Search

PURPOSE To investigate efficacy and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)–low gastric or gastroesophageal junction (GEJ) adenocarcinoma. METHODS Patients with locally advanced or metastatic HER2-low (cohort 1, immunohistochemistry 2+/in situ hybridization–negative; cohort 2, immunohistochemistry 1+) gastric/GEJ adenocarcinoma treated with at least two prior regimens, including fluoropyrimidine and platinum, but anti-HER2 therapy naive, received T-DXd 6.4 mg/kg intravenously once every 3 weeks. The primary end point was confirmed objective response rate by independent central review. RESULTS Among 21 patients enrolled in cohort 1 and 24 enrolled in cohort 2, 19 and 21 patients, respectively, had central HER2 confirmation, received T-DXd, and had measurable tumors at baseline. The confirmed objective response rate was 26.3% (95% CI, 9.1 to 51.2) from five partial responses in cohort 1 and 9.5% (95% CI, 1.2 to 30.4) from two partial responses in cohort 2. Thirteen patients (68.4%) in cohort 1 and 12 (60.0%) in cohort 2 experienced reduced tumor size. The median overall survival was 7.8 months (95% CI, 4.7 to nonevaluable) in cohort 1 and 8.5 months (95% CI, 4.3 to 10.9) in cohort 2; the median progression-free survival was 4.4 months (95% CI, 2.7 to 7.1) and 2.8 months (95% CI, 1.5 to 4.3), respectively. The most common grade ≥ 3 treatment-emergent adverse events in cohorts 1 and 2 were anemia (30.0% and 29.2%), decreased neutrophil count (25.0% and 29.2%), and decreased appetite (20.0% and 20.8%). Drug-related interstitial lung disease/pneumonitis occurred in one patient in each cohort (grade 1 or 2). No drug-related deaths occurred. CONCLUSION This study provides preliminary evidence that T-DXd has clinical activity in patients with heavily pretreated HER2-low gastric/GEJ adenocarcinoma.

Purpose The purpose of this phase II trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, to preoperative chemoradiotherapy (CRT) with capecitabine confers a clinical benefit to patients with locally advanced rectal cancer (LARC).Materials and Methods Patients with LARC (defined by clinical stage T3/4 and/or lymph node positivity) received preoperative radiation (45-50.4 Gy in 25-28 daily fractions) with concomitant capecitabine (825 mg/m2 twice per day) and simvastatin (80 mg, daily). Curative surgery was planned 4-8 weeks after completion of the CRT regimen. The primary endpoint was pathologic complete response (pCR). The secondary endpoints included sphincter-sparing surgery, R0 resection, disease-free survival, overall survival, the pattern of failure, and toxicity.Results Between October 2014 and July 2017, 61 patients were enrolled; 53 patients completed CRT regimen and underwent total mesorectal excision. The pCR rate was 18.9% (n=10) by per-protocol analysis. Sphincter-sparing surgery was performed in 51 patients (96.2%). R0 resection was achieved in 51 patients (96.2%). One patient experienced grade 3 liver enzyme elevation. No patient experienced additional toxicity caused by simvastatin.Conclusion The combination of 80 mg simvastatin with CRT and capecitabine did not improve pCR in patients with LARC, although it did not increase toxicity.

ObjectiveFirst-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia.MethodsEligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary).ResultsA total of 187 patients were enrolled in Asia (pembrolizumab, n = 62; pembrolizumab plus chemotherapy, n = 64; chemotherapy, n = 61). Compared with the global population, higher proportions of patients had Eastern Cooperative Oncology Group performance status 0 and a diagnosis of stomach cancer. In the programmed death ligand 1 combined positive score ≥1 population, median overall survival was numerically longer with pembrolizumab versus chemotherapy (22.7 vs 13.8 months; hazard ratio, 0.54; 95% confidence interval, 0.35–0.82) and pembrolizumab plus chemotherapy versus chemotherapy (16.5 vs 13.8 months; hazard ratio, 0.78; 95% confidence interval, 0.53–1.16). In the programmed death ligand 1 combined positive score ≥10 population, median overall survival was also numerically longer with pembrolizumab versus chemotherapy (28.5 vs 14.8 months; hazard ratio, 0.43; 95% confidence interval, 0.21–0.89) and pembrolizumab plus chemotherapy versus chemotherapy (17.5 vs 14.8 months; hazard ratio, 0.86; 95% confidence interval, 0.45–1.64). The grade 3–5 treatment-related adverse event rate was 19.4%, 75.8% and 64.9% for patients receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively.ConclusionsThis post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1–positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with ClinicalTrials.gov, NCT02494583.

HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification.This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing.Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths.These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies.Zymeworks.

PURPOSE The combination of oxaliplatin and fluoropyrimidine for 6 months is one of the standard options for adjuvant therapy for high-risk stage II and III colorectal cancers (CRCs). The optimal duration of oxaliplatin to diminish neurotoxicity without compromising efficacy needs to be clarified. PATIENTS AND METHODS This open-label, randomized, phase III, noninferiority trial randomly assigned patients with high-risk stage II and III CRC to 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine groups (3- and 6-month arms, respectively). The primary end point was disease-free survival (DFS), and the noninferiority margin was a hazard ratio (HR) of 1.25. RESULTS In total, 1,788 patients were randomly assigned to the 6-month (n = 895) and 3-month (n = 893) arms, and 83.6% in the 6-month arm and 85.7% in the 3-month arm completed the treatment. The neuropathy rates with any grade were higher in the 6-month arm than in the 3-month arm (69.5% v 58.3%; P < .0001). The 3-year DFS rates were 83.7% and 84.7% in the 6-month and 3-month arms, respectively, with an HR of 0.953 (95% CI, 0.769 to 1.180; test for noninferiority, P = .0065) within the noninferiority margin. Among patients with stage III CRC treated by capecitabine plus oxaliplatin, the 3-year DFS of the 3-month arm was noninferior as compared with that of the 6-month arm with an HR of 0.713 (95% CI, 0.530 to 0.959; P = .0009). However, among patients with high-risk stage II and stage III CRC treated by infusional fluorouracil, leucovorin, and oxaliplatin, the noninferiority of the 3-month arm compared with the 6-month arm was not proven. CONCLUSION This study suggests that adding 3 months of oxaliplatin to 6 months of capecitabine could be considered an alternative adjuvant treatment for stage III CRC (ClinicalTrials.gov identifier: NCT01092481 ).

