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Background: Lenvatinib is approved for patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, its clinical outcomes in patients experiencing HCC recurrence after liver transplantation (LT) remain unclear. Thus, we investigated the efficacy and safety of lenvatinib in patients with recurrent HCC after LT.Methods: This multinational, multicenter, retrospective study included 45 patients with recurrent HCC after LT who received lenvatinib at six institutions in three countries (Korea, Italy, and Hong Kong) from June 2017 to October 2021.Results: At the time of lenvatinib initiation, 95.6% (n = 43) of patients were Child–Pugh A, with 35 (77.8%) and 10 (22.2%) patients classified as albumin-bilirubin (ALBI) grades 1 and 2, respectively. The objective response rate was 20.0%. With a median follow-up duration of 12.9 months (95% confidence interval [CI]: 11.2–14.7), median progression-free survival and overall survival (OS) were 7.6 (95% CI: 5.3–9.8) months, and 14.5 (95% CI: 0.8–28.2) months, respectively. Patients with ALBI grade 1 showed significantly better OS (52.3 months, [95% CI: not assessable]) than patients with ALBI grade 2 (11.1 months [95% CI: 0.0–30.4 months], p = 0.003). The most common adverse events were hypertension (n = 25, 55.6%), fatigue (n = 17, 37.8%), and anorexia (n = 14, 31.1%).Conclusion: Lenvatinib showed consistent efficacy and toxicity profiles in patients with recurrent HCC after LT compared to the results of previous studies of non-LT HCC patients. The baseline ALBI grade was correlated with better OS in lenvatinib-treated patients with LT.

This study aimed to determine the equivalence between definitive chemoradiotherapy (DCRT) and radical esophagectomy in clinical T1bN0M0 esophageal squamous cell carcinoma (ESCC).Among 282 patients with cT1bN0M0 ESCC, 238 underwent radical esophagectomy and 44 underwent DCRT. Both treatments were retrospectively compared overall survival (OS), progression-free survival (PFS), and complications.The DCRT group exhibited poorer patient characteristics than the surgery group, especially with mean age (73 vs. 63 years), Eastern Cooperative Oncology Group (ECOG) status, and Charlson Comorbidity Index (p 0.001, each). The median follow-up duration was 49.5 (range, 0.4-97.0) and 45.5 months (range, 5.0-112.0) in the surgery and DCRT groups, respectively. In the DCRT group, clinical complete response was achieved in 43 patients (97.7%) at 1 month after treatment. The 5-year OS rates were 75.8% and 68.8% (p = 0.135) and the 5-year PFS were 63.8% and 57.8% (p = 0.637) for the surgery and DCRT groups, respectively. Local recurrence rates were identical between the two groups (11.4% and 11.4%), but the distant metastasis rate was lower in the DCRT group (n = 1, 2.27% vs. n = 29, 12.15%). Grade 3-4 hematologic toxicities were observed in 11 patients (25%) of the DCRT group, and 56 patients (23.5%) in the surgery group showed grade 3-5 surgical complications, including mortality (n = 5).Based on the non-inferior survival rates, recurrence patterns, and complication rates without critical surgical mortality, DCRT was comparable to esophagectomy for cT1bN0 esophageal squamous cell carcinoma.

Background: Immune checkpoint inhibitors have shown survival benefits in unresectable/metastatic gastric cancer (GC), esophageal cancer (EC), and hepatocellular carcinoma (HCC). Based on scientific rationale for neoadjuvant immunotherapy, we conducted a phase II study of neoadjuvant IMC-001, a novel PD-L1 targeting fully human monoclonal antibody, for resectable GC, EC, and HCC. Methods: This is a prospective, phase II study of neoadjuvant IMC-001 (20 mg/kg iv every 2 weeks for 2 cycles) across three cohorts of resectable GC, EC, and HCC. The primary endpoint is major pathologic response rate ( Results: From Sep. 2019 to Nov. 2022, 50 patients (pts) were enrolled and treated (safety analysis population), and among them, 48 pts were evaluable for the efficacy analysis (16 HCC; 16 GC; 16 EC); male (81%), median age=62 yrs (range, 39-77), and clinical stage (AJCC 8th ed.) I (56%)/II (33%)/III (10%). All tumors were microsatellite stable and 33% of tumors were PD-L1+. 45 pts (94%) completed 2 cycles of neoadjuvant IMC-001, all pts underwent surgery, and only one pt’s surgery was delayed due to immune-related hepatitis. No pts had disease progression during neoadjuvant therapy, and among the 17 pts with measurable lesion(s) by RECIST 1.1, 3 pts (18%) showed partial response (PR) and 14 pts (82%) had stable disease (SD). Among 30 metabolic response-evaluable pts by EORTC criteria, 7 pts (15%) showed metabolic PR, 20 pts (43%) had metabolic SD, and 3 pts (6%) had metabolic PD. Among 2 of 3 pts with metabolic PD, surgical pathology showed increased tumor infiltrating lymphocytes and tumor regression. The median change of the sum of SUVmax was -13% (range, -76% to 59%). All pts underwent R0 resection with pathologic stage of I (75%)/II (13%)/III (13%). Although there was no major pathologic response, 51% of pts showed various degree of tumor necrosis or fibrosis and 7 pts (15%) had residual viable tumor cells less than 50%. Except for grade 3 AST/ALT elevation (6%), all treatment-related adverse events (TRAEs) were grade 1 or 2. TRAEs occurring in ≥5% of pts were hyperthyroidism (18%), hypothyroidism (14%), fatigue (14%), pruritus (12%), skin rash (8%), infusion-related reaction (6%), and diarrhea (6%). Conclusions: Neoadjuvant IMC-001 was well tolerated and demonstrated antitumor activity in microsatellite stable, resectable GC, EC, and HCC pts. The updated clinical and biomarker results will be presented. Citation Format: Sook Ryun Park, Joon Seon Song, In Hye Song, Moon-Won Yoo, Yong-Hee Kim, Hyeong Ryul Kim, Ju Hyun Shim, Danbi Lee, Jonggi Choi, Ki Won Song. A phase II study of neoadjuvant immune checkpoint inhibitor IMC-001 (anti-PD-L1 antibody) in patients with resectable upper gastrointestinal cancers (Neo-Chance Study) [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 CT147.

