bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-epidermal growth factor receptor therapy in combination with chemoradiotherapy for the treatment of locally advanced anal canal carcinoma: Results of a phase II study with panitumumab (FFCD 0904).
Authors: Aparicio Thomas , Ronchin Philippe , Bazire Louis , Le Malicot Karine , Lemanski Claire , Mirabel Xavier , Etienne Pierre-Luc , Lièvre Astrid , Cacheux Wulfran , Darut-Jouve Ariane , De La Fouchardiere Christelle , Breysacher Gilles , Argo Leignel Delphine , Tessier Alexandre , Magne Nicolas , Ben Abdelghani Meher , Lepage Come , Vendrely Veronique
Published: May 2019

3570

Background: Standard treatment of anal squamous cell carcinoma is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase II study studied the tolerance and complete response (CR) rate at 8 weeks of panitumumab (Pmab) combined with MMC-5FU based CRT. Methods: Patients with locally advanced tumor without metastases (Stage T2, T3 or T4, whatever N stage; Stage N1-N3 whatever T stage) were treated with two RT periods (45Gy in 5 weeks and a boost of 20Gy in 2 weeks) with concomitant CT sessions of 5FU/MMC at RT weeks 1 and 5. Pmab was administered on RT weeks 1, 3, 5 and 7 according to the doses defined by a previous phase 1.study (MMC: 10 mg/m² at J1 and J29; 5FU: 400 mg/m² from J1 to J4 and from J29 to J32, Pmab: 3mg/kg). The expected rate of CR at 8 weeks to continue in phase III was 80%. Results: Forty-five patients (male: 9 (20%), female: 36 (80%); median age: 60.1 [41.5-81]) were enrolled in 15 French centers. All patients but one completed the CRT. Median duration of CRT was 52 days [30-76].Fourteen patients had a RT interruption because of toxicity. Most common related grade 3-4 toxicities observed were digestive (51.1%), hematologic (lymphopenia: 73.4%; neutropenia: 11.1%), radiation dermatitis (28.8%) and asthenia (11.1%). On patient died because of mesenteric ischemia during the CRT (total dose: 36 Gy). In ITT analysis, the CR rate at 8 weeks after CRT was 66.7% [90%CI: 53.4-78.2]. Median follow-up was 16.2 months [14.1-18.2]. Overall survival, recurrence-free and colostomy-free survival at one year were 94.6% [95%CI: 75.8-98.7], 72.2% [95%CI: 55.0-83.7] and 78.2% [95%CI: 60.6 – 88.6] respectively. Six (13%) patients had a colostomy with abdomino-perineal amputation due to a tumour recurrence. Conclusions: Despite an acceptable tolerance, panitumumab in combination with CRT for locally advanced anal cancer failed to meet the expected CR rate to justify further clinical trials. Clinical trial information: NCT01581840.
Association of TGF-β expression with intratumoral infiltration of cytotoxic T lymphocytes in patients with microsatellite-stable colorectal cancer.
Authors: Mehrvarz Sarshekeh Amir , Katkhuda Riham , Verma Anuj , Advani Shailesh M , Overman Michael J. , Maru Dipen M. , Kopetz Scott
Published: May 2019

3577

Background: Transforming growth factor- β pathway (TGF-β) has an established role in promoting growth, invasion, metastasis as well as epithelial to mesenchymal (EMT) transition. Among 4 different described molecular subtypes of colorectal cancer (CRC), consensus molecular subtype 4 (CMS4) comprises up to 25% of CRC pts, distinguished by activation of this pathway, and is associated with higher relapse rate and poor prognosis. Recently, it has also been proposed that TGF-β activation drives immune evasion in murine models, but these findings have not been clinically validated. Methods: Using multi-gene RNA expression profiling, fresh-frozen paraffin-embedded samples of 35 patients with CRC were analyzed to determine TGF-β and EMT expression levels. Multiplexed IHC staining was performed on FFPE tumor blocks by using the Opal 7-Color fIHC Kit and the stained slides were scanned by a Vectra multispectral microscope (PerkinElmer) to measure infiltration of immune cells (i.e., T lymphocytes, cytotoxic T lymphocytes (CTL), T cell antigen-experienced, macrophages, etc.) in the tumor, stroma, and both components. TGF-β and EMT expression levels – as continuous variables - were compared with the infiltration of various immune cells using Spearman’s rank correlation analysis. Results: Among 35 pts, 28 pts had non-CMS1/MSS CRC. TGF-β RNA expression in the tumor microenvironment of these samples was inversely associated with the infiltration of CTL into the tumor (r=-0.43, p= 0.022). In contrast, there was no association of TGF-β with non-cytotoxic T-cells or macrophage infiltration. The tumor and stromal CTL infiltration differed substantially by CMS ( p=0.04, p=0.02, respectively) with tumor infiltration lowest in CMS4 (n=7). Consistent with this, EMT gene signature, which includes TGF-β expression, showed a similar inverse correlation with CTL infiltration (r=-0.48, p=0.009). Conclusions: TGF-β and EMT gene signatures have important roles in the exclusion of CTL in the tumor microenvironment of CRC pts. Inhibiting TGF-β pathway can potentially increase the intratumoral infiltration of CTL, which is a necessary (but not sufficient) step for immunotherapy response in MSS CRC. Clinical trials evaluating this hypothesis are currently ongoing (NCT03436563).
Performance comparison of the methylated BCAT1/IKZF1 ctDNA test (COLVERA) with the CEA assay for detection of recurrent colorectal cancer.
Authors: Symonds Erin L. , Pedersen Susanne Kartin , Murray David , Byrne Susan E , Hollington Paul , Rabbitt Philippa , Jones Frederick S. , Segelov Eva , Lazarus Tadd Scott , Lapointe Lawrence Charles , Young Graeme P.
Published: May 2019