Background: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to efficiently treat desmoid tumor. However, molecular mechanism of why imatinib works remains poorly understood. Here, we describe the potential roles of NOTCH2 and HES1 in association with clinical response to imatinib as in genome and transcriptome levels. Methods: We identified all somatic mutations in coding and non-coding regions via whole genome sequencing using desmoid tumor samples. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale Whole-genome sequencing (WGS) and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results: Among 20 patients, 4 (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥1 year. With gene-wise functional analyses, we detected significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on PCAWG data analyses, NOTCH2 mutations affect its expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders Conclusions: Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, which provides an important therapeutic consideration for desmoid tumor. Trial Registration: ClinicalTrials.gov, NCT02495519, Registered July 13, 2015- Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02495519

PURPOSE Subset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date. PATIENTS AND METHODS A total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments–approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB). RESULTS Sixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi. CONCLUSION Patients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

The aim of this study is to determine the optimal indications for preoperative pelvic radiotherapy (RT) in patients with metastatic rectal cancer who underwent curative-intent surgical resection and/or ablation.Between January 2000 and October 2019, 246 patients who met our inclusion criteria were enrolled. Preoperative RT was performed in 22 patients (8.9%). Lower margin below the peritoneal reflection (p0.001), mesorectal fascia (MRF) invasion (p = 0.02), and lateral pelvic lymph node (LPLN) involvement (p = 0.005) were more frequent in the preoperative RT group.During the median follow-up period of 13.3 months (interquartile range [IQR]: 6.0-36.3 months), local recurrence (LR) was identified in 60 patients (24.4%). It was the first site of recurrence in 45 of them (18.3%). Among them, three patients were in the preoperative RT group. On multivariable analysis, lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, carcinoembryonic antigen (CEA) level ≥ 10 ng/mL before treatment, and preoperative RT were significant prognostic factors for LR-free survival (LRFS). In the patient group without any risk factors, the 2-year LRFS rate was 94.9% without preoperative RT. In the patient group with one or more risk factors, the 2-year LRFS was 64.4% without and 95.2% with preoperative RT.LR developed in about 25% of patients within 2 years. Preoperative RT should be considered, especially in patients with a risk factor for LR, including lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, or CEA ≥ 10 ng/mL before treatment.

ObjectiveTo date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery.DesignThe primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort.ResultsFrom the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction pConclusionUsing machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit.Trial registration numberUMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial)

Aberrations in the fibroblast growth factor receptor2 (FGFR2) gene, including genetic alterations and chromosomal rearrangements, lead to the development and progression of cancer with poor prognosis. However, the mechanisms underlying the FGFR2 signaling pathway to facilitate the development of FGFR2-targeted therapies have not been fully explored. Here, we examined the clinicopathological features of FGFR2 amplification and fusion in gastrointestinal tract/genitourinary tract cancers. FGFR2 amplification and fusion were identified in approximately 1.5% and 1.1% of all cancer types in 1,373 patients, respectively, with both FGFR2 amplification and fusion occurring together at a rate of approximately 0.6%. Of all cancer types screened, gastric cancer (GC) was the most common cancer type with FGFR2 amplification (87.5% of all FGFR2 amplification case) or fusion (46.7% of all cases). In addition, FGFR2 alteration had poorer overall survival (OS, 13.7 months vs. 50.2 months, P = 0.0001 ) and progression-free survival (PFS, 5.6 months vs. 11.4 months, P = 0.0005 ) than did those without FGFR2 alteration, respectively. Taken together, our data underscore to screen solid cancer patients for FGFR2 aberrations in oncology clinic.

BackgroundThe MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20).MethodsIn 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety.ResultsIn MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred.ConclusionAtezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent’s known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).

Chemotherapy is ubiquitous in first-line treatment of advanced gastric cancer, yet responses are heterogeneous, and little is known about mediators of chemotherapy response. To move forward, an understanding of the effects of standard chemotherapy on the tumor–immune microenvironment (TME) is needed. Coupling whole-exome sequencing, bulk RNA and single-cell transcriptomics from paired pretreatment and on-treatment samples in treatment-naïve patients with HER2-positive and HER2-negative gastric cancer, we define features associated with response to platinum-based chemotherapy. Response was associated with on-treatment TME remodeling including natural killer (NK) cell recruitment, decreased tumor-associated macrophages, M1-macrophage repolarization, and increased effector T-cell infiltration. Among chemotherapy nonresponders, we observed low/absent PD-L1 expression or modulation, on-treatment increases in Wnt signaling, B-cell infiltration, and LAG3-expressing T cells coupled to an exodus of dendritic cells. We did not observe significant genomic changes in early on-treatment sampling. We provide a map of on-treatment TME modulation with standard chemotherapy and nominate candidate future approaches. Significance: Using paired pretreatment and on-treatment samples during standard first-line chemotherapy, we identify chemotherapy-induced NK-cell infiltration, macrophage repolarization, and increased antigen presentation among responders. Increased LAG3 expression and decreased dendritic cell abundance were seen in nonresponders, emphasizing remodeling of the TME during chemotherapy response and resistance. This article is highlighted in the In This Issue feature, p. 873

Summary Background Both innate and adaptive immune responses are important components of anticancer immunity. The CD47–SIRPα interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours. Methods We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks) until disease progression, voluntary withdrawal from the study, or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities during the first cycle, and was assessed in all patients who had received at least one dose of evorpacept. Secondary outcomes included the safety, tolerability, and antitumour activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety, and tolerability were assessed in all patients who had received at least one dose of evorpacept, and antitumour activity was assessed in those who recieved at least one dose of study treatment and underwent at least one post-baseline tumor assessment. This trial is registered with ClinicalTrials.gov , NCT03013218 . Findings Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept (n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30), and were included in the safety analysis. Median follow-up was 29·1 months (95% CI not calculable [NC]–NC) in the single-agent cohort, 27·0 months (25·1–28·8) in the evorpacept plus pembrolizumab cohort, and 32·7 months (27·0–32·7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received single-agent evorpacept; neutropenia with an associated infection in one patient with gastroesophageal junction cancer who received 3 mg/kg once per week, and thrombocytopenia with associated bleeding in one patient with pancreatic cancer who received 30 mg/kg once every other week. No maximum tolerated dose was reached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg once every other week. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with single-agent evorpacept (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received single-agent evorpacept, four treatment-related serious adverse events were reported. Five serious treatment-related adverse events related to evorpacept plus pembrolizumab were reported, and one serious adverse event related to evorpacept plus trastuzumab was reported. In response-evaluable patients in the dose-escalation phase (n=15) receiving single-agent evorpacept once per week, four (27%) had a best overall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg, and one received 10 mg/kg); in the 11 patients who received single-agent evorpacept at the highest dose of 30 mg/kg once every other week, two (18%) had stable disease. In the dose-expansion cohort, overall responses were recorded in four (20·0%; 95% CI 5·7–43·7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab, in one (5·0%; 0·1–24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab, and in four (21·1%; 6·1–45·6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab. Interpretation The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC. Funding ALX Oncology.