Background Various cell-free DNA (cfDNA) features including methylation and genomic profiles have been investigated for their potential use in early cancer detection. We developed deep learning models based the data generated by the enzymatic conversion based whole methylome sequencing of cfDNA. Methods Cell-free whole genome Enzymatic Methyl sequencing(cfWEMseq) data were generated from 198 cancer patients (stage I: 11%, II: 17%, III: 22%, IV: 20%, unknown: 31%) and 69 healthy controls. The cancer types were consisted of breast (n=31), liver (n=24), esophageal (n=38), pancreatic (n=30), colon (n=34), ovarian (n=18), and lung (n=23). Sequence data was produced on average of 200 million reads using Novaseq 6000 (Illumina). For model training and evaluation, data partitioning was stratified by cancer type, and 5-fold cross validation was used. Coverage and methylation beta values ​​were calculated by binning at fixed size of 100K, 1M, and 5M base and variable size from Topologically Associated Domains (TAD). Genome Coverage (GC), Genome Methylation Beta values ​​(GMB), and Mutation Signature (MS) features were trained using a one-dimensional convolutional neural network (1D-CNN). The performance of the model was evaluated by measuring the average value of the results measured in each test set of 5 fold. Results We tested the cancer detection performance of various feature combinations using all data from cfWEMseq (n=267). Regardless of the bin size, the GMB single model achieved higher performance than the GC single model. The best-performing model is the ensemble model of GMB (100k bin) and MS. The cancer detection performance of this ensemble model reached an accuracy 96% (CI: 93.6% to 98.1%), AUC 0.99 (CI: 0.97 to 1.0) and sensitivity 98.0% (CI: 92.4% to 99.5%) with a specificity of 90%. Conclusions These results provide an opportunity for higher accuracies by integrating methylation information and genomic data using cfWEMseq. This research was supported through the National Research Foundation (NRF) funded by the Ministry of Science and ICT (2020M2D9A3094213). Citation Format: Juntae Park, Minjung Kim, Sook Ryun Park, Ki-Byung Song, Eunsung Jun, Dongryul Oh, Jeong-Won Lee, Young Sik Park, Ki-Won Song, Jeong-Sik Byeon, Bo Hyun Kim, Chang-Seok Ki, Eunhae Cho. Deep learning algorithm for cancer detection using multimodal characteristics of whole methylome sequencing of cf-DNA. [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 6697.

The advent of receptor tyrosine kinase inhibitors (RTKi) are important contributions to treat NSCLC patients harboring genetic aberration effectively. Nevertheless, the emergence of acquired or intrinsic RTKi resistance by other RTK activation bypass finally limits their efficacy. First of all, in this study, we identified MED12 mutation in TKI-resistant NSCLC cells based-on NGS analysis. Although MED12 was known to controls the response to multiple cancer drugs through regulation of TGF-beta receptor signaling reportedly, we additionally found that MED12 mutation activates not only TGF-beta receptor not also other ones, such as EGFR, meaning that blocking TGF-beta receptor or EGFR alone may not effective to overcome MED12 mutation-induced RTKi resistance. To overcome the RTKi resistance in NSCLC harboring MED12 mutation, we elaborated the two downstream signaling of RTK in MED12 knock-out NSCLC cells and observed that PI3K/AKT signaling is downregulated but MEK/ERK signaling is upregulated. We observed that only MEK inhibitor (MEKi), not PI3K/mTOR inhibitor, shows effective anti-cancer effect. Therefore, we explored why MEKi alone is effective in RTKi resistant NSCLC cells harboring MED12 mutation and presented that MED12 mutation directly suppressed activation of YAP via blocking a large mediator complex of MED12, MED13, CDK8 and CCNC, thereby increasing PTEN expression by inhibition of miR-29 expression. Increased PTEN inhibits reactivation of PI3K/AKT pathway. In conclusion, we first identified that MED12 mutation induces RTKi resistance though activating other RTKs, such as TGF-beta receptor or EGFR, and blocks PI3K/AKT pathway via dysregulation of YAP/PTEN/AKT interaction. Therefore, among two downstream signaling of RTK, activated MEK/ERK pathway can be a definitive target enough to overcome RTKi resistant NSCLC patients harboring MED12 mutation and MEKi could be a primary treatment option for resistant patients harboring MED12 mutation among NSCLC patients with repetitive recurrence of RTKi resistance by another RTK activation bypass. Citation Format: Hyun-Min Ryu, Deokhoon Kim, Shinkyo Yoon, Ho-Su Lee, Eunjin Lee, Chang Hoon Lee, Wanlim Kim, Seyoung Seo, Kyung Hae Jung, Sook Ryun Park, Sang-We Kim, Kang-Seo Park, Dae Ho Lee. RTK inhibitor resistance in NSCLC harboring MED12 mutation is overcome by only blocking MEK signaling, not AKT due to mutated MED12-induced YAP-PTEN dysregulation [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 424.

The vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemoresistance. We conducted a phase 1 clinical trial with 32 patients with refractory solid tumors to evaluate the safety, pharmacokinetics, and pharmacodynamics of combinations of VEGF-targeting pazopanib and the putative c-MET inhibitor ARQ197 (tivantinib) at 5 dose levels (DLs). Patients either took pazopanib and tivantinib from treatment initiation (escalation phase) or pazopanib alone for 7 days, with paired tumor sampling, prior to starting combination treatment (expansion phase). Hypertension was the most common adverse event. No more than 1 dose limiting toxicity (DLT) occurred at any DL, so the maximum tolerated dose (MTD) was not determined; DL5 (800 mg pazopanib daily and 360 mg tivantinib BID) was used during the expansion phase. Twenty of 31 evaluable patients achieved stable disease lasting up to 22 cycles. Circulating VEGF, VEGFR2, HGF, and c-MET levels were assessed, and only VEGF levels increased. Tumor c-MET levels (total and phosphorylated) were determined in paired biopsies before and after 7 days of pazopanib treatment. Total intact c-MET decreased in 6 of 7 biopsy pairs, in contrast to previously reported c-MET elevation in response to VEGF inhibition. These results are discussed in the context of our previously reported analysis of epithelial-mesenchymal transition in these tumors. Supplementary information The online version contains supplementary material available at 10.1007/s10637-021-01138-x.

BACKGROUND & AIMS The optimal systemic chemotherapy for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) has not yet been defined. The definition and classification of cHCC-CCA has changed recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC-CCA. METHODS Among 254 patients with histologically confirmed cHCC-CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were retrospectively evaluated. RESULTS Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first-line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow-up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non-platinum containing first-line chemotherapy remained as significant prognostic factors for poorer OS. CONCLUSIONS The efficacy outcomes according to first-line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.

Introduction: Atezolizumab-bevacizumab is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, the optimal sequence of therapy after disease progression on atezolizumab-bevacizumab is unclear. Methods: This multinational, multicenter, and retrospective study assessed clinical outcomes of patients with advanced HCC who received subsequent systemic therapy after progression on atezolizumab-bevacizumab between July 2016 and April 2019. Results: Among 71 patients treated with atezolizumab-bevacizumab, a total of 49 patients who received subsequent systemic therapy were included in this analysis; the median age was 60 years (range, 37–80) and 73.5% were male. All patients were classified as Child-Pugh A and Barcelona-Clinic Liver Cancer stage C. Multikinase inhibitors (MKIs), including sorafenib (n = 29), lenvatinib (n = 19), and cabozantinib (n = 1), were used as second-line therapy for all patients. The objective response rate and disease control rate were 6.1 and 63.3%, respectively, in all patients. With a median follow-up duration of 11.0 months, median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI] 1.8–4.9) and 14.7 months (95% CI 8.1–21.2) in all patients. Median PFS with lenvatinib was significantly longer than that with sorafenib (6.1 vs. 2.5 months; p = 0.004), although there was no significant difference in median OS (16.6 vs. 11.2 months; p = 0.347). Treatment-related adverse events (TRAEs) of any grade and grade 3 occurred in 42 (85.7) and 8 (16.3%) of patients. Common TRAEs included hand-foot syndrome (n = 26, 53.1%), fatigue (n = 14, 28.6%), hypertension (n = 14, 28.6%), and diarrhea (n = 12, 24.5%). Conclusion: Second-line treatment with MKIs, mostly sorafenib and lenvatinib, showed comparable efficacy and manageable toxicities in patients with advanced HCC after disease progression on atezolizumab-bevacizumab.

Background: Regorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients. Objective: We performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib–regorafenib compared with sorafenib and physician’s choice in a real-life setting. Patients and Methods: A propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S–R) and the arm treated with sorafenib and physician’s choice (S–P). Survival analysis was conducted on the matched population. Results: After the application of propensity score matching, we analysed 99 patients in the arm treated with S–R and 99 patients in the arm treated with S–P. For the S–R group, the median overall survival was 22.2 months (95% CI 17.1–27.4), compared to 17.9 months (95% CI 15.1–50.0) for the S–P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S–R (p = 0.0382) compared to patients treated with S–P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread. Conclusion: This study provides additional proof of the superiority of the S–R treatment over the S–P treatment approach in advanced HCC patients from a real-life setting.

