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This study explored the effect of transdermal buprenorphine on quality of life and six symptoms in cancer patients with pain.Transdermal opioids offer advantages over traditional routes of administration. The impact of transdermal buprenorphine on quality of life for patients with cancer in Asian populations is unknown.This study employed a single-arm observational repeated measures design. Cancer patients with pain were evaluated prior to treatment (baseline). Over a 4-week treatment period, quality of life and symptoms were assessed at 2 and 4 weeks. This study adhered to the recommendations of STROBE guidelines.This multi-site study was conducted in six hospitals located across northern, middle and southern Taiwan. Adult cancer patients whose pain was previously stable with opioid analgesics and, based on clinical judgement, were able to convert to transdermal buprenorphine treatment were invited to participate. Quality of life was measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).Generalised estimating equations showed participants who completed at least one follow-up measurement (N = 80) over 4-weeks had a significant improvement in overall quality of life. Functional status only improved for social functioning. However, symptom severity decreased significantly for nausea/vomiting, pain, insomnia and constipation.The study provides initial evidence supporting transdermal buprenorphine for providing beneficial effects of improving quality of life and reducing severity of symptoms in Asian patients with cancer.The findings of this study can inform the clinical practice that the use of transdermal buprenorphine in cancer patients with pain may also reduce the severity of other symptoms and improve overall quality of life.This study was registered in ClinicalTrials.gov. Identifier: NCT04315831.

Background/Objective Preparing family caregivers, cognitively, emotionally, and behaviorally, for their relative's death is an actionable component of high-quality end-of-life care. We aimed to examine the never-before-examined associations of conjoint cognitive prognostic awareness and emotional preparedness for death with caregiving outcomes and end-of-life care received by cancer patients. Design/Setting/Participants/Main measures For this longitudinal study, associations of death-preparedness states (no-death-preparedness, cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) with subjective caregiving burden, depressive symptoms, and quality of life (QOL) and patients’ end-of-life care (chemotherapy and/or immunotherapy, cardiopulmonary resuscitation, intensive care unit care, intubation, mechanical ventilation support, vasopressors, nasogastric tube feeding, and hospice care) were evaluated using multivariate hierarchical linear and logistic regression modeling, respectively, for 377 caregivers in cancer patients’ last 6 months and 1 month, respectively. Key results Caregivers in the cognitive-death-preparedness-only state experienced a higher level of subjective caregiving burden than those in the sufficient-death-preparedness state. Caregivers in the no-death-preparedness and cognitive-death-preparedness-only states reported significantly more depressive symptoms and worse QOL than those in the sufficient-death-preparedness state. Cancer patients with caregivers in the sufficient-death-preparedness state were less likely to receive chemotherapy and/or immunotherapy, intubation, mechanical ventilation, and nasogastric tube feeding than patients with caregivers in other death-preparedness states. However, patients’ receipt of hospice care was not associated with their caregivers’ death-preparedness states. Conclusion Family caregivers’ death-preparedness states were associated with caregiving outcomes and their relative's end-of-life care. Cultivating caregivers’ accurate prognostic awareness and improving their emotional preparedness for their relative's death may facilitate more favorable end-of-life-caregiving outcomes and may limit potentially nonbeneficial end-of-life care.

Background: A “surgery as needed” approach may be offered to patients with esophageal cancer (EC) who achieve major histopathological response (MaHR) after neoadjuvant chemoradiotherapy (nCRT). However, the utility of clinical response assessment (CRE) for predicting histopathological response to nCRT remains limited. Circulating tumor cells (CTCs) hold promise as biomarkers of response to nCRT. Methods: We analyzed the clinical utility of post-nCRT CTCs, alone or in combination with CRE, in the prediction of MaHR. We defined MaHR as either the lack or a limited presence (≤10%) of vital residual tumor cells in the resected esophageal specimen in the absence of nodal involvement. Results: Of the 48 study patients, 27 (56%) achieved MaHR. Patients with MaHR had a significantly lower CTCs count compared with those without (3.61 ± 4.53 versus 6.83 ± 5.22 per mL of blood, respectively; P = 0.027). Using a cutoff for positivity of 5 CTCs per mL of blood, the combination of CTCs and CRE allowed achieving a negative predictive value for MaHR of 93% (95% confidence interval [CI] = 70–99%) along with a false negative rate of 5% (95% CI = 1–33%). Conclusion: CTCs count assessed in combination with CRE can potentially help identify patients with EC who achieved MaHR after nCRT.

Preparing family surrogates for patient death and end-of-life (EOL) decision making may reduce surrogate decisional conflict and regret. Preparedness for patient death involves cognitive and emotional preparedness. We assessed the associations of surrogates' death-preparedness states (that integrate both cognitive and emotional preparedness for patient death) with surrogates' decisional conflict and regret.Associations of 173 surrogates' death-preparedness states (no, cognitive-only, emotional-only, and sufficient preparedness states) with decisional conflict (measured by the Decision Conflict Scale) and heightened decisional regret (Decision Regret Scale scores25) were evaluated using hierarchical linear modeling and hierarchical generalized linear modeling, respectively, during a longitudinal observational study at a medical center over cancer patients' last 6 months.Surrogates reported high decisional conflict (mean [standard deviation] = 41.48 [6.05]), and 52.7% of assessments exceeded the threshold for heightened decisional regret. Surrogates in the cognitive-only preparedness state reported a significantly higher level of decisional conflict (β = 3.010 [95% CI = 1.124, 4.896]) than those in the sufficient preparedness state. Surrogates in the no (adjusted odds ratio [AOR] [95% CI] = 0.293 [0.113, 0.733]) and emotional-only (AOR [95% CI] = 0.359 [0.149, 0.866]) preparedness states were less likely to suffer heightened decisional regret than those in the sufficient preparedness state.Surrogates' decisional conflict and heightened decisional regret are associated with their death-preparedness states. Improving emotional preparedness for the patient's death among surrogates in the cognitive-only preparedness state and meeting the specific needs of those in the no, emotional-only, and sufficient preparedness states are actionable high-quality EOL-care interventions that may lessen decisional conflict and decisional regret.

Background Patients with esophageal squamous cell carcinoma (SCC) have limited treatment options. Blocking transforming growth factor-β (TGFβ), which can be overexpressed in these tumors, may enhance responses to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] inhibitors. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβ receptor II (TGFβRII) (a TGFβ “trap”) fused to a human IgG1 monoclonal antibody blocking PD-L1. Objective The objective of this study was to investigate the safety and efficacy of bintrafusp alfa in Asian patients with pretreated, PD-L1–unselected esophageal SCC. Patients and Methods In a phase 1 study, Asian patients with pretreated esophageal SCC received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was safety/tolerability with a goal of exploring clinical activity. Results By the database cutoff of August 24, 2018, 30 patients (76.7% had two or more prior anticancer regimens) received bintrafusp alfa for a median of 6.1 weeks; two remained on treatment. Nineteen patients (63.3%) had treatment-related adverse events, seven (23.3%) with grade 3/4 events, and there were no treatment-related deaths. The confirmed objective response rate (ORR) per independent review was 10.0% (95% confidence interval [CI] 2.1–26.5); responses lasted 2.8–8.3 + months. All responses occurred in immune-excluded tumors. Investigator-assessed confirmed ORR was 20.0% (95% CI 7.7–38.6). Median overall survival was 11.9 months (95% CI 5.7–not reached). Conclusions Bintrafusp alfa demonstrated a manageable safety profile and efficacy in Asian patients with pretreated esophageal SCC. Clinical Trials Registration NCT02699515. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00810-9.

