Radioembolization plus Immune Checkpoint Inhibitor Therapy Compared with Radioembolization plus Tyrosine Kinase Inhibitor Therapy for the Treatment of Hepatocellular Carcinoma.

PURPOSE: To investigate if combination therapy with immune checkpoint inhibitor (ICI) and yttrium-90 (90Y) radioembolization results in superior outcomes than those yielded by tyrosine kinase inhibitor (TKI) therapy and 90Y for the treatment of intermediate- to advanced-stage hepatocellular carcinoma (HCC). METHODS: A retrospective review of patients presented at an institutional multidisciplinary liver tumor board between January 1, 2012 and August 1, 2023 was conducted. In total, 44 patients with HCC who underwent 90Y 4 weeks within initiation of ICI or TKI therapy were included. Propensity score matching was conducted to account for baseline demographic differences. Kaplan-Meier analysis was used to compare median progression-free survival (PFS) and overall survival (OS), and univariate statistics identified disease response and control rate differences. Duration of imaging response was defined as number of months between the first scan after therapy and the first scan showing progression as defined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or immune Response Evaluation Criteria in Solid Tumors (iRECIST). Adverse events were analyzed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Patients in the 90Y+ICI therapy group had better objective response rates (ORRs) (89.5% vs 36.8%; P < .001) and disease control rates (DCRs) (94.7% vs 63.2%; P < .001) by mRECIST and iRECIST (ORR: 78.9% vs 36.8%; P < .001; DCR: 94.7% vs 63.2%; P < .001). Median PFS (8.3 vs 4.1 months; P = .37) and OS (15.8 vs 14.3 months; P = .52) were not statistically different. Twelve patients (63.1%) in the 90Y+TKI group did not complete systemic therapy owing to adverse effects compared with 1 patient (5.3%) in the 90Y+ICI group (P < .001). Grade 3/4 adverse events were not statistically different (90Y+TKI: 21.1%; 90Y+ICI: 5.3%; P = .150). CONCLUSIONS: Patients with HCC who received 90Y+ICI had better imaging response and fewer regimen-altering adverse events than those who received 90Y+TKI. No significant combination therapy adverse events were attributable to radioembolization.

Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study.

BACKGROUND: Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC. METHODS: Patients from REFLECT who received lenvatinib (n = 476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8 weeks. RESULTS: A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7 weeks (median); the worst grade CSTE-HTN occurred at 4.1 weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4 weeks: 16.3 vs. 11.6 months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8 weeks: 13.5 vs. 11.6 months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4 weeks: 6.6 vs. 6.4 months; HR, 0.887; 95% CI, 0.680-1.157; at 8 weeks: 5.7 vs. 6.4 months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%). CONCLUSIONS: In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately.

A dose escalation/expansion study evaluating dose, safety, and efficacy of the novel tyrosine kinase inhibitor surufatinib, which inhibits VEGFR 1, 2, & 3, FGFR 1, and CSF1R, in US patients with neuroendocrine tumors.

Surufatinib, is a potent inhibitor of vascular endothelial growth factor receptors 1-3; fibroblast growth factor receptor-1; colony-stimulating factor 1 receptor. This Phase 1/1b escalation/expansion study in US patients with solid tumors evaluated 5 once daily (QD) surufatinib doses (3 + 3 design) to identify maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and evaluate safety and efficacy at the RP2D in 4 disease-specific expansion cohorts including pancreatic neuroendocrine tumors [pNET] and extrapancreatic NETs [epNET]. MTD and RP2D were 300 mg QD (escalation [n = 35]); 5 patients (15.6%) (Dose Limiting Toxicity [DLT] Evaluable Set [n = 32]) had DLTs. Pharmacokinetics were dose proportional. Estimated progression-free survival (PFS) rates at 11 months were 57.4% (95% confidence interval [CI]: 28.7, 78.2) and 51.1% (95% CI: 12.8, 80.3) for pNET and epNET expansion cohorts, respectively. Median PFS was 15.2 (95% CI: 5.2, not evaluable) and 11.5 (95% CI: 6.5,11.5) months. Response rates were 18.8% and 6.3%. The most frequent treatment-emergent adverse events (both cohorts) were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%). Pharmacokinetics, safety, and antitumor efficacy of 300 mg QD oral surufatinib in US patients with pNETs and epNETs are consistent with previously reported studies in China and may support applicability of earlier surufatinib studies in US patients. Clinical trial registration: Clinicaltrials.gov NCT02549937.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