As patients receiving definitive chemoradiotherapy (dCRT) for oesophageal squamous cell carcinoma (ESCC) are heterogeneous, we aimed to identify prognostic factors and failure patterns after dCRT. From 2006 to 2015, 327 patients who received dCRT for ESCC were reviewed. Treatment response to dCRT was evaluated based on EORTC‐PET criteria with endoscopy and CT results. After dCRT, 296 patients (90.5%) achieved disease stabilisation, with 132 cases of complete response (CR) (40.4%), 158 of partial response (PR) (48.3%) and 6 of stable disease (SD) (1.8%); 31 patients (9.5%) had progressive disease (PD). Median overall survival (OS) from response evaluation was 24.0 months in the overall population. Post‐treatment clinical response was the most significant prognostic factor for OS in the multivariate analysis (median OS, 65.0 months for CR, 17.3 months for PR, 4.4 months for SD and 4.0 months for PD; p, Patients with oesophageal squamous cell carcinoma treated with definitive chemoradiotherapy show highly different prognoses after treatment, especially according to the clinical response to chemoradiotherapy.

Background/aim Oxaliplatin-based chemotherapy is associated with hepatic sinusoidal obstruction syndrome (SOS). Patients and methods We analyzed patients from two prospective trials, in which capecitabine/oxaliplatin (XELOX, 8 cycles; n=51) and S-1/oxaliplatin [SOX, continuous (SOX-C, n=50), or intermittent (discontinuation after cycle 6 and restart on progression, SOX-I, n=50)] were administered. We compared severity (splenomegaly, thrombocytopenia, liver enzyme levels, and hepatic parenchymal heterogeneity), clinical significance (delay or dose-reduction of chemotherapy), and reversibility of SOS (splenomegaly and thrombocytopenia after stopping chemotherapy) between SOX and XELOX in gastric cancer patients. Results SOX was more likely to be associated with splenomegaly, thrombocytopenia, hyperbilirubinemia, and hepatic parenchymal heterogeneity than XELOX. Splenomegaly was partially reversible after stopping chemotherapy in both regimens, but recovery rate was lower in SOX. Proportion of delayed or dose-reduced chemotherapy cycles due to thrombocytopenia was significantly higher in SOX-C than in XELOX. Conclusion S-1 combination is more likely to worsen oxaliplatin-induced hepatic sinusoidal injuries than capecitabine in gastric cancer patients.

The American Joint Committee on Cancer 8th edition staging system presents separate classifications for pTNM and post-neoadjuvant ypTNM (ypTNM-8th) to enhance prognostic prediction after neoadjuvant therapy and surgery. We aimed to validate the ypTNM-8th staging system and to compare the prognostication performance of ypTNM-8th with that of pTNM-7th and pTNM-8th in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (nCRT).We reviewed 207 ESCC patients treated with nCRT between January 2007 and December 2014 and compared the Akaike information criterion (AIC) and Harrell's C-index to determine the prognostic performance of each TNM system.Survival curve analysis of pTNM-7th and -8th showed a stepwise drop in survival from ypT0N0 to advanced stages, whereas the survival outcome of ypStage III showed a better prognosis than that of ypStage II according to ypTNM-8th. Lymphovascular invasion, perineural invasion, and tumor regression grade were significantly associated with overall survival on univariate analysis. Each TNM system showed significant p-values for trend (p 0.0001 each), but after adjusting for prognostic factors, ypTNM-8th did not significantly predict survival (p = 0.15), whereas pTNM-7th remained significant (p 0.001). pTNM-7th incorporating ypT0N0M0 and ypT0 (is)N + M0 as separate groups was superior in prognostication as its AIC was smaller and its C-index was higher than those of pTNM-8th and ypTNM-8th, respectively.Because ypTNM-8th did not provide sufficient prognostication for patients with ESCC treated with nCRT followed by esophagectomy, more sophisticated prognostic classification should be developed for the ypTNM staging system in these patients.

In East Asia, S-1 plus cisplatin (SP) is one of the standard first-line chemotherapy regimens for metastatic or recurrent gastric cancer (MRGC). Oxaliplatin is generally less toxic and more convenient to administer than cisplatin. This was a multicenter, phase III study assessing whether S-1/oxaliplatin (SOX) was non-inferior/superior to SP in terms of progression-free survival (PFS). Patients with MRGC were randomized 1:1 to receive either SOX (S-1 80 mg/m2/day on days 1–14; oxaliplatin 130 mg/m2 on day 1; every 3 weeks) or SP (S-1 80 mg/m2/day on days 1–14; cisplatin 60 mg/m2 on day 1; every 3 weeks [SP3]). Between October 2012 and October 2014, 338 patients were randomized. The median age was 56 years, and 51% of patients had measurable lesions. SOX was significantly non-inferior but not superior to SP3 in terms of PFS [median 5.6 versus 5.7 months; hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.67–1.07]. In patients with measurable disease, objective response rates were similar between SOX and SP3 (58% versus 60%). Overall, the survival in both groups did not differ (median 12.9 versus 11.4 months; HR 0.86; 95% CI 0.66–1.11). Treatment was well tolerated in both arms. Anemia, leucopenia, neutropenia, febrile neutropenia, and oral mucositis were more common with SP3. In contrast, thrombocytopenia, nausea, vomiting, and peripheral neuropathy were more common with SOX. SOX was non-inferior to SP3. The two regimens were well tolerated with different toxicity profiles. The SOX regimen can be recommended as a first-line treatment for MRGC. ClinicalTrials.gov: NCT01671449

