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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

Investigations for programmed cell death-1 (PD-1) blockade-induced hyperprogressive disease (HPD) have not been stringently conducted in patients with advanced gastric cancer (AGC). We explored the occurrence of HPD and its clinical implications in patients with AGC and treated with PD-1 inhibitors.We enrolled 169 patients with AGC and treated with either the PD-1 blockade (nivolumab or pembrolizumab; N = 112) or irinotecan monotherapy (N = 57) as a single agent. Tumour growth dynamics based on tumour growth kinetics and tumour growth rate (TGR) and time to treatment failure were analysed to define HPD. The incidence, clinical consequences and predictive markers of HPD were investigated.The optimal criteria for HPD were 4-fold increases in both tumour growth kinetics and TGR ratios and a 40% increase in TGR based on the analysis for patients treated with irinotecan. In total, 10.7% (12/112) of patients experienced HPD after PD-1 inhibitor treatment. Patients with HPD had both shorter progression-free survival (hazard ratio: 2.318; 95% confidence interval: 1.205-4.460) and overall survival (hazard ratio: 2.542; 95% confidence interval: 1.314-4.918) than patients with progressive disease without HPD, losing opportunities for subsequent systemic treatments. Although other variables including PD-L1 expression were not associated with the occurrence of HPD, hypoalbuminemia (lt;3.25 mg/dL) at baseline was significantly associated with the occurrence of HPD (P lt; 0.001) and inferior survival outcomes.HPD occurs in a proportion of patients with AGC and treated with PD-1 inhibitors. PD-1 inhibitor-induced HPD is associated with worse outcome, loss of eligibility for subsequent treatment and hypoalbuminemia, warranting further investigation.

Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.

Aim: Data are limited on PD-L1 expression and its association with overall survival (OS) in gastric cancer (GC) patients receiving routine care in different regions. Materials & methods: In a retrospective study, PD-L1 expression was assayed using the 22C3 pharmDx on GC tumor samples collected between 2003 and 2017 at South Korean and US cancer centers. PD-L1 positivity was defined as combined positive score (CPS) ≥1. The relationship between PD-L1 and OS was analyzed. Results: Of 574 GC tumor samples, 67.4% were CPS ≥1 (68.7% in Korean and 65.7% in US patients). PD-L1 expression was not associated with OS (adjusted hazard ratio: 0.94; 95% CI: 0.75–1.17). Conclusion: PD-L1 prevalence and its association with OS was similar between South Korean and US GC patients.

3G study protocol

Purpose:Monotherapy with eribulin or gemcitabine has been found to be moderately effective in treating soft-tissue sarcomas (STS). In this study, we evaluated the efficacy and safety of eribulin–gemcitabine combination therapy for the two most common histologic types of STS, liposarcoma and leiomyosarcoma.Patients and Methods:In this nonrandomized, multicenter, phase II study, we included patients with progressive disease who had received one or two courses of chemotherapy that included doxorubicin. Patients were administered 1.4 mg/m2 eribulin and 1,000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks), with null and alternative hypotheses of PFSR12wks ≤20.0% and ≥40.0%, respectively. Exploratory biomarker analyses with next-generation sequencing (NGS) were performed on pretreatment tumor samples.Results:Among the 37 patients included, the overall PFSR12wks was 73.0%, achieving the primary endpoint. The objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 5.6 months, and 31.9 months, respectively, without differences according to histologic type. New safety signals and treatment-related deaths were not documented. NGS-based transcriptome analysis revealed that functional enrichment in the TGFβ pathway was mostly associated with a poor outcome, whereas single genetic alterations largely failed to predict treatment outcome.Conclusions:Eribulin–gemcitabine combination therapy showed promising activity and an acceptable safety profile in patients with liposarcoma or leiomyosarcoma. Gene expression profiling with pathway enrichment analysis would have possibilities to have predictive value for survival outcome, necessitating further investigation to confirm.

