Search

Introduction EGFRT790M mostly exists subclonally and is acquired as the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs). Nevertheless, because de novo EGFRT790M-mutant NSCLC is rare, little is known on acquired resistance mechanisms to third-generation EGFR TKIs. Methods Acquired resistance mechanisms were analyzed using tumor and plasma samples before and after third-generation EGFR TKI treatment in four patients with de novo EGFRT790M-mutant NSCLC. Genetic alterations were analyzed by whole-exome sequencing, targeted sequencing, fluorescence in situ hybridization, and droplet digital PCR. MTORL1433S, confirmed for oncogenicity using the Ba/F3 system, was reproduced in H1975 cell lines using CRISPR/Cas9-RNP. Results Of seven patients with NSCLC with de novo EGFRT790M/L858R mutation, four (LC1–4) who received third-generation EGFR TKIs acquired resistance after achieving a partial response (median = 27 mo, range: 17–48 mo). Novel MTORL1433S and EGFRC797S/L798I mutations in cis, MET amplification, and EGFRC797S mutation were identified as acquired resistance mechanisms to third-generation EGFR TKIs. The MTORL1433S mutation was oncogenic in Ba/F3 models and revealed resistance to osimertinib through AKT signaling activation in NCI-H1975 cells harboring the MTORL1433S mutation edited by CRISPR/Cas9 (half-maximal inhibitory concentration, 800 ± 67 nM). Osimertinib in combination with mTOR inhibitors abrogated acquired resistance to osimertinib. Conclusions Activation of bypass pathways and the EGFRC797S or EGFRC797S/L798I mutation were identified as acquired resistance mechanisms to third-generation EGFR TKIs in patients with NSCLC with de novo EGFRT790M mutation. In addition, MTORL1433S- and EGFRL858R/T790M-mutant NSCLC cells were sensitive to osimertinib plus mTOR inhibitors.

Purpose NKG2A, an inhibitory receptor expressed on NK cells and T cells, leads to immune evasion by binding to HLA-E expressed on cancer cells. Here, we investigated the relationship between HLA-E surface expression on head and neck squamous cell carcinoma (HNSCC) cell lines and the efficacy of monalizumab, an NKG2A inhibitor, in promoting NK cell activity. Methods Six HNSCC cell lines were used as target cells. After exposure to IFN- γ, HLA-E surface expression on HNSCC cell lines was measured by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from healthy donors and isolated NK cells were used as effector cells. NK cells were stimulated by treatment with IL-2 and IL-15 for 5 days, and NK cell-induced cytotoxicity was analyzed by CD107a degranulation and51Cr release assays. Results We confirmed that HLA-E expression was increased by IFN-γ secreted by NK cells and that HLA-E expression was different for each cell line upon exposure to IFN-γ. Cell lines with high HLA-E expression showed stronger inhibition of NK cell cytotoxicity, and efficacy of monalizumab was high. Combination with cetuximb increased the efficacy of monalizumab. In addition, stimulation of isolated NK cells with IL-2 and IL-15 increased the efficacy of monalizumab, even in the HLA-E low groups. Conclusion Monalizumab efficacy was correlated with HLA-E surface expression and was enhanced when NK cell activity was increased by cetuximab or cytokines. These results suggest that monalizumab may be potent against HLA-E-positive tumors and that monalizumab efficacy could be improved by promoting NK cell activity.

Purpose This single-arm phase II trial investigate the efficacy and safety of S-1 plus oxaliplatin (SOX) in patients with metastatic breast cancer.Materials and Methods Patients with metastatic breast cancer previously treated with anthracyclines and taxanes were enrolled. Patients received S-1 (40-60 mg depending on patient’s body surface area, twice a day, day 1-14) and oxaliplatin (130 mg/m2, day 1) in 3 weeks cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumor 1.1. Secondary endpoints included time-to-progression (TTP), duration-of-response (DoR), overall survival (OS), and adverse events.Results A total of 87 patients were enrolled from 11 institutions in Korea. Hormone receptor was positive in 54 (62.1%) patients and six (6.9%) had human epidermal growth factor receptor 2–positive disease. Forty-eight patients (85.1%) had visceral metastasis and 74 (55.2%) had more than three sites of metastases. The ORR of SOX regimen was 38.5% (95% confidence interval [CI], 26.9 to 50.0) with a median TTP of 6.0 months (95% CI, 5.1 to 6.9). Median DoR and OS were 10.3 months (95% CI, 5.5 to 15.1) and 19.4 (95% CI, not estimated) months, respectively. Grade 3 or 4 neutropenia was reported in 28 patients (32.1%) and thrombocytopenia was observed in 23 patients (26.6%).Conclusion This phase II study showed that SOX regimen is a reasonable option in metastatic breast cancer previously treated with anthracyclines and taxanes.

Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population.In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice-web response system; both patients and investigators were masked to study treatment. Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first 100 randomly assigned patients (objective response rate intention-to-treat [OITT] population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients.Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was 6·2 months (IQR 3·4-9·2) for the ITT population and 8·9 months (7·1-10·5) for the OITT population. An objective response in the OITT population was achieved in ten (15%; 99% CI 5·8-29·3) of 67 patients in the cabozantinib group versus 0 (0%; 0-14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5·7-not estimable [NE]) versus 1·9 months (1·8-3·6); hazard ratio 0·22 (96% CI 0·13-0·36; p0·0001). Grade 3 or 4 adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the most frequent of which were palmar-plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11 [9%] vs 2 [3%]), and fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths.Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care.Exelixis.

Background Unilateral vocal cord paralysis may result from nerve compression by tumors or direct nerve injuries during tumor resections, which can cause dysphonia or dysphagia, and reduced quality of life. Objectives This prospective, single-group study aimed to investigate the effect of percutaneous injection laryngoplasty on voice and swallowing function in patients with cancer-related unilateral vocal cord paralysis. Methods Patients underwent percutaneous injection laryngoplasty with hyaluronic acid under local anesthesia. Stroboscopy and videofluoroscopic swallowing study were conducted to evaluate the voice- and swallowing-related outcome measures, respectively. The participants were evaluated before injection laryngoplasty, as well as after two weeks and three months. Results Injection laryngoplasty significantly improved the glottal gap, vocal fold position, Maximum Phonation Time, and Voice Handicap Index-10. Post-hoc analysis using Bonferroni correction showed that the improvements occurred within two post-treatment weeks and remained at three post-treatment months. In the subgroup analysis, the patients who underwent injection laryngoplasty within 8 weeks from onset showed significantly higher improvements in the videofluoroscopic dysphagia scale and swallowing function than the patients who received the procedure after 8 weeks or more. Conclusion Percutaneous injection laryngoplasty improves glottal closure and voice in patients with cancer-related unilateral vocal cord paralysis. Early injection laryngoplasty may lead to greater benefits on swallowing function. Level of evidence 4.