Background Diffuse‐type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. Hence, more optimized treatment strategy is urgently needed in diffuse‐type GC. Methods Using a panel of 10 GC cell lines and 3 GC patient‐derived cells (PDCs), we identified cell lines with high EMTness which is a distinct feature for diffuse‐type GC. We treated GC cells with high EMTness with ramucirumab alone, TGF‐β receptor kinase inhibitor (TEW‐7197) alone, or in combination to investigate the drug's effects on invasiveness, spheroid formation, EMT marker expression, and tumor‐induced angiogenesis using a spheroid‐on‐a‐chip model. Results Both TEW‐7197 and ramucirumab treatments profoundly decreased invasiveness of EMT‐high cell lines and PDCs. With a 3D tumor spheroid‐on‐a‐chip, we identified versatile influence of co‐treatment on cancer cell‐induced blood vessel formation as well as on EMT progression in tumor spheroids. The 3D tumor spheroid‐on‐a‐chip demonstrated that TEW‐7197 + ramucirumab combination significantly decreased PDC‐induced vessel formation. Conclusions In this study, we showed TEW‐7197 and ramucirumab considerably decreased invasiveness, thus EMTness in a panel of diffuse‐type GC cell lines including GC PDCs. Taken together, we confirmed that combination of TEW‐7197 and ramucirumab reduced tumor spheroid and GC PDC‐induced blood vessel formation concomitantly in the spheroid‐on‐a‐chip model., Diffuse‐type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. In this study, we sought a drug candidate for this type of cancer treatment and confirmed that combination of TEW‐7197 and ramucirumab reduced tumor spheroid invasiveness and GC PDC‐induced blood vessel formation concomitantly in the spheroid‐on‐a‐chip model.

Microsatellite status is a prognostic biomarker in advanced gastric cancer. This retrospective study aimed to investigate the usefulness of microsatellite status in predicting prognosis and response to adjuvant treatment in pT1N1 gastric cancer. Among 875 patients who underwent radical gastrectomy for pT1N1 gastric cancer at two tertiary hospitals, 838 with available microsatellite instability (MSI) data were included and classified into two groups according to microsatellite status: microsatellite stable (MSS) and MSI-high (MSI-H). Recurrence-free survival rate and risk factors for tumor recurrence were analyzed. Of 838 gastric cancer patients, 100 (11.9%) were MSI-H and 307 (36.6%) received adjuvant treatment. During median follow-up of 70 months, 42 (5.0%) patients experienced gastric cancer recurrence; hematogenous recurrences were the most common (45.2%). Recurrence-free survival was similar in the MSS and MSI-H groups (p = 0.27), and adjuvant treatment did not show an oncological benefit over surgery alone for pT1N1 gastric cancer (p = 0.53). On univariate analysis, age, operation period, and Lauren classification were significantly associated with tumor recurrence, while adjuvant treatment and MSI status were not associated with tumor recurrence. On multivariate analysis, MSI status was not associated with tumor recurrence, and adjuvant treatment worsened the tumor recurrence risk [hazard ratio (HR) 2.373, 95% confidence interval (CI) 1.125–5.006, p = 0.023). MSI status may not be a prognostic factor for tumor recurrence or a predictor of response to adjuvant treatment in pT1N1 gastric cancer patients. Considering that the effect of adjuvant treatment to decrease the risk of tumor recurrence is not clear, it may not be indicated in pT1N1 patients.

Introduction IMC-001 is a fully human IgG1 monoclonal antibody that binds to human PD-L1 (programmed death-ligand 1). This study evaluated the safety, pharmacokinetics, and pharmacodynamics of IMC-001 in patients with advanced solid tumors. Materials and Methods This open-labeled phase I study used a standard 3 + 3 dose-escalation design, with doses ranging from 2 to 20 mg/kg. IMC-001 was administered intravenously every 2 weeks until disease progression or unacceptable toxicity. The dose-limiting toxicity window was defined as 21 days from the first dose. Results Fifteen subjects were included in 5 dose-escalation cohorts. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common adverse events (AEs) were general weakness, decreased appetite, fever, and cough. No grade 4 or 5 treatment emergent AEs were reported during the study. One subject in the 2 mg/kg cohort showed grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be related to IMC-001. Over the dose range of 2–20 mg/kg IMC-001, the AUC0–14d, AUC0—∞, and Cmax generally increased in a dose-proportional manner for each step of dose escalation. Of the 15 enrolled patients, 1 subject with rectal cancer showed a partial response, and the disease control rate was 33.3%. Conclusions IMC-001 demonstrated a favorable safety profile up to 20 mg/kg administered intravenously every 2 weeks and showed preliminary efficacy in patients with advanced solid tumors. Based on pharmacokinetic and pharmacodynamic data, 20 mg/kg was selected as the recommended phase II dose. Clinical trial identification NCT03644056 (date of registration: August 23, 2018).

Gastric cancer is a major global health burden, especially when patients are diagnosed with recurrent or metastatic gastric cancer. Despite recent advances in treatment options with palliative chemotherapy, the median overall survival of patients with gastric cancer remains within 1 or 2 years after the diagnosis of metastatic disease. Gastric cancer is significantly more prevalent in eastern Asia (e.g., Japan and Korea). Next-generation sequencing is rapidly being adopted as part of clinical practice in Korea and Japan, especially in patients with gastric cancer. Approximately 10% to 15% of the patients with gastric cancer who undergo next-generation sequencing of their tumor specimen are allocated to target-matched clinical trials in Japan and Korea. In Japan and Korea, a cell-free DNA next-generation sequencing panel is also actively being investigated as an alternative next-generation sequencing test for patients with gastric cancer, which may reflect the tumor heterogeneity of gastric cancer. In Japan and Korea, multiple biomarkers, such as HER2, mismatch repair, Epstein-Barr virus, PD-L1 (combined positive score), EGFR, FGFR2, and CLDN18.2, are routinely assessed through immunohistochemistry or in situ hybridization before initiation of the first-line treatment in all patients with gastric cancer. Most tertiary cancer centers in Korea routinely perform HER2, mismatch repair, Epstein-Barr virus, and PD-L1 next-generation sequencing before palliative chemotherapy in patients with gastric cancer. Biomarker evaluation for all patients with metastatic gastric cancer enables clinicians to identify available biomarker-based clinical trials early during the course of treatment, which expands treatment opportunities while patients are medically fit for clinical trials, if available. Comprehensive genomic profiling using a tissue or circulating tumor DNA next-generation sequencing panel is considered necessary during second-line or subsequent treatment. It is hoped that a comprehensive molecular profiling strategy will facilitate greater use of precision medicine through molecularly targeted therapies for patients with gastric cancer in the near future.

Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein. Patients and Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. Results: The RP2D was established as ceralasertib 240 mg BD days 1–14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5–35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0–51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0–5.8), the median duration of response was 9.9 months (95% CI, 3.7–23.2), and the mOS was 7.4 months (95% CI, 5.7–11.9). Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment. See related commentary by Ashworth, p. 4667

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: To aid in oncology drug development, we investigated MET proto-oncogene receptor tyrosine kinase gene aberrations in 2,239 oncology patients who underwent next-generation sequencing (NGS) in clinical practice.Materials and methods: From November 2019 to January 2021, 2,239 patientswith advanced solid tumors who visited oncology clinics underwent NGS. The NGS panel included >500 comprehensive NGS tests using archival tissue specimens. Programmed death-ligand 1(PD-L1) 22C3 assay results and clinical records regarding initial chemotherapy were available for 1,137 (50.8%) and 1,761 (78.7%) patients, respectively for overall survival (OS) analysis.Results: The 2,239 patients represented 37 types of cancer. The NGS panel included >500 genes, microsatellite instability status, tumor mutational burden, and fusions. The most common cancer types were colorectal (N = 702), gastric (N = 481), and sarcoma (N = 180). MET aberrations were detected in 212 patients. All MET-amplified tumors had microsatellite stable status, and 8 had a high tumor mutational burden. Of 46 patients with MET-amplified cancers, 8 had MET-positive protein expression by immunohistochemistry (2+ and 3+). MET fusion was detected in 10 patients. Partner genes of MET fusion included ST7, TFEC, LRRD1, CFTR, CAV1, PCM1, HLA-DRB1, and CAPZA2. In survival analysis, patients with amplification of MET gene fusion had shorter OS and progression-free survival (PFS) than those without. Thus, MET aberration was determined to be a factor of response to chemotherapy.Conclusion: Approximately 2.1% and 0.4% of patients with advanced solid tumors demonstrated MET gene amplification and fusion, respectively, and displayed a worse response to chemotherapy and significantly shorter OS and PFS than those without MET gene amplification or fusion.

Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. Patients and Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity. Results: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer. Conclusion: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.

Background: Immune checkpoint inhibitors (ICIs) show clinical benefit in patients with refractory advanced gastric cancer (GC). The ICIs in routine clinical practice have been used in various treatment lines. Therefore, we investigated the timing for application of ICI in patients with refractory advanced GC. Methods: We analyzed 187 patients with refractory advanced or recurrent GC who received ICIS as a 3rd- or 4th-line treatment between September 2015 and October 2020. Clinical outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were evaluated. Results: Among 187 patients, 105 received ICIs as a 3rd-line treatment and 82 as a 4th line. The ORR for ICIs was 10.5% (11/105) in 3rd line and 8.5% (7/82) in 4th line. The DCR for ICIs was 36.2% (38/105) in 3rd-line treatment and 31.7% (26/82) in 4th line. There was no significant difference for ORR (P = 0.819) or DCR (P = 0.870). The median PFS and OS to ICIs was 1.4 months (95% CI, 1.1 to 1.8 months) and 4.4 months (95% CI, 1.6 to 7.2 months) in 3rd line and 1.8 months (95% CI, 1.4 to 2.3 months) and 2.8 months (95% CI, 2.2 to 3.4 months) in 4th line. The median PFS and OS to ICIs was not different between 3rd line and 4th line (P = 0.495 and P=0.208, respectively). There were also no significant difference for PFS and OS between PD-L1-positive tumors (CPS≥1) and PD-L1-negative tumors (P = 0.910 and P=0.931, respectively). Conclusions: ICIs showed similar clinical benefits in the 3rd-line and 4th-line settings. ICIs might be a reasonable approach for patients with refractory GC in the setting of 3rd-line or 4th-line treatment options.

Background: Aflibercept and fluorouracil, leucovorin, irinotecan (FOLFIRI) is commonly used as a second-line treatment for metastatic colorectal cancer (CRC). However, the biomarkers to guide the choice of this regimen from among treatment options remain unclear. Patients and Methods: We performed exploratory analyses to validate potential prognostic factors for patients receiving aflibercept plus FOLFIRI as a second-line systemic treatment for metastatic CRC between January 2015 and July 2019. Patient characteristics, histopathologic data, laboratory and radiologic data, and treatment outcomes were collected and reviewed. Results: Included were 52 patients: 50 (96.2%) received bevacizumab plus fluorouracil, leucovorin, oxaliplatin (FOLFOX) as prior first-line treatment. Among the 52 patients receiving aflibercept and FOLFIRI, four complete responses and 21 partial responses were observed in analyzed patients for an overall response rate of 48.1%. Median progression-free survival (PFS) was 7.0 months and overall survival (OS) was 16.8 months. Response to first-line treatment (median PFS, 8.0 versus 4.2 months), left-side location of primary tumor (7.9 versus 4.9 months), low baseline CEA level (8.0 versus 5.9 months), and no RAS/RAF mutation (9.9 versus 6.4 months) were remained significant prognostic factors for PFS in the multivariate backward stepwise Cox regression model, and the latter three factors were also significantly related to OS. Conclusions: Significant prognostic factors for PFS with aflibercept plus FOLFIRI as second-line therapy were extracted and validated in the multivariate OS model. These findings could provide useful information for selecting patients for aflibercept plus FOLFIRI as second-line therapy.

We investigated the combined effects of sarcopenia and inflammation on outcomes in patients with HCC treated with nivolumab. We reviewed 102 patients treated with nivolumab between 2017 and 2018. Sarcopenia was diagnosed when the L3 skeletal muscle indices were

PURPOSE Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.