Characterization and Management of Adverse Reactions in Patients With Unresectable Hepatocellular Carcinoma Treated With Lenvatinib.

Aims: Advanced practice providers (APPs) play a vital role in monitoring for and managing adverse reactions (ARs). As lenvatinib ARs can resemble cirrhosis (commonly presenting with hepatocellular carcinoma [HCC]), APP input is important for timely detection and management of ARs and to promote medication adherence. Design: The goal of this post-hoc analysis of the REFLECT trial was to characterize key ARs associated with lenvatinib, and to discuss management strategies. Methods: In REFLECT, patients with unresectable HCC were randomized to either daily lenvatinib (12 mg/day for patients who weighed ≥ 60 kg or 8 mg/day for those < 60 kg) or sorafenib 400 mg twice daily. Adverse events in the lenvatinib arm were grouped into ARs (hypertension, fatigue, palmar-plantar erythrodysesthesia syndrome, proteinuria, and decreased appetite) per the United States Prescribing Information (USPI) for lenvatinib. Results: Key ARs in the lenvatinib arm (n = 476) generally occurred within months of starting lenvatinib. Some cases of proteinuria, decreased appetite, and diarrhea were first reported at about 2 years of treatment. Conclusions: The onset of key ARs associated with lenvatinib treatment can be predicted and generally be managed (per the lenvatinib USPI and REFLECT) by withholding lenvatinib and resuming it at a reduced dose after the severity decreases. However, lenvatinib should generally be discontinued if the AR is life-threatening.

Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced hepatocellular carcinoma. Integrated use of transarterial chemoembolization (TACE), a locoregional inducer of immunogenic cell death, with ICI has not been formally assessed for safety and efficacy outcomes. METHODS: From a retrospective multicenter dataset of 323 patients treated with ICI, we identified 31 patients who underwent >1 TACE 60 days before or concurrently, with nivolumab at a single center. We derived a propensity score-matched cohort of 104 patients based on Child-Pugh Score, portal vein thrombosis, extrahepatic metastasis and alpha fetoprotein (AFP) who received nivolumab monotherapy. We described overall survival (OS), progression-free survival (PFS), objective responses according to modified RECIST criteria and safety in the multimodal arm in comparison to monotherapy. RESULTS: Over a median follow-up of 9.3 (IQR 4.0-16.4) months, patients undergoing multimodal immunotherapy with TACE achieved a significantly longer median (95% CI) PFS of 8.8 (6.2-23.2) vs 3.7 (2.7-5.4) months (log-rank 0.15, p<0.01) in the monotherapy group. Multimodal immunotherapy with TACE demonstrated a numerically longer OS compared with ICI monotherapy with a median 35.1 (16.1-Not Evaluable) vs 16.6 (15.7-32.6) months (log-rank 0.41, p=0.12). In the multimodal treatment group, there were three (10%) grade 3 or higher adverse events (AEs) attributed to immunotherapy compared with seven (6.7%) in the matched ICI monotherapy arm. There were no AEs grade 3 or higher attributed to TACE in the multimodal treatment arm. At 3 months following each TACE in the multimodal arm, there was an overall objective response rate of 84%. There were no significant changes in liver functional reserve 1 month following each TACE. Four patients undergoing multimodal treatment were successfully bridged to transplant. CONCLUSIONS: TACE can be safely integrated with programmed cell death 1 blockade and may lead to a significant delay in tumor progression and disease downstaging in selected patients.

Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial.

BACKGROUND: Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma. METHODS: For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8+ T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing. FINDINGS: Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks. INTERPRETATION: This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma. FUNDING: Regeneron Pharmaceuticals.

Comparative assessment of standard and immune response criteria for evaluation of response to PD-1 monotherapy in unresectable HCC.

PURPOSE: To assess response to programmed death-1 (PD-1) monotherapy (nivolumab) in hepatocellular carcinoma (HCC) patients using RECIST1.1, modified RECIST (mRECIST), and immune RECIST (iRECIST). A secondary objective was to identify clinicolaboratory and imaging variables predictive of progressive disease (PD) and overall survival (OS). METHODS: Patients with HCC treated with nivolumab at a single institution from 5/2016 to 12/2019 with MRI or CT performed ≥ 4 weeks post treatment were retrospectively assessed. Patients who received concurrent locoregional, radiation, or other systemic therapies were excluded. Response was assessed by 2 observers in consensus using RECIST1.1, mRECIST, and iRECIST at 3/6/9/12-month time points. Time to progression (TTP) and OS were recorded. Clinicolaboratory and imaging variables were evaluated as predictors of PD and OS using uni-/multivariable and Cox regression analyses. RESULTS: Fifty-eight patients (42M/16F) were included. 118 target lesions (TL) were identified before treatment. Baseline mean TL size was 49.1 ± 43.5 mm (range 10-189 mm) for RECIST1.1/iRECIST and 46.3 ± 42.3 mm (range 10-189 mm) for mRECIST. Objective response rate (ORR) was 21% for mRECIST/iRECIST/RECIST1.1, with no cases of pseudoprogression. Median OS and median TTP were 717 days and 127 days for RECIST1.1/mRECIST/iRECIST-iUPD (unconfirmed PD). Older age, MELD/Child-Pugh scores, AFP, prior transarterial radioembolization (TARE), and larger TL size were predictive of PD and/or poor OS using mRECIST/iRECIST. The strongest predictor of PD (HR = 2.49, 95% CI 1.29-4.81, p = 0.007) was TARE. The strongest predictor of poor OS was PD by mRECIST/iRECIST at 3 months (HR = 2.26, 95% CI 1.00-5.10, p = 0.05) with borderline significance. CONCLUSION: Our results show ORR of 21%, equivalent for mRECIST, iRECIST, and RECIST1.1 in patients with advanced HCC clinically treated with nivolumab.

Baseline Liver Function and Subsequent Outcomes in the Phase 3 REFLECT Study of Patients with Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Baseline liver function among patients starting treatment for unresectable hepatocellular carcinoma (uHCC) impacts survival and could impact efficacy outcomes and safety profiles of treatments. This post hoc analysis of the phase 3 REFLECT study examined the efficacy and safety outcomes for lenvatinib and for sorafenib in patients with uHCC, assessed by Child-Pugh score (CPS) and albumin-bilirubin (ALBI) grade. METHODS: Efficacy and safety were assessed in patient cohorts from REFLECT according to study entry baseline ALBI grade and CPS. RESULTS: Lenvatinib treatment generally provided survival benefits in all groups. Median overall survival (OS) among patients with an ALBI grade of 1 was consistently higher than among patients with an ALBI grade of 2 for both the lenvatinib and sorafenib arms (lenvatinib: 17.4 vs. 8.6 months; sorafenib: 14.6 vs. 7.7 months, respectively). Median OS among patients with a CPS of 5 was consistently higher than among patients with a CPS of 6 (lenvatinib: 15.3 vs. 9.4 months; sorafenib: 14.2 vs. 7.9 months, respectively). Progression-free survival and objective response rates for these ALBI grades and CPS demonstrated similar patterns. Among patients who received lenvatinib and experienced a treatment-related treatment-emergent adverse event leading to withdrawal, 6.6% had an ALBI grade of 1, while 13.3% had an ALBI grade of 2, and 7.9% had a CPS of 5, while 12.1% had a CPS of 6. CONCLUSIONS: Better liver function at baseline, as measured by ALBI grade or CPS, may be prognostic for better survival outcomes in patients with uHCC undergoing treatment with lenvatinib or sorafenib.

Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL. METHODS: REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice-web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266. FINDINGS: Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69-0·99), pain (0·80, 0·66-0·96), and diarrhoea (0·52, 0·42-0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73-1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months. INTERPRETATION: HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma. FUNDING: Eisai and Merck Sharp & Dohme.

Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT.

BACKGROUND: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group. METHODS: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed. RESULTS: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5-15.7] compared to 13.7 months (95% CI 12.0-15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4-9.2; ≥ 60 kg group: 95% CI 6.9-9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group. CONCLUSIONS: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups. CLININCAL TRIAL: Trial registration ID: ClinicalTrials.gov # NCT01761266.

A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a rare cancer type that originates in the salivary glands. Tumors commonly invade along nerve tracks in the head and neck, making surgery challenging. Follow-up treatments for recurrence or metastasis including chemotherapy and targeted therapies have shown limited efficacy, emphasizing the need for new therapies. Here, we report a Drosophila-based therapeutic approach for a patient with advanced ACC disease. A patient-specific Drosophila transgenic line was developed to model the five major variants associated with the patient's disease. Robotics-based screening identified a three-drug cocktail-vorinostat, pindolol, tofacitinib-that rescued transgene-mediated lethality in the Drosophila patient-specific line. Patient treatment led to a sustained stabilization and a partial metabolic response of 12 months. Subsequent resistance was associated with new genomic amplifications and deletions. Given the lack of options for patients with ACC, our data suggest that this approach may prove useful for identifying novel therapeutic candidates.

Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy.

Nivolumab is an immune checkpoint inhibitor (ICI) approved for treatment of many cancers, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. To date, the morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. We identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for HCC. Demographics, laboratory values, and imaging results were obtained from medical records. All available slides from resection specimens were evaluated for tumor necrosis, tumor-infiltrating lymphocytes (TILs), and features of liver injury. Patients in the study included 16 males and 4 females with median age of 56 years. The underlying liver disease was HBV in 10, HCV in 6, and unknown/other in 4. Twelve patients were treated with nivolumab in the neoadjuvant setting, whereas eight were treated with nivolumab, usually along with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients (all from the neoadjuvant group) demonstrated marked treatment response attributable to nivolumab. TILs were present in 17/20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes (IELs) in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). Our findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct IELs are rare findings in cases treated with nivolumab but, when seen, may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients apt to respond to ICI therapy and further characterize patterns of ICI-related liver injury.

Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma.

Little is known about the mutational landscape of advanced hepatocellular carcinoma (HCC), and predictive biomarkers of response to systemic therapies are lacking. We aimed to describe the mutational landscape of advanced HCC and to identify predictors of primary resistance to systemic therapies using circulating tumor DNA (ctDNA). We prospectively enrolled 121 patients between October 2015 and January 2019. We performed targeted ultra-deep sequencing of 25 genes and Digital Droplet PCR of TERT promoter, including sequential samples throughout treatment. Primary endpoint was progression-free survival (PFS) stratified by mutation profiles in ctDNA. Secondary endpoints were overall survival and objective response rate. The most frequent mutations in ctDNA of advanced HCC were TERT promoter (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%). TP53 and CTNNB1 mutations were mutually exclusive. Patients with mutations in the PI3K/MTOR pathway had significantly shorter PFS than those without these mutations after tyrosine kinase inhibitors (2.1 vs 3.7 months, p < 0.001), but not after immune checkpoint inhibition (CPI). WNT pathway mutations were not associated with PFS, overall survival, or objective response after CPI. Serial profiling of ctDNA in a subset correlated with treatment response. Mutation profiling of ctDNA in advanced HCC shows similar mutation frequencies for known HCC drivers compared to early stages and identifies predictive biomarkers of response to systemic therapies.

