Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial.

PURPOSE: KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy. PATIENTS AND METHODS: KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability. RESULTS: Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23-29). ORR was 16% [95% confidence interval (CI), 7-29] and was similar across key subgroups. Median DOR was 16 months (range, 3-24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2-8), and median TTP was 4 months (95% CI, 3-9). Median OS was 17 months (95% CI, 8-23). Grade ≥3 treatment-related adverse events occurred in 16% of patients. CONCLUSIONS: In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC.

Understanding the patient experience in hepatocellular carcinoma: a qualitative patient interview study.

PURPOSE: This study aimed to elucidate the patient experience of hepatocellular carcinoma (HCC) to guide patient-centered outcome measurement in drug development. METHODS: Patients with HCC participated in qualitative interviews to elicit disease-related signs/symptoms and impacts, using discussion guides developed from literature searches and discussions with oncologists. Interview participants rated the disturbance of their experiences (0-10 scale). A conceptual model was developed and mapped against patient-reported outcome (PRO) instruments identified from database reviews. RESULTS: Interviews were conducted with 25 individuals with HCC (68% were men; median age: 63 years; 12% Barcelona clinic liver cancer (BCLC) stage A; 32% stage B; and 56% stage C) in the USA. Fifty-one HCC-related concepts were identified from the interviews and were grouped into eight sign/symptom categories (eating behavior/weight changes; extremities [arms, legs]; fatigue and strength; gastrointestinal; pain; sensory; skin; other) and four impact categories (emotional; physical; cognitive function; other) for the conceptual model. The most prevalent and disturbing experiences across the disease stages were fatigue/lack of energy and emotional impacts such as frustration, fear, and depression. Abdominal pain and skin-related issues were particularly common and disturbing in individuals with HCC stage C. The EORTC QLQ-C30 and HCC18 were identified as commonly used PRO instruments in HCC studies and captured the relevant signs/symptoms associated with the patient experience. CONCLUSION: Patients with HCC reported a range of signs/symptoms and impacts that negatively affect daily functioning and quality of life. Including PRO measures in HCC clinical trials can provide meaningful patient perspectives during drug development.

A Pilot Study of Preoperative Vandetanib on Markers of Proliferation and Apoptosis in Breast Cancer.

INTRODUCTION: Preclinical data supports antitumor activity of tyrosine kinase inhibitor vandetanib with Ret as the therapeutic target in breast cancer. We investigated the effect of preoperative vandetanib on markers of proliferation and apoptosis in breast cancer. METHODS: Patients with invasive breast cancer were randomly assigned vandetanib 300 mg or placebo PO daily for 2 weeks before operative resection from January 2014 to June 2017. Pretreatment and posttreatment specimens were analyzed by immunohistochemistry for Ki-67, TUNEL, and p-ERK with stratification by Ret expression by immunohistochemistry. RESULTS: Ten patients were enrolled. There was no statistically significant difference in ERK activation compared with placebo (P=0.45); however, ERK activation was reduced 74% compared with pretreatment biopsy with vandetinib treatment (P=0.005) without a significant reduction in the placebo group (-29%, P=0.55). Mean change in Ki-67 after vandetanib treatment was +0.3% compared with +2.0% in placebo treated patients, P=0.72. Mean change in TUNEL was +0.48 apoptotic nuclei per HPF in the vandetanib arm compared with +1.02 in the placebo arm, P=0.32. In vandetanib treated patients, Ki-67 was reduced 0.3% in RET-positive tumors compared with increased 1.0% in RET-negative tumors, P=0.43 and TUNEL was increased 0.77 in RET-positive tumors and 0.2 in RET-negative tumors, P=0.21. CONCLUSIONS: In this pilot study, no statistically significant differences on prespecified markers were seen with vandetanib compared with placebo. In accordance with the investigational hypothesis, there was a nonsignificant trend with vandetanib treatment of reduction in p-ERK and increased effects in Ret expressing tumors.

Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: Impact of liver disease aetiology.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load. METHODS: Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study). RESULTS: Baseline characteristics were generally balanced between arms in each subgroup (HBV: N = 225, HCV: N = 127, Other: N = 190). No significant difference in treatment effect by aetiology subgroup was detected (OS interaction P-value = .23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74, 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82, 95% CI 0.55-1.23) for HCV and 8.5 versus 5.4 (HR 0.56, 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function and liver-specific adverse events. CONCLUSIONS: Ramucirumab improved survival across aetiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.

Performing thermal ablations for hepatomas - is it a worthy skill for hepatologists?

INTRODUCTION AND OBJECTIVES: The role of hepatologists in the management of hepatocellular carcinoma (HCC) is not well defined. We conducted a cross-sectional study to assess the feasibility of hepatology-directed HCC treatment. PATIENTS: We evaluated 107 patients with newly diagnosed HCC, undergoing locoregional therapy as the first therapy between January 2017 and February 2019. RESULTS: The hepatologist directly participated in most of the microwave ablations. This descriptive cross-sectional study reveals the feasibility of the hepatologist-directed thermal ablation therapy, with decent outcome including response rate. CONCLUSIONS: Hepatologists can play a key role in the management of HCC in the current era of multidisciplinary team approach. Training fellows in performing ultrasound guided thermal ablation techniques would be one step forward in this direction.

Ixabepilone plus capecitabine in advanced breast cancer patients with early relapse after adjuvant anthracyclines and taxanes: a pooled subset analysis of two phase III studies.

BACKGROUND: Metastatic breast cancer (MBC) patients with rapid disease relapse after neo/adjuvant chemotherapy including anthracyclines and taxanes have limited treatment options and their efficacy is marginal. Two phase III studies compared ixabepilone plus capecitabine vs. capecitabine alone as first-line treatment in MBC patients pretreated with anthracyclines and taxanes in the neo/adjuvant setting. Here we report the efficacy and safety of these treatments in a prespecified subset of patients whose disease relapsed within 12 months. PATIENTS AND METHODS: Of 1973 patients across two studies, 293 relapsed within 12 months of neo/adjuvant treatment and received ixabepilone plus capecitabine (n = 149) or capecitabine alone (n = 144) as first-line chemotherapy for MBC. Analysis included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and toxicity. RESULTS: In 293 patients, ixabepilone plus capecitabine, as compared to capecitabine alone, increased PFS (median: 5.6 months vs. 2.8 months; hazard ratio, 0.58; p < 0.0001), ORR (46% vs. 24%) and OS (median: 15.1 months vs. 12.5 months; hazard ratio, 0.84; p = 0.208). Major toxicities of this regimen included neuropathy, neutropenia and hand-foot syndrome, but were manageable. CONCLUSIONS: Patients with breast cancer with early relapse following neo/adjuvant treatment with anthracyclines and taxanes may benefit from ixabepilone plus capecitabine. (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433.).

Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma.

PURPOSE: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has demonstrated encouraging antitumor activity in preclinical and phase I studies. We performed a phase II open-label study of brivanib as first-line therapy in patients with unresectable, locally advanced, or metastatic hepatocellular carcinoma. EXPERIMENTAL DESIGN: Brivanib was administered orally at a dose of 800 mg once daily. The primary objective was 6-month progression-free survival, progression-free survival rate; secondary objectives were tumor response rate, time to response, duration of response, median progression-free survival, median overall survival, disease control rate (complete response, partial response, or stable disease ≥ 42 days), and safety and tolerability. RESULTS: Between March 2007 and May 2009, 55 patients were treated and were evaluable for response. Patients were assessed using modified World Health Organization (mWHO) criteria. According to mWHO criteria and as assessed by Independent Response Review Committee, the six-month progression-free survival rate (95% CI) was 18.2% (9.1%-30.9%). Median progression-free survival (95% CI) was 2.7 months (1.4-3.0). One patient achieved a complete response and three achieved a partial response. Twenty-two had stable disease. Median overall survival (95% CI) was 10 (6.8-15.2) months. Brivanib was generally well tolerated; the most common adverse events included fatigue, hypertension, and diarrhea. CONCLUSION: Brivanib as first-line therapy demonstrates promising antitumor activity and a manageable safety profile in patients with advanced, unresectable HCC.