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).

T-cell factor 1 (TCF1)sup+/supProgrammed cell death-1 (PD-1)sup+/suptumour-infiltrating lymphocytes (TILs) are a recently defined subset of exhausted T-cells (Texh-cells) that exhibit a progenitor phenotype. They have been associated with a response to immune checkpoint inhibitor (ICI) therapy in murine tumour models and in patients with malignant melanoma. We investigated the significance of TCF1sup+/supPD-1sup+/supTILs as a predictive biomarker for ICI therapy response in non-small-cell lung cancer (NSCLC).Two different cohorts of NSCLC patients treated with ICI targeting the PD-1/PD-L1 pathway were included. RNA-seq was performed using NSCLC tissues obtained from 234 patients prior to immunotherapy (RNA-seq cohort). Double immunostaining of TCF1 and PD-1 and single immunostaining of other immunologic markers were performed in resected tumour tissues from another 116 patients (immunohistochemistry cohort).In the RNA-seq cohort, both Texh-cell and progenitor Texh-cell gene sets were enriched in responders compared with non-responders. Larger Texh-cell fractions and increased progenitor Texh-cell gene sets were significantly associated with better progression-free survival (PFS). In the immunohistochemistry cohort, the TCF1sup+/supPD-1sup+/supTIL number and PD-L1 tumour proportion score were significantly higher in responders than in non-responders. A high number of TCF1sup+/supPD-1sup+/supTILs was significantly associated with both PFS and overall survival (OS) after ICI therapy, and it independently predicted a better PFS and OS according to multivariate analysis.TCF1sup+/supPD-1sup+/supTILs, representing progenitor Texh-cells, predict both better response and survival in NSCLC patients after ICI therapy. Thus, they may be a useful predictive biomarker for ICI therapy in NSCLC.

General control nonderepressible 2 (GCN2) senses amino acid deprivation and activates activating transcription factor 4 (ATF4), which regulates many adaptive genes. We evaluated the impact of AST-0513, a novel GCN2 inhibitor, on the GCN2-ATF4 pathway. Additionally, we evaluated the antitumor effects of AST-0513 in amino acid deprivation in head and neck squamous cell carcinoma (HNSCC) cell lines.GCN2 expression in HNSCC patient tissues was measured by immunohistochemistry. Five HNSCC cell lines (SNU-1041, SNU-1066, SNU-1076, Detroit-562, FaDu) grown under amino acid deprivation conditions, were treated with AST-0513. After AST-0513 treatment, cell proliferation was measured by CCK-8 assay. Flow cytometry was used to evaluate apoptosis and cell cycle phase. In addition, immunoblotting was performed to evaluate the effect of AST-0513 on the GCN2-ATF4 pathway, cell cycle arrest, and apoptosis.We demonstrated that GCN2 was highly expressed in HNSCC patient tissues. AST-0513 inhibited the GCN2-ATF4 pathway in all five HNSCC cell lines. Inhibiting the GCN2-ATF4 pathway during amino acid deprivation reduced HNSCC cell proliferation and prevented adaptation to nutrient stress. Moreover, AST-0513 treatment led to p21 and Cyclin B1 accumulation and G2/M phase cycle arrest. Also, apoptosis was increased, consistent with increased bax expression, increased bcl-xL phosphorylation, and decreased bcl-2 expression.A novel GCN2 inhibitor, AST-0513, inhibited the GCN2-ATF4 pathway and has antitumor activity that inhibits proliferation and promotes cell cycle arrest and apoptosis. Considering the high expression of GCN2 in HNSCC patients, these results suggest the potential role of GCN2 inhibitor for the treatment of HNSCC.

Background: Kinase domain duplication (KDD) is recently recognized as an oncogenic driver. Therapeutic potential has been established in EGFR-KDDs in non-small cell lung cancer, and our group recently showed resistance mechanism in lung cancers harboring EGFR-KDDs treated with EGFR tyrosine kinase inhibitors (TKIs). However, the frequency and oncogenic role of KDDs in other receptor tyrosine kinases has been elusive. Methods: To investigate the frequency of KDDs in advanced cancer patients, we developed in-house algorithm to detect KDDs in high-depth panel sequencing dataset and evaluated its performance using large-scale panel sequencing data from Seoul National University Hospital (SNUH). In short, the algorithm collects reads with soft clips from a modified GATK best practice pipeline for clinical NGS data processing. The collected reads are then grouped according to their matched position and insert size, and evidences of each group (number of splitting and spanning reads) are collected to yield a set of initial candidates. Finally, the initial candidates were manually inspected after quality control by removing false-positive candidates, such as non-target genes or consistent findings. Then, we established cell lines transfected with KDDs of FGFR1 and MET to validate oncogenic role of identified KDDs in the cohort. Using these transformed cell lines, we investigated carcinogenicity with cell viability assay, immunoblot assay and colony formation assay. FGFR TKIs and MET TKIs were used to uncover the possibility of therapeutic targets in the KDDs. Results: Using the in-house algorithm, we identified FGFR1-KDDs from brain tumors (n=4), EGFR-KDDs from lung (n=1) and brain (n=2) tumors, and MET-KDD from a lung tumor (n=1) in a total of 3,932 cancer samples, with 0.2% frequency. All three kinds of KDDs contained full-length of kinase domains of each gene. Ba/F3 cells transfected with the FGFR1-KDD constructs proliferated well without IL-3 (1239- and 1019-fold higer than wild-type FGFR1), while wild-type FGFR1 Ba/F3 cells did not. This growth potential was diminished by FGFR TKIs BGJ398 (IC50, 0.063 ± 0.065nM), PD173074 (IC50, 1.498 ± 1.021nM), and ponatinib (IC50, 5.69 ± 3.05nM). Reduced expressions of downstream pathway proteins including phospho-FGFR1, phospho-Akt, and phospho-Erk were confirmed by immunoblot assays. NIH-3T3 cells transfected with MET-KDD construct also showed growth advantage compared to wild-type MET NIH-3T3 cells. Capmatinib, a MET TKI, inhibited colony formation of MET-KDD NIH-3T3 cells with reduced phospho-MET expression. Conclusion: In this study, we validated newly developed KDD-detection computational methods using targeted DNA sequencing data. Using this algorithm, we found 0.2% of KDDs in 3,932 cancer samples, including EGFR, FGFR1, and MET. In addition to EGFR-KDDs, our study reveals that both FGFR1- and MET-KDD can be oncogenic and therapeutic targets in brain and lung cancer patients. Citation Format: Chaelin Lee, Sungyoung Lee, Hongseok Yun, Jeonghwan Youk, Tae Min Kim, Soyeon Kim, Bhumsuk Keam, Miso Kim, Dong-Wan Kim. Kinase domain duplications of FGFR1 and MET are potential therapeutic targets. [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 3918.

