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PURPOSE: Colorectal cancer (CRC) incidence in patients younger than 50 years of age, commonly defined as early-onset (EO-CRC), is rising. EO-CRC often presents with distinct clinicopathologic features. However, data on prognosis are conflicting and outcomes with modern treatment approaches for metastatic disease are still limited. MATERIALS AND METHODS: We prospectively enrolled patients with metastatic CRC (mCRC) to a biobanking and clinical data collection protocol from 2014 to 2018. We grouped the cohort based on age at initial diagnosis: < 40 years, 40-49 years, and ≥ 50 years. We used regression models to examine associations among age at initial diagnosis, treatments, clinicopathologic features, and survival. RESULTS: We identified 466 patients with mCRC (45 [10%] age < 40 years, 109 [23%] age 40-49 years, and 312 [67%] age ≥ 50 years). Patients < 40 years of age were more likely to have received multiple metastatic resections (odds ratio [OR], 3.533; P = .0066) than their older counterparts. Patients with EO-CRC were more likely to receive triplet therapy than patients > 50 years of age (age < 40 years: OR, 6.738; P = .0002; age 40-49 years: OR, 2.949; P = .0166). Patients 40-49 years of age were more likely to have received anti-EGFR therapy (OR, 2.633; P = .0016). Despite differences in care patterns, age did not predict overall survival. CONCLUSION: Despite patients with EO-CRC receiving more intensive treatments, survival was similar to the older counterpart. However, EO-CRC had clinical and molecular features associated with worse prognoses. Improved biologic understanding is needed to optimize clinical management of EO-CRC. The cost-benefit ratio of exposing patients with EO-CRC to more intensive treatments has to be carefully evaluated.

Therapeutic combinations targeting innate and adaptive immunity and predictive biomarkers of response in esophagogastric cancer (EGC) are needed. We assessed safety and clinical utility of DKN-01 (a novel DKK1-neutralizing IgG4 antibody) combined with pembrolizumab and retrospectively determined DKK1 tumoral expression as a biomarker. Patients with advanced EGC received intravenous DKN-01 (150 or 300 mg) on days 1 and 15 with pembrolizumab 200 mg on day 1 in 21-day cycles. Clinical response was assessed by RECIST v1.1. Association of tumoral DKK1 mRNA expression (H-score: high ≥ upper-tertile, low < upper-tertile) with response was assessed with PD-L1 levels as a covariate. Sixty-three patients received DKN-01 150 mg (n = 2) or 300 mg (n = 61) plus pembrolizumab. Common adverse events were fatigue, anemia, blood alkaline phosphatase elevation, aspartate aminotransferase elevation, and hyponatremia. Among evaluable anti-PD-1/PD-L1-naïve patients receiving DKN-01 300 mg and pembrolizumab, objective response rate (ORR) was 11.4% (5/44) and 18.5% (5/27) in patients with gastroesophageal junction or gastric cancer (GEJ/GC). Among response-evaluable anti-PD-1/PD-L1-naïve patients with GEJ/GC and known tumoral DKK1 expression, ORR was 50% in DKK1-high and 0% in DKK1-low patients, median PFS was 22.1 vs. 5.9 weeks (HR, 0.24; 95% CI, 0.08–0.67), respectively, and median OS was 31.6 weeks vs. 17.4 weeks (HR, 0.41; 95% CI, 0.16–1.07), respectively. Association of DKK1 expression with PFS was independent of PD-L1 expression (adjusted HR, 0.21; 95% CI, 0.06–0.69). DKN-01 combined with pembrolizumab was well tolerated with no new safety signals. Antitumor activity was enriched in anti-PD-1/PD-L1-naïve patients with GEJ/GC whose tumors expressed high DKK1.

Background Weight loss is common in advanced gastric and gastroesophageal junction adenocarcinoma (G/GEA); however, the prognostic implications of weight loss during the first cycle (C1) of chemotherapy remain poorly characterized. In this study, we investigated the impact of early weight loss during systemic treatment as a potential prognostic factor for overall survival (OS) in patients with advanced G/GEA. Materials and Methods We performed a post hoc analysis of three phase III studies of ramucirumab. Patients were categorized into two groups: weight loss of ≥3% and, This article analyzes the impact of early weight loss during systemic therapy as a potential prognostic factor for overall survival in patients with gastric and gastroesophageal junction adenocarcinoma.

Purpose: Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection. Experimental Design: A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence. Results: Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (n = 39) or completion of adjuvant therapy (n = 45). In “landmark” plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive value (PPV), 100%; HR, 11.28 (P < 0.0001)]. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%–36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence [HR, 1.84 (P = 0.18); PPV = 53.9%]. Conclusions: Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection. See related commentary by Bent and Kopetz, p. 5449

Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti–PD-1 antibodies. However, 50% of microsatellite instability–high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)–derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1+ CD8+ T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. Significance: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features. See related commentary by Fontana and Smyth, p. 2126. This article is highlighted in the In This Issue feature, p. 2113

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti–CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non–weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non–weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4–6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non–weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).

Data are limited concerning the survival outcomes of locally advanced gastric cancer patients according to the multimodality therapy (MMT) administered. Single institution, retrospective analysis of 235 patients with locally advanced gastric cancer from 2001 to 2015. All patients met criteria for curative-intent surgery and chemotherapy ± radiation therapy. Treatment regimens were: (1) surgery first with adjuvant chemoradiation therapy (S + Adj); (2) perioperative chemotherapy + surgery (Periop); and (3) total neoadjuvant therapy followed by surgery (TNT + S). One hundred twenty-eight (60.0%) patients received S + Adj, 69 (26.8%) Periop, and 38 (13.2%) TNT + S. Of the 235 patients, 222 (94.5%) received surgery. All intended therapy was received by 81.6% of TNT + S, 44.5% of S + Adj, and 42.0% of Periop patients. MMT was significantly more likely to be completed by TNT + S patients (HR 6.67, p

BACKGROUND Patient-reported outcomes (PROs) assessing quality of life (QOL) and symptom burden correlate with clinical outcomes in patients with cancer. However, to the authors' knowledge, data regarding associations between PROs and treatment response are lacking. METHODS The authors prospectively approached consecutive patients with advanced gastrointestinal cancer who were initiating a new treatment. Prior to treatment, patients reported their QOL (Functional Assessment of Cancer Therapy-General [FACT-G], 4 subscales: Functional, Physical, Emotional, Social; higher scores indicate better QOL) and symptom burden (Edmonton Symptom Assessment System [ESAS], Patient Health Questionnaire-4 [PHQ-4]; higher scores represent greater symptoms). Regression models were used to examine associations of baseline PROs with treatment response (clinical benefit or progressive disease [PD] at time of first scan), healthcare utilization, and survival. RESULTS From May 2019 to April 2020, a total of 112 patients with advanced gastrointestinal cancer were enrolled. For treatment response, 64.3% had CB and 35.7% had PD. Higher baseline ESAS-Physical (odds ratio, 1.04; P = .027) and lower FACT-G Functional (odds ratio, 0.92; P = .038) scores were associated with PD. Higher ESAS-Physical (hazard ratio [HR], 1.03; P = .044) and lower FACT-G Total (HR, 0.96; P = .005), FACT-G Physical (HR, 0.89; P < .001), and FACT-G Functional (HR, 0.87; P < .001) scores were associated with a greater hospitalization risk. Lower FACT-G Total (HR, 0.96; P = .009) and FACT-G Emotional (HR, 0.86; P = .012) scores as well as higher ESAS-Total (HR, 1.03; P = .014) and ESAS-Physical (HR, 1.04; P = .032) scores were associated with worse survival. CONCLUSIONS Baseline PROs are associated with treatment response in patients with advanced gastrointestinal cancer, namely physical symptoms and functional QOL, in addition to health care use and survival. The findings of the current study support the association between PROs and important clinical outcomes, including the novel finding of treatment response.

BackgroundMetastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches.Patients and MethodsPatients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non–MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group.ResultsWe identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and ConclusionMET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes.Implications for PracticeThis article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.

Gastric carcinoma (GC) disproportionately affects Asian Americans. We examined whether history of upper gastrointestinal (GI) endoscopy was associated with lower stage at GC diagnosis among Asian Americans and whether origin of providers influenced referral for endoscopy. We employed Surveillance Epidemiology and End Results–Medicare data on Asian Americans diagnosed with GC in 2004–2013 (n = 1,554). Stage distribution, GI conditions at diagnosis, and history of endoscopy were compared between Asian ethnic groups. Multivariate logistic regression adjusting for age, sex, poverty level, tumor location, and histology was used to examine the association of ethnicity and endoscopic history with stage I disease at diagnosis of GC. Koreans were more likely to be diagnosed with stage I, T1a GC and have prior history of endoscopy, compared with other Asian ethnicities (24% vs. 8% for stage I, T1a; 40% vs. 15% for endoscopy). Patients with primary care providers of concordant ethnic origin were more likely to have history of endoscopy. Asian American patients with GC with history of endoscopy were more likely to be diagnosed with GC at stage I disease (adjusted OR, 3.07; 95% confidence interval, 2.34–4.02). Compared with other Asian Americans, Koreans were diagnosed with GC at earlier stages owing to common history of endoscopy, which was more often undergone by patients with primary care providers of concordant ethnic origin. Overall, upper GI endoscopy was associated with early detection of GC in Asian Americans. Novelty and Impact. It is well-established that Asian Americans in the United States are disproportionately affected by gastric cancer. In our study we found that Asian American patients treated by physicians of similar ethnic background are more likely to undergo upper GI endoscopy in the United States, leading to early detection of gastric cancer and longer survival. Given this, targeted endoscopic screening in Asian Americans should be considered for early detection of GC.

Background The increasing molecular characterization of colorectal cancers (CRCs) has spurred the need to look beyond RAS, BRAF, and microsatellite instability (MSI). Genomic alterations, including ERBB2 amplifications and mutations, POLE mutations, MSI, and NTRK1–3 fusions, have emerged as targets for matched therapies. We sought to study a clinically annotated Chinese cohort of CRC subjected to genomic profiling to explore relative target frequencies. Methods Tumor and matched whole blood were collected from 609 Chinese patients with CRC. Extracted DNA was analyzed for all classes of genomic alterations across 450 cancer‐related genes, including single‐nucleotide variations (SNVs), short and long insertions and deletions (indels), copy number variations, and gene rearrangements. Next‐generation sequencing–based computational algorithms also determined tumor mutational burden and MSI status. Results Alterations in TP53 (76%), APC (72%), and KRAS (46%) were common in Chinese patients with CRC. For the first time, the prevalence of NTRK gene fusion was observed to be around 7% in the MSI‐high CRC cohort. Across the cohort, MSI was found in 9%, ERBB2 amplification in 3%, and POLE pathogenic mutation in 1.5% of patients. Such results mostly parallel frequencies observed in Western patients. However, POLE existed at a higher frequency and was associated with large tumor T‐cell infiltration. Conclusion Comparing to the Western counterparts, POLE mutations were increased in our cohort. The prevalence of NTRK gene fusion was around 7% in the MSI‐high CRC cohort. Increased adoption of molecular profiling in Asian patients is essential for the improvement of therapeutic outcomes. Implications for Practice The increasing use of genomic profiling assays in colorectal cancer (CRC) has allowed for the identification of a higher number of patient subsets benefiting from matched therapies. With an increase in the number of therapies, assays simultaneously evaluating all candidate biomarkers are critical. The results of this study provide an early support for the feasibility and utility of genomic profiling in Chinese patients with CRC., The emergence of precision medicine has identified genomic variants, such as NTRK gene fusion, microsatellite instability (MSI), HER2 amplification, and POLE pathogenic mutation, as potential agonistic biomarkers for immune or targeted therapies. This article examines NTRK, HER2, and POLE in a cohort of Chinese patients with colorectal cancer.

Background Platinum and fluoropyrimidine combinations typically comprise first‐line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second‐line (2L) and third‐line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA. Materials and Methods We conducted a systematic search of peer‐reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression‐free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively. Results In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2‐overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single‐agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination. Conclusion For advanced G/GEA, review of trial results from 2009–2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity. Implications for Practice The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first‐line platinum‐based regimens, identification of those with the best benefit‐to‐risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first‐line platinum/fluoropyrimidine combination and, for second‐line trials, patients with platinum/fluoropyrimidine‐refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first‐line regimen(s) followed by a strategy for subsequent regimens., This review evaluates evidence‐based treatment sequencing strategies for advanced gastric cancer and gastroesophageal junction adenocarcinoma, focusing on randomized controlled trials in which the commonly recommended platinum/fluoropyrimidine‐backbone was used in first‐line treatment and, for second‐line treatment, included a prior platinum and/or fluoropyrimidine.

OPINION STATEMENT Data supporting the use of immunotherapy in the treatment of gastroesophageal cancer continues to evolve. The promising results from adjuvant immunotherapy and trials combining immunotherapy plus chemotherapy in the 1L setting have led to broad US FDA approvals. Among the PD-L1 negative subgroups, the magnitude of benefit is diminished; effective therapy for this population remains an unmet need. A detailed biologic understanding of the PD-L1 negative (and low) population represents a barrier to developing effective combination therapies, although combination angiogenesis inhibitors and immunotherapy look encouraging. Early phase clinical trials, particularly with pembrolizumab plus lenvatinib (EPOC 1706), demonstrated a clear signal independent of PD-L1, and a confirmatory phase III trial of pembrolizumab plus lenvatinib is planned. Conceptually, it is important to think of immune checkpoint inhibitor therapy as targeted therapy, most active in clearly defined biomarker-selected populations. Pre-planned analyses have reliably shown a clear trend toward a greater magnitude of benefit in patients with higher PD-L1 expression, particularly CPS ≥ 5 and ≥ 10. Whether there is a linear relationship at higher cutoffs is not well known, though it likely represents smaller and smaller populations. Although beyond the scope of this clinically oriented review, recognition of the spatial and temporal heterogeneity in PD-L1 expression is important and repeat testing from progression samples across lines of therapy should be considered. Questions about additional predictive biomarkers, particularly plasma-derived, remain. Responses by tumor histology and location also differ, and special attention to these factors as well as MSI-H, HER2, and EBV subgroups in future trials is warranted. Questions regarding the incorporation of immunotherapy after progression on 1L immunotherapy plus chemotherapy combinations will arise as these combinations are used more frequently, and this represents a key area of future investigation. Overall, the role of immunotherapy continues to expand in GEA, and we welcome any additional tools for this difficult-to-treat group of cancers.