A phase 2 study of a fixed combination of uracil and ftorafur and leucovorin given orally in a twice-daily regimen to treat patients with recurrent metastatic breast cancer.

BACKGROUND: UFT, a combination of uracil and ftorafur, was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin is combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provide higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. METHODS: Ninety-four patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m(2), which was given in 2 divided doses every 12 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (OR = complete response [CR] + partial response [PR]) and overall survival (OS). RESULTS: Of the 94 patients enrolled, 68 were evaluable for efficacy. Although no CRs were observed, 9 patients achieved PRs, for an OR of 13.2% in the evaluable population. The median TTP for the evaluable population was 10.3 weeks, and the proportion of patients free of disease progression at 6 months was 17%. The median OS was 61.6 weeks for all patients enrolled. The most common drug-related >or= grade 3 adverse events (graded using the National Cancer Institute Common Toxicity Criteria version 2) were diarrhea, asthenia, nausea, and dehydration. CONCLUSIONS: The combination of UFT and leucovorin administered orally in a twice-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.

Hemolysis and elevated transaminases imitating severe preeclampsia.

BACKGROUND: Illnesses coincident with pregnancy may present similarly to preeclampsia or may be mistaken for severe preeclampsia or hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Distinguishing these imitators from preeclampsia is important to allow for appropriate treatment and to avoid unnecessary delivery. CASE: A primigravida at 32 2/7 weeks of gestation transferred to our institution with flu-like symptoms, anemia, jaundice, and elevated liver function tests. The team caring for her was concerned about HELLP or acute fatty liver. After extensive workup, she was found to have a cold agglutinin. Her laboratory test results improved, and she was discharged undelivered with a presumptive diagnosis of cold agglutinin autoimmune hemolytic anemia. CONCLUSION: When patients present with atypical features of HELLP syndrome, clinicians should take time to consider other "imitators of preeclampsia" before rapidly progressing to delivery to avoid inappropriate treatment of the disorder.

Effects of intravenous amino acid administration with Y-90 DOTA-Phe1-Tyr3-Octreotide (SMT487[OctreoTher) treatment.

Y-90-DOTA-Phe1-Tyr3-Octreotide (90Y-SMT 487, OctreoTher) has shown potential for effectively treating patients with neuroendocrine tumors. The dose-limiting organ for this agent is the kidney. The purpose of this work is to assess the effectiveness of a commercially available amino acid solution on reducing renal uptake of 90Y-SMT 487 and determine the safety profile of this solution. Subjects with In-111 pentetreotide positive tumors and normal creatinine levels were treated with 3 cycles of 90Y-SMT 487, 120 mCi/cycle, at 6-9 week intervals. During each treatment two liters of an amino acid solution containing arginine and lysine (Aminosyn II 7%, Abbott Laboratories, Abbott Park, IL) were infused IV over 4 hours. Adverse events were recorded. To assess the effect of Aminosyn II on renal uptake of 90Y-SMT 487, a subgroup of subjects underwent bremsstrahlung imaging 24 hours following infusion. Kidney to liver (K/L) count density ratios were generated from the baseline In-111 pentetreotide images (performed without amino acid infusion) and the 90Y bremsstrahlung images. Follow-up creatinine levels were obtained. Thirty-seven subjects received a total of 89 90Y-SMT 487 treatments. The number of amino-acid infusions associated with one or more episodes of emesis was 53 (62%). During 13 (15%) of these infusions, the Aminosyn II rate had to be reduced because of severe nausea and vomiting. Symptomatic flushing occurred during 16 (18%) of the infusions. One subject experienced a near syncopal event shortly after completing the infusion. Creatinine levels remained normal in 34 of 36 subjects during a mean follow-up period of 9.8 months. Fourteen subjects underwent bremsstrahlung imaging following infusion of 90Y-SMT 487. Kidney uptake appeared to decrease with administration of the amino acid solution in 13 of 14 subjects. For the 28 individual kidneys, the mean percent decrease in the Kidney/Liver uptake ratio with the amino acid solution was found to be 32%. We conclude that 2 L of Aminosyn II 7% infused over 4 hours appears to notably reduce renal uptake of 90Y-SMT 487. Aminosyn is generally well tolerated, particularly at lower infusion rates with occasional moderate to severe nausea and vomiting at higher rates.