3589

Background: Early detection of recurrent colorectal cancer (CRC) will improve treatment options, but the current standard blood test of carcinoembryonic-antigen (CEA) has suboptimal sensitivity for recurrence. This study compared performance of a quantitative circulating tumor DNA (ctDNA) assay for methylated BCAT1 and IKZF1 (COLVERA) with that of CEA. Methods: 301 patients were monitored for recurrence after clearance of primary CRC. Blood was collected at scheduled intervals and concentrations of CEA and ctDNA were measured using the LIAISON CEA test (Diasorin) and the COLVERA ctDNA test (Clinical Genomics). Surveillance for recurrent disease was examined using regular CT scans. Sensitivity of each blood test for recurrence was assessed in the sample collected closest to the time of imaging confirming recurrence status. Absence of recurrence was defined as at least two consecutive clear CT scans. Receiver operator characteristic (ROC) analyses were used to determine optimal positivity threshold for Colvera. Results: 131 patients underwent satisfactory assessment for recurrence and had blood testing performed within 12 months of determining recurrence status (61.8% male, mean age 62.6 ±.12.2(SD)y). Of the 47 recurrence cases, 37 (74%) were distant. The areas under the ROC curves were 0.7761 and 0.8188 for CEA and COLVERA, respectively (each p < 0.001). An optimal cut-off of 12.8pg/sample was determined for COLVERA and the standard 5ng/mL cut-off was selected for CEA. COLVERA had a significantly higher sensitivity for detecting recurrence as compared to CEA (68.1% vs 31.9%, p < 0.001) with a similar specificity (97.6% Vs 96.4%, p = 0.6547). A multivariate analysis determined COLVERA to be a predictor of recurrence independent of CEA with positive COLVERA samples being 66.4 times (95%CI 14.0-315.8) more likely to have recurrence confirmed within the study timeframe, whereas CEA was not a significant predictor of recurrence (p = 0.228). Conclusions: These findings indicate that COLVERA, reporting in quantitative mode, is a more sensitive test than CEA. It provides a viable alternative for sensitive and early detection of recurrent CRC. Clinical trial information: 12611000318987.
Gene expression and genetic variants in Parkinson's disease (PD) genes to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3 phase III trial.
Authors: Battaglin Francesca , Cao Shu , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Arai Hiroyuki , Berger Martin D. , Ning Tricia , Soni Shivani , Lo Jae Ho , Barzi Afsaneh , Millstein Joshua , Zhang Wu , Heinemann Volker , Stintzing Sebastian , Lenz Heinz-Josef
Published: May 2019

3595

Background: PD is one of the most common age-related neurodegenerative disorders. Large epidemiological studies have consistently reported a reduced risk of CRC in PD patients (pts), but the biology behind this evidence is unclear. The methylation status of SNCA, one of the causal PD genes, has been identified as a tool for CRC screening and early diagnosis when detected in stool samples, and alterations in core PD genes are prevalent across human malignancies including CRC. Methods: The impact on outcome of 13 SNPs within 6 core PD genes ( SNCA, PRKN, UCHL1, PINK1, DJ-1, LRRK2) was analyzed in pts enrolled in the randomized FIRE-3 trial. Genomic DNA from blood samples of pts treated with first-line FOLFIRI-cetuximab (cet, n = 129) and FOLFIRI-bevacizumab (bev, n = 107) was genotyped through the OncoArray, a custom array manufactured by Illumina. Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the cet cohort, pts carrying the G/G variants of SNCA rs356165 and rs2736990 had significantly shorter mOS (30 vs 41.1 mo) compared to any A genotype in both uni- and multivariable analysis (adjusted P[ Padj] = .047 and .042, respectively). LRKK2 rs3761863 T/T allele carriers showed shorter mPFS (9.5 vs 13.3 mo, Padj = .01), while rs11564148 any A carriers had longer mPFS (14.2 vs 10.2 mo, Padj = .01) compared to reference genotypes. LRKK2 rs11564148 any A carriers also showed longer mOS in multivariable analysis (43.7 vs 33.2 mo, Padj = .044). Any C allele carriers of PINK1 rs1043424 showed longer mPFS in uni- and multivariable analysis ( Padj < .001). No significant interaction was found with gender, tumor location and RAS status. These associations were not observed in bev arm. High SNCA expression was associated with worse mPFS (log2 > 7.89, 5.9 vs 11.2 mo) and mOS (log2 > 7.68, 17.9 vs 31.1 mo) in FIRE-3 cet arm ( P < .05). Conclusions: We provide the first evidence that gene expression and genetic variants in PD genes may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment. Our findings open new perspectives on the role of PD genes in CRC biology warranting further investigation.
The 55 STAR study: Prognostic and predictive value of the 55-gene classifier (55GC) in stage III colon cancer.
Authors: Ishikawa Toshiaki , Oki Eiji , Shinto Eiji , Shimokawa Mototsugu , Yamaguchi Shigeki , Ishiguro Megumi , Hasegawa Seiji , Takii Yasumasa , Ishida Hideyuki , Kusumoto Tetsuya , Morita Masaru , Tomita Naohiro , Shiozawa Manabu , Tanaka Masafumi , Ozawa Heita , Hashiguchi Yojiro , Ohnuma Shinobu , Tada Sachiyo , Matsushima Tomoko , Hase Kazuo
Published: May 2019