Supplementary Figure from Phase II Clinical Trial of Eribulin–Gemcitabine Combination Therapy in Previously Treated Patients With Advanced Liposarcoma or Leiomyosarcoma

Supplementary Data from Phase II Clinical Trial of Eribulin–Gemcitabine Combination Therapy in Previously Treated Patients With Advanced Liposarcoma or Leiomyosarcoma

(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-β signaling pathway. Moreover, we selected the combination treatment comprising TGF-β inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-β inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.

Background The effect of long‐term surveillance for asymptomatic patients after curative resection of gastric cancer is being debated. We compared the prognosis of Korean patients with recurrent gastric cancer according to the presence or absence of cancer‐related symptoms at the time of recurrence detection. Methods We retrospectively reviewed the medical records of 305 Korean patients who experienced recurrence after curative resection of primary gastric cancer between March 2002 and February 2017 at Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. Results The median follow‐up duration was 169.8 months (1–267.2), and the median age at first recurrence was 58.1 years (23.4–81.9). Among 305 patients with recurrence, 97 of 231 (42.0%) patients with early recurrence (≤5 years after curative surgical resection) and 47 of 74 (63.5%) patients with late recurrence (>5 years after curative surgical resection) had cancer‐related symptoms at recurrence (p = 0.001). For survival after recurrence, detection of asymptomatic recurrence was an independent favorable factor (hazard ratio, 0.527; 95% confidence interval, 0.409–0.681; p, Asymptomatic detection of recurrence possibly improved the survival of gastric cancer long‐term survivors after curative surgical resection. The possibility of local control and targeted‐ or immunotherapy for the recurrent disease was related to the favorable survival outcomes. ​

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in soft tissue sarcoma (STS). Further, we performed molecular characterisation with whole exome and transcriptomic sequencing to identify the determinants of response. In this single-arm, phase 2 trial (NCT#03798106), we enrolled patients with metastatic and/or recurrent STS who had received up to two previous lines of systemic anticancer therapy and had at least one measurable lesion. Treatment consisted of pazopanib 800 mg orally, administered once a day, continuously, and durvalumab 1500 mg administered via intravenous infusion once every 3 weeks. The primary endpoint was the overall response rate. Between September 2019 and October 2020, fourteen (30.5%) of the 46 evaluable patients showed an objective response, including in alveolar soft-part sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, and desmoplastic small round cell tumour. During a median follow-up period of 18.4 months, the median progression-free survival (PFS) was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (n = 9), elevated aspartate aminotransferase (n = 7) and alanine aminotransferase (n = 5) levels, and thrombocytopenia (n = 4). In the exploratory analysis, the B lineage signature was a significant key determinant of overall response (P=0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS than those with low B cell infiltration and vessel density (P=6.5 × 10−4) as well as better response (50% vs 12%, P=0.019). In conclusion, durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile. Our findings provide insights into combined high B cell infiltration and vessel density as potentially relevant biomarkers for the selection of patients who may benefit to a greater extent from PD-L1 blockade and VEGF inhibitor combination. Citation Format: Hee Jin Cho, Kum-Hee Yun, Su-Jin Shin, Young Han Lee, Seung Hyun Kim, Wooyeol Baek, Yoon Dae Han, Sang Kyum Kim, JooHee Lee, Iksung Cho, Heounjeong Go, Jiwon Ko, Inkyung Jung, Min Kyung Jeon, Hyang Joo Ryu, Sun Young Rha, Hyo Song Kim, Hyun Jung Jun. Comprehensive molecular characterization of clinical response to durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: A phase 2 clinical trial [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 CT038.

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.

