Shah, Manish A

ImportanceThe prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone.ObjectiveTo assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes.Data SourcesLiterature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023.Study SelectionTwo blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach.Main Outcomes and MeasuresOverall and disease-free survival, postoperative morbidity, and mortality.ResultsThe analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]).Conclusions and RelevanceIn this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.

Gastrointestinal (GI) cancers, including esophageal, gastroesophageal junction, gastric, duodenal and distal small bowel, biliary tract, pancreatic, colon, rectal, and anal cancer, comprise a heterogeneous group of malignancies that impose a significant global burden. Immunotherapy has transformed the treatment landscape for several GI cancers, offering some patients durable responses and prolonged survival. Specifically, immune checkpoint inhibitors (ICIs) directed against programmed cell death protein 1 (PD-1), either as monotherapies or in combination regimens, have gained tissue site-specific regulatory approvals for the treatment of metastatic disease and in the resectable setting. Indications for ICIs in GI cancer, however, have differing biomarker and histology requirements depending on the anatomic site of origin. Furthermore, ICIs are associated with unique toxicity profiles compared with other systemic treatments that have long been the mainstay for GI cancer, such as chemotherapy. With the goal of improving patient care by providing guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of GI cancer. Drawing from published data and clinical experience, the expert panel developed evidence- and consensus-based recommendations for healthcare professionals using ICIs to treat GI cancers, with topics including biomarker testing, therapy selection, and patient education and quality of life considerations, among others.

TPS4175 Background: Platinum/fluoropyrimidine (FP) with PD-1 inhibitor is now established as the standard first-line therapy for most patients with advanced HER2 negative gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinoma. The FP doublet chemotherapy backbone, most commonly FOLFOX, is recommended based on marginal survival benefits of taxane-containing triplet therapy at the cost of increased toxicity. Although several agents are approved as standard treatment options in later lines, only about 10% of patients in the US receive a third line of therapy, and very few have the opportunity to benefit from all approved agents in this disease. This challenge will only increase as more agents and targeted therapies are approved. FOLFIRINOX is a triplet regimen commonly used in gastrointestinal malignancies with established safety and often with superior efficacy. Two single arm phase II trials of FOLFIRINOX have reported promising activity in GEA with manageable toxicities. Reported median overall survival (OS) from these trials is around 15 months, which is superior to what is expected from FP doublet first-line chemotherapy (about 11 months). We hypothesize that using upfront triplet therapy with a more effective and less toxic triplet combination will result in improved patient outcomes by optimization of available therapies in GEA. Methods: This study is a randomized phase III, open-label, multicenter clinical trial with the primary objective to determine whether modified FOLFIRINOX (FU 2400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 every 2 weeks) as first-line treatment improves OS compared to mFOLFOX in patients with advanced HER2 negative GEA. Eligible patients will have unresectable or metastatic adenocarcinoma of esophagus, GEJ, or stomach with no prior systemic treatment. Patients must have adequate organ function, and measurable or evaluable disease as defined by RECIST 1.1. Prior neoadjuvant or adjuvant therapy is allowed if completed at least 1 year prior to registration. Patients who will receive nivolumab (mandatory for PD-L1 combined positive score > 5) in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors. Patients with treated, asymptomatic and stable brain metastases are eligible. The total sample size is 382 evaluable patients for this study (191 patients per arm). The study accrual began January 2023. Clinical trial information: NCT05677490 .

4147 Background: Retrospective studies of phosphorylated STAT3 (pSTAT3, a regulator of gene expression) in cancer-lineage cells have suggested it is a biomarker of poor prognosis. We analyzed data from 3 phase 3 RCTs (BRIGHTER [T1; NCT02178956], CO.23 [T2; NCT01830621], CanStem111P [T3; NCT02993731]) to evaluate the prognostic impact of pSTAT3 on OS in GI cancer patients (pts). Methods: pSTAT3 was evaluated in archival tumor tissue from pts with gastric or gastroesophageal junction adenocarcinoma (T1), colorectal cancer (T2), or pancreatic cancer (T3) who received standard of care in the control arms (CTL) of their respective trials. pSTAT3 positive (+) or negative (−) status was determined by detecting pSTAT3 in both tumor and tumor microenvironment (TME) cells in a laboratory-developed immunohistochemistry (IHC) assay (T1; T2), later developed into the investigational pSTAT3 IHC D3A7 assay (Agilent Technologies, Inc.) (T3). The positivity cutoff requires a sample have both a TME score of 2 and ≥5% of tumor cells staining positively for pSTAT3. Pre-analytical variables (eg, specimen collection, handling, and processing), tumor indication, and slight differences in the assays used for each study may contribute to relative differences in evaluable rates between studies. In an exploratory analysis, OS was compared in pSTAT3+ vs pSTAT3− pts via an unstratified log-rank test. Results: In each study, intent-to-treat pts with evaluable pSTAT3 results were considered pSTAT3-evaluable. This abstract includes pSTAT3-evaluable pts randomized to the CTL arms (T1: n/N=248/357, 69.5%; T2: n/N=110/144, 76.4%; T3: n/N=243/569, 42.7%). Baseline characteristics are presented in the table. Median (m) OS was shorter in pts with pSTAT3+ tumors across all studies (T1 hazard ratio [HR]=1.32 [95% confidence interval (CI): 1.00, 1.74]; T2 HR=2.40 [1.50, 3.83]; T3 HR=1.08 [0.77, 1.50]). Conclusions: In pSTAT3-evaluable populations from 3 RCTs across GI cancers, CTL pts with pSTAT3+ (vs pSTAT3−) tumors had shorter mOS. These results suggest that pSTAT3 positivity may be a biomarker of poor clinical outcome. Clinical trial information: NCT02178956; NCT01830621; NCT02993731. [Table: see text]