Evaluating the clinical effectiveness of 90Y-SMT 487 in patients with neuroendocrine tumors.

UNLABELLED: Because of the presence of cell membrane somatostatin receptors (SSTRs), many neuroendocrine tumors will bind analogs of somatostatin. (90)Y-Dodecanetetraacetic acid-Phe1-Tyr3-octreotide (SMT 487) is an SSTR radiopharmaceutical currently under investigation as a therapeutic option for neuroendocrine tumors. Although there are a variety of methods for evaluating response to a given cancer therapy, an important indicator of success is the impact on the clinical status of the patient. The purpose of this work was to develop a semiquantitative method and assess the clinical effectiveness of (90)Y-SMT 487 therapy in patients with neuroendocrine tumors. METHODS: A scoring system was developed to evaluate clinical response that included the following parameters: weight, health status score (determined by the patient), Karnofsky score, and tumor-related symptoms. RESULTS: We applied this scoring system to 21 patients who had completed 3 cycles of therapy with (90)Y-SMT 487. Fourteen of the 21 showed a favorable clinical response, whereas 5 were clinically stable after treatment and 2 showed evidence of clinical progression. There was also a significant reduction in the amount of octreotide being used after completion of (90)Y-SMT 487 therapy in the 20 patients who were on this medication. CONCLUSION: Using this scoring method, (90)Y-SMT 487 appears effective in improving the clinical status of patients with (111)In-pentetreotide-positive neuroendocrine tumors.

Assessment of hepatic toxicity from treatment with 90Y-SMT 487 (OctreoTher(TM)) in patients with diffuse somatostatin receptor positive liver metastases.

The purpose of this study was to determine whether there is evidence for hepatocellular radiation injury following treatment with (90)Y-SMT487 ((90)Y-DOTA-tyr3-octreotide, OctreoTher(TM)) in patients with extensive liver metastases from neuroendocrine tumors. Patients reported in this study participated in a Phase II trial of efficacy and safety of (90)Y-SMT487. The trial design called for three treatment cycles of 120 mCi each (4400 MBq) of (90)Y-SMT487. (111)In-pentetreotide SPECT images were used to determine the extent of liver metastases. Serum AST, ALT, and alkaline phosphatase levels were obtained at baseline and following each cycle of therapy. Least squares fit was applied to the serial liver enzyme measurements in patients with extensive liver metastases. Post-therapy liver enzyme measurements were also evaluated using WHO common toxicity criteria. Repeated-measures ANOVA and paired t-test were applied to the serial enzyme measures. There were 21 subjects. Fifteen of these had hepatic metastases with 12 demonstrating extensive (defined as 25% or more) liver involvement. In only 4 of these 15 did any of the three enzyme levels increase in WHO toxicity grade from baseline to final follow-up. We conclude that patients with diffuse SSTR positive hepatic metastases can be treated with a cumulative administered activity of 360 mCi (90)Y-SMT487 with only a small chance of developing mild acute or subacute hepatic radiation injury.