PURPOSE In response to the COVID-19 pandemic, the ASCO launched a Global Webinar Series to address various aspects of cancer care during the pandemic. Here we present the lessons learned and recommendations that have emerged from these webinars. METHODS Fifteen international health care experts from different global regions and oncology disciplines participated in one of the six 1-hour webinars to discuss the latest data, share their experiences, and provide recommendations to manage cancer care during the COVID-19 pandemic. These sessions include didactic presentations followed by a moderated discussion and questions from the audience. All recommendations have been transcribed, categorized, and reviewed by the experts, who have also approved the consensus recommendations. RESULTS The summary recommendations are divided into different categories, including risk minimization; care prioritization of patients; health care team management; virtual care; management of patients with cancer undergoing surgical, radiation, and systemic therapy; clinical research; and recovery plans. The recommendations emphasize the protection of patients and health care teams from infections, delivery of timely and appropriate care, reduction of harm from the interruption of care, and preparation to handle a surge of new COVID-19 cases, complications, or comorbidities thereof. CONCLUSION The recommendations from the ASCO Global Webinar Series may guide practicing oncologists to manage their patients during the ongoing pandemic and help organizations recover from the crisis. Implementation of these recommendations may improve understanding of how COVID-19 has affected cancer care and increase readiness to manage the current and any future outbreaks effectively.

We evaluated the tolerability, pharmacokinetics (PK) and preliminary efficacy of KML001, an oral trivalent arsenical, as a monotherapy in patients with advanced solid tumors.With a standard 3 + 3 design for dose-escalation stage, the planned dose levels of KML001 were 5, 7.5, 10, 12.5, and 15 mg/day for 28 days. Once the maximum tolerated dose was determined, 22 subjects were additionally enrolled for dose-expansion stage. PK analysis was performed in the 5, 10, and 15 mg/day cohort at the dose-escalation stage and also at the dose-expansion stage. Moreover, response was assessed using the standard RECIST 1.1.A total of 45 Korean subjects were enrolled. No DLT was reported at the dose-escalation stage. Three DLTs, two cases of prolonged QTc interval and one of neutropenia, were reported in the 12.5 mg/day cohort at the dose-expansion stage. Higher total daily doses up to 12.5 mg/day of KML001 resulted in higher trough plasma concentrations. Among the 18 subjects who completed 2 cycles of therapy, 15 had progressive disease and 3 had stable disease.Doses equal to or greater than 10 mg/day KML001 alone were tolerable and produced plasma concentrations higher than biologically relevant targets.

Purpose High microsatellite instability (MSI) is related to good prognosis in gastric cancer. We aimed to identify the prognostic factors of patients with recurrent gastric cancer and investigate the role of MSI as a prognostic and predictive biomarker of survival after tumor recurrence. Materials and methods This retrospective cohort study enrolled patients treated for stage II/III gastric cancer who developed tumor recurrence and in whom the MSI status or mismatch repair (MMR) status of the tumor was known. MSI status and the expression of MMR proteins were evaluated using polymerase chain reaction and immunohistochemical analysis, respectively. Results Of the 790 patients included, 64 (8.1%) had high MSI status or MMR deficiency. The tumor-node-metastasis stage, type of recurrence, Lauren classification, chemotherapy after recurrence, and interval to recurrence were independently associated with survival after tumor recurrence. The MSI/MMR status and receiving adjuvant chemotherapy were not associated with survival after recurrence. In a subgroup analysis of patients with high MSI or MMR-deficient gastric cancer, those who did not receive adjuvant chemotherapy had better treatment response to chemotherapy after recurrence than those who received adjuvant chemotherapy. Conclusion Patients with high MSI/MMR-deficient gastric cancer should be spared from adjuvant chemotherapy after surgery, but aggressive chemotherapy after recurrence should be considered. Higher tumor-node-metastasis stage, Lauren classification, interval to recurrence, and type of recurrence are associated with survival after tumor recurrence and should thus be considered when establishing a treatment plan and designing clinical trials targeting recurrent gastric cancer.

Background PIK3CA contributes to cell growth via the PI3K-AKT-mammalian target of rapamycin (mTOR) signaling pathway. Mutations in the pathway are frequently observed in solid tumors. We assessed the efficacy and safety of sirolimus, an mTOR inhibitor, in chemotherapy-refractory solid tumors with PIK3CA mutations or amplifications. Methods This was an open-label, single-arm, multicenter pilot study. Twenty-four patients with solid tumors harboring a PIK3CA mutation were treated with sirolimus between July 2017 and March 2019. Treatment was continued until disease progression, unacceptable adverse events, or death. The primary end points were the overall response rate (ORR), disease control rate (DCR), and safety. Results The median follow-up time was 6.1 months. Two patients with rapid disease progression-related death, one who withdrew, and one with a non-target lesion only were excluded from the analysis. Among 20 evaluable patients, 6 patients showed stable disease and 14 showed progressive disease (ORR 0%, DCR 30%). The median progression-free survival was 2.39 months (95% confidence interval, 1.97–2.81 months). The most common adverse event was abdominal pain (20.8%), followed by anemia (16.7%) and fatigue (16.7%). The adverse events were generally manageable. Conclusions Although safe, sirolimus monotherapy did not show meaningful antitumor activity in chemotherapy-refractory solid tumors with PIK3CA mutations. Combinations of mTOR inhibitors for stabilization and other antitumor agents with beneficial effects on tumor volume may improve outcomes.

Background Alterations in claudin expression can impair tight junction function, influence signaling pathways, and act as a tumor-promoting event in some epithelial cancers. Recently, zolbetuximab, a highly potent and tumor cell-selective therapeutic antibody against claudin 18.2, has been developed and investigated in clinical trials. Methods We conducted a prospective study using claudin 18.2 immunohistochemistry in 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Results Claudin 18.2 expression was evaluated in 96.3% of the patients (414/430) using immunohistochemistry. In total, 4.1% (17/414) of the patients were claudin 18.2-positive, including patients with pancreatic (16.7%, 1/6), gastric (14.1%, 12/85), biliary tract (6.3%, 1/16), genitourinary/miscellaneous (2.2%, 1/46), and colorectal (0.9%, 2/203) cancers. Twelve of 17 patients positive for claudin 18.2 had gastric cancers (GCs); this subgroup showed no statistical differences by gender, age, disease extent, primary tumor site, pathologic differentiation, human epidermal growth factor receptor 2, or Epstein-Barr virus status with or without claudin 18.2 expression. However, claudin 18.2 was more frequently positive in intestinal-type compared with diffuse-type as assessed by Lauren classification (P=0.026). There was no significant difference in overall survival (OS) between patients with and without claudin 18.2 expression (P=0.101). Conclusions Our results add to the emerging literature about claudin 18.2 expression in various cancer types and support the need for extended clinical exploration of zolbetuximab.