723 Background: The US FDA approved pembro for treating pts with 1) recurrent locally advanced or metastatic G/GEJ adenocarcinoma, whose disease has progressed on or after ≥2 prior therapies and whose tumors express PD-L1 (combined positive score [CPS] ≥1), and 2) unresectable or metastatic, microsatellite instability-high (MSI-H) solid tumors that have progressed after prior therapy and who have no fitting options. We report Asian subgroup analyses from cohort 1 of KEYNOTE-059 (NCT02335411), a global, phase 2 study in advanced G/GEJ cancer. Methods: Eligible pts had measurable recurrent or metastatic G/GEJ adenocarcinoma whose disease has progressed on ≥2 prior chemotherapy regimens. Pts received pembro 200 mg Q3W up to 2 y. PD-L1+ tumors had a CPS ≥1. Primary end points were ORR (RECIST 1.1, by central review) and safety. Results: Cohort 1 enrolled 259 pts; 57% had PD-L1+ tumors. MSI status was evaluable in 174 tumor samples; of these, 7 were MSI-H. At data cutoff (4/21/2017), median (range) follow-up was 6 mo (1-25). Overall ORR was 12% (95% CI, 8-17) and median (range) DOR was 14 mo (2-19+). PFS6-mo rate was 15% and OS6-mo rate was 46%. In pts with PD-L1+ tumors, ORR was 16% (95% CI, 11-23) and median (range) DOR was 14 mo (3+-19+). In pts with PD-L1+ tumors, PFS6-mo rate was 20% and OS6-mo rate was 50%. In pts with MSI-H tumors, ORR was 57% (95% CI, 18-90) and median (range) DOR was not reached (5-14+ mo). In cohort 1, 41 pts were Asian and 218 pts were non-Asian. PD-L1+ tumors occurred in 42% of Asian pts and 60% of non-Asian pts. ORR was 12% (95% CI, 2-36) in Asian pts with PD-L1+ tumors and 17% (95% CI, 11-24) in non-Asian pts with PD-L1+ tumors. One of 7 pts with MSI-H tumors was Asian; this pt had CR. Grade 3-5 treatment-related AEs occurred in 17% and 18% of Asian and non-Asian pts, similar to the overall cohort. Conclusions: Pembro showed durable clinical benefit in previously treated pts with advanced G/GEJ cancer, especially those with PD-L1+ or MSI-H tumors. Safety and efficacy were similar in Asian and non-Asian pts. These findings highlight pembro as a standard treatment option in Asian and non-Asian pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.

TPS4135 Background: Gastric cancer is a prevalent and morbid illness for which new treatment strategies are needed. Peri-operative therapy is a standard approach that is associated with only a 15% improvement in overall survival. Early FDG-PET scanning, performed prior to cycle 2, can distinguish patients (pts) responding to chemotherapy from those who are not. FDG-PET non-responding pts have poorer survival. This study addresses the question of salvage therapy in pts who are PET non-responders. Specifically, does salvage chemotherapy with docetaxel /irinotecan improve pt survival in FDG-PET-nonresponding pts with locally advanced gastric cancer. Methods: This is a multicenter, cooperative group, NCI supported, randomized phase II study of salvage chemotherapy + surgery versus surgery and post-operative chemoradiotherapy in pts who are FDG-PET non-responders (defined as a decrease in SUVmaxof the primary tumor of less than 35%). A total of 176 pts with locally advanced, resectable gastric cancer who were FDG-PET non-responders to cycle 1 of platinum/capecitabine based chemotherapy will be randomized in a 1:1 manner to receive either (Arm A) surgery followed by fluoropyrimidine-sensitized radiotherapy (4500 cGy), or (Arm B) salvage chemotherapy with docetaxel / irinotecan (DI) for 2 cycles followed by standard resection and 3 cycles DI post-operatively. DI is administered as D 30 mg/m2, I 50 mg/m2 given on D1, D8 of a 21 day cycle. 416 pts will be screened to yield 162 non-responders (81 FDG-PET non-responders per treatment group). With expected 120 events, the study will have 80% power to detect a hazard ratio of 0.625 for improved survival at the one-sided significant level of 0.15. Pts will be required to provide tissue at the time of resection, as well as whole blood prior to resection for correlative studies associated with platinum sensitivity, FDG avidity, and prognostic markers. This study is available through all cooperative groups (SWOG, ACRIN/ECOG, Alliance, and NRG) and the National Clinical Trials Network. Enrollment began in November 2015. Support: U10CA180821, U10CA180882; Clinical Trial Information: NCT02485834 .