In an annotated series of gastroesophageal adenocarcinomas differences in PD-L1 expression and tumor mutation burden occur between both paired contemporaneous primary and metastatic biopsies and pre/posttreatment samples. This work has implications for optimizing patient selection, serial testing, need for mechanistic understanding, and may underlie variable responses to checkpoint inhibitors in gastroesophageal cancers. See related article by Zhou et al., p. 6453

Background Locally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC. Methods This was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naive LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status. Findings Thirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15 fractions). Sixteen DLTs were identified in 12 patients. Grade ≥ 3 adverse events included lymphopenia (96%) and anemia (36%). Median OS for all patients was 15 months. Median OS for DDR pathway gene altered and intact cases was 19 months (95% CI: 6.2–27.2) and 14 months (95% CI: 10.0–21.8), respectively. There were no significant associations between levels of PAR, TMB, or MSI with outcomes. The DDR transcripts PARP3 and RBX1 significantly correlated with OS. Interpretation This is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study. Fund Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.

BACKGROUND: Metabolomics is widely used to identify potential novel biomarkers for cancer risk. No investigation, however, has been conducted to prospectively evaluate the role of perturbation of metabolome in gastric cancer development. METHODS: Two hundred fifty incident cases diagnosed with primary gastric cancer were selected from the Shanghai Women’s Health and the Shanghai Men’s Health Study, and each was individually matched to one control by incidence density sampling. An untargeted global profiling platform was used to measure ~1,000 metabolites in prediagnostic plasma. Conditional logistic regression was utilized to generate odds ratios (ORs) and p-values. RESULTS: Eighteen metabolites were associated with gastric cancer risk at p-value < 0.01. Among them, 11 metabolites were lysophospholipids or lipids of other classes; for example, 1-(1-enyl-palmitoyl)-GPE (P-16:0) (OR = 1.56, p = 1.89×10(−4)). Levels of methylmalonate, a suggested biomarker of vitamin B12 deficiency, was correlated with increased gastric cancer risk (OR = 1.42, p = 0.004). Inverse associations were found for three biomarkers for coffee/tea consumption (3-hydroxypyridine sulfate, quinate and N-(2-furoyl) glycine), although the associations were only significant when comparing cases who were diagnosed within 5 years after the blood collection to matched controls. Most of the identified associations were more profound in women and never smokers than their male or ever smoking counterparts and some with notable significant interactions. CONCLUSIONS: Our study identified multiple potential risk biomarkers for gastric cancer independent of H. pylori infection and other major risk factors. IMPACT: New risk-assessment tools to identify high-risk population could be developed to improve prevention of gastric cancer.

PURPOSE In pancreatic cancer (PC), the RAF family alterations define a rare subset of patients that may predict response to inhibition of the BRAF/MEK/ERK signaling pathway. A comprehensive understanding of the molecular and clinical characteristics of RAF-mutated PC may support future development of RAF-directed strategies. METHODS Clinical outcomes were assessed across a multi-institutional case series of 81 patients with RAF family-mutated PC. Mutational subgroups were defined on the basis of RAF alteration hotspots and therapeutic implications. RESULTS The frequency of RAF alterations in PC was 2.2% (84 of 3,781) within a prevalence cohort derived from large molecular databases where BRAF V600E (Exon 15), BRAF ΔNVTAP (Exon 11), and SND1-BRAF fusions were the most common variants. In our retrospective case series, we identified 17 of 81 (21.0%) molecular profiles with a BRAF V600/Exon 15 mutation without any confounding drivers, 25 of 81 (30.9%) with BRAF or RAF1 fusions, and 18 of 81 (22.2%) with Exon 11 mutations. The remaining 21 of 81 (25.9%) profiles had atypical RAF variants and/or multiple oncogenic drivers. Clinical benefit from BRAF/MEK/ERK inhibitors was observed in 3 of 3 subjects within the V600 subgroup (two partial responses), 4 of 6 with fusions (two partial responses), 2 of 6 with Exon 11 mutations (one partial response), and 0 of 3 with confounding drivers. Outcomes analyses also suggested a trend favoring fluorouracil-based regimens over gemcitabine/nab-paclitaxel within the fusion subgroup (P = .027). CONCLUSION Prospective evaluation of RAF-directed therapies is warranted in RAF-mutated PC; however, differential responses to targeted agents or standard regimens for each mutational subgroup should be a consideration when designing clinical trials., In KRAS wild-type PDAC, certain RAF alterations predict benefit from map-kinase targeted therapy

The use of genomic testing is rapidly emerging as an important clinical tool both for cancer diagnosis and for guiding treatment decisions in a wide range of malignancies, including gastrointestinal (GI) cancers such as colorectal cancer (CRC). Advances in technologies such as polymerase chain reaction and next-generation sequencing methods have made it possible to noninvasively screen for CRC through, for example, the use of blood- or stool-based testing, with high specificity. Tests are also available that can provide prognostic information beyond traditional clinicopathologic factors such as tumor size, grade, and nodal status, which can enable clinicians to more accurately risk stratify patients for recurrence. Lastly, in the setting of resected CRC, tests are now available that can detect circulating tumor DNA as a means for noninvasive minimal/molecular residual disease monitoring, thereby potentially guiding the use of adjuvant chemotherapy and/or escalating or de-escalating therapy. The Gastrointestinal Cancer Therapy Expert Group (GICTEG) recently convened a virtual meeting to discuss current issues related to genomic testing in GI cancer, with the goal of providing guidance on the use of these tests for the practicing community oncologist, for whom GI cancer may be only one of many tumor types encountered. This article provides a summary of the discussion and highlights the key opinions of the GICTEG on this topic. Implications for Practice The Gastrointestinal Cancer Therapy Expert Group seeks to provide practical guidance and opinion on the treatment of gastrointestinal malignancies, including colorectal cancer (CRC), for the practicing community oncologist in situations for which guidelines from established bodies, such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology, may be less clear. In the present report, clinical guidance on the use of molecular assays for a range of clinical indications in CRC is presented, including the use of circulating tumor DNA to detect minimal/molecular residual disease in patients with successfully resected early-stage CRC.