Introduction: ALK-positive ALCL accounts for 0.8% of Korean lymphoma patients. ALK TKIs are effective and durable, but clinical outcomes after treatment discontinuation are unknown. We analyzed outcomes and minimal residual disease (MRD) in adult ALK-positive ALCL patients who discontinued ALK TKIs after achieving treatment-free remission. Methods: Six patients who achieved responses to crizotinib (N=5) and ceritinib (N=1) were analyzed. RNA extracted from the blood or tissues before TKI treatment were subjected to multiplex PCR-based next generation sequencing (NGS) using ARCHER® RNA Fusionplex® to detect NPM-ALK fusion. MRD was assessed by droplet digital PCR (ddPCR) of peripheral blood mononuclear cells (PBMCs) after the treatment discontinuation. Undetectable MRD was defined as less than one lymphocytic cell per 10,000 leukocytes (10-4) in peripheral blood. Results: Patients received ALK TKIs as second line (N=3) or third line and beyond (N=3). All achieved complete metabolic responses after median 28.5 months (range, 1.7-93.9) of treatments (Table 1). Before TKI, LY1 patient had no morphologic evidence of bone marrow involvement, but NPM1-ALK fusions were detected by NGS and ddPCR in blood, bone marrow, and tissue. LY1 patient remained in remission at 27.8 months after crizotinib discontinuation. In all patients, NPM1-ALK fusion were not detected in the PBMCs after discontinuing ALK TKIs for median 38.2 months (range, 0-61.9). No patient re-initiated anti-lymphoma therapies. Conclusion: Out data demonstrated that treatment-free remission was durable for more than two years in ALK-positive ALCL patients following the cessation of ALK TKIs. MRD-guided discontinuation decision may be considered for ALK-positive ALCL patients treated with ALK inhibitors who had undetectable MRD. Table 1. Summary of patient characteristics and outcomes of ALK TKI discontinuation No. Sex Age at diagnosis Ann Arbor stage ALK TKI Lines of prior therapy Treatment duration of ALK TKI (months) Reason for cessation Duration of ALK TKI cessation (months) Best response to ALK TKI Time of MRD assessment after TKI cessation MRD after TKI cessation 1 M 22 IIB Crizotinib 3 93.9 Fertility 27.8 CR 5.6 Negative 2 F 20 IVB Crizotinib 1 90.9 Fertility 25.9 CR 0.0 Negative 3 M 23 IV Ceritinib 1 42.7 Adverse event 61.9 CR 61.9 Negative 4 F 58 IV Crizotinib 3 1.7 Cost 86.6 CR 72.1 Negative 5 F 64 IVB Crizotinib 1 13.6 Cost 31.0 CR 14.4 Negative 6 M 75 IV Crizotinib 2 11.7 Cost 80.2 CR 62.0 Negative Citation Format: Jinyong Kim, Soyeon Kim, Tae Min Kim, Jeonghwan Youk, Miso Kim, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo. Treatment-free remission after discontinuation of ALK tyrosine kinase inhibitors (TKIs) in patients with ALK-positive anaplastic large cell lymphoma (ALCL) [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 2181.

PURPOSE Angiosarcoma is a highly aggressive mesenchymal tumor. Although systemic chemotherapy is often considered for the inoperable or metastatic angiosarcoma, the outcome of such treatment is unsatisfactory and poorly delineated. Materials and Methods We reviewed electronic medical records of 75 patients with angiosarcoma who were treated with systemic chemotherapy for inoperable or metastatic disease. Patients were classified as having liver involvement if they had either primary or metastatic hepatic lesions. RESULTS Among the patients evaluated, 51 patients (68%) were male and 24 patients (32%) had primary cutaneous angiosarcoma. Liver involvement was present in 28 patients (37.3%). A total of 59 patients received first-line weekly paclitaxel (wPac) and showed an objective response rate (ORR) of 23.7% (n=14), a median progression-free survival (mPFS) of 4.0 months (95% confidence interval [CI], 3.0 to 6.1), and a median overall survival (mOS) of 10.2 months (95% CI, 7.0 to 14.6). Among patients without liver involvement, patients receiving wPac (n=35) had significantly prolonged mPFS (5.8 months vs. 3.2 months, respectively; p=0.014) with a tendency for prolonged mOS (13.8 months vs. 11.6 months, respectively; p=0.13) than those receiving other regimens (n=12). A total of 24 patients received second- or later-line pazopanib monotherapy and showed an ORR of 16.7% (n=4), a mPFS of 2.4 months (95% CI, 1.8 to 4.3) and a mOS of 5.4 months (95% CI, 3.5 to not available). CONCLUSION Treatment with first-line wPac and later-line pazopanib seems to provide survival benefit, especially for patients with advanced angiosarcoma without liver involvement.

Immune checkpoint inhibitor (ICI) has an emerging role in several types of cancer. However, the mechanisms of acquired resistance (AR) to ICI have not been elucidated yet. To identify these mechanisms, we analyzed the pre- and post-ICI paired tumor samples in patients with AR. Six patients with renal cell carcinoma, urothelial cell carcinoma, or head and neck cancer, who showed an initial response to ICI followed by progression and had available paired tissue samples, were retrospectively analyzed. Whole exome sequencing, RNA sequencing, and multiplex immunohistochemistry were performed on pre-treatment and resistant tumor samples. The median time to AR was 370 days (range, 210 to 739). Increased expression of alternative immune checkpoints including TIM3, LAG3, and PD-1 as well as increased CD8+ tumor-infiltrating lymphocytes were observed in post-treatment tumor than in pre-treatment tumor of a renal cell carcinoma patient. In contrast, CD8+ T cells and immunosuppressive markers were all decreased at AR in another patient with human papillomavirus-positive head and neck squamous cell carcinoma. This patient had an evident APOBEC-associated signature, and the tumor mutation burden increased at AR. Resistant tumor tissue of this patient harbored a missense mutation (E542K) in PIK3CA. No significant aberrations of antigen-presenting machinery or IFN-γ pathway were detected in any patient. Our study findings suggest that the observed increase in immunosuppressive markers after ICI might contribute to AR. Moreover, APOBEC-mediated PIK3CA mutagenesis might be an AR mechanism. To validate these mechanisms of AR, further studies with enough sample size are required.