Safety and Efficacy of Locoregional Treatment during Immunotherapy with Nivolumab for Hepatocellular Carcinoma: A Retrospective Study of 41 Interventions in 29 Patients.

PURPOSE: To assess the safety of locoregional treatment (LRT) combined with nivolumab for intermediate and advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A single-center retrospective review included 29 patients undergoing 41 LRTs-transarterial chemoembolization or yttrium-90 transarterial radioembolization-60 days before or concurrently with nivolumab. Demographic, clinical, and laboratory values and adverse events were reviewed before and after nivolumab initiation and after each LRT. Treatment response and time to progression were assessed using Modified Response Evaluation Criteria in Solid Tumors. Clinical events, including nivolumab termination, death, and time of last follow-up, were assessed. RESULTS: Over a median nivolumab course of 8.1 months (range, 1.0-30) with a median of 14.2 2-week cycles (range, 1-53), predominantly Child-Pugh A (22/29) patients-12 Barcelona Clinic Liver Cancer (BCLC) B and 17 BCLC C-underwent 20 transarterial chemoembolization and 21 transarterial radioembolization LRTs at a median of 67 days (range, 48-609) after nivolumab initiation. Ten patients underwent multiple LRTs. During a median follow-up of 11.5 months (range, 1.8-35.1), no grade III/IV adverse events attributable to nivolumab were observed. There were five instances of grade III/IV hypoalbuminemia or hyperbilirubinemia within 3 months after LRT. There were no nivolumab-related deaths, and 30-day mortality after LRT was 0%. CONCLUSIONS: LRTs performed concurrently with nivolumab immunotherapy demonstrate an acceptable safety profile in patients with intermediate and advanced HCC.

Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma.

PURPOSE: The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS: In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS: A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION: Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

Predictive value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in advanced hepatocellular carcinoma patients treated with anti-PD-1 therapy.

BACKGROUND: Currently, there are no recognized or validated biomarkers to identify hepatocellular carcinoma patients (HCC) likely to benefit from anti-PD-1 therapy. We evaluated the relationship between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) and survival outcomes, pretreatment and after three doses (posttreatment) of nivolumab in HCC patients. METHODS: Medical records of HCC patients treated with nivolumab between June 2016 and July 2018 were reviewed. Kaplan-Meier analysis and the log-rank test were used to calculate and compare overall survival between NLR < 5 Vs ≥ 5 and among PLR tertiles. RESULTS: A total of 103 patients were identified. Median age was 66 (29-89) years. Median treatment duration was 26 (2-149) weeks. Sixty-four (62%) patients had Child-Pugh class A (CP-A) liver function. Barcelona Clinic Liver Cancer stage was B in 20 (19%) and C in 83 (81%) patients. CP-A patients who achieved a partial or complete response had significantly lower posttreatment NLR and PLR (P < .001 for both) compared to patients who had stable disease or progression of disease. No relationship was observed between response and pretreatment NLR and PLR. NLR < 5 was associated with improved OS compared to NLR ≥ 5 both pretreatment (23 Vs10 months, P = .004) and posttreatment (35 Vs 9 months, P < .0001). Survival also differed significantly among PLR tertiles both pre- (P = .05) and posttreatment (P = .013). In a multivariable model, posttreatment NLR (HR = 1.10, P < .001) and PLR (HR = 1.002, P < .001) were strongly associated with survival. In a composite model of posttreatment NLR and PLR, a combination of high NLR and PLR was associated with an eightfold increased risk of death (HR = 8.3, P < .001). CONCLUSIONS: This study suggests a strong predictive role of these inflammatory cell ratios in the posttreatment setting in HCC patients treated with anti anti-PD-1 therapy and should be evaluated in a larger cohort.

First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma.

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7-not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. SIGNIFICANCE: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.See related commentary by Subbiah and Pal, p. 1646.This article is highlighted in the In This Issue feature, p. 1631.

Correction: Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma.

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