SummaryPurpose This study aimed to evaluate the safety and pharmacokinetic (PK) profiles of HLX07, a novel, recombinant, humanized anti-epidermal growth factor receptor (EGFR) antibody, in patients with advanced solid cancers who had failed standard therapy or for whom no standard therapy was available. Methods In this prospective, open-label, Phase I dose escalation study, patients aged ≥18 years (≥20 years for patients in Taiwan) with histologically-confirmed metastatic or recurrent epithelial carcinoma that had no K-RAS or B-RAF mutations were enrolled in a ‘3 + 3’ escalation design. HLX07 was administered weekly by 2-h intravenous infusion at doses ranging from 50 to 800 mg. The primary endpoint was summary listing of participants reporting treatment-emergent adverse events (TEAEs). Secondary endpoints included PK analysis, serum anti-HLX07 antibody assessments and efficacy. Results In total, 19 patients were enrolled between 1 October 2016 and 16 July 2019 to receive HLX07 at doses of 50 (n = 3), 100 (n = 3), 200 (n = 3), 400 (n = 3), 600 (n = 3) and 800 (n = 4) mg per week. All patients experienced at least one TEAE, most commonly fatigue (68.4%), nausea (47.4%), paronychia (31.6%) and vomiting (31.6%). Serious TEAEs were reported in 11 patients but only one serious TEAE (dyspnea in 600 mg cohort) was regarded as possibly related to study treatment. No dose limiting toxicity (DLT) was reported. Systemic exposure to HLX07 increased proportionally with dose. Anti-HLX07 antibodies were not detected in any patients. Conclusion HLX07 was well tolerated (at dose levels up to 800 mg/week) and promising in patients with advanced solid cancers.Clinical Trial Registration: The study was registered at ClinicalTrials.gov: NCT02648490 (Jan 7, 2016).

Anti-Programmed cell Death protein 1 (Anti-PD1) or Programmed Death-Ligand 1 (PDL1) immune checkpoint inhibitors provide treatment options for advanced HCC patients with low response rates. Combination therapy is becoming a major issue to improve the unmet need. Proton beam radiotherapy (PBT) could effectively control the local tumor with a low-risk injury to peripheral liver parenchyma. We retrospectively reviewed the patients who have received PBT combined with anti-PD1/PDL1 to evaluate the efficacy and safety of the advanced HCC patients. This study reviewed 29 advanced HCC patients who have received PBT and anti-PD1/PDL1 during 2016 and 2019. All were Child-Pugh A and performance status 0-1. Seventeen patients (58.6%) had extrahepatic spreading. Concurrent PBT started during anti-PD1/PDL1 with a median of 96.6 grays equivalent dose. The PBT field covered all tumors in 13 (44.8%) patients under curative intent. Other patients (55.2%) received palliative PBT that covered only the principal tumors. All patients have completed the concurrent PBT protocol. The median anti-PD1/PDL1 duration was 3.9 months. After a median follow-up of 13.2 months, the rates of 1-year PBT infield tumor control, 1-year outfield tumor control, and overall response were 90.5%, 90.9%, and 61.5%, and 70.8%, 69.2%, and 43.8%, respectively for curative-intent and palliative-control PBT. Complete response was found in 4 (30.8%) curative-intent and 1 (6.3%) palliative-control patients. The median overall progression-free survival was 27.2 months for curative-intent patients and 15.9 months for palliative-control patients. The overall survival was non-reached for both groups. The ALBI grade and Child-Pugh score change at 3-month and 6-month after PBT initiation were nonsignificant. No unexpected adverse event occurred except nine patients (31.0%) had treatment-related adverse events higher than or equal to Grade 3, including 2 (6.9%) had a radiation-induced liver injury. PBT combined with anti-PD1/PDL1 was safe without unexpected adverse events. The concurrent therapy could effectively treat advanced HCC through sustained local tumor necrosis and effective systemic tumor control for the patients who received curative-intent or palliative-control PBT combined with anti-PD1/PDL1.

OBJECTIVE Death preparedness involves cognitive prognostic awareness and emotional acceptance of a relative's death. Effects of retrospectively assessed cognitive prognostic awareness and emotional preparedness for patient death have been individually investigated among bereaved family caregivers. We aimed to prospectively examine associations of caregivers' death-preparedness states, determined by conjoint cognitive prognostic awareness and emotional preparedness for death, with bereavement outcomes. METHODS Associations of caregivers' death-preparedness states (no-death-preparedness, cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) at last preloss assessment with bereavement outcomes over the first two bereavement years were evaluated among 332 caregivers of advanced cancer patients using hierarchical linear models with the logit-transformed posterior probability for each death-preparedness state. RESULTS Caregivers with a higher logit-transformed posterior probability for sufficient death-preparedness state reported less prolonged-grief symptoms, lower likelihoods of severe depressive symptoms and heightened decisional regret, and better mental health-related quality of life (HRQOL). Caregivers with a higher logit-transformed posterior probability for no-death-preparedness state reported less prolonged-grief symptoms, a lower likelihood of severe depressive symptoms, and better mental HRQOL. A higher logit-transformed posterior probability for cognitive-death-preparedness-only state was associated with bereaved caregivers' higher likelihood of heightened decisional regret, whereas that for emotional-death-preparedness-only state was not associated with caregivers' bereavement outcomes. CONCLUSIONS Caregivers' bereavement outcomes were associated with their preloss death-preparedness states, except for physical health-related QOL. Interventions focused on not only cultivating caregivers' accurate prognostic awareness but also adequately preparing them emotionally for their relative's forthcoming death are actionable opportunities for high-quality end-of-life care and are urgently warranted to facilitate caregivers' bereavement adjustment.

Background & Aims Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. Methods CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. Results There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. Conclusion Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. Lay summary The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.