Regorafenib and nivolumab are drugs approved for second‐line treatment of patients with hepatocellular carcinoma (HCC) after sorafenib failure. However, the effectiveness of regorafenib and nivolumab following sorafenib has not been directly compared. This study retrospectively evaluated 373 patients with HCC who were treated with regorafenib (n = 223) or nivolumab (n = 150) after sorafenib failure between July 2017 and February 2019. Progression‐free survival (PFS; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69‐1.06; P = 0.150), time to progression (TTP; HR, 0.95; 95% CI, 0.77‐1.19; P = 0.680), and overall survival (OS; HR, 0.83; 95% CI, 0.64‐1.07; P = 0.154) did not differ significantly between groups of patients treated with regorafenib and nivolumab, findings consistently observed by multivariable‐adjusted, propensity score‐matched, and inverse probability treatment weighting (IPTW) analyses. However, the objective response rate was significantly higher in the nivolumab than in the regorafenib group (13.3% vs. 4.0%; P = 0.002). When the effectiveness of regorafenib and nivolumab was compared in nonprogressors to treatment, defined as patients who achieved complete response, partial response, or stable disease after first response evaluation, PFS (HR, 0.50; 95% CI, 0.33‐0.75; P = 0.001), TTP (HR, 0.48; 95% CI, 0.31‐0.73; P, In this retrospective comparative study, the effectiveness of regorafenib and nivolumab following sorafenib in HCC was investigated. The oncological outcomes were not different between the regorafenib and nivolumab groups. However, nivolumab showed better outcomes than regorafenib when progressors to each were excluded.

Background: Cabozantinib, a multiple kinase inhibitor, was recently approved for patients with previously treated unresectable hepatocellular carcinoma (uHCC). We investigated the real-world safety and efficacy profiles of cabozantinib. Methods: This multicenter retrospective study included 110 patients with uHCC who received cabozantinib after progression on other systemic treatments between October 2019 and May 2021. Results: The median age was 58 (range, 20–77) years, and 98 (89.1%) were male. Prior to cabozantinib, all patients were treated with other systemic therapies: sorafenib ( n = 104, 94.5%) and regorafenib ( n = 91, 82.7%) were the most commonly used agents. Immune checkpoint inhibitors were previously used in 93 patients (84.5%). Cabozantinib was used beyond the third-line of therapy in most patients ( n = 90, 81.8%). With a median follow-up duration of 11.9 months [95% confidence interval (CI), 10.8–17.2], the median progression-free survival (PFS) was 3.7 months (95% CI, 3.1–4.9), and the median overall survival (OS) was 7.5 months (95% CI, 5.5–9.5). The disease control rate and overall response rate (ORR) were 66.3% and 3.6%, respectively. In the Child–Pugh A cohort ( n = 88), the ORR was 4.5%, and the median PFS and OS were 4.3 months (95% CI, 3.6–5.8) and 9.0 months (95% CI, 7.5–11.7), respectively. Conclusion: Cabozantinib showed consistent efficacy outcomes with a prior phase III trial, although in this study, it was used as later-line therapy for patients who were refractory to multiple systemic treatments, including immune checkpoint inhibitors.

Background This study was conducted to compare the reported adverse event (AE) profiles and unexpected use of medical services during chemotherapy between before and after the healthcare reimbursement of AE evaluation in patients with cancer. Patients and Methods Using the electronic medical record database system, extracted patients with breast, lung, gastric, and colorectal cancers receiving neoadjuvant or adjuvant chemotherapy between September 2013 and December 2016 at four centers in Korea were matched using the 1:1 greedy method: pre‐reimbursement group (n = 1084) and post‐reimbursement group (n = 1084). Unexpected outpatient department (OPD), emergency room (ER) visit, hospitalization rates, and chemotherapy completion rates were compared between the groups. Results The baseline characteristics were well‐balanced between the groups. By chemotherapy cycle, hospitalization (1.8% vs. 2.3%; p = 0.039), and ER visit rates (3.3% vs. 3.9%; p = 0.064) were lower in the post‐reimbursement group than that in the pre‐reimbursement group. In particular, since cycle 2, ER visit and hospitalization rates were significantly lower in the post‐reimbursement group than those in the pre‐reimbursement group (2.6% vs. 3.3%; p = 0.020 and 1.4% vs. 2.0%; p = 0.007, respectively), although no significant differences were observed during cycle 1. The OPD visit rates were similar between both groups, regardless of cycles. The post‐reimbursement group had a higher proportion of patients who completed chemotherapy as planned than the pre‐reimbursement group (93.5% vs. 90.1%; p = 0.006). Post‐reimbursement group had more AEs reported, including alopecia, fatigue, diarrhea, anorexia, and peripheral neuropathy, during cycle 1 than the pre‐reimbursement group, which significantly decreased after cycle 2. Conclusion The introduction of healthcare reimbursement for AE evaluation may help physicians capture and appropriately manage AEs, consequently, decreasing hospital utilization and increasing chemotherapy completion rates.