4003 Background: Pembro has shown promising antitumor activity and manageable safety in a phase 1 study of pts with previously treated advanced gastric cancer. We conducted a global, multicohort, phase 2 study of pembro in pts with advanced gastric or gastroesophageal junction (G/GEJ) cancer (KEYNOTE-059;NCT02335411). Methods: Cohort 1 enrolled 259 pts, aged ≥18 y with measurable recurrent or metastatic G/GEJ adenocarcinoma who had progressed on ≥2 prior chemotherapy regimens and had ECOG PS 0-1. Pts received pembro 200 mg Q3W up to 2 y or up to disease progression, investigator/pt decision to withdrawal, or unacceptable toxicity. PD-L1+pts had expression in ≥1% tumor or stromal cells using IHC (22C3 antibody). Primary end points: ORR (RECIST 1.1, by central review), safety, and tolerability. Results: Of 259 pts in cohort 1, 76.4% were men; median age was 62.0 y. 51.7% and 48.3% received pembro as 3rd-line (3L) and 4L+ therapy, respectively. 57.1% had PD-L1+ tumors. At data cutoff (Oct 19, 2016), median duration of follow-up was 5.4 mo (range, 0.5 to 18.7). Overall ORR (CR + PR) was 11.2% (95% CI, 7.6-15.7); 1.9% of pts (95% CI, 0.6-4.4) had CR, 9.3% had PR (95% CI, 6.0-13.5), 17% (95% CI, 12.6-22.1) had SD, and 55.6% (95% CI, 49.3-61.7) had PD. Median DOR was 8.1 mo (range, 1.4+ to 15.1+). ORR was 14.9% (95% CI, 9.4-22.1) in 3L pts and 7.2% (95% CI, 3.3-13.2) in 4L+. In PD-L1+ pts, ORR was 15.5% (95% CI, 10.1-22.4) with 2.0% (95% CI, 0.4-5.8) CR and 13.5% (95% CI, 8.5-20.1) PR; in PD-L1– pts, ORR was 5.5% (95% CI, 2.0-11.6), with 1.8% (95% CI, 0.2-6.5) CR and 3.7% (95% CI, 1.0-9.1) PR. In 3L pts with PD-L1+ tumors, ORR was 21.3% (95% CI, 12.7-32.3), with 4.0% (95% CI, 0.8-11.2) CR; in 3L pts with PD-L1– tumors, ORR was 6.9% (95% CI, 1.9-16.7), with 3.4% (95% CI, 0.4-11.9) CR. Grade 3-5 treatment-related AEs (TRAEs) occurred in 43 pts (16.6%). TRAEs led to discontinuation in 2 pts (abnormal LFT, bile duct stenosis) and were fatal in 2 pts (acute kidney injury, pleural effusion). Conclusions: Pembro showed encouraging efficacy and manageable safety after ≥2 prior lines of therapy in pts with advanced G/GEJ cancer in this large phase 2 trial. Survival and additional biomarker data, including MSI status, will be presented. Clinical trial information: NCT02335411.

TPS3619 Background: Cancer stem cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapeutics, including 5-FU and irinotecan. Encouraging anticancer activity in advanced CRC was observed in a phase Ib/II (Bendell et al, GI ASCO 2017) study of 63 pts with disease control rate (DCR) of 93% (28/30) and overall response rate (ORR) of 33% (10/30) in FOLFIRI-naïve pts who have had an on-study RECIST evaluation. On the basis of these data, a phase III trial is being conducted in North America, Europe, Australia, and Asia. Methods: This study (ClinicalTrials.gov NCT02753127) will assess the efficacy of napabucasin+FOLFIRI vs FOLFIRI in pts with mCRC (n = 1250). Addition of bevacizumab (bev) is permissible per investigator choice. Pts must have failed 1 prior line of therapy with oxaliplatin and a fluoropyrimidine +/- bev for metastatic disease. Pts are randomized 1:1 to receive napabucasin 240 mg PO BID plus FOLFIRI bi-weekly, or FOLFIRI bi-weekly (bev may be added to FOLFIRI by investigator choice) and stratified by geography, time to progression on 1st-line therapy, RAS mutation status, bev as part of study treatment and primary tumor location. Treatment will continue until disease progression, or another discontinuation criterion. Primary endpoint is overall survival (OS) in the general study population (ITT) (HR 0.80 for OS improvement from 12.54 to 15.68 months); secondary endpoints include OS in the biomarker positive (biomarker+) population, progression free survival (PFS) in the ITT population, PFS in biomarker+ population, ORR and DCR in the ITT and in biomarker+ populations, safety and quality of life. Also, blood and tumor archival tissue will be assessed for PK and biomarker analyses. Global enrollment is underway. Clinical trial information: NCT02753127.