3597

Background: Patient prognosis can be predicted based on cancer subtypes classified according to DNA microarray results. The most robust classification system involves the consensus molecular subtypes, which uses over 600 genes for classification. To simplify this classification, we recently constructed a 55-gene classifier (55GC) to classify colon cancer (CC) into three subtypes with different recurrence rates: “microsatellite instability (MSI)-like,” “chromosomal instability (CIN)-like,” and “stromal” colon cancers. The 55GC has been reported to be a useful and reproducible grading system for stage II CC recurrence risk stratification. This study aimed to explore the usefulness of 55GC for classifying stage III CC patients. Methods: We retrospectively identified stage III CC patients aged 20-79 years who underwent curative surgery and received adjuvant chemotherapy with or without oxaliplatin (OX) between 2009 and 2012 from 15 institutions. Propensity score matching was used to adjust for the number of lymph node metastases, tumor location, sex, and age. Results: Among 938 eligible patients, 203 and 201 cases involving adjuvant chemotherapy with and without OX were selected, respectively, using propensity score matching. Ninety-five cases each from groups were analyzed after exclusion of cases involving low-quality specimens and those involving chemotherapy for < 3 months. The 5-year relapse-free survival (RFS) in patients receiving adjuvant chemotherapy with and without OX were 77.1% and 73.7%, respectively. Classification of the stage III CC according to 55GC and related 5-year RFS rates were as follows: stromal (N = 60), 66.6%; CIN-like (N = 78), 80.5%; and MSI-like (N = 52), 78.4%. The HRs for 5-year RFS for adjuvant chemotherapy with and without OX in each subtype were as follows: stromal, HR = 0.791 (95% CI = 0.329-1.901); CIN-like, HR = 1.241 (95% CI = 0.465-3.308); and MSI-like, HR = 0.495 (95% CI = 0.145-1.692). Conclusions: The stromal subtype showed poor prognosis in stage III as well as stage II patients. Oxaliplatin had a good additive effect in adjuvant chemotherapy for MSI-like subtype. The 55GC is useful for predicting the efficacy of adjuvant chemotherapy for CC.
Gender differences in prognostic value of immune-related biomarkers in colon cancer patients randomized to surgery or surgery and adjuvant chemotherapy treatment.
Authors: Villabona Lisa , Masucci Giuseppe V. , Ragnhammar Peter
Published: May 2019

3603

Background: HLA-A*02, a common allele in the Scandinavian population, is a negative prognostic factor in epithelial ovarian cancer. It is a strong predictor of patient outcome, only inferior to clinical staging. This prognostic trait in epithelial ovarian cancer is stronger by the presence of the gene compared with the expression of its protein, MHC class I. Microsatellite instability (MSI) is used as a biomarker for prognosis and is suggested an increased tumor mutational burden which can make the tumor more susceptible for T cell mediated immunotherapy. Our aim was to analyze the prognostic markers HLA-A*02 genotype, MHC class I on tumor cells, the CD8+ lymphocyte infiltration and MSI status in colon cancer patients with randomized treatment. Methods: Clinical information and primary tumors were collected from 520 colon cancer patients and followed for overall survival for 120 months. Patients hade stage II and III colon cancer and were randomized to surgery alone or surgery and adjuvant chemotherapy. HLA-A*02 genotype was determined by conventional PCR. MHC class I, MSI status and CD8+ lymphocyte infiltration were determined by immunohistochemistry. Results: Female patients with a stage III tumor and HLA-A*02 genotype had a better outcome if they had received adjuvant chemotherapy instead of just surgery (p = 0.03), whereas this was not the case for patients with other HLA-A genotypes or in the male patients where HLA-type did not correlate to outcome. MHC class I expression did not act as a prognostic factor, however the presence of CD8+ lymphocytes in the invasive margin and inside the tumor was a positive prognostic factor for overall survival (p = 0.01), although only statistically significant in the male patients (p = 0.03). 21% patients had a tumor with MSI (23% of the female and 19% of the male patients respectively). MSI tumors had a slightly better outcome and this was irrespective of gender and HLA-type. Conclusions: The prognostic traits of HLA-A*02 appear in this colon cancer cohort to act differently in male and female patients. Also CD8+ infiltration is different between genders. These findings suggest that men and women may have two different immune responses to malignancy.
ARTIST 2: Interim results of a phase III trial involving adjuvant chemotherapy and/or chemoradiotherapy after D2-gastrectomy in stage II/III gastric cancer (GC).
Authors: Park Se Hoon , Zang Dae Young , Han Boram , Ji Jun Ho , Kim Tae Gyu , Oh Sung Yong , Hwang In Gyu , Kim Jung Hoon , Shin Dongbok , Lim Do Hoon , Kim Kyoung Mee , An Ji Yeong , Choi Min-Gew , Lee Jun-Ho , Sohn Tae Sung , Bae Jae-Moon , Kim Sung , Kim Seung , Lee Jeeyun , Kang Won Ki
Published: May 2019

4001

Background: Adjuvant chemotherapy and/or chemoradiotherapy have been the standard of care in GC for years, supported by randomized trials. We compared the efficacy of different chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II/III, node-positive GC. Methods: From Feb 2013 through Nov 2018, we randomly assigned, in a 1:1:1 ratio, patients with pathologically-staged II or III, node-positive, D2-resected GC, to receive adjuvant S-1 (40-60 mg twice daily 4-weeks-on/2-weeks-off) for one year, S-1 (2-weeks-on/1-week-off) plus oxaliplatin 130 mg/m2 (SOX) for six months, or SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to the type of surgery (total or subtotal gastrectomy), stage (II or III), and Lauren histologic classification (diffuse or intestinal). The primary endpoint was disease-free survival (DFS). A total of 900 patients had to be enrolled to demonstrate superiority of SOX or SOXRT to S-1 (hazard ratio [HR] 0.667), with 90% power at a two-sided significance level of 5%. Results: A total of 538 patients were included for this interim efficacy analysis. Median age was 58 years, men constituted 65%, and stage II and III were 31% and 69%, respectively. Baseline tumor and patient characteristics were balanced between treatment arms. Adverse events were as anticipated in each arm, generally well-tolerated and manageable. DFS in the control arm (S-1) were significantly shorter than in SOX and SOXRT arms (stratified HR for recurrence): S-1 vs. SOX, 0.617 (P = 0.016) and S-1 vs. SOXRT, 0.686 (P = 0.057). The DFS at 3-years was found to be 65%, 78% and 73% in S-1, SOX and SOXRT arms, respectively. No difference in DFS between SOX and SOXRT was found (HR 0.910, P = 0.667). Based on the results after the observation of 145 recurrence events at the cutoff date of Dec 27, 2018, the independent data monitoring committee considered the results sufficient to meet the endpoint of the trial and recommended early stopping of the trial. Conclusions: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared to S-1 monotherapy. Clinical trial information: NCT0176146.
Prospective randomized phase II trial of pazopanib versus placebo in patients with progressive carcinoid tumors (CARC) (Alliance A021202).
Authors: Bergsland Emily K. , Mahoney Michelle R. , Asmis Timothy R. , Hall Nathan , Kumthekar Priya , Maitland Michael L. , Niedzwiecki Donna , Nixon Andrew B. , O'Reilly Eileen Mary , Schwartz Lawrence Howard , Strosberg Jonathan R. , Meyerhardt Jeffrey A.
Published: May 2019