PurposeThis study aimed to evaluate the long-term effect of esophagectomy in patients with esophageal squamous cell carcinoma (ESCC) by comparing the chemoradiotherapy (CRT)-only group and the trimodality treatment (TMT) group who received concurrent CRT followed by surgery.Materials and MethodsWe included 412 operable ESCC patients treated with TMT or CRT between January 2005 and December 2015. The oncological outcomes of the two groups were compared using a weighted Cox proportional-hazards model with inverse probability of treatment weighting (IPTW).ResultsThe median survival time was 64 and 32 months in the TMT (n=270) and CRT (n=142) groups, respectively (p < 0.001). After IPTW, the median overall survival (OS) remained significantly higher in the TMT group than in the CRT group (61 months vs. 32 months, p=0.016). Moreover, the TMT group showed a better local recurrence-free rate (LRFR, p < 0.001) and distant metastasis-free rate (p=0.007). In the subgroup of patients with clinical complete response (cCR), the OS was not significantly different between the two groups, both before and after IPTW adjustment (p=0.35 and p=0.93). However, among non-cCR patients, the OS was significantly higher in the TMT group (64% vs. 45%, p < 0.001). ConclusionIn patients with locally advanced ESCC, TMT was superior to CRT in terms of OS and LRFR. Such difference was more prominent in the non-cCR subgroup. In patients who achieved cCR, esophagectomy was effective in improving LRFR but not OS, suggesting that esophagectomy may be omitted in complete responders.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Despite recent advances, more effective therapeutic options for patients with advanced HCC are still required. The aim of this Phase 2, multicenter, multinational, randomized, double-blind, placebo-controlled study (NCT02528643) was to investigate the potential benefit of enzalutamide in the treatment of patients with advanced HCC.Patients aged ≥ 18 years diagnosed with advanced HCC (Barcelona Clinic Liver Cancer stage B or C and Child-Pugh class A at screening who had progressed on, or were intolerant to, sorafenib or other anti-vascular endothelial growth factor therapies) were randomized 2:1 to receive either enzalutamide 160 mg daily or placebo. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and safety.In total, 165 patients were randomized to enzalutamide (n = 110) or placebo (n = 55). The hazard ratio (HR) (95% confidence interval [CI]) for OS was 1.15 (0.774-1.696) and median OS was 7.8 months and 7.7 months for enzalutamide and placebo, respectively. The HR (95% CI) for PFS was 1.04 (0.732-1.474) and median PFS was 2.2 months and 1.9 months for enzalutamide and placebo, respectively. The overall frequency of treatment-emergent adverse events (TEAEs) was broadly similar between the groups: 105 (98.1%) enzalutamide patients experienced ≥1 TEAEs compared with 49 (89.1%) placebo patients.The results of this study indicate that enzalutamide does not provide a benefit in patients with advanced HCC. No unexpected safety findings were observed in the trial. CLINICALTRIALS.NCT02528643.

Background This study analyzed the clinical results of palliative radiotherapy for bleeding control in patients with unresectable advanced gastric cancer. Methods We retrospectively reviewed the medical records of patients who met the following inclusion criteria between January 2002 and June 2018: histologically proven gastric cancer, gastric tumor bleeding confirmed by upper gastrointestinal endoscopy, and palliative radiotherapy performed for hemostasis. The median radiotherapy dose was 30 Gy, with a daily dose ranging from 1.8 to 3 Gy. Results Sixty-one patients were included in this analysis. The study population was predominantly male (72.1%), with a median age of 62 years (range: 32–92). The median baseline hemoglobin level was 7.1 g/dL, and the most common presenting symptom of gastric tumor bleeding was melena (85.2%). Bleeding control was achieved in 54 (88.5%) patients. The median levels of hemoglobin at 1, 2, and 3 months after completion of radiotherapy were 10.1 g/dL, 10.2 g/dL, and 10.4 g/dL, respectively; these values were significantly different from that before radiotherapy (7.1 g/dL; p p = 0.007) and additional chemotherapy after radiotherapy (p = 0.004) were significant factors for prolonging the time to re-bleeding. Conclusions Tumor bleeding was adequately controlled by radiotherapy in patients with unresectable advanced gastric cancer.

Background Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib. Methods This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients. Results The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; P

Perception has recently been highlighted as a critical determinant for participation in clinical trials (CTs) among cancer patients. We evaluated cancer patients’ current perceptions of CTs using the PARTAKE questionnaires, focusing on differences between patients with common and rare cancers. From November 2015 to May 2017, we prospectively surveyed patients who had received anti-cancer treatment at Asan Medical Center. Among 333 respondents, 70.9% had common and 29.1% had rare cancers. In the cohort, 87.7% of patients with common cancers and 75.3% of patients with rare cancers answered that they heard of and knew about CTs. However, willingness to participate in CTs was expressed only in approximately 56% of patients, although it was significantly associated with awareness and perception. Surprisingly, patients with rare cancers when compared with patients with common cancers showed significantly lower levels of awareness and perception (64.2% vs 79.9%, p = 0.003 and 77.3% vs 91.9%, p