Backgrounds: There are scarce data on whether immune checkpoint inhibitors (ICIs) increase the risk of cardiac dysfunction when used with cardiotoxic agents. Thus, we evaluated cardiac dysfunction in patients with sarcoma receiving doxorubicin with or without ICI using echocardiography and left ventricular global longitudinal strain (LVGLS). Methods: A total of 95 patients were included in this study. Echocardiography and LVGLS were evaluated at baseline and follow-up (at 3 and 6 months of chemotherapy) and compared with the doxorubicin (Dox; n = 73) and concomitant ICI with doxorubicin (Dox-ICI; n = 22) groups. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a left ventricular ejection fraction (LVEF) drop of >10% and LVEF of 10%, LVEF of ≥50%, and LVGLS relative reduction of >15% (probable CTRCD) at six months. Results: There were no significant differences in age, cumulative dose of doxorubicin, and cardiovascular risk factors between the two groups. At baseline, the LVEF was similar in the Dox and Dox-ICI groups (p = 0.493). In the Dox group, LVEF decreased to 59 ± 6% (Δ −7 ± 1.3%, p < 0.001) and LVGLS decreased from −17.3 ± 3.2% to −15.4 ± 3.2% (Δ −10.1 ± −1.9%, p < 0.001) at six months. In the Dox-ICI group, LVEF decreased to 55 ± 9% (Δ −9 ± 2.1%, p < 0.001), along with a significant decrease in LVGLS (from −18.6 ± 1.9% to −15.3 ± 3.6%, Δ −12.4 ± −2.4%, p < 0.001). Over a median follow-up of 192 days, there were no cases with clinical manifestations of fulminant myocarditis. In the Dox group, definite and probable CTRCD were observed in seven (10.1%) and five (7.4%) patients, respectively. In the Dox-ICI group, definite and probable CTRCD were observed in four (19%) and four (19%) patients, respectively. The total number of patients who developed CTRCD was significantly higher in the Dox-ICI group than in the Dox group (38.1% vs. 17.4%, p = 0.042). Serum troponin-T level was significantly higher in the Dox-ICI group than in the Dox group (53.3 vs. 27.5 pg/mL, p = 0.023). Conclusions: ICIs may increase the risk of CTRCD when used with cardiotoxic agents. CTRCD should be monitored in patients treated with ICIs by cardiac biomarkers and echocardiography, including LV-GLS.

The canonical mutations in gastrointestinal stromal tumors (GISTs) are typically activating mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA). GISTs with non-canonical mutations are a heterogeneous group. Here, we examined tropomyosin-related kinase (TRK) fusion in GIST cases without KIT/PDGFRA mutations (KIT/PDGFRA wild-type (WT) GISTs). We retrospectively analyzed patients who were diagnosed with GISTs at the Yonsei Cancer Center, Severance Hospital, between January 1998 and December 2016. Thirty-one patients with KIT/PDGFRA WT GISTs were included in the analysis. TRK expression in tumor samples was assessed by pan-TRK immunohistochemistry (IHC), and the neurotrophic tyrosine receptor kinase (NTRK: the gene encoding TRK) rearrangement was analyzed by fluorescence in situ hybridization (FISH). IHC analyses revealed that five cases in this cohort exhibited a weak to moderate TRK expression. NTRK1 fusions were detected in three tumor samples, and two samples harbored NTRK3 fusions. The remaining 26 samples did not harbor NTRK fusions. Two types of NTRK fusions were detected, and the overall NTRK fusion frequency in KIT/PDGFRA WT GIST cases was 16% (5/31). Our data provide insights into the molecular alterations underpinning KIT/PDGFRA WT GISTs. More effort should be devoted to improve methods to identify this distinct disease subtype within the KIT/PDGFRA WT GIST group.