A taxane plus ramucirumab as second-line therapy followed by a checkpoint inhibitor (CPI) in third line has become a standard treatment strategy for advanced gastric cancer. Herein, we investigated the impact of prior ramucirumab use on the efficacy of third-line immunotherapy and performed an exploratory analysis to identify potential biomarkers for the success of immunotherapy. We retrospectively analyzed patients receiving CPI as a third-line treatment for advanced gastric cancer between January 2015 and March 2019. Clinicopathologic data, including patient characteristics, histopathologic reports, and treatment types and outcomes, were reviewed. Of the 74 patients included in this study, 45 (61%) received nivolumab and 29 (39%) received pembrolizumab as a third-line CPI. For second-line therapy, 41 patients (55%) were treated with ramucirumab plus a taxane, and 33 (45%) received a chemotherapy regimen without ramucirumab. The disease control rates of CPIs were not statistically different according to prior use of ramucirumab. The overall survival (OS) with CPI was higher in patients receiving second-line therapy without ramucirumab compared with those receiving ramucirumab and taxane (5.6 vs 4.8 months, HR 0.56, 95% confidence interval [CI] 0.33–0.96; p = 0.03); however, this was not significant in a multivariate analysis. Patients achieving a response to second-line ramucirumab and a taxane showed greater benefit from subsequent CPI treatment compared with those not achieving a response (median OS 9.9 vs 2.3 months, HR 0.20, 95% CI 0.07–0.54; p

Purpose Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy.Materials and Methods We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA.Results Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10–4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker.Conclusion Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

Purpose: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. Patients and Methods: Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. Results: At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0–38.2]; median PFS was 13.8 months (95% CI, 10.1–19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8–89.1) and median intracranial DoR was 22.1 (95% CI, 7.4–not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. Conclusions: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.

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

Background: For human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC), a combination of fluoropyrimidines and platinum agents was the standard first-line treatment. After the failure of the first-line therapy, ramucirumab plus paclitaxel was the standard second-line treatment. In the CheckMate 649 study, nivolumab plus chemotherapy has been considered a new standard first-line treatment in previously untreated AGC. However, the role of ramucirumab plus paclitaxel as 2nd line after the failure of nivolumab plus chemotherapy is not confirmed. Methods: We analyzed AGC patients with ramucirumab plus paclitaxel as second-line therapy, who failed the nivolumab plus chemotherapy (capecitabine plus oxaliplatin (XELOX) or 5-fluorouracil plus oxaliplatin (FOLFOX)) as frontline therapy at Samsung Medical Center, South Korea. Results: Under the routine clinical practice, 23 AGC patients, who progressed after first-line chemotherapy with nivolumab plus chemotherapy, were treated with ramucirumab plus paclitaxel between Dec 2021 to Sep 2022. The median age was 56 (range, 24-76), and 18 (78.3%) patients received nivolumab plus XELOX, while 5 (21.7%) patients received nivolumab plus FOLFOX. The overall response rate (ORR) to ramucirumab plus paclitaxel was 10.0% (2 of PR) and the disease control rate was 55.0%. At the median follow-up of 4.5 months, the median progression-free survival (PFS) from second-line ramucirumab plus paclitaxel commencement was 2.7 months (95% confidence interval (CI), 1.7-3.7); 6.9 months (95% CI, not calculated) in the first nivolumab plus chemotherapy responders(n=7), and 2.3 months (95% CI, 1.6-3.0) in non-responders(n=15) (p=0.232). At the time of data cutoff, 6 patients continued to receive ramucirumab plus paclitaxel and the median OS was 6.3 months (95% CI, 4.9-7.7). Conclusions: This analysis showed that ramucirumab plus paclitaxel as 2nd line therapy was not sufficient in AGC patients after the failure for nivolumab plus chemotherapy. The new innovative 2nd line therapy might be needed in AGC patients after nivolumab plus chemotherapy. Citation Format: Youngkyung Jeon, Sun Young Jeong, Jaeyeon Jang, Ye Ji Jung, Daeho Choi, Joohyun Hong, Seung Tae Kim, Won ki Kang, Jeeyun Lee. Ramucirumab plus paclitaxel as second-line treatment in patients with advanced gastric cancer who previously treated with first-line nivolumab plus chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6756.

Purpose: This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab±chemotherapy versus chemotherapy in KEYNOTE-062. Patients and Methods: In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb. Results: TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non–MSI-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated. Conclusions: This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first-line pembrolizumab-based therapy in patients with advanced gastric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.

BackgroundTrastuzumab is a HER2-trargeted humanized monoclonal antibody that has been studied as a first-line treatment for patients with HER2-positive advanced gastric cancer (AGC). The effect of anti-HER2 therapy according to tumor mutational burden (TMB) in HER2-positive AGC remains unclear.MethodsWe performed next-generation sequencing (NGS), including TMB analysis, in 31 HER2-positive AGC patients with trastuzumab plus chemotherapy as first-line therapy for recurrent (n=8) or metastatic (n=23) tumors. The TruSight Oncology 500 Assay from Illumina (San Diego, CA, USA) was used to evaluate TMB.ResultsAmong 31 patients, 30 had tumors with immunohistochemistry (IHC) 3+, and one was IHC 2+ and silver in situ hybridization (SISH) positive. The median age was 57.0 years old (range, 35-76), and the majority had tumors with low TMB (87.1%, n=27/31). Only four (12.9%) had tumors with high TMB. Of these four, three achieved complete response (CR) or partial response (PR) to treatment, and the remaining patient was not evaluable for tumor response. Objective response rate (ORR) to trastuzumab plus chemotherapy showed a favorable trend in patients with high TMB (75.0%, n=3/4) compared to patients with low TMB (59.3%, n=16/27) (P=0.546). The median progression-free survival (PFS) was not reached in the TMB-high group but was 8.0 months (95% CI, 7.6-8.5) in the TMB-low group (P=0.019)ConclusionThe status of TMB could be a novel biomarker in predicting the efficacy of trastuzumab plus chemotherapy in HER2-positive AGCs.