Purpose: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer prognosis in various cancer types. However, ICIs may trigger accelerated tumor progression, regarded as hyperprogressive disease (HPD), in certain patients, and it is still challenging to define HPD. We aimed to investigate the landscape of HPD and the prognostic value of its different definitions in advanced solid cancer patients treated with ICIs. Methods: We conducted a multicenter, prospective cohort study for solid cancer patients receiving ICIs. Among them, only unresectable or metastatic cancer patients were included in this analysis. Tumor response was evaluated according to RECIST 1.1. In patients who showed progressive disease (PD) by RECIST 1.1 at the first tumor evaluation, HPD was defined according to the following three criteria: A) tumor growth kinetics (TGK) ratio (TGKpost-ICI/TGKpre-ICI >=2, B) >=10mm increase in sum of target lesion (SUMtarget)and at least one of the following two criteria - 1) >=40% increase in SUMtarget or 2) >=20% increase in SUMtarget and the appearance of new lesions in at least two different organs, C) TGK ratio >=2 and >50% increase in SUMtarget. The discriminatory ability of three definitions in terms of overall survival (OS) were evaluated by the chi-square, C-statistics, and prediction error with integrated Brier score. Results: A total of 427 patients were included; head and neck (n=22, 5.2%), lung (n=173, 40.5%), breast (n=8, 1.9%), gastrointestinal tract (n=99, 23.2%), hepatobiliary pancreas (n=57, 13.3%), genitourinary (n=56, 13.1%), melanoma (n=5, 1.2%), and others (n=7, 1.6%). Incidences of HPD were 4.9%, 14.8%, and 11.5% in definition A, B, C, respectively. The incidence of HPD was relatively low (2.7%-9.5%) in non-small cell lung cancer compared to other cancer types (10.1%-21.5% in esophagogastric cancer, 3.9%-21.6% in hepatobiliary pancreas cancer, and 5.5%-22.5% in genitourinary cancer). Median OS was the worst for patients with HPD, which ranged from 4.8 months to 4.9 months according to definition A-C. After multivariate analysis adjusting for cancer types, ICIs types, and the number of prior anti-cancer therapy, each definition remained a significant factor for OS (P Conclusions: Incidences of HPD appear to be various according to its definitions and cancer types. Given that the RECIST-based definition B not requiring pre-ICI imaging, showed similar discriminatory ability to predict dismal OS compared to TGK-based ones, it may be the most feasible and convenient measure to capture HPD in daily clinical practice. Citation Format: Jwa Hoon Kim, Soohyeon Lee, Min Hee Hong, Jee Hyun Kim, Eun Joo Kang, Tae-Yong Kim, Yeon Hee Park, Ji-Youn Han, Il-Hwan Kim, Sang-We Kim, Dae Ho Lee, Jae Lyun Lee, Jae Cheol Lee, Chang-Min Choi, Changhoon Yoo, Shinkyo Yoon, Jae Ho Jeong, Seyoung Seo, Sun Young Kim, Jin-Hee Ahn, Sook Ryun Park. Hyperprogression in various solid cancers treated with immune checkpoint inhibitors in the real world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5209.

Purpose: Several cell-free DNA (cf-DNA) features, such as genome-wide coverage, fragment size, and fragment end motif frequency, have shown their potentials for cancer detection. In this study, we developed two independent models, GC (gross chromatin), and FEMS (fragment end motif frequency and size). Each model uses images generated from genome-wide normalized sequencing coverage and cf-DNA fragment end motif frequencies according to the different cf-DNA size profiles. Then we integrated them into a single ensemble model to improve cancer detection and multi-cancer type classification accuracy. Methods: Low depth cf-WGS data was generated from 1,396 patients (stage I: 14.9%, stage II: 35.6%, stage III: 24.9%, stage IV: 24.2%, unknown: 0.4%) with breast (n=702), liver (n=213), esophageal (n=155), ovarian (n=151), pancreatic (n=85), lung (n=53), head and neck (n=16), biliary tract (n=15), and colon cancer (n=6) and 417 healthy individuals. Samples were randomly split into training, validation, and test set stratifying cancer type and stages. Cancer types with a small number of samples ( Results: For cancer detection, the ensemble model achieved sensitivities of 85.2% [95% confidence interval (CI): 71.8% to 94.5%], 74.9% (CI: 68.0% to 88.0%), 73.2% (CI: 66.7% to 85.9%) at a specificity of 95%, 98% and 99% and the AUC value of 0.97(CI: 0.95-0.99) in the test dataset. By the cancer stages, sensitivity was 62.8% (CI: 48.8% to 83.7%) in stage I, 66.3% (CI: 57.7% to 82.7%) in stage II, 85.9% (CI: 77.5% to 94.4%) in stage III, and 76.1% (CI: 63.4% to 87.3%) in stage IV at 99% specificity. For multi-cancer classification, the overall accuracy of 85.1% (CI: 80.4% to 89.3%) was achieved including 6 cancer types. Conclusions: Highly sensitive and accurate deep learning model for cancer detection and multi-cancer classification was generated by combining different types of cf-DNA features. This result provides the opportunity for general population multi-cancer screening using various cf-DNA features. Citation Format: Tae-Rim Lee, Jin Mo Ahn, Joo Hyuk Sohn, Sook Ryun Park, Min Hwan Kim, Gun Min Kim, Ki-Byung Song, Eunsung Jun, Dongryul Oh, Jeong-Won Lee, Joseph J Noh, Young Sik Park, Sun-Young Kong, Sang Myung Woo, Bo Hyun Kim, Eui Kyu Chie, Hyun-Cheol Kang, Youn Jin Choi, Ki-Won Song, Jeong-Sik Byeon, Junnam Lee, Dasom Kim, Chang-Seok Ki, Eunhae Cho. Deep learning algorithm for multi-cancer detection and classification using cf-WGS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6371.