Background: Desmoid tumor and leiomyoma are abdominal wall tumors with similar clinical, radiographic, and histological features. However, differentiation between these two diseases is important because each may be linked to different systemic diseases, and their managements are entirely different. We proposed that misdiagnosis is possible in some cases. Patients and Methods: Between 1983 and 2010, patients with a history of uterine surgeries and diagnosed with either abdominal wall desmoid tumors or leiomyomas were studied. All the images reviewed by an independent radiologist and surgical specimen were reexamined by immunohistochemistry (IHC) techniques as a standard method to confirm the diagnoses. Results: Fifteen female patients (desmoid tumors, n = 10; leiomyomas, n = 5) were included. The diagnosis of IHC revealed that two cases initially thought to be leiomyomas were desmoid tumors, whereas the remaining 13 cases maintained their initial diagnoses. The accuracy of hematoxylin and eosin staining was 86.7%. All tumors excised without complications, except for one desmoid tumor that recurred and underwent another excision. Conclusion: Preoperative magnetic resonance imaging (MRI) can be considered to differentiate the two diseases, as well as the elimination of other associated systemic diseases should be performed routinely. If MRI is inaccessible or unavailable, preoperative fine-needle biopsy is recommended. Optional IHC staining is required if the primary histological assessment is equivocal or inconclusive.

e16181 Background: The effect of checkpoint inhibitor therapy on HBV infection is uncertain. TIS, an anti-PD-1 antibody, was clinically active and well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). Objective response rate by independent committee review (IRC) in pts with a history of HBV infection was consistent with the overall population (12.5% vs 13.3%, respectively). We explored whether TIS treatment was associated with increased HBV DNA and the clinical significance of HBV DNA elevations. Methods: Pts with ≥ 1 prior systemic therapy for advanced HCC received TIS 200 mg IV Q3W. Pts with inactive, chronic, or active HBV were eligible if HBV DNA levels were < 500 IU/mL at screening (pts with detectable hepatitis B surface antigen [HBsAg] or detectable HBV DNA were required to be managed per treatment guidelines). HBV DNA testing was conducted every 4 cycles if HBV DNA was detectable at screening, or when clinically indicated. Results: Among 249 enrolled pts, 128 had a history of HBV infection. Of these pts, 114 were HBsAg positive at baseline (BL), 36 had detectable HBV DNA at BL, and 32 had detectable HBV DNA and HBsAg at BL. Clinically significant increases in HBV DNA levels from BL were reported in 7 pts, with no pattern relative to the time of TIS initiation (Table). All 7 pts were HBsAg positive at BL and had been receiving antiviral treatment for ≥ 3 months before the first dose of TIS. Six out of the 7 pts had increases in alanine transaminase (ALT) from BL during the study (Table), 4 of whom had ≥ 3-fold increases in ALT which were observed concurrently or soon after HBV DNA increases. IRC-assessed best overall response (BOR) was partial response (PR) for 1 pt with increased HBV DNA and progressive disease for the remaining 6. HBV-related treatment-emergent adverse events (TEAEs) were reported in 6 of the 7 pts (2 pts had a Grade 3 TEAE of hepatitis B; 2 pts had a Grade 2 TEAE of HBV reactivation; 2 pts had a TEAE of increased HBV DNA, with one Grade 1 and one Grade 3 event). All HBV-related TEAEs were non-serious and did not result in discontinuation of TIS. Conclusions: Clinically significant increases in HBV DNA from BL were reported in a small number of pts, which does not suggest that TIS is associated with increased HBV DNA. Tumor responses in these pts were consistent with the overall population and HBV-related TEAEs were manageable and did not require discontinuation of TIS, demonstrating that HBV DNA increases did not impact treatment. The effects of TIS in pts with HBV infection will be further investigated in an ongoing Phase 3 trial (NCT03412773). Clinical trial information: NCT03419897. [Table: see text]

Background Family caregivers’ distinct depressive-symptom trajectories are understudied and have been examined independently during end-of-life (EOL) caregiving or bereavement, making it difficult to validate two competing hypotheses (wear-and-tear vs. relief) of caregiving effects on bereavement. Existing studies may also miss short-term heterogeneity in depressive symptoms during the immediate postloss period due to lengthy delays in the first postloss assessment. Purpose This secondary-analysis study examined distinct depressive-symptom trajectories for caregivers of advanced cancer patients from EOL caregiving through the first 2 bereavement years with closely spaced assessments. Methods Depressive symptoms were measured monthly during EOL caregiving and 1, 3, 6, 13, 18, and 24 months postloss among 661 caregivers using the Center for Epidemiologic Studies-Depression scale. Depressive-symptom trajectories were identified using latent-class growth analysis while controlling for gender and age. Results We identified seven distinct depressive-symptom trajectories (prevalence) characterized by the timing, intensity, and duration of depressive symptoms: minimal-impact resilience (20.4%), recovery (34.0%), preloss-grief only (21.6%), delayed symptomatic (9.1%), relief (5.9%), prolonged symptomatic (6.5%), and chronically persistent distressed (2.5%). Conclusion Caregivers of advanced cancer patients responded heterogeneously to the stresses of EOL caregiving and bereavement. The majority of caregivers was resilient while providing caregiving and quickly rebounded to healthy levels of psychological functioning during bereavement, whereas a minority experienced delayed-symptomatic, prolonged-symptomatic, or chronically-persistent-distressing depressive-symptom trajectories. Linking caregivers’ psychological experiences from caregiving through bereavement by closely spaced assessments can more comprehensively illustrate their depressive-symptom trajectories, which confirm both the wear-and-tear and relief hypotheses, and help in targeting interventions for distinct depressive-symptom trajectories.