Background The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan-ErbB kinase inhibitor, in patients with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M-ESCC). Methods Patients with R/M-ESCC that was refractory to platinum-based chemotherapy were enrolled in the current multicenter, single-arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, overall survival, the disease control rate, and the safety profile. To identify predictive biomarkers, single-nucleotide variations, short insertions/deletions, and somatic copy number alterations were assessed using whole-exome sequencing and their associations with clinical outcomes were analyzed. Results Among 49 enrolled patients, the objective response rate and disease control rate were 14.3% and 73.3%, respectively. With a median follow-up of 6.6 months, the median progression-free survival and overall survival were 3.4 months and 6.3 months, respectively. Treatment-related adverse events were noted to have occurred in 33 patients (67.3%), with the majority being of grade 1 to 2 (adverse events were graded and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). Whole-exome sequencing demonstrated that the ESCC genomes of patients who demonstrated a response to afatinib were enriched with genomic alterations of TP53 and epidermal growth factor receptor (EGFR). As a predictive marker, a score derived from TP53 disruptive mutations and EGFR amplifications and/or missense mutations demonstrated a significant association with the response to afatinib. The score based on the mutational status of EGFR and TP53 achieved a performance of an area under the curve of 0.86 in predicting the sensitivity of afatinib. Conclusions The results of the current study demonstrated that afatinib can confer modest clinical benefits with manageable toxicity in patients with platinum-resistant R/M-ESCC. Identification of TP53 alterations and EGFR amplifications may serve as predictive markers with which to identify patients with R/M-ESCC who may benefit from afatinib. Lay summary Esophageal squamous cell carcinoma (ESCC) is a type of cancer with a dismal prognosis and very limited treatment options. The clinical efficacy of afatinib was evaluated in patients with recurrent and/or metastatic ESCC, with adverse events demonstrating the modest efficacy with manageable toxicity of this irreversible, pan-ErbB kinase inhibitor. Whole-exome sequencing analysis of 41 cases of ESCC further revealed that the patients harboring epidermal growth factor receptor (EGFR) amplifications and disruptive TP53 mutations are more likely to benefit from treatment with afatinib. The results of the current study have highlighted the clinical value of EGFR and TP53 as predictive biomarkers of platinum-resistant recurrent and/or metastatic ESCC for afatinib sensitivity.

Background: Inhibitors of programmed death-ligand 1 (PD-L1) have potential therapeutic value in gastric cancer. We investigated PD-L1 expression patterns in paired biopsy and resection specimens. Patients and Methods: Thirty-nine formalin-fixed, paraffin-embedded paired samples were assessed using PD-L1 22C3 pharmDx immunohistochemistry technique. Combined positive score (CPS) was calculated as the ratio of PD-L1 stained cells (tumor cells, lymphocytes, and macrophages) to the total number of viable tumor cells, multiplied by 100. The CPS ≥1 indicated PD-L1 positivity. Results: PD-L1 positivity was evident for 33 (84.6%) of 39 resection cases; all displayed low positivity (1≤CPS

Background: Developing personalized strategies for cancer has shown good efficacies. Methods: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. Results: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL– tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). Conclusions: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.

Purpose: Monotherapy with eribulin or gemcitabine has been found to be moderately effective in treating soft-tissue sarcomas (STS). In this study, we evaluated the efficacy and safety of eribulin–gemcitabine combination therapy for the two most common histologic types of STS, liposarcoma and leiomyosarcoma. Patients and Methods: In this nonrandomized, multicenter, phase II study, we included patients with progressive disease who had received one or two courses of chemotherapy that included doxorubicin. Patients were administered 1.4 mg/m2 eribulin and 1,000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks), with null and alternative hypotheses of PFSR12wks ≤20.0% and ≥40.0%, respectively. Exploratory biomarker analyses with next-generation sequencing (NGS) were performed on pretreatment tumor samples. Results: Among the 37 patients included, the overall PFSR12wks was 73.0%, achieving the primary endpoint. The objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 5.6 months, and 31.9 months, respectively, without differences according to histologic type. New safety signals and treatment-related deaths were not documented. NGS-based transcriptome analysis revealed that functional enrichment in the TGFβ pathway was mostly associated with a poor outcome, whereas single genetic alterations largely failed to predict treatment outcome. Conclusions: Eribulin–gemcitabine combination therapy showed promising activity and an acceptable safety profile in patients with liposarcoma or leiomyosarcoma. Gene expression profiling with pathway enrichment analysis would have possibilities to have predictive value for survival outcome, necessitating further investigation to confirm.