4005

Background: Patients (pts) with progressive advanced well-differentiated neuroendocrine tumors arising outside of the pancreas have limited systemic treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor with activity against VEGFR-2,-3, PDGFR-α, and β, and c-KIT, with initial data suggesting efficacy in CARC. Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive CARC. Key eligibility: low-intermediate grade CARC, radiologic progressive disease (PD) < 12 months (mo), and adequate end-organ function. Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint was progression-free survival (PFS), defined as time from randomization to PD by central review or death. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The trial had 85% power to detect a difference in median PFS of 14 v 9 mo (hazard ratio [HR] 0.64) at one-sided alpha = 0.1. A stratified log-rank test based on the intend-to-treat (ITT) principle was used. Unblinding and crossover were allowed if PD confirmed by central review. Results: 171 (97 PZ, 74 PL) pts were randomized between 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up of 31 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS was 11.6 and 8.5 mo in PZ and PL, respectively (HR = 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, p = 0.0005) which crossed the pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS was 41 and 42 mo in PZ and PL, respectively (HR = 1.13, 1-sided 90% UCL 1.51, p = 0.70). RR data will be presented. Notable grade 3+ adverse events were (PZ v. PL %) hypertension (35 v. 8), fatigue (11 v. 4), ALT (10 v. 0), AST (10 v. 0), and diarrhea (7 v. 4). Conclusions: PZ compared to PL was associated with significant improvement in PFS in patients with progressive CARC. The results confirm that VEGF signaling pathway is a valid target for therapy in CARC. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org . Clinical trial information: NCT01841736.
Optimizing chemotherapy for frail and elderly patients (pts) with advanced gastroesophageal cancer (aGOAC): The GO2 phase III trial.
Authors: Hall Peter S , Swinson Daniel , Waters Justin S. , Wadsley Jonathan , Falk Stephen , Roy Rajarshi , Tillett Tania , Nicoll Jonathan , Cummings Sebastian , Grumett Simon Aird , Kamposioras Konstantinos , Garcia Angel , Allmark Christine , Marshall Helen , Ruddock Sharon , Katona Eszter , Velikova Galina , Petty Russell D. , Grabsch Heike I. , Seymour Matthew T.
Published: May 2019

4006

Background: Many pts with aGOAC are elderly and/or frail. We previously compared epirubin/ oxaliplatin/ capecitabine (EOCap) vs OCap vs Cap in a pick-the-winner study and found OCap best. GO2 was designed to find the optimum dose of OCap and to explore the use of an objective baseline geriatric assessment to individualize doses for maximum Overall Treatment Utility (OTU), a composite of clinical benefit, tolerability, QL and patient value. Methods: Pts with aGOAC were eligible if unsuitable for full-dose EOCap due to age or frailty, but fit for OCap; GFR ≥ 30, bili <2x ULN. Baseline assessment included global QL; symptoms; functional scales; comorbidity; frailty. Randomization was 1:1:1 to dose Level A (Ox 130 mg/m2d1, Cap 625 mg/m2bd d1-21, q21d), B (80% Level A doses) or C (60% Level A doses). Pts with GFR 30-50 ml/min or bili 1.5-2.0 xULN received 75% of the allocated dose of Cap. At 9 wks, pts were scored for OTU. Continuation thereafter was based on clinical judgement. Non-inferiority (vs A) was assessed using PFS censored at 12 months, with boundary HR 1.34 (based on discussion with pts and clinicians), needing 284 PFS events per 2-way comparison. Baseline fitness was assessed as predictive of OTU, overall and by interaction with dose level. Results: 514 pts were randomised, 2014-17, at 61 UK centres. Clinical trial information: 44687907. Non-inferiority of PFS is confirmed for Level B vs A (HR 1.09, CI 0.89-1.32) and for Level C vs A (HR 1.10, CI 0.90-1.33). Level C pts had less toxicity and better OTU outcomes than A or B. When analysed by baseline age, frailty and PS, Level C produced the best OTU even in younger, less frail and better PS patients; no group was identified who benefit more from the higher dose levels. Conclusions: This is the largest RCT to date specifically investigating frail and/or elderly aGOAC pts, and should guide future treatment. The lowest dose tested was non-inferior in terms of PFS and produced less toxicity and better overall treatment utility.[Table: see text]
Efficacy and safety of pembrolizumab (pembro) alone or in combination with chemotherapy (chemo) in patients (pts) with advanced gastric or gastroesophageal (G/GEJ) cancer: Long-term follow up from KEYNOTE-059.
Authors: Wainberg Zev A. , Yoon Harry H. , Catenacci Daniel V.T. , Jalal Shadia Ibrahim , Muro Kei , Garrido Marcelo , Golan Talia , Doi Toshihiko , Geva Ravit , Ku Geoffrey Yuyat , Bleeker Jonathan Scott , Bang Yung-Jue , Hara Hiroki , Chung Hyun Cheol , Wang Jiang Dian , Hazzard Andrea , Shah Sukrut , Fuchs Charles S.
Published: May 2019