Background The gut microbiome is associated with the immune function of the host. No consensus has been reached regarding to the association between microbiota and the treatment response to immune checkpoint inhibitor (ICI). This study is designed to explore the relationship between gut microbiome composition and clinical outcomes in patients with advanced cancer treated with ICI. Methods Fifty patients were enrolled in this study. Fecal samples were collected at the baseline, 3 months after treatment and when disease progression was noted. To explore the gut microbiota as a potential predictive biomarker for immunotherapy, 16S ribosome RNA gene sequencing was used to analyze the gut microbiota profiles. Peripheral immunity parameters were determined by multicolor flow cytometry and cytokine array. Alpha-diversity of healthy individuals was used as a cut-off. Results When subgrouping patients into benefiter and non-benefiter according to the clinical response assessed, non-benefiter patients harbored lower alpha-diversity of gut microbiome at the baseline. Patients with low microbiome diversity had poor progression-free survival (HR=0.569, p=0.219) when compared to those with high diversity. Compositional difference was observed between the two groups as well with the enrichment of g_Fusicatenibacter in benefiters whereas f_Veillonellaceae enriched in non-benefiters. Analysis of immune responses using multicolor flow cytometry revealed that patients with a high diversity of gut microbiota had decreased CD4+/CD25+/FoxP3+ regulatory T cells in response to ICI. After ICI treatment the CD4/CD8 ratio of PBMCs was decreased in clinical benefiter. The serum MIF and CXCL12 levels were decreased in clinical benefiter. Conclusions Low alpha diversity of the gut microbiota is associated with poor response to immune checkpoint inhibitors in patients with advanced cancer. Further confirmation in the clinical trials is warranted. Acknowledgements The authors thank all the members of the Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, for their invaluable help. The study and data collection processes were funded by the grants to John WC Chang from Chang Gung Memorial Hospital (Grant No. CIRPG3H0061~2). Ethics Approval The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, approval number 201801261B0. Consent Written informed consent was obtained from the patients for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Background PD-1/L1 inhibitors are treatment options for patients with HCC who have progressed after first-line sorafenib treatment. Tislelizumab, an anti-PD-1 monoclonal antibody, has demonstrated single-agent antitumor activity in patients with advanced, previously treated HCC in two early phase studies (NCT02407990, NCT04068519). Association of biomarkers, including PD-L1 expression and gene expression profiles (GEP), with response and resistance to tislelizumab were explored. Methods PD-L1 expression was evaluated on tumor cells (TC) using the VENTANA PD-L1 (SP263) assay in baseline tumor samples collected before or after sorafenib treatment. GEP were assessed using the 1392-gene HTG GEP EdgeSeq panel. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures (GS). Wilcoxon rank-sum test was used to analyze differential gene signatures (DEG); GS association with PFS and OS was evaluated using Cox proportional hazards models. Results Single-agent tislelizumab demonstrated antitumor activity in advanced, previously treated HCC (ORR=13%; CB [PR+SD >6 months]=31%, median PFS=3.3 months; median OS=13.3 months). PD-L1+ (TC≥1%) prevalence and GEP showed different patterns in samples collected before and after sorafenib exposure (figure 1). While non-exposed samples (n=16) were enriched for immune suppressive signatures, sorafenib-exposed samples (n=41) showed higher PD-L1+ prevalence (53.7% vs 25%; P=0.08) and immune-cell activation signatures along with co-inhibition molecules. In sorafenib-exposed samples, PD-L1 expression was positively correlated with CB (P=0.0027) and a trend of longer PFS (HR=0.56, 95% CI:0.28–1.13). ORR was higher in PD-L1+ than PD-L1− sorafenib-exposed samples (23.8% vs 0%; P=0.049). DEG analysis in sorafenib-exposed samples demonstrated that NK-mediated cytotoxicity GS was positively correlated with CB (P=0.03), as well as a trend of longer PFS (HR=0.43, 95% CI:0.17–1.06). Across the different analyses, no correlation with OS was observed. Patients considered non-responders (NRs) were found clustered into three distinct GEP subgroups (NR1, NR2, NR3). Compared with responders, NR1 had enhanced angiogenesis signatures (P=0.01), including TEK, KDR, HGF, and EGR1. Despite high inflamed tumor signatures, NR2 had increased expression of T-cell inhibition GS scores (P=0.01), including CD274, CTLA4, TIGIT, and CD96. The NR3 subgroup showed higher cell-cycle GS scores compared with responders (P=0.05), including E2F7, FOXA1, and FANCD2. Conclusions Prior sorafenib exposure appears to be associated with increased PD-L1 expression and tumor microenvironment-related GS, as well as response and PFS from tislelizumab in advanced HCC patients. Elevated angiogenesis, immune exhaustion, and cell-cycle GS levels may indicate resistance to single-agent PD-1 inhibitors and is suggestive of potential treatment strategies. Validation is warranted in future clinical trials (NCT03412773). Acknowledgements This study was sponsored by BeiGene, Ltd. Writing and editorial assistance was provided by Regina Switzer, PhD, and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago. IL), and funded by the study sponsor. Trial Registration NCT02407990, NCT04068519

BackgroundThe programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.MethodsPatients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.ResultsBetween May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.ConclusionsTislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.Trial registration numberNCT02407990.

Background Developing accurate prognostic awareness, a cornerstone of preference-based end-of-life (EOL) care decision-making, is a dynamic process involving more prognostic-awareness states than knowing or not knowing. Understanding the transition probabilities and time spent in each prognostic-awareness state can help clinicians identify trigger points for facilitating transitions toward accurate prognostic awareness. We examined transition probabilities in distinct prognostic-awareness states between consecutive time points in 247 cancer patients' last 6 months and estimated the time spent in each state. Methods Prognostic awareness was categorized into four states: (a) unknown and not wanting to know, state 1; (b) unknown but wanting to know, state 2; (c) inaccurate awareness, state 3; and (d) accurate awareness, state 4. Transitional probabilities were examined by multistate Markov modeling. Results Initially, 59.5% of patients had accurate prognostic awareness, whereas the probabilities of being in states 1-3 were 8.1%, 17.4%, and 15.0%, respectively. Patients' prognostic awareness generally remained unchanged (probabilities of remaining in the same state: 45.5%-92.9%). If prognostic awareness changed, it tended to shift toward higher prognostic-awareness states (probabilities of shifting to state 4 were 23.2%-36.6% for patients initially in states 1-3, followed by probabilities of shifting to state 3 for those in states 1 and 2 [9.8%-10.1%]). Patients were estimated to spend 1.29, 0.42, 0.68, and 3.61 months in states 1-4, respectively, in their last 6 months. Conclusion Terminally ill cancer patients' prognostic awareness generally remained unchanged, with a tendency to become more aware of their prognosis. Health care professionals should facilitate patients' transitions toward accurate prognostic awareness in a timely manner to promote preference-based EOL decisions. Implications for practice Terminally ill Taiwanese cancer patients' prognostic awareness generally remained stable, with a tendency toward developing higher states of awareness. Health care professionals should appropriately assess patients' readiness for prognostic information and respect patients' reluctance to confront their poor prognosis if they are not ready to know, but sensitively coach them to cultivate their accurate prognostic awareness, provide desired and understandable prognostic information for those who are ready to know, and give direct and honest prognostic information to clarify any misunderstandings for those with inaccurate awareness, thus ensuring that they develop accurate and realistic prognostic knowledge in time to make end-of-life care decisions.