Background/Aims: Adenoid cystic carcinoma (ACC) is a rare salivary gland tumor characterized by indolence, with a high rate of local recurrence and distant me tastasis. This study aimed to investigate the effect of concurrent chemoradiation (CCRT) on locally advanced unresectable ACC. Methods: We retrospectively analyzed clinical data from 10 patients with patho logically confirmed ACC of the head and neck who received CCRT with cisplatin in Seoul National University Hospital between 2013 and 2018. Results: Ten patients with unresectable disease at the time of diagnosis or with positive margins after surgical resection received CCRT with weekly cisplatin. Eight patients (80%) achieved complete remission, of which three later developed distant metastases without local relapse; one patient developed distant metastasis and local relapse. Two patient achieved partial remission without progression. Patients experienced several toxicities, including dry mouth, radiation dermatitis, nausea, and salivary gland inflammation of mostly grade 1 to 2. Only one patient showed grade 3 oral mucositis. Median relapse-free survival was 34.5 months (95% confidence interval, 22.8 months to not reached). Conclusions: CCRT with cisplatin is effective for local control of ACC with man ageable toxicity and may be an effective treatment option for locally advanced un resectable ACC.

Purpose This study was conducted to determine the effectiveness of immune checkpoint inhibitors (ICIs) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum-containing chemotherapy. We also identified clinical biomarkers which may be predictive of patient prognosis.Materials and Methods We analyzed 125 patients with R/M HNSCC who received ICIs, retrospectively. Overall response rate (ORR) was the primary study outcome. Overall survival (OS) and progression-free survival (PFS) were the secondary study outcomes.Results The patients received anti–programmed cell death protein-1 (PD-1) (n=73, 58%), anti–programmed death-ligand 1 (PD-L1) (n=24, 19%), or a combination of anti–PD-1/PD-L1 and anti–cytotoxic T-lymphocyte antigen 4 (n=28, 22%). The median age was 57 years (range, 37 to 87). The location of the primary tumor was in the oral cavity in 28% of the cases, followed by oropharynx (27%), hypopharynx (20%), and larynx (12%). The ORR was 15% (19/125). With 12.3 months of median follow-up, median PFS was 2.7 months. Median OS was 10.8 months. A neutrophil-to-lymphocyte ratio (NLR) > 4 was significantly associated with poor response to ICIs (odds ratio, 0.30; p=0.022). A sum of the target lesions > 40 mm (hazard ratio [HR], 1.53; p=0.046] and a NLR > 4 (HR, 1.75; p=0.009) were considered to be predictive markers of short PFS. A poor performance status (HR, 4.79; p < 0.001), a sum of target lesions > 40 mm (HR, 1.93; p=0.025), and an NLR > 4 (HR, 3.36; p < 0.001) were the significant predictors for poor survival.Conclusion ICIs exhibited favorable antitumor activity in R/M HNSCC. Clinically, our findings can be used to recognize patients benefit from receiving ICI.

Cabozantinib; Medullary thyroid cancer; Tyrosine kinase inhibitor Cabozantinib; Càncer medul·lar de tiroides; Inhibidor de la tirosina cinasa Cabozantinib; Cáncer medular de tiroides; Inhibidor de la tirosina cinasa Background: Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC. Methods: In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics. Results: At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm (n = 123) and the 140 mg/day capsules arm (n = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90–1.70; p = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points. Conclusions: PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs. This work was supported by Exelixis, Inc., Alameda, CA, USA (no grant number). Exelixis was involved in the study design, the collection, analysis, and interpretation of data, the writing of the report, and the decision to submit for publication.

Background Pulmonary sarcomatoid carcinoma (PSC) is rare with a poor outcome and is resistant to conventional cytotoxic chemotherapy. The efficacy and safety of durvalumab and tremelimumab for treating recurrent or metastatic PSCs were assessed by a nonrandomized, open‐label, phase II study. Methods A total of 18 patients with recurrent or metastatic PSC received 1500 mg of durvalumab and 75 mg of tremelimumab every four weeks, followed by 750 mg of durvalumab every two weeks until the disease progressed, or an unacceptable toxicity level was reached. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression‐free survival (PFS), overall survival (OS), and toxicity. Genomic profiling of PSC by next‐generation sequencing (NGS) and determination of peripheral blood lymphocyte subsets using flow cytometry were performed for exploratory analysis. Results A total of 15 out of 18 patients were evaluated for the analysis of the primary endpoint. At the data cutoff point, the ORR of 26.7% (95% confidence interval [CI]: 7.8–55.1) was achieved with the median follow‐up duration of 12.0 months (range, 8.4–16.1). Median PFS and OS were 5.9 months (95% CI: 1.1–11.9) and 15.4 months (95% CI: 11.1‐not reached), respectively. Treatment‐related adverse events (AEs) of any grade were reported in 16 patients; the most common AEs were pruritus (n = 5), pneumonitis (n = 4), and rash (n = 4). Treatment was discontinued in two patients due to AEs of grade ≥ 3. Conclusions Durvalumab and tremelimumab demonstrated clinical benefit with a prolonged survival and manageable toxicity profile in patients with recurrent or metastatic PSC., This first prospective phase II trial for recurrent or metastatic pulmonary sarcomatoid carcinomas demonstrated that durvalumab and tremelimumab was effective with a confirmed ORR of 26.7%. The combination of durvalumab and tremelimumab was well‐tolerated with favorable toxicity profiles.

Background By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice. Methods This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care. Results A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24–89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620). Conclusions In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.

Although immune-checkpoint inhibitors (ICIs) have emerged as therapeutic options for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC), concerns have been raised on exceptional acceleration of tumor growth during treatment with ICIs, a condition described as hyperprogressive disease (HPD). This study examined the incidence, potential predictors, and clinical impact of HPD in R/M-HNSCC.We retrospectively collected data of patients with R/M-HNSCC treated with ICIs between January 2013 and June 2018 from 11 medical centers in Korea. HPD was defined as tumor growth kinetics ratio (TGKr) 2, which was calculated by comparing TGK on ICIs with that before treatment with ICIs.Of 125 patients, 68 (54.4%) obtained progressive disease as their best responses (progressors). HPD was identified in 18 (26.5% of progressors, 14.4% of total) patients. Relatively younger age, primary tumor of oral cavity, and previous locoregional irradiation were significant predictors of HPD according to multivariable analysis (p = 0.040, 0.027, and 0.015, respectively). Compared to patients without HPD, patients with HPD had significantly shorter median progression-free survival (PFS) (1.2 vs. 3.4 months, p 0.001) and overall survival (OS) (3.4 vs. 10.7 months, p = 0.047). However, interestingly, HPD did not significantly affect the therapeutic benefit of post-ICIs chemotherapy.Younger patients with oral cavity cancer or prior treatment with locoregional radiotherapy could be regarded potential risk groups for HPD in patients with R/M-HNSCC treated with ICIs. Although HPD could consistently predict poorer survival outcomes, patients who experienced HPD with ICIs should not be excluded from the subsequent salvage chemotherapy treatments.