374 Background: Anti-PD-1 monotherapy did not improve overall survival compared with paclitaxel in second-line treatment for advanced gastric cancer (AGC) in KEYNOTE-061 trial. Recent studies suggest that inhibition of transforming growth factor beta (TGF-β) signaling reverses immunosuppressive tumor microenvironment into improved responses to cancer immunotherapy. Especially, genomically stable subtype of AGC showed the increased level of TGF-β pathway. Here, we report the results of phase Ib/II trial of bintrafusp alfa (M7824), a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII fused to a human IgG1 mAb blocking PD-L1, in combination with paclitaxel as a 2nd line treatment for AGC. Methods: This investigator-initiated, single-arm, open-label, phase Ib/II study enrolled HER2-negative, histologically confirmed AGC patients with evaluable disease who failed prior palliative 1st line treatment. Prior immune checkpoint inhibitor was not allowed. Phase 1b was planned to enroll 3 to 12 patients in a 3+3 design (bintrafusp alfa 1200mg on days 1 and 15 plus paclitaxel 80 mg/m2 (level 1) or 70 mg/m2 (level -1) on days 1, 8 and 15) every 28 days). The primary endpoints were to determine recommended phase II dose (RP2D) for phase Ib, and progression-free survival (PFS) at 6 months for phase II. Secondary endpoints included PFS, OS, ORR, DCR, and safety. Exploratory endpoints included immune-related biomarker changes from serial liquid biopsies (NCT04835896). Results: In phase 1b, dose limiting toxicities were not observed, and the RP2D was determined as dose level 1. During phase II, enrollment was stopped after 30 patients were recruited, following negative readouts from bintrafusp alfa trials in other indications. With a median follow-up duration of 10.9 months (95% CI 9.5–12.6), 7 patients remained on treatment (treatment duration range: 1.0 to 15.1 months) as of September, 2022. Median PFS was 3.8 months (95% CI, 2.6-7.8) and PFS rate at 6 months was 36.7% (95% CI, 20.1-53.4). Median OS was 9.6 months (95% CI, 4.1-not reached). In patients with measurable lesions (n=25), ORR was 28% (PR, n=7) and DCR was 68%. No patient was EBV-related. Patients with MSI-H (n=3; mPFS, 7.8 months; mOS, not reached) or PD-L1-positive (CPS≥1) (n=9; mPFS, 7.8 months; mOS, not reached) showed durable efficacy. Treatment-related AEs (≥G3) occurred in 23 pts (76.7%), including anemia (G3, n=12, 40%) and neutropenia (G3, n=9, 30%). Immune-related AE included urticaria (G3, n=2, 6.7%; G2, n=4, 13.3%), rash (G3, n=1, 3.3%), and pneumonitis (G3, n=1, 3.3%). Conclusions: Combination of bintrafusp alfa and paclitaxel was feasible with modest efficacy as 2nd line treatment for AGC. There was subset of patients with durable responses. Analyses of targeted next-generation sequencing from serial ctDNA sampling are ongoing. Clinical trial information: NCT04835896 .

Introduction: There is scarce data on whether immune checkpoint inhibitor (ICI) increase the risk of cardiomyopathy, especially when used with cardiotoxic agents. Hypothesis: We evaluated the cardiotoxicity of the ICI in sarcoma patients receiving doxorubicin with or without ICI by echocardiographic parameters and left ventricular global longitudinal strain (LVGLS). Methods: A total of 89 patients were included. Echocardiography and LVGLS were evaluated at baseline and follow-up (after 3 and 6months) and compared between the doxorubicin (n=67) and concomitant ICI with doxorubicin (n=22) groups. Cancer-therapy related cardiac dysfunction (CTRCD) was defined as LVEF drop of >10% and LVEF of 10%, LVEF of > 50% and LVGLS relative reduction of >15% (probable CTRCD) at 6months. Results: There was no significant difference in age, cumulative dose of doxorubicin and cardiovascular risk factors between two groups. At baseline, LVEF was similar between two groups (p=0.493). In doxorubicin group, LVEF decreased to 59±6 % (p Conclusions: ICI increases risk of CTRCD, when concomitantly treated with cardiotoxic agents. Thus, cardiomyopathy should be monitored in patients with ICI by comprehensive echocardiographic assessment including myocardial strain.

Next-generation sequencing (NGS) is becoming essential in the fields of precision oncology. With implementation of NGS in daily clinic, the needs for continued education, facilitated interpretation of NGS results and optimal treatment delivery based on NGS results have been addressed. Molecular tumor board (MTB) is multidisciplinary approach to keep pace with the growing knowledge of complex molecular alterations in patients with advanced solid cancer. Although guidelines for NGS use and MTB have been developed in western countries, there is limitation for reflection of Korea’s public health environment and daily clinical practice. These recommendations provide a critical guidance from NGS panel testing to final treatment decision based on MTB discussion.