Background After neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer, high pathologically complete response (pCR) rates are being achieved especially in patients with squamous cell carcinoma (SCC). An active surveillance strategy has been proposed for SCC patients with clinically complete response (cCR) after nCRT. To justify omitting surgical resection, patients with residual disease should be accurately identified. The aim of this study is to assess the accuracy of response evaluations after nCRT based on the preSANO trial, including positron emission tomography with computed tomography (PET-CT), endoscopy with bite-on-bite biopsies and endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) in patients with potentially curable esophageal SCC. Methods Operable esophageal SCC patients who are planned to undergo nCRT according to the CROSS regimen and are planned to undergo surgery will be recruited from four Asian centers. Four to 6 weeks after completion of nCRT, patients will undergo a first clinical response evaluation (CRE-1) consisting of endoscopy with bite-on-bite biopsies. In patients without histological evidence of residual tumor (i.e. without positive biopsies), surgery will be postponed another 6 weeks. A second clinical response evaluation (CRE-2) will be performed 10–12 weeks after completion of nCRT, consisting of PET-CT, endoscopy with bite-on-bite biopsies and EUS with FNA. Immediately after CRE-2 all patients without evidence of distant metastases will undergo esophagectomy. Results of CRE-1 and CRE-2 as well as results of the three single diagnostic modalities will be correlated to pathological response in the resection specimen (gold standard) for calculation of sensitivity, specificity, negative predictive value and positive predictive value. Discussion If the current study shows that major locoregional residual disease (> 10% residual carcinoma or any residual nodal disease) can be accurately (i.e. with sensitivity of 80.5%) detected in patients with esophageal SCC, a prospective trial will be conducted comparing active surveillance with standard esophagectomy in patients with a clinically complete response after nCRT (SINO trial). Trial registration The preSINO trial has been registered at ClinicalTrials.gov as NCT03937362 (May 3, 2019).

e16113 Background: Management of advanced hepatocellular carcinoma (HCC) remains a challenge. IMbrave150, a pivotal trial reported impressive overall survival benefit using combination strategy of atezolizumab and bevacizumab compared to sorafenib. We wonder the efficacy and safety when combining radiotherapy with immune checkpoint inhibitors (ICIs), which radiation might provide better local treatment and possible trigger abscopal effect. The aim of this study is retrospectively reporting the real-world efficacy and tolerability of proton beam or photon radiation plus ICIs in patients with advance stage HCC. Methods: We retrospectively reviewed all BCLC stage C HCC patients who have received combination therapy with ICIs plus proton or photon therapy with well documented basic characteristics and prompt treatment efficacy evaluation between 1st of January 2016 to 31st of October 2019 at a single medical center in Taiwan. 20 patients had ICIs plus proton and 32 patients had ICIs plus photon were included for analysis. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier estimator. Results: Baseline characteristics were generally similar between ICIs plus proton or ICIs plus photon, while most patients in proton group did not receive prior systemic treatment and had less local therapies prior ICIs combine with radiotherapy. Median follow-up time was 10.7 months. The median Progression free survival (PFS) was not reached in ICIs plus proton group and 3.6 months (95% CI 2.7-4.6) in ICIs plus photon group (P = 0.007). The median OS was not reach in ICIs plus proton group and 12.1months (95% CI 6.4-17.7) in ICIs plus photon group (P = 0.007). Comparing ICIs plus proton group versus photon group, objective tumor response is 50% versus 9%, disease control rate is 80% versus 47% in each group. During follow-up, 7 patients (35%) in proton group achieved complete remission (CR). There was difference in radiation filed, 19 patients (95%) in proton group and 15 patients (47%) in photon group targeted on liver tumors, and more patient received > 50Gy treatment dose in proton group compared to photon group (90% versus 20%). Proton group has lower failure rate in both inner- or out-field compared to photon group. Grade 1 to grade 2 skin-dermatological and gastrointestinal toxicity remained the most frequent reported adverse events in both groups. There are only one therapy related grade 3 dermatitis in ICIs plus proton group and one grade 3 hepatitis, one grade 5 pneumonitis in ICIs plus photon group. Conclusions: This study reported real-world efficacy and safety of ICIs in combination with proton or photon therapy. Most adverse events were manageable. The combination of ICIs and proton therapy has impressive CR rate and OS benefit. Further prospective randomized trial is warranted for confirm our finding.

269 Background: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) followed by NIVO 240 mg Q2W is approved in the US for sorafenib-treated pts with aHCC based on initial results from CheckMate 040 (NCT01658878), which reported objective response rate (ORR) of 32% and median overall survival (mOS) of 22.8 months (mo).1 We present 44-mo long-term follow-up results from the CheckMate 040 NIVO+IPI cohort. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Safety and tolerability, ORR (blinded independent central review per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS were assessed. Data cutoff was May 26, 2020. Results: 148 pts were randomized. Minimum follow-up was 44 mo. mOS remained at 22.2 mo in arm A, 12.5 mo in arm B, and 12.7 mo in arm C; 36-mo OS rates were 42%, 26%, and 30%, respectively. Durable responses were achieved across treatment arms, with DOR approaching 4 years in some cases. DCR was higher in arm A than arms B and C. In all arms, responses were observed regardless of baseline programmed death ligand 1 expression ( < 1% or ≥ 1%) or baseline alpha-fetoprotein level ( < 400 µg/L or ≥ 400 µg/L). Pts with hepatitis B or C virus (HBV or HCV) etiology had higher ORR than uninfected pts in arms B (29% vs 43% vs 9%) and C (31% vs 42% vs 0%). ORR was independent of etiology in arm A (HBV, 32%; HCV, 29%; uninfected, 31%). Additional efficacy data are in the table. There were no additional discontinuations due to treatment-related adverse events or immune-mediated adverse events (IMAEs) since the primary analysis. IMAEs were reported more frequently in arm A than arms B and C; the most common were rash, hepatitis, and adrenal insufficiency. Most IMAEs were reversible and resolved when treated using established algorithms. Conclusions: At a minimum follow-up of 44 mo, second-line NIVO1+IPI3 continued to demonstrate clinically meaningful responses and long-term survival benefit in aHCC. The safety profile was manageable and no new safety signals were identified with longer follow-up. Clinical trial information: NCT01658878. [Table: see text]

Aims The BRAF V600 mutation has been shown to be clinically meaningful in terms of both the prognosis and sensitivity of BRAF inhibitors in patients with metastatic melanoma. Recently, a BRAF V600E mutation-specific antibody, VE1, was generated for the detection of tumors bearing BRAF V600E mutations. To determine the clinical value of immunohistochemical testing, we compared the prevalence of mutant BRAF detected by VE1 with direct sequencing results. Methods Paraffin-embedded, formalin-fixed melanoma biopsies were analyzed for the BRAF mutation status by immunohistochemistry with the VE1 antibody. Sanger sequencing was applied to verify the immunohistochemical results. Results A total of 73 melanoma cases with tumor samples from primary lymph nodes and metastatic sites were selected for this study. Direct sequencing demonstrated that 18 of 73 cases (24.6%) harbored the BRAF V600 mutation: 17 with V600E and one with V600K. All 18 tumors shown to harbor the BRAF V600E/K mutations were VE1-positive. One additional case was false-positive for VE1. The sensitivity and specificity of VE1 was 100% (18/18) and 98% (54/55), respectively. The overall concordance between the immunohistochemical method and direct sequencing was excellent (98.6%). Conclusions Our findings demonstrate that immunohistochemical analysis using VE1 constitutes a highly sensitive test for the detection of BRAF mutations and suggest that this cost-effective method is suitable as a rapid diagnostic approach complementary to molecular testing.