A caregiver’s prognostic awareness can affect clinical decisions for the patient. The purpose of this study was to examine the impact of family caregivers’ prognostic awareness on the quality of life (QOL) and emotional state of both patients with advanced cancer and their caregivers. This prospective cohort study was conducted from December of 2016 to January of 2018. A total of 159 patients with advanced cancer and an equal number of caregivers participated. The investigation tools used include the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C15-Palliative, the McGill Quality of Life Questionnaire, and the Patient Health Questionnaire-9, and evaluation was performed at baseline, 3 months, and 6 months. Covariance analysis with a general linear modeling was used to compare changes in quality of life scores according to the caregivers’ awareness of the prognosis. Mean patient overall QOL score increased in the group of caregivers who were aware of prognosis and decreased in the caregivers who were not aware of the prognosis (p = 0.018). The changes over time in the patients’ QOL scores associated with symptoms improved with caregiver awareness (pain, p = 0.017; dyspnea, p = 0.048; appetite loss, p = 0.045). The percentage of depressed patients was smaller after 3 months in the group with caregivers aware of the prognosis (baseline to 3 months p = 0.028). Caregivers who did not understand their patients’ prognosis exhibited better existential well-being (p = 0.036), and the incidence of depression was lower in this group at 3 months (p = 0.024). Caregivers’ prognostic awareness may improve the quality of life and mood in patients with advanced cancer; however, this awareness may harm the quality of life and mood of the caregivers. These results may aid in developing in-depth interventions regarding prognosis for both patients and their caregivers.

Purpose This study was aim to evaluate the patterns of failure according to radiotherapy (RT) target volume for cervical lymph nodes in metastases of unknown primary origin in head and neck region (HNMUO). Materials and Methods Sixty-two patients with HNMUO between 1998 and 2016 were retrospectively reviewed. We analyzed the clinical outcomes and primary site failure depending on the radiation target volume. The target volume was classified according to whether the potential head and neck mucosal sites were included and whether the neck node was treated involved side only or bilaterally. Results Potential mucosal site RT (mucosal RT) was done to 23 patients and 39 patients did not receive mucosal RT. Mucosal RT showed no significant effect on overall survival (OS) and locoregional recurrence (LRR). The location of primary site failure encountered during follow-up period was found to be unpredictable and 75% of patients with recurrence received successful salvage therapies. No significant differences in OS and LRR were found between patients treated to unilateral (n = 35) and bilateral neck irradiation (n = 21). Treatment of both necks resulted in significantly higher mucositis. conclusions We found no advantages in OS and LRR of patients with HNMUO when mucosal sites and bilateral neck node were included in the radiation target volume.

Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid cancers to discover potential therapeutic targets. Here, we describe the results of a clinical NGS panel in patients with advanced melanoma. Thirty-six tumor tissues from patients with BRAF wild-type melanoma at Seoul National University Hospital (SNUH; Seoul, Republic of Korea) were collected and deep-sequenced using the SNUH FIRST-Cancer NGS panel to assess single-nucleotide variants, small insertions/deletions, copy number variations, and structural variations to estimate tumor mutation burden (TMB). We discovered 106 oncogenic alterations and most of the patients (n = 33, 92%) harbored at least one oncogenic alteration, including 2 patients who were initially diagnosed as BRAF V600E–negative but were later confirmed to be positive. Altogether, 36 samples were classified into RAS/BRAF/NF1–mutant (n = 14, 39%) or triple wild-type (n = 22, 61%) melanoma subtypes. The estimated median TMB was 8.2 mutations per Mb, ranging from 0 to 146.67 mutations per Mb. Of the 36 patients, 25 (70%) had actionable alterations with currently developed drugs, and 7 (19.4%) were enrolled in clinical trials with an RAF inhibitor, multiple receptor tyrosine kinase inhibitor, and anti-programmed cell death-1 (PD-1) antibody. TMB tended to associate with progression-free survival (PFS) of treatment with anti-PD-1/PDL-1 antibody (HR, 0.96; 95% confidence interval, 0.92–1.00; P = 0.07). High-TMB (≥13) group was associated with longer PFS than the low-TMB group (median 34.0 vs. 11.0 weeks, P = 0.04). Overall, the clinical use of a NGS panel in patients with advanced melanoma shows association with clinical outcomes and several therapeutic strategies.

Background/Aim: Uniform treatment of hepatocellular carcinoma (HCC) with molecular targeted drugs (e.g., sorafenib) results in a poor overall tumor response when tumor subtyping is absent. Patient stratification based on actionable gene expression is a method that can potentially improve the effectiveness of these drugs. Here we aimed to identify the clinical application of actionable genes in predicting response to sorafenib. Methods: Through quantitative real-time reverse transcription PCR, we analyzed the expression levels of seven actionable genes (VEGFR2, PDGFRB, c-KIT, c-RAF, EGFR, mTOR, and FGFR1) in tumors versus noncancerous tissues from 220 HCC patients treated with sorafenib. Our analysis found that 9 responders did not have unique clinical features compared to nonresponders. A receiver operating characteristic curve evaluated the predictive performance of the treatment benefit score (TBS) calculated from the actionable genes. Results: The responders had significantly higher TBS values than the nonresponders. With an area under the curve of 0.779, a TBS combining mTOR with VEGFR2, c-KIT, and c-RAF was the most significant predictor of response to sorafenib. When used alone, sorafenib had a 0.7–3% response rate among HCC patients, but when stratifying the patients with actionable genes, the tumor response rate rose to 15.6%. Furthermore, actionable gene expression is significantly correlated with tumor response. Conclusions: Our findings on patient stratification based on actionable molecular subtyping potentially provide a therapeutic strategy for improving sorafenib’s effectiveness in treating HCC.