4001 Background: To explore proper agents for AGC patients as 2nd-line treatment based on optimal biomarker, we conducted K-Umbrella GC study with standard of care (SOC) controlled umbrella trial design. Methods: HER2-negative AGC patients from 6 Korean cancer centers were centrally screened for druggable targets by IHC and in situ hybridization. Patients were randomized to the biomarker vs. control group with SOC as 4:1 ratio. In the biomarker group, patients were treated with specific targeted agents in combination with weekly paclitaxel; 1) EGFR 2+/3+ patients for pan-ERBB inhibitor (afatinib; EGFR cohort), 2) PTEN loss/null (H-score

e18789 Background: Methylation analysis of cfDNA has been used to diagnose cancer in its early stages. Previous research has concentrated on local methylation signals using cancer type specific methylation markers. We used not just methylation markers, but also global methylation patterns for sensitive cancer detection. Methods: We generated methylation data from cancer patients (N = 717) and normal controls (N = 190) using cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq, N = 907) and cell free whole genome enzymatic methyl seq (cfWGEM-seq, N = 162) from cancer patients (N = 137) and normal controls (N = 25). We analyzed at the Illumina 450K methylation microarray (N = 3,479) from The Cancer Genome Atlas (TCGA) to find differentially methylated regions (DMR) in 6 cancer types (breast, lung, liver, ovarian, esophageal, and pancreatic cancer). After determining the overlapping DMRs of each dataset, the best 1661 regions that differed the most between the cancer patient group and the normal group were left. The selected marker-based model was cross-validated using cfMeDIP samples separated into training, validation, and test sets. Additionally, global methylation count values of cfMeDIP-seq data were used to train convolutional neural network. Finally, the global methylation pattern deep learning algorithm and the marker-based algorithm were combined to detect cancer. Results: Deep learning models based on selected markers and global methylation patterns achieved test data accuracy of 0.88-0.92 and 0.90-0.91, respectively, with AUC 0.94-0.96 and 0.95-0.96. The ensemble model of two models showed test data accuracy 0.91-0.92 and AUC 0.96-0.97 with the detection of early stage of cancers (stage 1:detection rate of 88-100%, stage 2:detection rate of 75-100%, stage 3:detection rate of 90-97%, stage 4:detection rate of 92-100%). Conclusions: In this study, we selected best markers by using tissue methylation dataset (TCGA) and cfDNA methylation datasets (cfMeDIP-seq, cfWGEM-seq). To train cancer detection models, we used not only the DMR pattern but also the global methylation pattern. And the ensemble model that included these features outperformed a single model. In the field of early cancer detection, our models show potential.

Regorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients.We performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib-regorafenib compared with sorafenib and physician's choice in a real-life setting.A propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S-R) and the arm treated with sorafenib and physician's choice (S-P). Survival analysis was conducted on the matched population.After the application of propensity score matching, we analysed 99 patients in the arm treated with S-R and 99 patients in the arm treated with S-P. For the S-R group, the median overall survival was 22.2 months (95% CI 17.1-27.4), compared to 17.9 months (95% CI 15.1-50.0) for the S-P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S-R (p = 0.0382) compared to patients treated with S-P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread.This study provides additional proof of the superiority of the S-R treatment over the S-P treatment approach in advanced HCC patients from a real-life setting.

PurposeHeat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.Materials and MethodsWe established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.ResultsWe identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.ConclusionThe synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.

Purpose This study aimed to evaluate the real-world efficacy of immune checkpoint inhibitors (ICIs), and to identify clinicolaboratory factors to predict treatment outcomes in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving ICIs.Materials and Methods Sixty patients with metastatic or unresectable ESCC treated with nivolumab (n=48) or pembrolizumab (n=12) as ≥ second-line treatment between 2016 and 2019 at Asan Medical Center were included.Results The median age of the patients was 68 years (range, 52 to 76 years), and 93.3% were male. Most patients had metastatic disease (81.7%) and had been previously treated with fluoropyrimidines, platinum, and taxane. In 53 patients with measurable disease, the overall response rate and disease control rate were 15.1% and 35.8%, respectively. With a median follow-up duration of 16.0 months, the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval [CI], 1.54 to 2.19) and 6.4 months (95% CI, 4.77 to 8.11), respectively. After multivariate analysis, recent use of antibiotics, low prognostic nutrition index (< 35.93), high Glasgow Prognosis Score (≥ 1) at baseline, and ≥ 1.4-fold increase in neutrophil-to-lymphocyte ratio after one cycle from baseline were significantly unfavorable factors for both PFS and OS. Younger age (< 65 years) was a significant factor for unfavorable PFS and hyponatremia (< 135 mmol/L) for unfavorable OS.Conclusion The use of ICIs after the failure of chemotherapy showed comparable efficacy in patients with advanced ESCC in real practice; this may be associated with host immune-nutritional status, which could be predicted by clinical and routine laboratory factors.