In this retrospective review of prospectively collected data, we sought to investigate whether early FDG-PET assessment of treatment response based on total lesion glycolysis measured using a systemic approach (TLG-S) would be superior to either local assessment with EORTC (European Organization for Research and Treatment of Cancer) criteria or single-lesion assessment with PERCIST (PET Response Criteria in Solid Tumors) for predicting clinical outcomes in patients with metastatic lung adenocarcinoma treated with erlotinib. We also examined the effect of bone flares on tumor response evaluation by single-lesion assessment with PERCIST in patients with metastatic bone lesions. We performed a retrospective review of prospectively collected data from 23 patients with metastatic lung adenocarcinoma treated with erlotinib. All participants underwent FDG-PET imaging at baseline and on days 14 and 56 after completion of erlotinib treatment. In addition, diagnostic CT scans were performed at baseline and on day 56. FDG-PET response was assessed with TLG-S, EORTC, and PERCIST criteria. Response assessment based on RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) from diagnostic CT imaging was used as the reference standard. Two-year progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. We identified 13 patients with bone metastases. Of these, four (31 %) with persistent bone uptake due to bone flares on day 14 were erroneously classified as non-responders according to the PERCIST criteria, but they were correctly classified as responders according to both the EORTC and TLG-S criteria. Patients who were classified as responders on day 14 based on TLG-S criteria had higher rates of 2-year PFS (26.7 % vs. 0 %, P = 0.007) and OS (40.0 % vs. 7.7 %, P = 0.018). Similar rates were observed in patients who showed a response on day 56 based on CT imaging according to the RECIST criteria. Patients classified as responders on day 14 according to the EORTC criteria on FDG-PET imaging had better rates of 2-year OS than did non-responders (36.4 % vs. 8.3 %, P = 0.015). TLG-S criteria may be of greater help in predicting survival outcomes than other forms of assessment. Bone flares, which can interfere with the interpretation of treatment response based on PERCIST criteria, are not uncommon in patients with metastatic lung adenocarcinoma treated with erlotinib.

// Ming-Mo Hou 1, 3, * , Zhijie Wang 4, * , Filip Janku 1 , Sarina Piha-Paul 1 , Aung Naing 1 , David Hong 1 , Shannon Westin 2 , Robert L. Coleman 2 , Anil K. Sood 2 , Apostolia M. Tsimberidou 1 , Vivek Subbiah 1 , Jennifer Wheler 1 , Ralph Zinner 1 , Karen Lu 2 , Funda Meric-Bernstam 1 , Siqing Fu 1 1 Departments of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 4 Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Beijing Institute for Cancer Research, Beijing, China * These authors have contributed equally to this work Correspondence to: Siqing Fu, e-mail: siqingfu@mdanderson.org Keywords: epithelial ovarian cancer, anti-angiogenesis, tumor progression, progression-free survival, overall survival Received: March 01, 2016 Accepted: April 10, 2016 Published: April 27, 2016 ABSTRACT High-grade epithelial ovarian cancer (HG-EOC) is the most lethal gynecologic malignancy worldwide Once patients develop chemoresistance, effective novel strategies are required to improve prognosis We analyzed characteristics and outcomes of 242 consecutive patients with HG-EOC participating in 94 phase I clinical trials at The University of Texas MD Anderson Cancer Center. Baseline lactate dehydrogenase levels, albumin levels, and number of metastatic sites were independent predictors of overall survival (OS). Receiving more than 1 phase I protocol was associated with improved OS (p < 0.001). Regimens including a chemotherapeutic agent plus bevacizumab or Aurora A kinase inhibitor led to a median progression-free survival (PFS) duration of more than 6 months. Although patients receiving bevacizumab-based regimens in the phase I clinical trials had significantly longer PFS than those receiving other anti-angiogenic therapies (p = 0.017), patients treated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) had significantly longer OS (12.2 months) than those not treated with VEGFR-TKIs (8.6 months, p = 0.015). In conclusion, anti-angiogenic therapy is one of the most important strategies for the treatment of HG-EOC, even in those who have already experienced tumor progression. Therefore, eligible patients with HG-EOC should be encouraged to participate in novel phase I studies of anti-angiogenic therapies, even after disease progression.

Background/Objective Self-perceived burden to others (SPB) is a major concern of terminally ill cancer patients and is frequently factored into end-of-life (EOL) care decision-making. However, changes in and determinants of SPB and its longitudinal impact on preferences for EOL care over the dying process have not been investigated. Our study was aimed at filling this gap in knowledge. Methods A convenience sample of 325 cancer patients was followed until death. High SPB was identified as scoring >20 on the Self-perceived Burden Scale. Preferences for EOL care included EOL-care goals, life-sustaining treatments, and hospice care. Factors potentially precipitating/minimizing patients' high SPB included demographics, disease characteristics and burden, and social support and were examined by multivariate logistic regression modeling with the generalized estimating equation. Results Prevalence of high SPB increased as death approached (51.78%, 58.26%, 62.66%, and 65.38% for 181–365, 91–180, 31–90, and 1–30 days before death, respectively). High SPB was precipitated by women, younger age, having inadequate financial resources, without religious affiliation, and suffering from severe symptom distress and heavy functional dependence but was independent of time proximity to patient death, disease characteristics, and social support. Furthermore, high SPB was not associated with EOL-care preferences, whether aggressive life-sustaining treatments or hospice care. Conclusions High SPB was prevalent among terminally ill cancer patients but independent of preferences for EOL care. Cancer patients' SPB may be lessened by adequate symptom relief to facilitate functional independence. These strategies to ease SPB may improve the quality of death and dying. Copyright © 2016 John Wiley & Sons, Ltd.

Cancer patients with predominantly hepatic metastases have poor outcomes and limited options. Hepatic arterial infusion (HAI) of a therapeutic agent may be an appropriate option for producing increased drug concentrations at the tumor sites while reducing systemic adverse effects in normal tissues.Patients with predominantly hepatic metastases (n = 48) were placed in 6 groups according to nanoparticle albumin-bound paclitaxel (nab-paclitaxel) dose level using a 3 + 3 design plus dose expansion for responsive tumor types. We evaluated the toxicity, antitumor activity, and pharmacokinetics of nab-paclitaxel delivered via HAI.Thirty-eight and ten patients underwent HAI over 1 and 4 h, respectively, at doses of up to 300 mg/m(2). The treatment was safe and exhibited antitumor activity. Pharmacokinetic analyses revealed that HAI of nab-paclitaxel over 4 h resulted in markedly lower peak drug concentrations (C max) and longer times to peak concentration (T max) than that over 1 h. The self-control pharmacokinetic studies showed that HAI of nab-paclitaxel led to much lower C max and areas under the curve (AUC), compared with intravenous infusion.HAI of nab-paclitaxel at up to 300 mg/m(2) over 4 h was well tolerated. Pharmacokinetic evaluation of C max, T max, and AUC implied that 4-h HAI enhanced hepatic extraction of nab-paclitaxel. Further preclinical and clinical studies are required to develop reliable methods of evaluation of hepatic extraction (clinicaltrials.gov registration number NCT00732836, first registered on August 8, 2008, and last updated on October 27, 2014).