4009

Background: Interim analysis of a global, phase 2 KEYNOTE-059 study (NCT02335411) reported manageable safety and promising antitumor activity for pembro alone or pembro + chemo in pts with G/GEJ cancer. Here we report long-term efficacy and safety data of all cohorts. Methods: Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled in 3 cohorts. Cohort 1 pts (PD-L1positive or negative) received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts (PD-L1positive or negative) received pembro + cisplatin (80 mg/m2 day 1) + 5-fluorouracil (800 mg/m2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m2 twice daily) as first-line. Cohort 3 pts (PD-L1positive, combined positive score ≥1% using the PD-L1 IHC 22C3 pharmDx assay) received pembro alone as first-line. All pts received pembro 200 mg Q3W for up to 2 years. End points included safety, ORR, DOR, and OS. Results: At data cutoff (Aug 8, 2018), median (range) follow-up was 6 (1-38), 14 (2-40), and 21 (2-36) months for cohorts 1 (n = 259), 2 (n = 25), and 3 (n = 31), respectively. In cohort 1, confirmed ORR (95% CI) was 11.6% (8-16) overall, 15.5% (10-22) in PD-L1positive, and 6.4% (3-13) in PD-L1negative tumors. In cohort 2, confirmed ORR was 60.0% (39-79) overall, 73.3% (45-92) in PD-L1positive, and 37.5% (9-76) in PD-L1negative tumors. In cohort 3, confirmed ORR was 25.8% (12-45). Median (range) DOR in months was 16.1 (2-35+), 4.6 (3-37+), and not reached (2.1-32.5+) in cohorts 1, 2, and 3, respectively. OS at 1 year/2 years was 24.6%/12.5%, 52%/32%, and 63.6%/40.1% in cohorts 1, 2, and 3, respectively. In cohorts 1, 2, and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 20 (80%), and 8 (26%) respectively. TRAEs led to discontinuation in 6 (2%) and 3 (12%) pts in cohorts 1 and 2, respectively, and to death in 2 (1%) pts in cohort 1. No TRAEs led to discontinuation or death in cohort 3. Conclusions: These updated results demonstrate manageable safety, durable clinically meaningful activity of pembro in heavily pretreated pts, and promising efficacy of first-line pembro (alone or + chemo) in pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.
First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma.
Authors: Janjigian Yelena Yuriy , Maron Steven Brad , Chou Joanne F , Gabler Amelia , Simmons Marc , Momtaz Parisa , Sanchez-Vega Francisco , Shcherba Marina , Ku Geoffrey Yuyat , Won Elizabeth , Chong Curtis Robert , Gerdes Hans , Kelsen David Paul , Ilson David H. , Solit David B. , Schultz Nikolaus , Shah Pari M. , Capanu Marinela , Hechtman Jaclyn Frances
Published: May 2019

4011

Background: Trastuzumab stimulates HER2-specific T cell responses and increases tumor PD-L1 expression, and anti-PD-1 antibody can help enhance T cell-specific immunity of trastuzumab. We conducted a phase II trial of pembrolizumab with chemotherapy/trastuzumab. Methods: Patients (pts) with previously untreated HER2 IHC 3+ or FISH+ tumors irrespective of PD-L1 status received intravenous P 200 mg flat dose, T 6 mg/kg (after 8 mg/kg load), O 130 mg/m2 every 3 weeks and oral C 850 mg/m2 2 weeks on/1 week off. 22 pts received 1 cycle of induction P/T prior to initiation of chemotherapy. The primary endpoint was 6-months PFS; with target accrual of 37 pts. Secondary endpoints included safety, OS, ORR, and biomarker analysis. Results: Accrual completed and 100% of the 32 evaluable pts had tumor regression (ranging from -20% to -100%). The RECIST 1.1 ORR was 87% (25 PR, 3 CRs), and 12 (52%) of pts that received induction P/T x 1 cycle showed reduction in target lesions. Median PFS was 11.3 months (mo), with 67% 6 mo PFS. Median follow up was only 6.6 mo. In pts with available material, 14/36 (40%) had PD-L1 CPS >1 and median TMB was 4.4 mut/Mb (0-10.6). There was no correlation between PD-L1 status and PFS or OS. ERBB2 amplification was evident by tissue-NGS in 17/29 (61%) and ctDNA-NGS in 17/30 (58%) pre-treatment, while the remaining pts were ERBB2- by NGS likely due to tumor heterogeneity or low tumor content. CtDNA maxVAF decreased in 16/24 tested pts after 1 cycle of induction T/P alone. irAEs included interstitial nephritis Gr4 (3%), transaminitis Gr3 (11%), Gr4 (3%), colitis Gr3 (3%). Conclusions: Most pts (51%) remain on therapy, and so the primary endpoint should be reached by 6/19. Updated survival, correlative studies and will be presented. These promising preliminary safety and efficacy results led to initiation of a definitive phase III Keynote 811 trial. Clinical trial information: NCT02954536.
Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.
Authors: Yau Thomas , Kang Yoon-Koo , Kim Tae-You , El-Khoueiry Anthony B. , Santoro Armando , Sangro Bruno , Melero Ignacio , Kudo Masatoshi , Hou Ming-Mo , Matilla Ana , Tovoli Francesco , Knox Jennifer J. , He Aiwu Ruth , El-Rayes Bassel F. , Acosta-Rivera Mirelis , Neely Jaclyn , Shen Yun , Baccan Carlos , Dela Cruz Christine Marie , Hsu Chiun
Published: May 2019