414 Background: Minnelide is a prodrug that rapidly releases the active compound triptolide when exposed to phosphatases in the bloodstream. Triptolide is a diterpene that has been shown to inhibit tumor cell proliferation and induce apoptosis in various cancer types. The anti-tumor effect of triptolide is the result of inhibition of heat shock protein (HSP) 70 expression. In GC Minnelide inhibits Sp1 to decrease HSP70 and induce cell death in preclinical data. Methods: This phase 1 trial was designed to determine the maximum tolerated dose (MTD) of Minnelide monotherapy and the MTD of Minnelide in combination with paclitaxel in refractory GC patients. There were 6 cohorts tested in this trial: cohort A: Minnelide 1 mg qd D1-21, q 28 days; cohort B: Minnelide 1.25 mg qd D1-21, q 28 days; cohort C: 1.5 mg qd D1-21, q 28 days; cohort D: Minnelide 0.25 mg D1-21 + weekly paclitaxel 60 mg/m2 on D1, D8, D15; cohort E: Minnelide 0.5 mg qd D1-21+ weekly paclitaxel 80 mg/m2 on D1, D8, D15; cohort F: Minnelide 0.75 mg qd D1-21+ weekly paclitaxel 80 mg/m2 D1, D8, D15. Results: From Feb 2021 to Sep 2022, 23 GC patients were enrolled (cohort A – C, N=10; cohort D-F, N=12). All patients had metastatic disease at the time of study enrollment. 20 of 23 patients received the study treatment as >= 3rd-line (range, 2 – 6th line). In all, 3 patients had HER2 positive GC and 10 patients had PDL1 + tumor. In the monotherapy cohorts, there were no DLTs observed, and the regimen was tolerated well. One patient achieved confirmed PR which lasted for 6 months. For the combination arm (cohort D-F), there were no DLTs observed. Of the 11 patients who were evaluable for treatment response, there were 1 PR, 5 SDs and 5 PDs. Two of five patients who achieved stable disease had durable stable disease for > 6 months on study treatment. In the combination cohorts, the most common adverse events of any grade were neutropenia; however, there was no neutropenic fever or treatment related mortality. Conclusions: Minnelide in combination with weekly paclitaxel demonstrated promising anti-tumor activity with durable responses in refractory AGC. Clinical trial information: Underreview .

BackgroundRegulatory T-cells (Treg) are essential in maintaining self tolerance, but they can also suppress anti-tumor immunity in the tumor microenvironment (TME). Treg are recruited into tumors by C-C motif chemokine ligand 17 (CCL17), and 22 (CCL22), which are produced by tumor cells and other cells in the TME. These chemokines serve as a ”homing signal” to Treg by binding to their cognate receptor, C-C chemokine receptor type 4 (CCR4), the predominant chemokine receptor on human Treg.1 2 3 FLX475, is an orally available and selective small-molecule antagonist of CCR4. In preclinical studies it has demonstrated potent inhibition of CCL17- and CCL22-induced CCR4-mediated chemotaxis, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human healthy volunteer study, the orally-available CCR4 antagonist was well tolerated, with solid safety profile. A receptor occupancy (RO) pharmacodynamic (PD) assay using peripheral blood Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors.4 The proposed mechanism of action, pharmacokinetics (PK), PD, and safety profile of FLX475 have enabled the optimized design of an ongoing Phase 2 study to assess the safety, efficacy of FLX475 in combination with pembrolizumab in patients with advanced or metastatic gastric cancer.MethodsThis clinical trial is a Phase 2, open-label study to assess the safety and efficacy of FLX475 in combination with pembrolizumab in patients with advanced or metastatic gastric cancer (NCT04768686). Approximately 90 subjects may be enrolled across 2 cohorts to examine the safety and efficacy when administered 100mg PO QD of FLX475 with 200mg IV Q3W of pembrolizumab. In cohort 1, checkpoint inhibitor naïve Epstein-Barr Virus (EBV)-negative gastric cancer subjects who have progressed on at least 2 prior systemic treatments for advanced or metastatic gastric cancer will be enrolled, and in cohort 2, checkpoint inhibitor naïve EBV-positive gastric cancer subjects who had at least 1 prior systemic treatment for advanced or metastatic gastric cancer will be enrolled. Both EBV negative and positive gastric cancer are predicted to express high levels of CCR4 ligands and enriched in Treg (i.e. ‘charged tumor’). The study is planned initially as a 2-stage design for each cohort, and an interim analysis reviewing efficacy and safety results as well as available PK and PD data for both cohorts will be performed prior to stage 2.AcknowledgementsThanks to the patients, and to their families and caregivers for allowing us to be part of the journey.RAPT Therapeutics, Inc., South San Francisco, CA, USA is providing FLX475 for the study.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA is providing pembrolizumab for the study.Trial RegistrationNCT04768686ReferencesTalay O, et al. Potent and selective C-C chemokine receptor (CCR4) antagonists potentiate anti-tumor immune responses by inhibiting regulatory T cells (Treg). J Immunother Cancer 2017;5(Suppl 2):P467 (SITC 2017).Curiel, Tyler J, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature medicine 10.9 (2004):942–949.Nakayama et al. Selective induction of Th2-attracting chemokines CCL17 and CCL22 in human B cells by latent membrane protein 1 of Epstein-Barr virus. J Virol 2004 February; 78(4):1665–74.van Marle S, et al. Pharmacokinetics, pharmacodynamics, and safety of FLX475, an orally-available, potent, and selective small-molecule antagonist of CCR4, in healthy volunteers. J Immunother Cancer 2018;6(Suppl 1):P484 (SITC 2018).

Background EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies. Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified mCRC. Methods In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs 1459 EGFR nonamplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs 439 EGFR nonamplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples. All statistical tests were 2-sided. Results EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 nonamplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared with EGFR-nonamplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months, 95% confidence interval [CI] = 50.7 to not available [NA]) vs EGFR-nonamplified ones (24.0 months; 95% CI = 22.8 to 25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20 to 0.44; P < .001; adjusted HR = 0.46, 95% CI = 0.30 to 0.69; P < .001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months, 95% CI = 35.2 to NA, vs 29.1 months, 95% CI = 27.0 to 31.9, respectively; HR = 0.46, 95% CI = 0.28 to 0.76; P = .002). Conclusion Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR-targeting strategies beyond single-agent monoclonal antibodies.

Background: The aims of this study were to detect circulating tumor cells (CTCs) at the single-cell level in cerebrospinal fluid (CSF) and to identify intrapatient heterogeneity of CTCs in a patient with gastric cancer (GC) with leptomeningeal metastasis (LM) using Di-Electro-Phoretic Array technology. Materials and Methods: The CSF samples were drawn from a patient who was diagnosed with GC with LM. The CSF samples were centrifuged and stained with antibody cocktail to recognize 4',6-diamidino-2-phenylindole, cytokeratin, and epithelial cell adhesion molecule (EpCAM). Gene sequencing was also conducted to evaluate the status of the gene alteration profile of CSFCTCs as compared with those of the CSF non-CTCs and the primary tumor tissue. Results: Among total 38 cells from the samples, 25 cells represented CK+ (EpCAM+), which boiled down to 0.53 CTCs in 1 mL of CSF. Each CTC was heterogeneous in terms of morphology and degree of marker expression. Some CTCs have a spindle-like shape, whereas others have a round shape. Based on molecular profiling between the 25 CK+ (EpCAM+) CTCs and 13 CK−/EpCAM− cells (i.e., the non-CTCs), CSFCTCs harbored mutations such as MDM2, TP53, KRAS, STK11, and ALK, whereas mutation of these genes was not observed in the CSF non-CTCs. Four genes of nine mutational genes totally observed in the CSFCTCs were also noted in the primary tumor tissue. Conclusions: We enriched CTCs through a single-cell sorting process in CSF samples of a GC patient with LM. We also demonstrated the intrapatient heterogeneity of the CTCs at the single-cell level.