In the original article [...]

Purpose The ability of the T‐cell–inflamed gene expression profile (GEP) to predict clinical outcome in esophageal cancer (EC) is unknown. This retrospective observational study assessed the prognostic value of GEP and programmed death ligand 1 (PD‐L1) expression in patients with EC treated in routine clinical practice. Methods Tumor samples of 294 patients from three centers in Denmark, South Korea, and the United States, collected between 2005 and 2017, were included. T‐cell–inflamed GEP score was defined as non‐low or low using a cutoff of −1.54. A combined positive score (CPS) ≥10 was defined as PD‐L1 expression positivity. Associations between overall survival (OS) and GEP status and PD‐L1 expression were explored by Cox proportional hazards models adjusting for age, sex, histology, stage, and performance status. Results Median age was 65 years; 63% of patients had adenocarcinoma (AC) and 37% had squamous cell carcinoma (SCC). Thirty‐six percent of tumors were GEP non‐low, with higher prevalence in AC (46%) than SCC (18%). Twenty‐one percent were PD‐L1–positive: 32% in South Korean samples versus 16% in non‐Asian samples and 26% in SCC versus 18% in AC. GEP scores and PD‐L1 CPS were weakly correlated (Spearman’s R = 0.363). OS was not significantly associated with GEP status (non‐low vs low; adjusted hazard ratio, 0.91 [95% CI, 0.69–1.19]) or PD‐L1 expression status. Conclusion Neither GEP nor PD‐L1 expression was a prognostic marker in Asian and non‐Asian patients with EC., In a cohort of 294 patients with esophageal adenocarcinoma and esophageal squamous cell carcinoma from Denmark, South Korea, and the United States, T‐cell–inflamed gene expression profile (GEP) score (non‐low vs low) and PD‐L1 expression status (CPS ≥10 vs CPS

Aim: There are limited data on the feasibility of programmed death ligand-1 (PD-L1) expression as a prognostic biomarker in metastatic angiosarcoma. Patients & methods: We retrospectively collected and analyzed the data on PD-L1 expression in 70 angiosarcoma patients who were diagnosed at our center between 2005 and 2019. Results: Thirteen (19%) patients had PD-L1 expression. Metastatic angiosarcoma patients who were PD-L1-negative (n = 24) showed longer median progression-free survival (4.9 vs 1.6 months; p = 0.04) and median overall survival (OS; 10.9 vs 5.4 months; p = 0.01) than those who were PD-L1-positive (n = 4). PD-L1 status proved to be a significant factor for OS. Conclusion: Metastatic angiosarcoma patients with PD-L1 expression showed shorter survival. PD-L1 status is an independent prognostic factor for OS in metastatic angiosarcoma patients., Lay abstract Angiosarcoma, a rare subtype of sarcoma, is highly aggressive and has poor prognosis. The majority of patients are diagnosed at advanced and metastatic stages, and treatment options for these subsets of patients are limited to cytotoxic chemotherapy. Validation of prognostic markers including PD-L1 expression remain to be fully carried out in metastatic angiosarcoma. In our study, we assessed the PD-L1 expression in metastatic angiosarcoma and its role as a prognostic biomarker.

Background and purpose To evaluate the safety and efficacy of preoperative chemotherapy (CTx) followed by chemoradiotherapy (CCRT) for high-risk gastric cancer (GC). Methods and materials The inclusion criteria were as follows: (1) Borrmann type 4; (2) large Borrmann type 3 (≥8 cm); (3) single bulky (≥3 cm × 1) or multiple lymph nodes (≥1.5 cm × 3). Patients received two 21-day courses of induction CTx of TS-1 (35 mg/m2, p.o, twice daily on days 1–14), docetaxel (30 mg/m2, i.v., days 1 and 8), and cisplatin (30 mg/m2, i.v., days 1 and 8) followed by CCRT (two courses of TS-1 and cisplatin in combination with 45 Gy radiation). Results Forty-two patients were enrolled between March 2014 and February 2016, and 39 of these completed sequential CTx and CCRT. Among the 33 patients who underwent R0 resection, the pathologic response rate was 39.4% [no residual carcinoma (n = 5, 15.2%), with 1–10% residual carcinoma (n = 8, 24.2%)]. Overall, 4 patients (12.1%) were pathologic stage 0, 7 (21.2%) were stage I, 10 (30.3%) were stage II, and 12 (36.4%) were stage III. The overall survival rate at 3 years was 77.9% for stages 0 and I, 66.8% for stages II–III, and 33.3% for unresectable cases (P = 0.001). Toxicity was mild to moderate with grade 4 neutropenia (n = 1) and neutropenic fever (n = 1) as the most prominent side-effects. Conclusions Sequential CTx and CCRT prior to surgery are feasible and effective for high-risk GC. Trial registration number: NCT02495493.