Intertumoral heterogeneity among actionable biomarkers including ERBB2, FGFR2 and EGFR has been observed to occur under therapeutic pressure in advanced gastric cancer. However, baseline intratumoral heterogeneity at diagnosis is understudied and may impact clinical outcomes. We sought to explore intratumoral heterogeneity in primary advanced gastric cancers via DNA sequencing from multi-region endoscopic sampling at diagnosis. Patients with newly diagnosed advanced gastric adenocarcinoma underwent endoscopic mapping and pre-determined 8-sector biopsy of the primary tumor with concurrent plasma cfDNA sampling. Biopsy samples were subjected to targeted next generation sequencing and plasma cfDNA was analyzed via a 28-gene cfDNA assay. Expectedly, we observed that the majority of genetic alterations were shared among multi-sector biopsies within the same gastric primary tumor. However, all samples contained private subclonal alterations between biopsy sectors, including actionable alterations in GNAS and STK11. Cell free DNA analyses also exhibited both shared and non-shared alterations between mutations detected in cfDNA and tumor tissue biopsies confirming baseline intertumoral heterogeneity. This is the first dataset to confirm baseline intratumoral heterogeneity and confirms that multi-sector endoscopic biopsy is feasible and capable of capturing intratumoral heterogeneity among relevant genomic alterations in gastric cancer. Both multi-sector endoscopic biopsies and cfDNA analyses are complementary in capturing the diverse mutational landscape at disease presentation.

Background: Gastric cancer (GC) is a leading cause of cancer-specific mortality with limited biologically informed treatments. The ataxia telangiectasia mutated (ATM) gene is critically involved in the repair of double-stranded DNA breaks and a component of DNA damage repair (DDR) pathways. Platinum salts are hypothesized to have increased efficacy in tumors deficient in DDR pathways. We sought to investigate an association between ATM status and response to XELOX in a homogenous first line GC patient cohort. Methods: A clinically annotated cohort of 137 Korean patients with advanced GC treated with first-line XELOX was retrospectively examined for ATM status by immunohistochemistry. Correlation between ATM expression and clinicopathologic variables was performed by two-tailed, unpaired t-tests and Fisher’s exact tests. Kaplan-Meier survival analysis curves and Cox proportional hazards models were used to evaluate for independent predictors of disease-free survival (DFS) and overall survival (OS). Results: Low ATM expression was observed in 19.0% (26/137) of patients and was not associated with clinicopathologic features or response rate to XELOX. Univariate, but not multivariable, logistic regression and Cox analysis identified ATM as an independent risk factor influencing OS and DFS. A higher ECOG score independently predicted worse survival [hazard ratio (HR) 2.96, P=0.016] and complete surgical resection independently protected against progression of disease (HR 0.69, P=0.007). Conclusions: Low ATM expression was not associated with increased response rates to XELOX in a single-institution cohort of advanced GC patients. Similarly, ATM status did not predict DFS or OS after platinum-based chemotherapy.

FOLFIRI‐Ram has emerged as a reasonable second‐line option for patients with advanced gastroesophageal adenocarcinoma. This article examines the safety and efficacy of second‐line FOLFIRI‐ram across a clinically‐annotated and molecularly characterized U.S. cohort., Background. The randomized phase III RAINBOW trial established paclitaxel (pac) plus ramucirumab (ram) as a global standard for second‐line (2L) therapy in advanced gastric and gastroesophageal junction adenocarcinoma, together gastroesophageal adenocarcinoma (GEA). Patients (pts) receiving first‐line (1L) FOLFOX often develop neuropathy that renders continued neurotoxic agents in the 2L setting unappealing and other regimens more desirable. As such, FOLFIRI‐ram has become an option for patients with 2L GEA. FOLFIRI‐ramucirumab (ram) has demonstrated safety and activity in 2L colorectal cancer, but efficacy/safety data in GEA are lacking. Subjects, Materials, and Methods. Patients with GEA treated with 2L FOLFIRI‐ram between August 2014 and April 2018 were identified. Clinicopathologic data including oxaliplatin neurotoxicity rates/grades (G), 2L treatment response, progression‐free survival (PFS), overall survival (OS), safety, and molecular features were abstracted from three U.S. academic institutions. Kaplan‐Meier survival analysis was used to generate PFS/OS; the likelihood ratio test was used to determine statistical significance. Results. We identified 29 pts who received 2L FOLFIRI‐ram. All pts received 1L platinum + fluoropyrimidine, and 23 of 29 (79%) had post‐1L neuropathy; 12 (41%) had G1, and 11 (38%) had G2. Patients were evenly split between esophagus/gastroesophageal junction (12; 41%) and gastric cancer (17; 59%). Among evaluable pts (26/29), the overall response rate was 23% (all partial response) with a disease control rate of 79%. Median PFS was 6.0 months and median OS was 13.4 months among all evaluable pts. Six‐ and 12‐month OS were 90% (n = 18/20) and 41% (n = 7/17). There were no new safety signals. Conclusion. We provide the first data suggesting FOLFIRI‐ram is a safe, non‐neurotoxic regimen comparing favorably with the combination of pac + ram used in the seminal RAINBOW trial. Implications for Practice. Results of this study provide initial support for the safety and efficacy of second‐line (2L) FOLFIRI‐ramucirumab (ram) after progression on first‐line platinum/fluoropyrimidine in patients with gastroesophageal adenocarcinoma (GEA). The overall response, progression‐free survival, overall survival, and toxicity profile compare favorably with paclitaxel (pac) + ram and highlight the importance of the ongoing phase II RAMIRIS trial examining FOLFIRI‐ram versus pac + ram in 2L GEA (NCT03081143). FOLFIRI‐ram may warrant consideration for inclusion as an alternate regimen in consensus guidelines for GEA.

Background: The clinical application of PD1/PD-L1 targeting checkpoint inhibitors in colorectal cancer (CRC) has largely focused on a subset of microsatellite instable (MSI-high) patients. However, the proposed genotype that sensitizes these patients to immunotherapy is not captured by MSI status alone. Estimation of tumor mutational burden (TMB) from comprehensive genomic profiling is validated against whole exome sequencing and linked to checkpoint response in metastatic melanoma, urothelial bladder cancer and non-small cell lung carcinoma. We sought to explore the subset of microsatellite stable (MSS) CRC patients with high TMB, and identify the specific genomic signatures associated with this phenotype. Furthermore, we explore the ability to quantify TMB as a potential predictive biomarker of PD1/PD-L1 therapy in CRC. Methods: Formalin-fixed, paraffin embedded tissue sections from 6,004 cases of CRC were sequenced with a CLIA-approved CGP assay. MSI and TMB statuses were computationally determined using validated methods. The cutoff for TMB-high was defined according to the lower bound value that satisfied the 90% probability interval based on the TMB distribution across all MSI-High patients. Results: MSS tumors were observed in 5,702 of 6,004 (95.0%) cases and MSI-H tumors were observed in 302 (5.0%) cases. All but one (99.7%) MSI-H cases were TMB-high (range, 6.3–746.9 mut/Mb) and 5,538 of 5,702 (97.0%) MSS cases were TMB-low (range, 0.0–10.8 mut/Mb). Consequently, 164 of 5,702 (2.9%) MSS cases were confirmed as TMB-high (range, 11.7–707.2 mut/Mb), representing an increase in the target population that may respond to checkpoint inhibitor therapy by 54% (466 vs . 302, respectively). Response to PD-1 inhibitor is demonstrated in MSS/TMB-high cases. Conclusions: Concurrent TMB assessment accurately classifies MSI tumors as TMB-high and simultaneously identifies nearly 3% or CRC as MSS/TMB-high. This subgroup may expand the population of CRC who may benefit from immune checkpoint inhibitor based therapeutic approaches.