To analyse the incidence of pneumonitis related to enfortumab vedotin (EV) in patients with metastatic urothelial cell carcinoma (mUC).Patients with mUC who participated in two EV clinical trials in South Korea were analysed for the incidence and clinical course of EV-related pneumonitis through retrospective, independent review. The clinical characteristics and radiologic attributes of potential pneumonitis were identified and reviewed by the participating investigators and pulmonologists.Between October 2018 and January 2020, 64 patients were enrolled in the EV-201 and EV-301 trials across eight institutions in South Korea and were treated with EV. Among them, 18 (28.1%) developed all-grade EV-related pneumonitis, from which 2 (11.1%) patients died. The median time between the last dosing of immunotherapy and the start of EV was 5.6 weeks (range, 0.71-143.1). The median time from the start of EV treatment to the onset of pneumonitis was 13 weeks (range, 2.7-51.0). Of the patients who developed pneumonitis, 7 (38.9%) were clinically asymptomatic. The most common radiologic finding was organising pneumonia (66.7%).Although we could not rule out the relationship with prior immunotherapy administration, EV-related pneumonitis occurred in approximately 25% of the patients who had received EV in two prospective clinical trials, from which two died. Clinicians should closely monitor patients who have experienced immunotherapy treatment failure for the development of pneumonitis. A delay between initiating EV after termination of immunotherapy should be considered with caution.

BackgroundTo characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study.MethodsAssociations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (TcellinfGEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106).ResultsTMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and TcellinfGEP (Spearman ρ=–0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between TcellinfGEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% ҡ=0.573) among patients whose HPV results were available using both methods.ConclusionsTMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed.Trial registration numberNCT01848834.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia., Highlights • This article provides ESMO expert recommendations adapted for the treatment of SCCHN (excluding nasopharyngeal carcinomas) in Asian patients. • The aim was to provide guidance for the optimisation of the management of such patients across Asia. • The availability and applicability of certain procedures as they relate to certain of the recommendations are discussed.

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

Circulating soluble programmed death-1 ligand (sPD-L1) is measurable in the serum of cancer patients. This study aimed to investigate the significance of sPD-L1 in cancer patients receiving immune checkpoint inhibitor therapy. Blood samples were obtained before and after immune checkpoint inhibitor therapy (January 2015 to January 2019). The study cohort consisted of 128 patients who were diagnosed with non-small cell lung cancer (n = 50), melanoma (n = 31), small cell lung cancer (n = 14), urothelial carcinoma (n = 13), and other cancers (n = 20). Patients with a high level (> 11.0 pg/μL) of sPD-L1 were more likely to exhibit progressive disease compared with those with a low level (41.8% versus 20.7%, p = 0.013). High sPD-L1 was also associated with worse prognosis; the median PFS was 2.9 (95% confidence interval [CI] 2.1–3.7) months versus 6.3 (95% CI 3.0–9.6) months (p = 0.023), and the median OS was 7.4 (95% CI 6.3–8.5) months versus 13.3 (95% CI 9.2–17.4) months (p = 0.005). In the multivariate analyses, high sPD-L1 was an independent prognostic factor for both decreased PFS (HR 1.928, p = 0.038) and OS (HR 1.788, p = 0.004). sPD-L1 levels did not correlate with tissue PD-L1 expression. However, sPD-L1 levels were positively correlated with neutrophil to lymphocyte ratios and negatively correlated with both the proportion and the total number of lymphocytes. We found that high pretreatment sPD-L1 levels were associated with progressive disease and were an independent prognostic factor predicting lower PFS and OS in these patients.

Simple Summary Despite the importance of vaccination against Coronavirus disease 2019 (COVID-19) in cancer patients, general vaccine uptake rates among cancer patients are known to be low. Here, we tried to investigate the attitude and acceptance rates for COVID-19 vaccine in cancer patients and identify predictive factors for vaccination that could be modified to promote vaccine uptake rates. Between February and April 2021, a total of 1001 cancer patients from five institutions participated in a paper-based survey, consisting of 58 items over six domains. Among the respondents, 61.8% were willing to receive the COVID-19 vaccine. Along with the previously reported predictors for COVID-19 vaccination, including male gender, older age, and influenza vaccination history, we distinctively found that patient’s disease status and health status (absence of cancer recurrence, time since cancer diagnosis over 5 years, and higher EuroQol Visual Analogue Scale scores) were associated with higher acceptance rates of vaccination. Furthermore, physician’s recommendations effectively reduced patient’s vaccine hesitancy. Abstract Considering the high morbidity and mortality of Coronavirus disease 2019 (COVID-19) in patients with malignancy, they are regarded as a priority for COVID-19 vaccination. However, general vaccine uptake rates among cancer patients are known to be lower than in their healthy counterparts. Thus, we aimed to investigate the attitude and acceptance rates for the COVID-19 vaccine in cancer patients and identify predictive factors for vaccination that could be modified to increase vaccine uptake rates, via a paper-based survey (58 items over six domains). A total of 1001 cancer patients participated in this nationwide, multicenter survey between February and April 2021. We observed that 61.8% of respondents were willing to receive the COVID-19 vaccine. Positive predictive factors found to be independently associated with vaccination were male gender, older age, obesity, previous influenza vaccination history, absence of cancer recurrence, time since cancer diagnosis over 5 years, and higher EuroQol Visual Analogue Scale scores. Along with the well-known factors that are positively correlated with vaccination, here, we report that patients’ disease status and current health status were also associated with their acceptance of the COVID-19 vaccination. Moreover, 91.2% of cancer patients were willing to be vaccinated if their attending physicians recommend it, indicating that almost 30% could change their decision upon physicians’ recommendation. Unlike other factors, which are unmodifiable, physicians’ recommendation is the single modifiable factor that could change patients’ behavior. In conclusion, we firstly report that Korean cancer patients’ acceptance rate of the COVID-19 vaccination was 61.8% and associated with disease status and current health status. Physicians should play a major role in aiding cancer patients’ decision-making concerning COVID-19 vaccines.

Among prospectively enrolled adult patients with cancer receiving immune checkpoint inhibitors (ICIs; n = 46) or cytotoxic agents (n = 90), seroprotection and seroconversion rates after seasonal quadrivalent influenza vaccinations were higher with ICI than with cytotoxic chemotherapy. These results support annual influenza vaccinations for cancer patients receiving ICIs. Clinical Trials Registration clinicaltrials.gov (NCT03590808).