Background The aim of this study is to profile the cytokines and immune cells of body fluid from metastatic gastric cancer (mGC), and evaluate the potential role as a prognostic factor and the feasibility as a predictive biomarker or monitoring source for immune checkpoint inhibitor. Methods Body fluid including ascites and pleural fluid were obtained from 55 mGC patients and 24 matched blood. VEGF-A, IL-10, and TGF-β1 were measured and immune cells were profiled by fluorescence assisted cell sorting (FACS). Results VEGF-A and IL-10 were significantly higher in body fluid than in plasma of mGC. Proportion of T lymphocytes with CD69 or PD-1, memory T cell marked with CD45RO, and number of Foxp3+ T regulatory cells (Tregs) were significantly higher in body fluid than those in blood of mGC. Proportion of CD8 T lymphocyte with memory marker (CD45RO) and activation marker (HLA-DR), CD3 T lymphocyte with PD-1, and number of FoxP3+ Tregs were identified as independent prognostic factors. When patients were classified by molecular subgroups of primary tumor, VEGF-A was significantly higher in genomically stable (GS)-like group than that in chromosomal instability (CIN)-like group while PD-L1 positive tumor cells (%) showed opposite results. Monitoring immune dynamics using body fluid was also feasible. Early activated T cell marked with CD25 was significantly increased in chemotherapy treated group. Conclusions By analyzing cytokines and proportion of immune cells in body fluid, prognosis of patients with mGC can be predicted. Immune monitoring using body fluid may provide more effective treatment for patients with mGC. Electronic supplementary material The online version of this article (10.1186/s40425-019-0708-8) contains supplementary material, which is available to authorized users.

Purpose We conducted a randomized, multicenter, phase III trial to compare S-1 plus docetaxel (DS) with S-1 plus cisplatin (SP) as adjuvant chemotherapy for stage III gastric cancer patients. Materials and Methods Stage III gastric cancer patients who had received curative gastrectomy with D2 lymphadenectomy were randomized into equal groups to receive adjuvant chemotherapy of eight cycles of DS (S-1 70 mg/m2/day on days 1-14 plus docetaxel 35 mg/m2on days 1 and 8) every 3 weeks or SP (S-1 70 mg/m2/day on days 1-14 plus cisplatin 60 mg/m2on day 1) every 3 weeks. The primary endpoint was 3-year disease-free survival (DFS) rate. Results Between November 2010 and July 2013, 153 patients (75 patients to DS and 78 patients to SP) were enrolled from 8 institutions in Korea. After the capecitabine plus oxaliplatin was approved based on the CLASSIC study, itwas decided to close the study early. With a median follow-up duration of 56.9 months, the 3-year DFS rate between two groups was not significantly different (49.14% in DS group vs. 52.5% in SP group). The most common grade 3-4 adverse event was neutropenia (42.7% in DS and 38.5% in SP, p=0.351). SP group had more grade 3-4 anemia (1.3% vs. 11.5%, p=0.037), whereas grade 3-4 hand-foot syndrome (4.1% vs. 0%, p=0.025) and mucositis (10.7% vs. 2.6%, p=0.001) were more common in DS group. Fifty-one patients (68%) in DS group and 52 (66.7%) in SP group finished planned treatment. Conclusion Our findings suggest that SP or DS is an effective and tolerable option for patients with curatively resected stage III gastric cancer.