Blockade of the programmed death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction (GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability (MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatment-refractory solid tumors with MSI status and the third-line or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.

The multidisciplinary management of locoregional esophagogastric cancers (GCs) has evolved significantly over the past two decades. While perioperative chemotherapy, adjuvant chemotherapy, and postoperative chemotherapy with chemoradiation (CRT) have demonstrated improved survival when compared to surgery alone, there is no universal standard for resectable gastroesophageal cancer. Current global management patterns vary by geographic region, partly related to phase III data originating from each global region. Herein we detail the landmark phase III trials that support the various multimodality treatment paradigms in resectable GC, with particular focus on findings from more recent phase III gastroesophageal cancer trials including FLOT4, MAGIC-B, OE05, and CRITICS. We highlight important ongoing and future approaches including the potential of molecular subtyping, predictive biomarkers, and immunotherapy as avenues to further improve outcomes in resectable gastroesophageal cancer.

Summary: Sanchez-Vega and colleagues prospectively demonstrate that both intra- and intertumoral differential expression of the receptor tyrosine kinases HER2, EGFR, and MET dictate sensitivity to the pan-HER inhibitor afatinib in a phase II trial of trastuzumab-refractory HER2-amplified gastroesophageal adenocarcinomas. Rapid autopsy, tissue-based genomic characterization, and molecular imaging provide complementary information and may aid in selecting optimal patients for targeted monotherapy versus combination approaches in gastroesophageal adenocarcinomas. See related article by Sanchez-Vega et al., p. 199.

Purpose Single agent PD-1 inhibitors have yielded durable responses in a minority of gastroesophageal cancers. Radiation therapy has been recognized to promote antitumor immune responses and may synergize with anti-PD-1 agents. We sought to evaluate if combining palliative radiation therapy with pembrolizumab can augment antitumor immune responses in gastroesophageal cancer. Methods and Materials Patients had metastatic gastroesophageal cancer with indication for palliative radiation therapy with ≥2 disease sites outside of the radiation field assessable for abscopal response and biopsies for laboratory correlative analyses. Palliative radiation was delivered to a dose of 30 Gy over 10 fractions. Pembrolizumab, 200 mg, was administered concurrently intravenously every 3 weeks until disease progression, unacceptable toxicity, or study withdrawal, for up to 2 years. Endpoints included PD-L1 expression in pre- and posttreatment biopsies and abscopal objective response rate per Response Evaluation Criteria in Solid Tumors. Results Of 14 enrolled patients, the objective response rate was 28.6% (95% confidence interval, 8.4%-58.1%), and the median duration of response was not reached (95% confidence interval, 6.9-NR months). Overall, 2 patients had treatment-related grade 3 to 4 adverse events with no grade 5 events. One patient discontinued therapy due to grade 4 colitis. We did not observe an association between radiation and abscopal changes in PD-L1 expression via assessment of an analogous PD-L1 Combined Positive Score, Tumor Proportion Score, Mononuclear Immune Cell Density Score, or proportion of PD-L1-expressing immune cells between pre- and posttreatment tumor biopsies. Conclusions Combining palliative radiation therapy and pembrolizumab provided promising durable responses in this patient population but we were unable to definitively distinguish abscopal biologic changes. Biomarker analyses beyond PD-L1 expression are needed to better understand putative mechanisms and identify patients who will benefit from this approach.

154 Background: PROs assessing quality of life (QOL) and symptoms at a single timepoint frequently correlate with clinical outcomes in patients with cancer, yet efforts to understand how longitudinal changes in PROs can predict for treatment outcomes are lacking. In practice, oncologists often use changes in serum TMs (CEA and CA19-9) to monitor patients with GI cancer, and thus we sought to examine associations of 1-month changes in PROs and TMs with treatment response and survival outcomes among patients with advanced GI cancer. Methods: We prospectively enrolled patients with metastatic GI cancer prior to initiating chemotherapy at Massachusetts General Hospital from 5/2019-12/2020. At baseline (start of treatment) and 1-month later, we collected PROs (QOL [Functional Assessment of Cancer Therapy General {FACT-G}], physical symptoms [Edmonton Symptom Assessment System {ESAS}], and psychological symptoms [Patient Health Questionnaire-4 {PHQ-4}]) and TMs. We used regression models to examine associations of 1-month changes in PROs and TMs with treatment response (clinical benefit [defined as decreased or stable tumor burden] or progressive disease at the time of first scan) and survival outcomes (progression-free survival [PFS] and overall survival [OS]), adjusted for baseline values of each respective variable. Results: We enrolled 159 of 191 patients approached (83.2% enrollment); 134 had 1-month follow-up data (median age = 64 years [range: 28 to 84 years], 64.2% male, 46.3% pancreaticobiliary cancer). For treatment response, 63.4% had clinical benefit and 36.6% had progressive disease at the time of first scan (mean time to first scan = 2.01 months). Changes in PROs (ESAS-Total: OR = 0.97, p = 0.022; ESAS-Physical: OR = 0.96, p = 0.027; PHQ-4 depression: OR = 0.67, p = 0.014; FACT-G: OR = 1.07, p = 0.001), but not TMs (CEA: OR = 1.00, p = 0.836 and CA19-9: OR = 1.00, p = 0.796), were associated with clinical benefit at the time of first scan. Changes in ESAS-Total (HR = 1.03, p = 0.004), ESAS-Physical (HR = 1.03, p = 0.021), PHQ-4 depression (HR = 1.22, p = 0.042), FACT-G (HR = 0.97, p = 0.003), and CEA (HR = 1.00, p = 0.001) were predictors of PFS. Changes in ESAS-Total (HR = 1.03, p = 0.006) and ESAS-Physical (HR = 1.04, p = 0.015) were predictors of OS, but 1-month changes in TMs (CEA: HR = 1.00, p = 0.377 and CA19-9: HR = 1.00, p = 0.367) did not significantly predict for OS. Conclusions: We found that 1-month changes in PROs can predict for treatment response and survival outcomes in patients with advanced GI cancers. Notably, 1-month changes in CEA only correlated with PFS, while changes in CA19-9 did not significantly predict treatment response or survival outcomes. These findings highlight the potential for early changes in PROs to predict treatment outcomes while underscoring the need to monitor and address PROs in patients with advanced cancer. Clinical trial information: NCT04776837.