Background/Aims: Since patients with human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) have favorable outcomes after treatment, treatment de-escalation for these patients is being actively investigat ed. However, not all HPV-positive HNSCCs are curable, and some patients have a poor prognosis. The purpose of this study was to identify poor prognostic factors in patients with HPV-positive HNSCC. Methods: Patients who received a diagnosis of HNSCC and tested positive for HPV from 2000 to 2015 at a single hospital site (n = 152) were included in this ret rospective analysis. HPV typing was conducted using the HPV DNA chip assay or liquid bead microarray system. Expression of p16 in the tumors was assessed by immunohistochemistry. To determine candidate factors associated with overall survival (OS), univariate and multivariable Cox regression analyses were per formed. Results: A total of 152 patients with HPV-positive HNSCC were included in this study; 82.2% were male, 43.4% were current or former smokers, and 84.2% had oropharyngeal cancer. By univariate analysis, old age, performance status ≥ 1, non-oropharyngeal location, advanced T classification (T3-4), and HPV genotype 18 were significantly associated with poor OS. By multivariable analysis, perfor mance status ≥ 1 and non-oropharyngeal location were independently associated with shorter OS (hazard ratio [HR], 4.36, p = 0.015; HR, 11.83, p = 0.002, respective ly). Furthermore, HPV genotype 18 positivity was also an independent poor prog nostic factor of OS (HR, 10.87, p < 0.001). Conclusions: Non-oropharyngeal cancer, poor performance status, and HPV gen otype 18 were independent poor prognostic factors in patients with HPV-positive HNSCC. Patients with these risk factors might not be candidates for de-escalation treatment.

Purpose We first analyzed the prognostic power of albumin-to-alkaline phosphatase ratio (AAPR) before radical radiotherapy (RT) in non-metastatic nasopharyngeal carcinoma (NPC) patients. Materials and methods The records of 170 patients with biopsy-proven, non-metastatic NPC treated by radical RT between 1998 and 2016 at our institution were retrospectively reviewed. Median follow-up duration was 50.6 months. All patients received intensity-modulated RT and cisplatin based chemotherapy before, during, or after RT. The major treatment of patients was based on concurrent chemoradiotherapy (92.4%). The AAPR was calculated by the last value of both albumin and alkaline phosphatase within 1 month immediately preceding RT. The optimal cut-off level of AAPR was determined by using Cutoff Finder, a web-based system. Propensity score matching (PSM) analysis was performed. Results The optimal cut-off level of AAPR was 0.4876. After PSM analysis of whole cohort, an AAPR was not related to survival outcomes. In PSM analysis for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC), an AAPR ≥ 0.4876 was related to better overall survival (OS), progression-free survival (PFS), and locoregional relapse-free survival (LRRFS) (OS: hazard ratio [HR], 0.341; 95% confidence interval [CI], 0.144 to 0.805; p=0.014; PFS: HR, 0.416; 95% CI, 0.189 to 0.914; p=0.029; and LRRFS: HR, 0.243; 95% CI, 0.077 to 0.769; p=0.016, respectively). Conclusion The AAPR, inexpensive and readily derived from a routine blood test, could be an independent prognostic factor for patients with LA-NPC. And it might help physicians determine treatment plans by identifying the patient's current status. Future prospective clinical trials to validate its prognostic value are needed.

Background Despite recent advances in treating non‐small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK‐positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK‐positive NSCLC. Methods Between 2011 and 2018, a total of 14 ALK‐positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD‐L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets. Results A total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2–8) courses of therapy. The study included nine patients (64.3%) who were PD‐L1‐high (>50%) and four (28.6%) who were PD‐L1‐low (, Key points From retrospective review of 14 ALK‐positive NSCLC patients in South Korea treated with ICIs, the role of ICI in ALK‐positive NSCLC was navigated. Despite high PD‐L1‐positive rates, ICIs show limited efficacy (ORR 14.3%; median PFS 2.18 months; median OS 5.67 months). From TCGA and NCCRI dataset analysis, decreased interferon‐γ‐related response may underlie these findings.

Background/Aims The role of [18F]-f luorodeoxyglucose positron emission tomography-computed tomography (PET/CT) in patients with diffuse large B-cell lymphoma (DLBCL) in first remission is unclear. Methods Medical costs within the first 3 years of treatment completion and clinical outcomes of 118 patients with DLBCL in first remission with and without surveillance PET/CT (PET/CT [+] group [n = 76] and PET/CT [–] group [n = 42], respectively) were retrospectively analyzed. Results In a propensity matched cohort with adjustment for International Prognostic Index risk and relapse, the PET/CT (+) group was shown to have similar medical costs as the PET/CT (–) group. Relapse-free survival (RFS) and overall survival (OS) were comparable between the two groups (median RFS not reached [NR] for both groups, p = 0.133; median OS NR, p = 0.542). Among 76 patients with surveillance PET/CT, 31 (40.8%) had findings suggestive of recurrence and 16 of these (51.6%) were later confirmed to have recurrent disease. Fifteen patients (48.4%) were confirmed to not have recurrence after follow-up CT or PET/CT evaluation (n = 10) and biopsy (n = 4). None of the patients with negative PET/CT findings had disease recurrence. Sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT for detection of recurrence were 1, 0.75, 0.52, and 1, respectively. Conclusions Surveillance PET/CT resulted in similar clinical outcomes and medical costs compared to no surveillance PET/CT. Approximately half of patients with PET/CT findings of recurrence had no recurrence after follow-up imaging and biopsy, which would not have been carried out if PET/CT had not been performed in the first place.

Background/aims This study was to evaluate the clinical significance of infusion-related reaction (IRR) of rituximab in diffuse large B-cell lymphoma (DLBCL) patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) as a first-line chemotherapy. Methods The medical records of 326 patients diagnosed with DLBCL were re trospectively analyzed. Both doctor's progress records and nursing records were reviewed. IRR was graded according to the National Cancer Institute Common Terminology Criteria. Results IRR was not associated with overall survival (OS) or progression-free survival (PFS) of DLBCL patients as compared to those who did not have IRR (OS: median 78.0 months vs. 69.0 months, p = 0.700; PFS: median 65.4 months vs. 64.0 months, p = 0.901). IRR grade did not affect OS or PFS. B symptoms was independently associated with IRR (hazard ratio [HR], 1.850; 95% confidence interval [CI], 1.041 to 3.290; p = 0.036). Further, bone marrow involvement was independently associated with re-IRR (HR, 4.904; 95% CI, 0.767 to 3.118; p = 0.029). Conclusion Our study shows that IRR of rituximab is not associated with OS or PFS of DLBCL patients who received R-CHOP. Furthermore, our study suggests a need for more careful observation for IRR in patients with B symptoms or bone marrow involvement.

Background Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid cancer expressing programmed death ligand 1 (PD-L1). Methods Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti–programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. Results Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7–34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1–29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2–14 months); median overall survival was not reached (95% CI, 22 months to not reached). Conclusions Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings. Trial registration Clinicaltrials.gov identifier: NCT02054806. Registered 4 February 2014. Electronic supplementary material The online version of this article (10.1186/s12885-019-5380-3) contains supplementary material, which is available to authorized users.