Importance Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. Objective To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. Design, Setting, and Participants CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). Interventions Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). Main Outcomes and Measures Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). Results Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). Conclusions and Relevance In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study. Trial Registration ClinicalTrials.gov Identifier:NCT01658878

512 Background: NIVO monotherapy is approved in the United States and other countries for pts with HCC treated with sorafenib (SOR) based on CheckMate 040 (NCT01658878) results, which reported 14% objective response rate (ORR) and 16-month median overall survival (mOS; El-Khoueiry et al. Lancet 2017). Primary efficacy and safety of NIVO + IPI in pts with aHCC previously treated with SOR were presented recently (Yau et al. J Clin Oncol 2019). Here, we will present subgroup analyses from this study. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety/tolerability, ORR, and duration of response (DOR; investigator assessment per RECIST v1.1). Key secondary endpoints included disease control rate (DCR), OS, and progression-free survival (blinded independent central review [BICR] per RECIST v1.1); key exploratory endpoints included ORR (BICR per RECIST v1.1). Data cutoff was January 2019. Results: A total of 148 pts were randomized. Minimum OS follow-up from last pt randomization date to data cutoff was 28 months. At baseline, 34% of all pts had vascular invasion; 82% had extrahepatic spread; and 91% had Barcelona Clinic Liver Cancer stage C; 84% discontinued SOR because of disease progression and 14% because of toxicity. For all treated pts, ORR was 31% (7 had complete response), with median DOR of 17 months; DCR was 49%; the 30-month OS rate was 37%. NIVO + IPI was well tolerated; 38% of pts had grade 3–4 treatment-related adverse events (TRAEs; most common any grade: pruritus and rash; most common grade 3–4: aspartate aminotransferase increase and lipase increase); 5% had grade 3–4 TRAEs leading to discontinuation. Subgroup analyses based on duration of prior SOR therapy and other pt characteristics will be presented. Conclusions: NIVO + IPI led to clinically meaningful benefits, with a manageable safety profile in pts previously treated with SOR. NIVO + IPI may provide a new treatment option for these pts. Clinical trial information: NCT01658878.

Context/Objective Half of advanced cancer patients do not have accurate prognostic awareness (PA). However, few randomized clinical trials (RCTs) have focused on facilitating patients' PA to reduce their life-sustaining treatments at end of life (EOL). To address these issues, we conducted a double-blinded RCT on terminally ill cancer patients. Methods Experimental-arm participants received an individualized, interactive intervention tailored to their readiness for advanced care planning and prognostic information. Control-arm participants received a symptom-management educational treatment. Effectiveness of our intervention in facilitating accurate PA and reducing life-sustaining treatments received, two secondary RCT outcomes, was evaluated by intention-to-treat analysis using multivariate logistic regression. Results Participants (N = 460) were randomly assigned 1:1 to experimental and control arms, each with 215 participants in the final sample. Referring to 151–180 days before death, experimental-arm participants had significantly higher odds of accurate PA than control-arm participants 61–90, 91–120, and 121–150 days before death (adjusted odds ratio [95% CI]: 2.04 [1.16–3.61], 1.94 [1.09–3.45], and 1.93 [1.16–3.21], respectively), but not one to 60 days before death. Experimental-arm participants with accurate PA were significantly less likely than control-arm participants without accurate PA to receive cardiopulmonary resuscitation (CPR) (0.16 [0.03–0.73]), but not less likely to receive intensive care unit care and mechanical ventilation in their last month. Conclusion Our intervention facilitated cancer patients' accurate PA early in their dying trajectory, reducing the risk of receiving CPR in the last month. Health care professionals should cultivate cancer patients' accurate PA early in the terminal-illness trajectory to allow them sufficient time to make informed EOL-care decisions to reduce CPR at EOL.

Context/Objectives Our study addressed important knowledge gaps about trajectories of distinct conjoint symptom-functional states, that is, patterns for different levels of combined symptom distress and functional impairment, over cancer patients' last year and their ability to predict survival. Methods We identified distinct symptom-functional states and explored their changes over 317 terminally ill cancer patients' last year by a transition model using hidden Markov modeling. These distinct symptom-functional states' ability to predict current survival probability, measured in the previous assessment, was evaluated by multivariate Cox regression models. Results We identified five worsening, conjoint symptom-functional states: 1) mild symptom distress with high functioning, 2) moderate symptom distress with mild functional impairment, 3) severe symptom distress with moderate functional impairment, 4) moderate symptom distress with severe functional impairment, and 5) profound symptom distress and functional impairment. Trajectories of these five states differed substantially by direction (downward vs. upward) and speed. Participants in States 1–4 had substantially lower risk of subsequent death than those in State 5 (adjusted hazard ratios [95% CI] ranged from 0.048 [0.028–0.081] to 0.434 [0.316–0.579]). The risk of subsequent death differed significantly between patients in any two distinct symptom-functional states, except between those in States 3 and 4. Conclusion Our identification of five distinct symptom-functional states and their unique transition patterns and prediction of mortality provides all stakeholders with guides for end-of-life care. Goals of end-of-life care should change toward palliative care and effective symptom management for patients with at least moderate symptom distress and substantial functional impairment.

Background Tislelizumab (BGB-A317), an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. Previous reports from early phase studies suggest tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors. Clinical effects of tislelizumab LTE (>12 mo) in pts enrolled in the first-in-human study (NCT02407990) are presented here. Methods Patients with advanced solid tumors received IV tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W, 2 or 5 mg/kg administered Q2W or Q3W, or 200 mg IV Q3W. Antitumor activity was assessed by RECIST v1.1 criteria; PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results As of 31 Aug 2018, 63 of the 451 pts received tislelizumab for >12 mo. In these 63 pts, median age was 64 yr and 70% had received ≥1 prior systemic therapy. Tislelizumab LTE was most common in NSCLC (n=9), HCC (n=7), and bladder and ovarian (n=5 each) cancers. Four of the 5 pts who achieved CR during this study had LTE to tislelizumab (Table); all 4 pts were PD-L1+ (≥1% expression on tumor cells). Across the LTE cohort, ORR was 66.7%; PR and SD were observed in both PD-L1+ and PD-L1- tumors. The median time to CR/PR (3.7 mo) and duration of CR/PR (21.1 mo) were longer in pts with LTE than pts who responded but did not remain on treatment for >12 mo (2.1 and 6.3 mo, respectively). Rash was the only treatment-related AE (TRAE) reported in ≥15% of pts. Most TRAEs were of mild or moderate severity; arthritis, diarrhea, fatigue, granuloma, hyperglycemia, and lichenoid keratosis (n=1 each) were the only grade ≥3 TRAEs reported with tislelizumab LTE. Conclusion Tislelizumab remained well tolerated for >12 mo and elicited durable responses in pts with a variety of tumor types regardless of PD-L1 status. PD-L1+ (n=35)PD-L1- (n=22)Missing (n=6)Total (N=63)CR4004 (6.3%)PR2113438 (60.3%)SD99220 (31.7%)PD1001 (1.6%)Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD stable disease. Citation Format: Jayesh Desai, Benjamin Markman, Michael Friedlander, Hui Gan, Lisa Horvath, Amanda Townsend, Michael Millward, Michael Jameson, Chia-Jui Yen, Ming-Mo Hou, Jeannie Hou, John Wu, Liang Liang, Sanjeev Deva. Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT084.