// Seung Tae Kim 1, * , Samuel J. Klempner 2, 3, * , Se Hoon Park 1 , Joon Oh Park 1 , Young Suk Park 1 , Ho Yeong Lim 1 , Won Ki Kang 1 , Kyoung-Mee Kim 4 and Jeeyun Lee 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 The Angeles Clinic and Research Institute, Los Angeles, CA, USA 3 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA 4 Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * Contributed equally, co-first authors Correspondence to: Jeeyun Lee, email: jyunlee@skku.edu Kyoung-Mee Kim, email: kkmkys@skku.edu Keywords: programmed death-ligand 1 (PD-L1), mismatch repair deficiency (dMMR), immunotherapy, biomarker, gastrointestinal cancer Received: June 01, 2017 Accepted: July 20, 2017 Published: August 24, 2017 ABSTRACT The identification of biomarkers associated with response to therapeutic agents is central to optimizing patient outcomes. Expression of the immune checkpoint proteins PD-1/L1, and DNA mismatch repair deficiency (dMMR) status may be predictive response biomarkers for immunotherapies, but their overlap requires further study. We prospectively conducted PD-L1 and MMR immunohistochemistry (IHC) on 430 consecutive patients with advanced gastrointestinal (GI) cancers, genitourinary (GU) cancers or rare cancers between June 2012 and March 2016. Overall 393/430 (91.4%) patients were evaluable for PD-L1 expression by IHC. The frequency of tumor PD-L1 positivity (PD-L1+) was 16.5% (65/393). Among anatomic tumor sites PD-L1+ was 28.6% in melanoma, 22.2% in GC, 20.9% in CRC, 12.5% in BTC, 7.1% in GU cancer, 6.7% in HCC, 0% in pancreatic cancer and 0% in sarcoma. Among the 394 evaluable for MLH1/MSH2 expression cases, 18 patients (4.5%) had dMMR tumors. The dMMR was most common in GC (7.1%) followed by 6.7% in HCC, 4.4% in CRC, and 2.7% in sarcoma. Of the 365 patients evaluable for both PD-L1 and MLH1/MSH2 expression, there was a significant association between the PD-L1 expression and MLH1/MSH2 loss ( P = 0.01), but not with overall survival within tumor types. PD-L1 status and dMMR are overlapping putative response biomarkers in immunoncology. Clinical trials with biomarker enrichment restricted to PD-L1+ or dMMR may be inadequate to capture the subset of patients who may benefit from immune mediated therapies. More robust immunotherapy biomarkers and careful clinical trial design are warranted.

Background Recurrent FGFR2 amplification is observed in gastroesophageal cancers but clinical implications are unknown. We investigated the association of FGFR2 amplification with cytotoxic chemotherapy outcome in gastroesophageal cancer (GC) patients. Methods Between 2016 and 2018, we identified 1045 metastatic GC patients who received palliative fluoropyrimidine/platinum-based chemotherapy and underwent tumor genomic profiling at a tertiary hospital in Korea and two US cancer centers. We retrospectively identified FGFR2-amplified cases and abstracted clinicopathologic features and treatment outcomes. Cox proportional hazard regression model was used to evaluate the variables that demonstrated effects on progression free and overall survival PFS and OS. Descriptive statistics were used to correlate level of FGFR2 copy number amplification CNA and clinicopathological parameters. Results The incidence of FGFR2-amplified GC was 4.0 %. A total of 42 FGFR2-amplified GC patients were included and divided into high and lower FGFR2 amplification values. Fifteen patients had an FGFR2 CNA greater than 30, and 27 had a CNA of 30 or less. There was no significant differences between age, sex, tumor localization, Lauren classification, or tumor staging. After a median follow-up duration of 11.4 months, patients with high FGFR2 amplification had significantly poorer median PFS (3.2 vs. 4.8 months, hazard ratio (HR) 2.08, 95 % CI, 1.03–4.22, P = 0.042) and significantly shorter median OS (10.1 vs. 26.3 months, HR 2.99, 95 % CI = 1.05–8.49, P = 0.040) than the low FGFR2 amplification group. Conclusion Recurrent FGFR2 amplification was observed in roughly 4.0 % of GC patients. High FGFR2 amplification was significantly associated with poor progression free survival and overall survival in GC patients. Clinical studies of FGFR2-directed therapies are warranted and should consider stratification by FGFR2 CNA.

Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)-the number of somatic mutations per DNA megabase (Mb)-has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next-generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole-exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ≥10 mutations per Mb to be predictive of longer progression-free survival in patients with non-small cell lung cancer. Multiple trials are underway to validate the predictive values of TMB across cancer types and in patients treated with other immunotherapies. Here we review the rationale, algorithm development methodology, and existing clinical data supporting the use of TMB as a predictive biomarker for treatment with ICPIs. We discuss emerging roles for TMB and its potential future value for stratifying patients according to their likelihood of ICPI treatment response. IMPLICATIONS FOR PRACTICE: Tumor mutational burden (TMB) is a newly established independent predictor of immune checkpoint inhibitor (ICPI) treatment outcome across multiple tumor types. Certain next-generation sequencing-based techniques allow TMB to be reliably estimated from a subset of the exome without the use of whole-exome sequencing, thus facilitating the adoption of TMB assessment in community oncology settings. Analyses of multiple clinical trials across several cancer types have demonstrated that TMB stratifies patients who are receiving ICPIs by response rate and survival. TMB, alongside other genomic biomarkers, may provide complementary information in selecting patients for ICPI-based therapies.

HER2 expression remains an important biomarker to guide the addition of the monoclonal antibody trastuzumab to first-line systemic chemotherapy in unresectable, metastatic gastroesophageal adenocarcinomas (GEA). However, in contrast to breast cancer, other HER2-targeted strategies to date have not improved outcomes in this molecular subtype of GEA. Since the initial development of HER2 biomarker testing guidelines, significant spatial intratumoral heterogeneity of HER2 overexpression has been recognized as a major characteristic of this disease. In this review, we aim to survey the seminal positive and negative trials investigating HER2-targeted agents for GEA. We also highlight emerging data on the genomic and temporal heterogeneity of molecular resistance alterations that have yielded further insight into the heterogeneity of therapeutic responses. We conclude with an overview of promising novel agents and strategies which may refine the therapeutic landscape.

The development of checkpoint inhibitors has redefined the treatment paradigm for advanced gastroesophageal cancer. While recent developments have improved clinical outcomes, the prognosis for the disease remains meager. In this review, we discuss the rationale and detail the results from recent phase I-III trials supporting the activity of PD-1 inhibitors. Specifically, we highlight the seminal clinical trials leading to the FDA approval of pembrolizumab for advanced gastroesophageal cancer. Finally, we review the current understanding and future considerations of molecular subtyping and predictive biomarkers to help guide therapy and the promise of combination therapy to further improve the efficacy of checkpoint inhibitors.