Purpose Despite the successful use of tyrosine kinase inhibitors (TKIs) in cancer patients, their effect on herpes zoster development has not been studied. The aim of this study was to evaluate and compare the effects of epidermal growth factor receptor (EGFR) TKI and cytotoxic chemotherapy on the risk of herpes zoster development in non-small cell lung cancer (NSCLC) patients. Materials and methods We conducted a medical review of all eligible NSCLC patients in Seoul National University hospital between 2002 and 2015. We classified patients based on whether they previously underwent EGFR TKI therapy into either the TKI group or the cytotoxic group. We compared the incidence rates of herpes zoster during TKI therapy and cytotoxic chemotherapy. Additionally, the longitudinal risk of herpes zoster from TKIs was analyzed using the incidence rate ratio (IRR) of the TKI group to the cytotoxic group and the log-rank test of the Kaplan-Meier method. Results Of the 2,981 NSCLC patients, 54 patients (1.54%) developed herpes zoster. In the TKI group (2,002 patients), the IRR of herpes zoster during TKI therapy compared to that during cytotoxic chemotherapy was 1.05 (95% confidence interval [CI], 0.53 to 2.09). The IRR of the TKI group compared to the cytotoxic group was 1.33 (95% CI, 0.64 to 2.76). The Kaplan-Meier cumulative risk of both groups was not significantly different. Conclusion Our results show that the incidence rate of herpes zoster in the TKI group was not statistically different from the incidence in the cytotoxic group during and after chemotherapy in NSCLC patients.

Purpose Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients. Materials and Methods Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data. Results Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)–negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%). Conclusion We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

Purpose We analyzed positron emission tomography-computed tomography (PET-CT) in patients with stage III non–small-cell lung cancer (NSCLC) undergoing concurrent chemoradiotherapy (CRT) to examine the prognostic value of PET-CT parameters according to histologic subtypes (squamous cell carcinoma [SqCC] and adenocarcinoma [ADC]). Methods A total of 130 patients with stage III NSCLC who underwent definitive CRT were identified. We obtained PET-CT parameters such as maximum (SUVmax) and mean (SUVmean) standardized uptake value, total lesion glycolysis (TLG), metabolic tumor volume (MTV), and coefficient of variation (CV). Each parameter was bifurcated based on the optimal cutoff, and propensity score matching was performed between the SqCC and ADC groups. Results There were 108 patients with SqCC or ADC, and 44 patients each were allocated to the SqCC and ADC groups via propensity score matching. SUVmax, SUVmean, TLG, and MTV values were significantly higher in SqCC than in ADC (P = .004, P = .006, P = .003, and P = .03, respectively). In the SqCC group, PET-CT parameters were not associated with survival outcomes. However, in the ADC group, SUVmax and SUVmean were related to locoregional progression-free survival (P = .008 and P = .017, respectively), and TLG and MTV were related to overall survival (P = .044 and P Conclusions PET-CT provided different prognostic implications between SqCC and ADC in patients with locally advanced NSCLC receiving radical CRT. This suggests that it is necessary to consider the histologic subtype and PET-CT parameters concurrently when predicting survival outcomes.

Background: The COVID-19 pandemic has disrupted healthcare delivery, which is widely discussed as the distraction effect. This study aimed to estimate the distraction effect of the COVID-19 pandemic in Korea by analyzing colorectal and gastric cancer screening rates in the years 2019 and 2020. Methods: Information of eligible population who had colorectal and gastric cancer screening provided by the National Cancer Screening Program in the years 2019 and 2020 was collected. Participation rates were analyzed by age group, sex, geographic region, and calendar month. Percentage change was calculated by dividing the percentage point difference by the screening rate of the reference period (2019). Results: Overall, the colorectal and gastric cancer screening rates had decreased in 2020, compared to the reference period. For colorectal cancer, the screening rate decreased from 68.3% in 2019 (5,886,319 participants/14,526,424 eligible population) to 54.6% in 2020 (5,135,218/9,410,525) For gastric cancer, the screening rates decreased from 61.9% in 2019 (7,194,489/11,625,627) to 54.6% in 2020 (6,244,491/11,439,246). In March, during the first wave, the screening rates declined sharply (percentage change: colorectal, 56.6%; gastric, 57.3%). Although the screening rates had rebounded aftermath, they declined again in December, during the third wave (percentage change: colorectal, 17.0%; gastric, 13.8%). According to specific-age group, we found a substantial decline in screening rates for older adults aged 80~84, and those over 85 (percentage change: colorectal, 19.0% & 23.0%; gastric, 17.4% & 25.1% respectively). Conclusion: During the COVID-19 pandemic, the screening rates for both colorectal and gastric cancer decreased. There was a substantial decline during the first and the third waves of the epidemic, in March and in December. The older adults group showed the highest reduction in screening rates. However, comparing the screening rate by region and sex, we did not find a significant difference. Delayed cancer diagnosis or excess death due to distraction effect of the COVID-19 pandemic has not yet been detected in Korea, therefore, further studies are needed. Citation Format: Seung Hee Seo, Hyeree Park, Jong Heon Park, Bhumsuk Keam, Shin Hye Yoo, Aesun Shin. Colorectal and gastric cancer screening rates in Korea during the COVID-19 pandemic [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 433.

Immune checkpoint inhibitors (ICIs) have become a standard treatment for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy. However, the prognostic factors for patients with mUC receiving ICIs are not well established. We retrospectively collected clinical and laboratory data and reviewed the survival outcomes of patients with mUC who were treated with ICIs after platinum-based chemotherapy. We used univariate and multivariable Cox proportional hazard models to identify independent prognostic factors, and the concordance index (C-index) to evaluate the performance of the new prognostic model. In addition, bootstrap analysis was employed for internal validation of the prognostic model. A total of 224 patients were included in the study. With a median follow-up of 10.5 months (interquartile range, 5.1-17.4 months), median overall survival (OS) was 13.6 months (95% confidence interval [CI], 9.7-17.3 months). In multivariable analysis, independent prognostic factors predicting adverse OS were the presence of liver metastasis (LM), hypoalbuminemia, and neutrophil-lymphocyte ratio (NLR)5. When patients were categorized into 3 risk groups, median OS was not reached (NR) (95% CI, 17.3-NR), 9.5 months (6.8-NR), and 2.9 months (2.3-4.4) for patients with a score of 0, 1, and 2+, respectively. The C-index for the new model was 0.763 (95% CI, 0.739-0.787). A novel prognostic model, including LM, hypoalbuminemia, and NLR, was developed and validated to estimate OS in patients with platinum-refractory disease on second- or subsequent-line ICI therapy. Further investigations, including prospective validation, are needed.