4012 Background: NIVO monotherapy (mono) is approved for sorafenib (SOR)-treated pts with HCC based on data from CheckMate 040 (NCT01658878), which reported an objective response rate (ORR) of 14% and median overall survival (mOS) of 16 months (mo). This is the first report of efficacy and safety of the NIVO + IPI combination in SOR-treated pts with aHCC. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety and tolerability. Secondary endpoints included ORR (BICR per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS. Cutoff was 25 Sep 2018. Results: 148 SOR-treated pts were randomized. Minimum follow-up for OS from last pt randomization date to data cutoff was 24 mo. At baseline: 88% had vascular invasion or extrahepatic spread, 91% had BCLC stage C, 84% discontinued SOR due to disease progression and 14% due to toxicity. Overall, ORR was 31% (7 had a complete response [CR]) with a median DOR of 17 mo; DCR was 49% and 24-mo OS rate was 40%. Pts in arm A had a mOS of 23 mo and 4 pts had a CR. The table shows additional efficacy results by arm. Overall, NIVO + IPI was well tolerated; 37% of pts had a grade 3–4 treatment-related adverse event (TRAE; most common: pruritus and rash); 5% had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + IPI led to clinically meaningful responses and had an acceptable safety profile in SOR-treated pts, with an ORR twice that of NIVO mono (31% and 14%, respectively). Pts in arm A had the most promising mOS of 23 mo. Clinical trial information: NCT01658878. [Table: see text]

Purpose Preclinical data showed that trientine, a copper-lowering agent, re-sensitized cancer cells to carboplatin through enhanced human copper transporter 1 (hCtr1) -mediated platinum uptake. Experimental Design We studied carboplatin and trientine in patients (n = 55; 45 who had failed platinum) with advanced malignancies (Phase I, modified 3 + 3 design). Results The most common cancers were head and neck (n = 13), non-small cell lung (n = 10) and epithelial ovarian (n = 8). The median number of prior regimens was four. No dose-limiting toxicity or treatment-related deaths were observed at doses up to carboplatin AUC 6 given with trientine. Eight patients achieved stable disease (SD) ≥ 6 months (six platinum failures) and one patient with platinum-resistant ovarian cancer, partial response (PR) (total SD ≥ 6 months/PR = 9, 16.4 %). The mean nadir serum copper level in the nine patients with SD ≥ 6 months/PR was 0.55 μg/mL (95 % CI, 0.34–0.75) versus 1.22 μg/mL (95 % CI, 1.02–1.42) (p

Problem presented Sarcomatoid carcinoma (SaCa) is a rare variant of squamous cell carcinoma (SCC) with sarcomatoid features. This study investigated the clinical presentation and outcomes of head and neck SaCa. In addition, reconstructive outcome for a subset of patients was also evaluated. Studies undertaken Seventy-eight SaCa cases including 72 men and 6 women were identified from 13,777 head and neck SCC cases. Clinical outcomes were evaluated based on locoregional control, distant metastases, and multivariate analyses. Reconstructive outcome was evaluated by flap survival rate. Result Of the 78 cases, 71% (55) of cases were located in the oral mucosa; 64% (50) of patients were classified as T3 or T4 at the time of diagnosis. The 5-year survival was only 16%. Multivariate analysis revealed better outcomes only when the patient had a history of previous SCC. Forty-five patients underwent flap reconstruction, with 98% flap survival rate but the functional result varied because of the inevitable adjuvant radiotherapy and advanced stage of tumor. Conclusions Sarcomatoid carcinoma is a different entity from the conventional SCC of the head and neck. Sarcomatoid carcinoma carries a poorer prognosis despite aggressive surgical intervention and concurrent adjuvant therapies. It remains a great challenge for clinical oncologists, and the optimal treatment strategy requires further studies. Free flap is still preferred for defect reconstruction but the design should be simplified to avoid complications.

Bereaved families endure tremendous grief. However, few studies have longitudinally investigated caregivers' bereavement grief for more than one year postloss and none is from family-oriented Asian countries.We explored longitudinal changes in and modifiable predictors of severe depressive symptoms for Taiwanese family caregivers of terminally ill cancer patients over the first two years postloss.For this descriptive, longitudinal study, severe depressive symptoms (Center for Epidemiological Studies Depression Scale score ≥16) were measured 1, 3, 6, 13, 18, and 24 months postloss. To identify modifiable factors (preloss depressive symptom levels, subjective caregiving burden, objective caregiving load, preparedness for patient death, and postloss social support) associated with postloss severe depressive symptoms, we used multivariate logistic regression modeling with the generalized estimating equation.Bereaved caregivers (N = 285) were recruited by convenience from a medical center in northern Taiwan.Bereaved family caregivers' prevalence of severe depressive symptoms peaked one month postloss (73.3%) and significantly decreased to 15.2% 24 months after the patient's death. After adjusting for confounders, bereaved caregivers were more likely to have severe depressive symptoms if they had heavy objective caregiving load and higher preloss depressive symptom levels. However, their likelihood of severe depressive symptoms was buffered by being better prepared for the patients' death and having greater social support.Bereaved family caregivers' severe depressive symptoms decreased significantly over the first two years postloss. Healthcare professionals should appropriately assess at-risk bereaved caregivers when patients are still alive and provide effective interventions to facilitate caregivers' return to normal life.

Oxaliplatin-based chemotherapy is an alternative systemic treatment for patients with metastatic hepatocellular carcinoma (HCC) who were refractory or intolerant to sorafenib. To date, there have been no biomarkers reported to monitor the therapeutic efficacy and to predict the outcomes of HCC patients receiving oxaliplatin-based chemotherapy. Methods: Eighty-one HCC patients with elevated baseline α-fetoprotein (AFP) levels and extrahepatic spreading who received oxaliplatin-based chemotherapy between 2012 and 2014 were retrospectively enrolled in this study. Two AFP tests were performed, at baseline and 2–4 weeks after the initiation of chemotherapy. The change in AFP levels was calculated for survival analysis. Results: In the AFP decline group (decreased compared to baseline), the median progression-free survival (PFS) and overall survival (OS) were 7.0 months and 12.3 months, respectively. In the AFP nondecline group, the median PFS and OS were 2.3 months and 3.0 months, respectively. The difference in OS between the two groups was significant (p