This phase-II study (ClinicalTrials.gov identifier: NCT03052478) aimed to evaluate the efficacy and safety of vismodegib, an inhibitor targeting the Hedgehog signaling pathway, in patients with refractory advanced gastric cancer. Patients with refractory advanced gastric cancer, whose disease had progressed after undergoing standard therapies, were enrolled in this phase-II trial of vismodegib. Vismodegib (150 mg) was administered orally once a day for a 21-day cycle. The primary endpoint was objective response rate, and the secondary endpoints were overall survival and safety profile. Tumor biopsies were obtained before vismodegib treatment. We conducted whole-exome and transcriptome sequencing to analyze biomarkers. Twenty-three patients were enrolled in this study. Among 19 patients who were eligible for response evaluation, only one showed stable disease, yielding a disease control rate of 5.3%. Median overall survival was 74 days (95% confidence interval, 74-151 days). Treatment-related adverse events of any grade were reported in seven patients (31.8%), and most were grade 1 or 2. Whole transcriptome data showed that the Hedgehog signaling pathway was not enriched in patient samples. This is the first clinical trial demonstrating the clinical activity and safety of vismodegib monotherapy in refractory advanced gastric cancer patients. Further well-designed clinical trials should be conducted to select advanced gastric cancer patients who are likely to benefit from vismodegib.

Treatment options for patients with chemotherapy-refractory solid tumors are limited.We conducted an open-label, single-arm, single-center phase II trial to evaluate the efficacy and safety of gefitinib in patients with chemotherapy-refractory solid tumors and EGFR amplification or sensitivity to an EGFR inhibitor identified through a drug-screening platform with patient-derived tumor cells (PDCs).EGFR amplification was detected by targeted sequencing. Sensitivity to an EGFR inhibitor was established in chemical screening using PDCs. Gefitinib (250 mg daily) was administered continuously in 28-day cycles until the occurrence of disease progression, unacceptable toxicity, or death due to any cause. The primary endpoint was the objective response rate (ORR).In total, 15 patients were assigned to the present study. The most common tumor type was glioblastoma multiforme (n = 9, 60%), followed by gastric cancer (n = 3, 20%), anal squamous cancer, rectal cancer, and sarcoma (each n = 1, 6.7%). Among 13 evaluable patients, one patient had a partial response and five had stable disease, with an ORR of 7.7% and a disease control rate of 46.1%. The median progression-free survival was 2.1 months (95% confidence interval [CI] 0.77-3.43). The most common adverse events were diarrhea (26.7%) and skin rash (26.7%).Gefitinib demonstrated modest anti-tumor activity and a manageable safety profile in chemotherapy-refractory solid tumors with EGFR amplification or sensitivity to an EGFR inhibitor identified through a drug-screening platform with PDCs. CLINICALTRIALS.NCT02447419.

Purpose: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. Patients and Methods: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. Results: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. Conclusions: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

Despite new agents to treat metastatic colorectal cancer (CRC), patients eventually progress and additional therapies are needed. We intended to evaluate the combination of pemetrexed/erlotinib in patients with high epidermal growth factor receptor (EGFR)-expressing (2+ or 3 on immunohistochemistry) metastatic CRC who experienced disease progression after standard chemotherapy. We investigated pemetrexed and erlotinib (pemetrexed 500 mg/m2 on Day 1 and erlotinib 100 mg/m2 on Days 1–21) as a salvage treatment, given every 3 weeks, until disease progression or intolerable toxicity. The primary outcome was overall response rate (RR). From May 2017 to April 2018, 29 metastatic CRC patients with high EGFR expression who had previously received standard therapies were enrolled into this trial. The regimen was well tolerated. Skin rash, vomiting, fatigue, and anorexia were common toxic effects but were mostly manageable and controllable side effects of grades 1 or 2 only. In an intent-to-treat analysis, three partial responses (PRs) were observed in enrolled patients, revealing an overall RR of 10.3%. This value supported the statistical hypothesis of this study. Fifteen patients had stable disease and the disease control rate (DCR) was 62.1%. All three patients who achieved a PR had a tumor EGFR expression of 3+. Among the eight patients with EGFR 3+ expression, the RR and DCR were 37.5% and 75.0%, respectively. This phase II trial using pemetrexed/erlotinib in metastatic CRC with high EGFR expression met the primary endpoint of tumor response. This study was registered at ClinicalTrials.gov (number NCT03086538).

Purpose: Gastroesophageal adenocarcinoma (GEA) has a poor prognosis and few therapeutic options. Utilizing a 73-gene plasma-based next-generation sequencing (NGS) cell-free circulating tumor DNA (ctDNA-NGS) test, we sought to evaluate the role of ctDNA-NGS in guiding clinical decision-making in GEA. Experimental Design: We evaluated a large cohort (n = 2,140 tests; 1,630 patients) of ctDNA-NGS results (including 369 clinically annotated patients). Patients were assessed for genomic alteration (GA) distribution and correlation with clinicopathologic characteristics and outcomes. Results: Treatment history, tumor site, and disease burden dictated tumor-DNA shedding and consequent ctDNA-NGS maximum somatic variant allele frequency. Patients with locally advanced disease having detectable ctDNA postoperatively experienced inferior median disease-free survival (P = 0.03). The genomic landscape was similar but not identical to tissue-NGS, reflecting temporospatial molecular heterogeneity, with some targetable GAs identified at higher frequency via ctDNA-NGS compared with previous primary tumor-NGS cohorts. Patients with known microsatellite instability-high (MSI-High) tumors were robustly detected with ctDNA-NGS. Predictive biomarker assessment was optimized by incorporating tissue-NGS and ctDNA-NGS assessment in a complementary manner. HER2 inhibition demonstrated a profound survival benefit in HER2-amplified patients by ctDNA-NGS and/or tissue-NGS (median overall survival, 26.3 vs. 7.4 months; P = 0.002), as did EGFR inhibition in EGFR-amplified patients (median overall survival, 21.1 vs. 14.4 months; P = 0.01). Conclusions: ctDNA-NGS characterized GEA molecular heterogeneity and rendered important prognostic and predictive information, complementary to tissue-NGS. See related commentary by Frankell and Smyth, p. 6893

Purpose:To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing.Experimental Design:Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated.Results:cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit.Conclusions:cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.See related commentary by Wang and Ajani, p. 6887