4012

Background: NIVO monotherapy (mono) is approved for sorafenib (SOR)-treated pts with HCC based on data from CheckMate 040 (NCT01658878), which reported an objective response rate (ORR) of 14% and median overall survival (mOS) of 16 months (mo). This is the first report of efficacy and safety of the NIVO + IPI combination in SOR-treated pts with aHCC. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety and tolerability. Secondary endpoints included ORR (BICR per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS. Cutoff was 25 Sep 2018. Results: 148 SOR-treated pts were randomized. Minimum follow-up for OS from last pt randomization date to data cutoff was 24 mo. At baseline: 88% had vascular invasion or extrahepatic spread, 91% had BCLC stage C, 84% discontinued SOR due to disease progression and 14% due to toxicity. Overall, ORR was 31% (7 had a complete response [CR]) with a median DOR of 17 mo; DCR was 49% and 24-mo OS rate was 40%. Pts in arm A had a mOS of 23 mo and 4 pts had a CR. The table shows additional efficacy results by arm. Overall, NIVO + IPI was well tolerated; 37% of pts had a grade 3–4 treatment-related adverse event (TRAE; most common: pruritus and rash); 5% had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + IPI led to clinically meaningful responses and had an acceptable safety profile in SOR-treated pts, with an ORR twice that of NIVO mono (31% and 14%, respectively). Pts in arm A had the most promising mOS of 23 mo. Clinical trial information: NCT01658878. [Table: see text]
Tumor mutational burden identifies chemorefractory gastric cancer with overall survival advantage after receiving toripalimab, a PD-1 antibody.
Authors: Xu Rui-Hua , Wang Feng , Wei Xiao-Li , Wang Fenghua , Xu Nong , Shen Lin , Dai Guanghai , Yuan Xianglin , Chen Ye , Yang Shujun , Shi Jianhua , Hu Xi-Chun , Lin Xiaoyan , Zhang Qingyuan , Feng Ji Feng , Ba Yi , Liu Yunpeng , Wu Hai , Feng Hui , Yao Sheng
Published: May 2019

4021

Background: Tumor mutational burden (TMB) is correlated with enhanced objective response rate (ORR) and progression-free survival for certain cancers receiving immunotherapy. This study aimed to investigate the safety and activity of toripalimab, a humanized PD-1 antibody, in advanced gastric cancer (AGC), and the efficacy predictive value of biomarkers including TMB and PD-L1. Methods: This study was a part of phase Ib/II trial evaluating the safety and activity of toripalimab as a single agent therapy or in combination with chemotherapy in chemo-refractory or treatment-naïve AGC, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. This report focused on the chemo-refractory AGC cohort receiving toripalimab (3 mg/Kg d1, Q2W) as a single agent therapy. Primary endpoint was ORR. Biomarkers including tumor PD-L1 expression, TMB, microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection status were evaluated for their correlation with clinical efficacy as preplanned. Tumor PD-L1 expression was assessed with the SP142 immunohistochemistry assay, and the other biomarkers were assessed with whole exome sequencing based on tumor samples. Results: There were 58 subjects included in this cohort. The ORR was 12.1% and the disease control rate was 39.7%. Only 1 subject was MSI-H and achieved partial response. One out of 4 EBV positive subjects achieved partial response. Significant higher ORR was observed in subjects with positive PD-L1 expression (ORR 37.5%, 3/8) or TMB ≥12 Mutations/Mb (ORR 33.3%, 4/8) than those with negative PD-L1 expression (ORR 8.5%) or TMB < 12 Mutations/Mb (ORR 7.0%). The TMB-high subgroup showed significant superior OS than the TMB-low subgroup (HR = 0.48 [96% CI 0.24 to 0.96], p = 0.038), while PD-L1 expression status failed to differentiate OS. Conclusions: Toripalimab demonstrated promising anti-tumor activity in chemo-refractory AGC patients. TMB might serve as a better predictive marker for OS than PD-L1 expression for chemo-refractory AGC patients receiving PD-1 blockade immunotherapy. Clinical trial information: NCT02915432.
Pooled safety analysis from phase 3 studies of trifluridine/tipiracil (FTD/TPI) in patients (pts) with metastatic gastric/gastroesophageal junction cancer (mGC/mGEJC) and metastatic colorectal cancer (mCRC).
Authors: Van Cutsem Eric , Hochster Howard S. , Shitara Kohei , Mayer Robert J. , Ohtsu Atsushi , Falcone Alfredo , Yoshino Takayuki , Doi Toshihiko , Ilson David H. , Arkenau Hendrik-Tobias , George Ben , McGuigan Sandra , Makris Lukas , Tabernero Josep
Published: May 2019

4039

Background: FTD/TPI was approved in 2015 for pretreated pts with mCRC based on the phase 3 RECOURSE trial. FTD/TPI recently demonstrating significantly improved overall survival vs placebo in pretreated pts with mGC/mGEJC in the phase 3 TAGS trial. Methods: We evaluated the pooled safety of FTD/TPI in TAGS and RECOURSE in all pts who received ≥1 dose of FTD/TPI (safety population). Pts were required to have ECOG PS 0/1 and to have received ≥2 previous chemotherapy lines. Results: FTD/TPI and placebo were administered to 335 and 168 pts, respectively, in TAGS, and 533 and 265 pts in RECOURSE. Baseline characteristics were balanced across treatment groups and reflected the disease populations. In the pooled population, 66% of pts were men and 75% had received ≥3 prior systemic treatments. The safety profile of FTD/TPI was comparable between studies (table). In TAGS and RECOURSE, the most common any-cause grade (gr) ≥3 AEs in FTD/TPI-treated pts were neutropenia (34%; 35%), anemia (19%; 17%), and leukopenia (9%; 13%). Gr ≥3 febrile neutropenia occurred in 2% and 4% of pts and gr ≥3 GI AEs in 21% and 12%. Gr ≥3 cardiac AEs were reported in 1% of FTD/TPI-treated pts (both studies), in contrast to results obtained with other third-line agents. Similar proportions of FTD/TPI-treated pts in both studies had AEs leading to dosing delay, dose reduction, or treatment discontinuation. Dosing delay was used more often than dose reduction to manage AEs. TRAEs leading to death occurred in one FTD/TPI-treated pt ( < 1%) in each trial. Conclusions: In a pooled analysis, FTD/TPI was well tolerated with a consistent safety profile in pts with mGC/mGEJC or mCRC. The most frequent AEs were hematologic and GI, which were managed with dosing delays/dose reductions. Clinical trial information: NCT02500043; NCT01607957. [Table: see text]
Efficacy and safety of sintilimab in combination with XELOX in first-line gastric or gastroesophageal junction carcinoma (GC/GEJC).
Authors: Xu Nong , Shen Lin , Jiang Haiping , Zheng Yulong , Qian Jiong , Mao Chenyu , Zhou Hui , Wang Shuyan
Published: May 2019