4045 Background: HER2 ( ERBB2) overexpression or amplification (amp) are biomarkers for approved anti-HER2 therapies. ERBB2amp may be a superior predictor of anti-HER2 therapy outcome compared to IHC/ISH, and degree of CN gain may further stratify patients (pts). We investigated the distribution of ERBB2amp in adv GEA and hypothesized that increased CN was associated with better outcome to trastuzumab (T). Methods: Genomic analysis was performed using the Foundation Medicine (FM) tissue database (DB) of 313,896 pts with solid tumors including 12,749 pts with GEA and 34,629 pts with breast cancer (BC) used for comparison. ERBB2amp was defined as predicted CN ≥5 with > 80% of exons amplified. Using the nationwide US-based Flatiron Health-FM clinico-genomic DB linking de-identified EHR-derived clinical data to FM genomic data, pts with ERBB2amp adv GEA (01/2011 - 12/2020) were selected. RW progression (rwP) was obtained via technology-enabled abstraction of EHR. Multivariable Cox proportional hazard models were used for outcome comparisons. Results: ERBB2amp was detected in 15% (1,920/12,749) of GEA samples; median CN 22 (IQR 9-73), and 97% of cases had full gene amp. Median ERBB2 amplicon size was 0.27Mbp (IQR 0.13-0.95). In comparison, ERBB2amp was detected in 9.2% (3,193/34,629) of BC samples; median CN 20 (IQR 9-40), median amplicon size 0.32Mbp (IQR 0.13-1.37). In both cancers, smaller amplicons were associated with higher CN (P < 0.001), excluding amplicons < 0.1Mbp where less than 100% target amp was common. ERBB2amp was additionally seen in 2.7% of other solid tumors, and specifically in 2.3% of NSCLC and 3.1% of CRC. In the RW DB of 183 pts with ERBB2amp adv GEA, chemo + T (45%) and chemo alone (17%) were the most common first therapies after genomic report. In 101 evaluable first-line T treated pts ERBB2 CN was a significant predictor of rwP free survival (rwPFS) as a continuous variable (aHR = 0.74 [95% CI: 0.61 - 0.89], P = 0.002) and a range of cutoffs were similarly predictive. For control, in ERBB2amp pts treated with chemo ERBB2 CN was not predictive of rwPFS (aHR = 0.93, [95% CI: 0.72 – 1.20], P = 0.060). Among T treated pts, co- PIK3CA mutation was more common with lower CN (p = 0.03 by Wilcox test); no significant differences were observed for primary tumor location, age, stage at adv diagnosis, co- KRASmut, EGFRamp or F GF R1/2amp. Conclusions: ERBB2amp was detected in 15% of GEA tissue samples, with significant diversity in ERBB2 CN and amplicon focality, but with a similar CN distribution and amplicon focality seen in ERBB2amp BC. ERBB2 CN was predictive of rwPFS as a continuous variable for pts with GEA treated with T in the RW setting. Further studies exploring the clinical utility of quantitative ERBB2 CN, and extending to ctDNA, particularly in the setting of the evolving anti-HER2 landscape and combination therapies, are warranted.

Introduction A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti-epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed. Materials and methods We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid-capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance. Results We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non-codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644 RAS/RAF wild-type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti-EGFR therapy in advanced CRC including mutations in PIK3CA, PTEN, EGFR, and ERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as microsatellite instability. Conclusion Extended genomic profiling reliably detects alterations associated with lack of benefit to anti-EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility. Implications for practice Comprehensive genomic profiling (CGP) detects diverse genomic alterations associated with lack of benefit to anti-epidermal growth factor receptor therapy in advanced colorectal cancer (CRC), as well as targetable alterations in many other genes. This includes detection of a broad spectrum of activating KRAS alterations frequently missed by focused molecular hotspot testing, as well as other RAS/RAF pathway alterations, mutations shown to disrupt antibody binding, RTK activating point mutations, amplifications, and rearrangements, and activating alterations in downstream effectors including PI3K and MEK1. The use of CGP in clinical practice is critical to guide appropriate selection of targeted therapies for patients with advanced CRC.

Adenocarcinomas of the stomach and gastroesophageal junction account for a high proportion of worldwide cancer-related mortality.

Patients with non-small-cell lung cancer (NSCLC) harboring activating mutations in EGFR benefit from treatment with EGFR small-molecule tyrosine-kinase inhibitors. However, the development of acquired resistance to EGFR inhibitors is universal and limits treatment efficacy. Over half of patients receiving first-generation EGFR inhibitors (erlotinib and gefitinib) develop resistance via the gatekeeper EGFR T790M (EGFRT790M) mutation, and therapies able to overcome T790M-mediated resistance have been an unmet need in NSCLC. Rociletinib (CO-1686) is a third-generation small-molecule EGFR inhibitor with potent activity against EGFRT790M currently in advanced clinical development in NSCLC. Early clinical data suggested significant activity in EGFR-mutant NSCLC harboring T790M alterations. However, important questions regarding side-effect profile, comparability to competitor compounds, acquired resistance, EGFR-therapy sequencing, and combination therapies remain. Here, we review the available preclinical and clinical data for rociletinib, highlight the comparison to other third-generation EGFR inhibitors, and discuss resistance implications and future directions in NSCLC.

249 Background: Limited data exists on how chemoradiation (CRT)-induced lymphopenia affects survival outcomes in patients with gastric and gastroesophageal junction (GEJ) cancer. We evaluated the association between severe lymphopenia and its association with survival in gastric and GEJ cancer patients treated with CRT. We hypothesized that severe lymphopenia would be a poor prognostic factor. Methods: We performed a retrospective analysis of 154 patients with stage 1-3 gastric or GEJ cancer who underwent CRT at our institution. Patients underwent photon-based radiation therapy (RT) with a median dose of 50.4 Gy (IQR 45.0-50.4 Gy) over 28 fractions and concurrent chemotherapy (CTX) with carboplatin/paclitaxel, 5-fluorouracil based regimen, or capecitabine. 49% received CTX prior to RT. 84% underwent surgical resection, 57% pre-CRT and 26% post-CRT. Absolute lymphocyte count (ALC) at baseline and at 2 months since initiating RT were analyzed. Severe lymphopenia, defined as Grade 3 or worse lymphopenia (ALC < 0.5 k/μl), was analyzed for any association with overall survival (OS). Results: Median time of follow up was 48 months. Median age was 65. 77% were male and 86% were Caucasian. ECOG PS was 0 or 1 in 90% and 2 in 10%. Tumor location was stomach in 38% and GEJ in 62%. Timing of CRT was preoperative among 68% and postoperative among 32%. The median ALC at baseline for the entire cohort was 1.6 k/ul (range 0.3-7.0 k/ul). At 2 months post-CRT, 49 (32%) patients had severe lymphopenia. Patients with severe lymphopenia post-CRT had a slightly lower baseline TLC compared to patients without severe lymphopenia (median TLC 1.4 k/ul vs. 1.6 k/ul; p = 0.005). There were no differences in disease and treatment characteristics between the two groups. On the multivariable Cox model, severe lymphopenia post-CRT was significantly associated with increased risk of death (HR = 3.99 [95% CI 1.55-10.28], p = 0.004). ECOG PS 2 (HR = 34.97 [95% CI 2.08-587.73], p = 0.014) and postoperative CRT (HR = 5.55 [95% CI 1.29-23.86], p = 0.021) also predicted worse OS. The 4-year OS among patients with severe lymphopenia was 41% vs. 61% among patients with vs. without severe lymphopenia (log-rank test p = 0.041). Conclusions: Severe lymphopenia significantly correlated with poorer OS in patients with gastric or GEJ cancer treated with CRT. CRT-induced lymphopenia may be an important prognostic factor for survival in this patient population. Closer observation in high-risk patients and treatment modifications may be potential approaches to mitigating CRT-induced lymphopenia.

