overall survival compared with sorafenib in patients with unresectable disease. However, as more immune checkpoint inhibitors are approved as first-line agents in gastrointestinal cancers, there have been few reports on whether sequential PD-1/PD-L1 blockade is beneficial in the treatment of these diseases. We present a patient with hepatocellular carcinoma who had disease progression on atezolizumab, a PD-L1 inhibitor, but subsequently had a remarkable response to pembrolizumab, a PD-1 inhibitor.

A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer.

BACKGROUND: FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. METHODS: Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. RESULTS: Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. CONCLUSIONS: SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell-mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.

Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Shallow neural networks trained to detect collisions recover features of visual loom-selective neurons.

Animals have evolved sophisticated visual circuits to solve a vital inference problem: detecting whether or not a visual signal corresponds to an object on a collision course. Such events are detected by specific circuits sensitive to visual looming, or objects increasing in size. Various computational models have been developed for these circuits, but how the collision-detection inference problem itself shapes the computational structures of these circuits remains unknown. Here, inspired by the distinctive structures of LPLC2 neurons in the visual system of Drosophila, we build anatomically-constrained shallow neural network models and train them to identify visual signals that correspond to impending collisions. Surprisingly, the optimization arrives at two distinct, opposing solutions, only one of which matches the actual dendritic weighting of LPLC2 neurons. Both solutions can solve the inference problem with high accuracy when the population size is large enough. The LPLC2-like solutions reproduces experimentally observed LPLC2 neuron responses for many stimuli, and reproduces canonical tuning of loom sensitive neurons, even though the models are never trained on neural data. Thus, LPLC2 neuron properties and tuning are predicted by optimizing an anatomically-constrained neural network to detect impending collisions. More generally, these results illustrate how optimizing inference tasks that are important for an animal's perceptual goals can reveal and explain computational properties of specific sensory neurons.

Association of Homologous Recombination-DNA Damage Response Gene Mutations with Immune Biomarkers in Gastroesophageal Cancers.

The prevalence of homologous recombination-DNA damage response (HR-DDR) genetic alterations is of therapeutic interest in gastroesophageal cancers. This study is a comprehensive assessment of HR-DDR mutation prevalence across gastroesophageal adenocarcinomas and squamous cell carcinomas. Here we investigate the association of HR-DDR mutations with known predictors for immune-checkpoint inhibition [deficiency in mismatch-repair (dMMRP), tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1)]. We confirmed HR-DDR mutations are present in a subset of gastroesophageal adenocarcinomas (23%) and gastroesophageal squamous cell carcinomas (20%). Biomarker expression of dMMRP (18% vs. 1%) and TMB-high with a cutoff of ≥10 mt/MB (27% vs. 9%) was significantly more prevalent in the DDR-mutated cohort compared with the non-DDR-mutated cohort. Mean combined positive score for PD-L1 in the total adenocarcinoma cohort was significantly higher in the DDR-mutated cohort compared with the non-DDR-mutated cohort (10.1 vs. 5.8). We demonstrated that alterations in ARID1A, BRCA2, PTEN, and ATM are correlated with dMMRP, TMB-high, and increased PD-L1 expression in gastroesophageal adenocarcinomas. Our findings show that a subset of gastroesophageal tumors harbor HR-DDR mutations correlated with established immune biomarkers. By better understanding the relationship between HR-DDR mutations and immune biomarkers, we may be able to develop better immunotherapy combination strategies to target these tumors.

ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma.

PURPOSE: Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. PATIENTS AND METHODS: Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. RESULTS: Forty patients were treated for a median duration of four cycles (range, 1-35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2-20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1-17.1) and median PFS (2.8 months; 95% CI, 2.7-4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. CONCLUSIONS: In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Induction Chemotherapy Plus Neoadjuvant Chemoradiation for Esophageal and Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy with concurrent radiotherapy (nCRT) is an accepted treatment regimen for patients with potentially curable esophageal and gastroesophageal junction (GEJ) adenocarcinoma. The purpose of this study is to evaluate whether induction chemotherapy (IC) before nCRT is associated with improved pathologic complete response (pCR) and overall survival (OS) when compared with patients who received nCRT alone for esophageal and GEJ adenocarcinoma. METHODS: Using the National Cancer Database (NCDB), patients who received nCRT and curative-intent esophagectomy for esophageal or GEJ adenocarcinoma from 2006 to 2015 were included. Chemotherapy and radiation therapy start dates were used to define cohorts who received IC before nCRT (IC + nCRT) versus those who only received concurrent nCRT before surgery. Propensity weighting was conducted to balance patient, disease, and facility covariates between groups. RESULTS: 12,460 patients met inclusion criteria, of whom 11,880 (95%) received nCRT and 580 (5%) received IC + nCRT. Following propensity weighting, OS was significantly improved among patients who received IC + nCRT versus nCRT (HR 0.82; 95% CI 0.74-0.92; p < 0.001) with median OS for the IC + nCRT cohort of 3.38 years versus 2.45 years for nCRT. For patients diagnosed from 2013 to 2015, IC + nCRT was also associated with higher odds of pCR compared with nCRT (OR 1.59; 95% CI 1.14-2.21; p = 0.007). CONCLUSION: IC + nCRT was associated with a significant OS benefit as well as higher pCR rate in the more modern patient cohort. These results merit consideration of a sufficiently powered prospective multiinstitutional trial to further evaluate these observed differences.