4042

Background: Immune checkpoint inhibitors have shown clinical benefit in advanced GC/GEJC. This phase 1b study evaluates the efficacy and safety of sintilimab, an anti-programmed cell death-1 antibody (PD-1 Ab) in combination with XELOX for GC/GEJC in first-line setting. Methods: This phase 1b study enrolled treatment-naïve unresectable locally advanced or metastatic GC/GEJC patients without HER2 amplification in cohort F. Patients received sintilimab 200mg IV q3w until disease progression, unacceptable toxicity or death, in combination with XELOX regimen (oxaliplatin 130mg/m2 IV D1 and capecitabine 1000mg/m2 PO BID D1-14) for up to 6 cycles. The primary objective was to evaluate the efficacy of the combination per RECIST v1.1 and safety and tolerability. Results: Totally 20 patients were enrolled in cohort F. As data cutoff (15 Jan 2019), median follow up was 5.8 months (range, 2.4 to 12.5). The median dose of sintilimab was 6.5 (range, 4 to 12). The objective response rate (ORR) was 85.0% (95%CI, 62.1 to 96.8) and disease control rate (DCR) was 100.0% (95%CI, 83.2 to 100.0). Among 17 patient with BOR of PR, two patients achieved a complete response (CR) of the target lesion. The median duration of response (DOR) and median progression free survival (PFS) had not been met. Three patients underwent resection of primary tumor after achieving a BOR of partial response (N=2) and stable disease (N=1). The incidence of treatment emergent adverse events (TEAEs) was 85.0%. Treatment-related AEs (TRAEs) occurred in 14 (70.0%) patients. The incidence of TRAE ≥ Grade 3 was 15%. AEs of immune-related etiology, occurred in 6 patients (30.0%). There were no AEs that resulted in death. As data cutoff, 12 patients were still in treatment and 8 had discontinued treatment and were under survival follow up. The biomarker analysis including PD-L1 expression in tumor specimen was ongoing. Conclusions: Sintilimab in combination with XELOX in first-line GC/GEJC shows promising anti-tumor efficacy and a tolerable safety profile. The further randomized, phase 3 study of Sintilimab in combination with XELOX in this setting is ongoing (NCT03745170). Clinical trial information: NCT02937116.
A phase II feasibility trial of neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: The PERFECT trial.
Authors: van den Ende Tom , de Clercq Nicolien C. , van Berge Henegouwen Mark I. , Gisbertz Suzanne S. , Meijer Sybren L. , Schokker Sandor , Bergman Jacques J.G.H.M. , Haj Mohammad Nadia , Ruurda Jelle P. , van Hillegersberg Richard , Mook Stella , Nieuwdorp Max , Soeratram Tanya T.D. , Ylstra Bauke , van Grieken Nicole C.T. , de Gruijl Tanja D. , Bijlsma Maarten F. , Hulshof Maarten C.C.M. , Van Laarhoven Hanneke W.M.
Published: May 2019

4045

Background: The CROSS study demonstrated the superiority of neoadjuvant chemoradiotherapy (nCRT) over surgery alone (van Hagen et al. NEJM. 2012). However, for resectable esophageal adenocarcinoma (rEAC) 5y survival is only 43%. PD1/PDL1 checkpoint inhibitors have shown promising efficacy for several cancer types, including esophageal cancer. To further improve outcomes in rEAC, we performed a phase II trial of nCRT combined with atezolizumab, a PD-L1 inhibitor. Methods: Pts with rEAC received standard dose CROSS regimen (5 cycles of IV: carboplatin AUC2, paclitaxel 50 mg/m2 and concurrent 23 fractions of 1.8 Gy on weekdays) with atezolizumab (5 cycles: 1200 mg IV, 3 weekly). Primary endpoint was the percentage of pts completing treatment with atezolizumab. Secondary endpoints included: toxicity, post-operative complications (Clavien-Dindo), Mandard score, R0 resection rate, PFS and OS. In total 40 pts will be enrolled. Results: Since July 2017, 39 pts have been enrolled (87% males, median age 63). Neoadjuvant treatment was completed by 31 pts and is ongoing in 8 pts. All cycles/fractions of nCRT were administered in 29/31 pts; 26 pts completed all cycles of atezolizumab, 24 pts finished complete neoadjuvant treatment. Reasons for missing any cycle of chemotherapy/atezolizumab included: toxicity (6 pts, in 3/6 pts immune-related adverse events (irAE)) and progression (1 pt). Grade 3-4 toxicity was observed in 15/31 pts (6/31 irAEs of any grade) which did not delay surgery. Thus far 23/31 pts were resected, 3 pts are planned for surgery, 3 pts had interval metastases preoperatively, 1 pt died during treatment (pulmonary embolism), and 1 pt declined surgery. Clavien-Dindo grade 3-4 complications were seen in 11/23 pts with no surgery related mortality. A pathological complete response (pCR), Mandard 1 was seen in 9/23 (39%) pts. All patients underwent an R0 resection. Updated results will be presented at the meeting. Conclusions: Based on data thus far, atezolizumab added to nCRT is feasible. A pCR was observed in 39% of patients, which is promising compared to 23% in the CROSS study. Treatment is associated with irAE which are manageable. Biomarker research will be performed on blood (circulating tumor DNA), tissue (immune microenvironment) and feces (microbiome). Clinical trial information: NCT03087864.
Clinical and molecular factors predicting resistance to first-line (1L) FOLFOX in patients (pts) with advanced esophagogastric cancer (EGA) and patterns of subsequent therapy.
Authors: Greally Megan , Walch Henry S , Chou Joanne F , Capanu Marinela , Kelsen David Paul , Ilson David H. , Janjigian Yelena Yuriy , Schultz Nikolaus , Ku Geoffrey Yuyat
Published: May 2019