TPS260 Background: Five-year survival with advanced G/GEJ is poor, and limited biomarkers exist to inform optimal treatment selection. Pembrolizumab, an anti–programmed death-1 receptor (PD-1) antibody, is approved for advanced/metastatic PD-ligand 1–positive (PD-L1+) G/GEJ that progressed after ≥2 lines of therapy. The transmembrane tight junction protein claudin 18.2 (CLDN18.2) is normally confined to gastric mucosa but is often overexpressed in G/GEJ with roughly one-third of patients (pts) having high expression (≥75%). Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity. Phase 2 (NCT01630083) results showed prolonged survival with zolbetuximab + epirubicin, oxaliplatin, and capecitabine (EOX) vs EOX alone in G/GEJ. Results of nonclinical studies showed enhanced antitumor activity with zolbetuximab + anti-murine PD-1 antibody, and it was hypothesized that a combination with pembrolizumab (new Cohort 3) might augment ADCC and antitumor immune response in CLDN18.2 overexpressing G/GEJ. Methods: This phase 2 open-label study (NCT03505320) will enroll ~112 adult pts from 22 sites in 5 countries into 3 cohorts; this abstract describes Cohort 3 (~62 pts). Key eligibility criteria are advanced/metastatic G/GEJ, measurable disease (RECIST v1.1), adequate organ function and performance status, and high/intermediate (Cohort 3A) or high (Cohort 3B) expression of CLDN18.2. Central testing of tumor tissue will determine CLDN18.2 expression; pts are considered CLDN18.2 positive (CLDN18.2+) if ≥75% (high) or ≥50% to < 75% (intermediate) of tumor cells demonstrate moderate-to-strong membranous IHC staining. Patients in Cohort 3B are required to be PD-L1+, defined as a combined positive score ≥1 (IHC staining per the Dako 22C3 PD-L1 assay). Patients will receive zolbetuximab + pembrolizumab in the third/later line in Cohort 3A and third line in Cohort 3B. In Cohort 3A (safety cohort), zolbetuximab will be administered at a loading dose of 800 mg/m2 IV on Day 1 Cycle 1 followed by 600 mg/m2 IV every 3 weeks; a reduction from 600 mg/m2 every 3 weeks is permitted. Pembrolizumab 200 mg IV will be administered on Day 1 of each 21-day cycle. Cohort 3B (expansion cohort) zolbetuximab dose is determined from results of Cohort 3A. Imaging will occur every 6 weeks for 24 weeks and every 12 weeks thereafter. The primary endpoint is objective response rate; additional endpoints include duration of response, disease control rate, and progression-free survival by independent review committee and investigator assessment. Pharmacokinetics, safety/tolerability, quality of life, and immunogenicity will be assessed. The study is currently recruiting pts. Clinical trial information: NCT03505320.

e16564 Background: In rGC ( > cT2), we investigated the impact of various neoadjuvant and/or adjuvant treatment modalities on pathologic complete response (pCR), surgical margins, and overall survival (OS). Methods: The National Cancer Database (NCDB) was interrogated to identify rGC patients (pts) between 2004-2015. Gastric adenocarcinoma cases that were cT2-T4b, any N, M0 and underwent definitive surgery were included. We analyzed the association of 9 treatment groups: neoadjuvant chemoradiation only (nCRT), neoadjuvant chemo only (nCT), adjuvant chemo only (aCT), adjuvant chemoradiation only (aCRT), neoadjuvant chemo and adjuvant radiation (nCTaRT), received any chemo at all (any CT), received any chemoradiation at all (any CRT), received any radiation at all (any RT), and no perioperative therapy (NT) across 3 endpoints: pCR, margin status, and OS using logistic regression and Cox proportional hazards models with adjustment for baseline characteristics. Results: From 183,204 GC cases screened, a total 3061 pts were available with a median follow-up of 41.6 mos and median OS of 29.0 mos. On multivariable analyses, nCRT was associated with the greatest odds of having a pCR (odds ratio or OR 59.6, 95% confidence interval (CI) 10.6-334.1, p < 0.001) with NT as the reference. Having received any RT (OR 0.42, 0.10-1.86), nCRT (OR 0.68, 0.33-1.37), or nCT (OR 0.83, 0.60-1.15) was associated with the lowest odds for having positive surgical margins although none reached p < 0.05. For OS, having received any CT (hazard ratio or HR 0.41, 0.35-0.48) was associated with the lowest risk of death followed by nCRT (HR 0.48, 0.35-0.66), aCT (HR 0.52, 0.43-0.62), aCRT (HR 0.55, 0.48-0.63), any CRT (HR 0.61, 0.41-0.91), nCT (HR 0.62, 0.54-0.71), and nCTaRT (HR 0.67, 0.52-0.87, all p < 0.05). Median OS was greatest in pts treated with any CT (53.9 mos) followed by nCRT (39.1 mos) and aCT (36.1 mos) with 2-year OS rates being 65.6% (95% CI 61.3-69.5%), 63.6% (52.3-73.0%), and 59.7% (54.2-64.7%), respectively. Conclusions: Although nCRT had a high pCR rate, receipt of any CT (neoadjuvant and/or adjuvant) afforded the greatest OS in this modality-by-modality comparison in a large cohort of rGC pts.

4543 Background: Treatment (tx) of advanced gastric cancer (GC/GEJ) is highly heterogeneous, with substantial variability in tx patterns. Frontline tx choice may affect outcomes of subsequent tx, thereby influencing choice/efficacy of second-line (2L) tx. In RAINBOW, 2L ramucirumab(R) plus paclitaxel(P) significantly improved overall survival (OS) of patients (pts) with GC/GEJ. Here we explore efficacy, safety and quality of life (QoL) based on prior tx. Methods: Pts were grouped into doublet (DB) or triplet (TP) regimens based on prior cytotoxic tx received. OS and PFS were estimated using Kaplan-Meier method and tx effects on OS and PFS were evaluated by Cox PH model; safety and QoL were assessed descriptively for DB vs TP. Results: Use of DB and TP was similar between arms, with 23% in R+P and 26% in placebo (PB)+P arm receiving TP. Baseline characteristics were generally balanced between tx arms within DB and TP subgroups, with majority of TP administered in western regions (91%). Pts ≥65 years of age was 40% for DB and 28% for TP. DB pts (n = 498; 75%) received S1+cis (n = 97, 15%) and cape+ox (n = 71; 11%) as most common prior tx, while TP pts (n = 163; 25%) received epi+cape+ox (n = 74, 11%) and epi+cis+5FU (n = 53, 8%). Similar to ITT population, R+P improved OS and PFS in both DB and TP subgroups (Table). Patterns of overall and Grade ≥3 TEAEs between arms were similar regardless of prior tx. Higher rates of serious TEAEs were reported in TP pts (57%, 49%) than DB pts (44%, 40%) in R+P and PBO+P arms, respectively. Similar trend was observed for TEAEs leading to discontinuation for TP (40%, 30%) vs DB (29%, 22%) in respective tx arms. Baseline QoL scores were similar between tx arms within subgroups, but mean scores were > 5 points worse (range 0-100) for prior TP for role functioning, fatigue, pain, and appetite loss. Changes in mean scores were generally similar between arms and within subgroups. Conclusions: This exploratory analysis of RAINBOW suggests that although safety-related outcomes were less favorable in pts with prior TP, regardless of tx arm, similar improvements in efficacy were noted for R+P irrespective of prior DB or TP. Clinical trial information: NCT01170663 . [Table: see text]