4047

Background: In the US, FOLFOX is the most widely used 1L treatment for advanced EGA. We evaluated if FOLFOX resistance (FR) impacted subsequent therapy and characterized the clinical and molecular factors that predict resistance to 1L FOLFOX. Methods: We reviewed pts with advanced Her2-negative EGA treated with 1L FOLFOX from Jan 2013 to Aug 2017. Response or stable disease (SD) at time of first restaging scan defined pts as FOLFOX sensitive (FS); progression defined FR. Pt characteristics were compared using Fisher’s exact and Wilcoxon Rank-Sum tests. Outcomes were correlated with clinical variables and MSK-IMPACT data. Microsatellite instable (MSI) pts were excluded from gene and pathway analysis. Overall survival (OS) was calculated from start of FOLFOX using Kaplan-Meier methods. Landmark analysis (2 months [mo] after starting FOLFOX) was used to compare OS between groups. Results: We identified 311 pts, median age 62, 73% male, 82% ECOG 0/1. 246 pts (79%) were FS and 65 (21%) were FR. FR pts had a higher number of metastatic sites, p = 0.001. Median OS was 13.4 mo in FS pts vs 4.3 mo in FR pts (p < 0.001). At time of analysis, 213 pts (172 FS pts and 41 FR pts) and 110 pts (90 FS pts and 20 FR pts) had received 2nd-line (2L) and 3rd-line (3L) chemo respectively. In pts who received 2L chemo (ctx), there was no difference in ctx duration between FS and FR pts (2.1 vs 1.4 mo, p = 0.67). However, in pts who received 3L ctx, the duration was longer in FS vs FR pts (1.6 vs 0.5 months, p = 0.002). In IMPACT tested pts (n = 130), univariate analysis identified EGFR (33.3% vs 10.7%, p = 0.032) and WNT pathway (26.7% vs 4.9%, p = 0.015) alterations more frequently in FR pts vs FS pts. 12 pts were MSI, all were FS (3 SD, 8 PR, 1 CR). Of 63 pts who had IMPACT germline testing, 7 (11%) had germline mutations identified, including CDH1 (n = 2) and ATM (n = 1), all were FS. No pts were enrolled on genotype-matched trials as a result of IMPACT testing. Conclusions: From time of first restaging scan, FR pts have inferior OS to FS pts. The duration of 3L ctx was longer in FS vs FR pts. Higher number of metastatic sites and EGFR and WNT pathway alterations were associated with FR; MSI was not. IMPACT did not facilitate enrolment on genotype-matched studies.
Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab.
Authors: Masuda Ken , Shoji Hirokazu , Nagashima Kengo , Yamamoto Shun , Ishikawa Masashi , Imazeki Hiroshi , Aoki Masahiko , Miyamoto Takahiro , Hirano Hidekazu , Honma Yoshitaka , Iwasa Satoru , Okita Natsuko , Takashima Atsuo , Kato Ken , Boku Narikazu
Published: May 2019

4049

Background: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. Therefore, in this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab. Methods: The subjects of this study were AGC patients that had received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups. Results: Of the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3–407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that high ALP level (HR = 2.88; 95% CI, 1.51 to 5.51) and absence of irAEs (HR = 3.06, 95% CI, 3.06 to 23.46 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), increased aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). One of the 14 patients experienced the irAE after discontinuation of nivolumab due to progression of disease. There were no grade 4 or 5 adverse events related to nivolumab. Conclusions: Development of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.
Molecular comparison between peritoneal metastases (PM) and primary gastric (GC) and gastroesophageal junction (GEJ) cancer.
Authors: Stein Matthew K , Xiu Joanne , Martin Michael Gary , Grothey Axel , Prouet Philippe , Owsley Jeffrey , Williard Forrest W , Glazer Evan Scott , Dickson Paxton Vandiver , Shibata David , Yakoub Danny , Goldberg Richard M. , Korn W. Michael , Shields Anthony Frank , Hwang Jimmy J. , Lenz Heinz-Josef , Deneve Jeremiah Lee
Published: May 2019

4053

Background: PM from GC or GEJ portend a poor prognosis and molecular differences are ill defined. Methods: We compared genomic profiles of primary (P) GC and GEJ with PM patients (pts) and other metastases (OM) sent to Caris Life Sciences. Testing comprised immunohistochemistry (IHC) including programmed death ligand 1 (PD-L1) combined positive score (CPS), copy number alterations (CNA), 592-gene next-generation sequencing (NGS), microsatellite instability (MSI) and tumor mutational burden (TMB). Results: 1366 cases were identified: 1041 GC (707 P, 98 PM, 236 OM) and 325 GEJ (248 P, 5 PM, 72 OM). PM were increased in GC versus GEJ (9% v. 2%, p < 0.0001). 91% GC and 93% GEJ were adenocarcinoma (AD); GC were more likely signet ring (SR) histology versus GEJ (11% v. 3%, p < 0.0001) and GC PM were more likely SR versus other OM or P (13% v. 12% v. 7%, p = 0.067). The mean age of PM pts (57 years) was younger than primary GC (63, p = 0.002) and OM (61; p = 0.044). More PM GC pts were female than P or OM (48% v. 35% v. 34%, p = 0.03). No molecular profiling differences were seen between GEJ and GC pts and they were combined for analysis; findings from 1246 AD pts are shown below (see Table). OM (9%, p = 0.041) had more CNA in CCNE1 than PM (2%, p = 0.041) or P (5%, p = 0.002). Conclusions: Compared to P and OM GC, PM pts were younger, more likely female and had a higher incidence of SR histology. PD-L1, HER2 IHC and ERBB2 CNA were reduced in PM versus P, suggesting novel therapeutic targets are needed. [Table: see text]