Changes in Posttreatment Spleen Volume Associated with Immunotherapy Outcomes for Advanced Hepatocellular Carcinoma.

Purpose: We investigated whether spleen volume (SV) changes were associated with treatment outcomes in advanced hepatocellular carcinoma (HCC) patients who received immunotherapy or first-line sorafenib. Patients and Methods: Patients with advanced HCC who underwent immunotherapy or first-line sorafenib at our institute were retrospectively analyzed. CT was used to measure SV before and within 3 months of treatment initiation. Tumor assessment followed Response Evaluation Criteria in Solid Tumors version 1.1. The association between SV change and tumor response or progression-free survival (PFS) was analyzed. The inverse probability of treatment weighting (IPTW) was used to adjust for differences in baseline characteristics. Results: The immunotherapy group comprised 143 patients (124 men, mean age, 59.8 years ± 11.2 [standard deviation]), while the sorafenib group had 57 (47 men, mean age, 59.6 years ± 9.9). SV increased in 108 (75.5%) immunotherapy and 21 (36.8%) sorafenib patients. In the immunotherapy group, patients with increased SV were more likely than those with decreased SV to have a higher disease control rate (76.9% vs 57.1%, p = 0.024) and durable clinical benefit (52.8% vs 25.7%, p = 0.005). It was also associated with extended PFS in the immunotherapy group in both the univariate (p = 0.028) and multivariate (p = 0.014) analysis. By contrast, in the sorafenib group, an increased in SV was not associated with treatment response but was presumably associated with reduced PFS (p = 0.072) in the multivariate analysis. After IPTW adjustment, the increase in SV remained a significant predictor for DCB and PFS in the immunotherapy group. Conclusion: Most patients exhibited an increase in SV after the initiation of immunotherapy, which may be used to predict response and prognosis. However, this association was not observed in patients who received sorafenib.

The study provides significant evidence that an increase in spleen volume is associated with better treatment outcomes in advanced hepatocellular carcinoma patients undergoing immunotherapy. These findings offer oncologists a new potential biomarker for optimizing treatment strategies. Specifically, increased spleen volume could be used to predict higher rates of disease control and durable clinical benefits, allowing for more personalized care.

Safety and dose escalation of the targeted oncolytic adenovirus OBP-301 for refractory advanced liver cancer: Phase I clinical trial.

OBP-301 is an oncolytic adenovirus modified to replicate within cancer cells and lyse them. This open-label, non-comparative, phase I dose-escalation trial aimed to assess its safety and optimal dosage in 20 patients with advanced hepatocellular carcinoma. Good tolerance was shown with a maximum tolerated dose of 6 × 1012 viral particles. The most common treatment-emergent adverse events were influenza-like illness, pyrexia, fatigue, decreased platelet count, abdominal distension, and anemia. Cohorts 4 and 5 had approximately 50% higher levels of CD8+ T cells in the peripheral blood after injection. The best target response occurred in 14 patients, 4 of whom had progressive disease. Multiple intratumoral injections of OBP-301 were well tolerated in patients with advanced hepatocellular carcinoma. The stable disease rate for the injected tumors was greater than the overall response rate, even with no obvious tumor response. OBP-301 might have a greater impact on local response as histological examination revealed that the presence of OBP-301 was consistent with the necrotic area at the injection site. Increased infiltration of CD8+ T cells and <1% PD-L1 expression were observed in tumors after injection. Improved antitumor efficacy might be achieved in future studies via viral injection with volume adjustment and in combination with other immuno-therapeutics.

Synergistic efficacy of telomerase-specific oncolytic adenoviral therapy and histone deacetylase inhibition in human hepatocellular carcinoma.

The telomerase-specific oncolytic adenovirus Telomelysin and the histone deacetylase inhibitor AR42 have demonstrated anticancer effects in preclinical models of human hepatocellular carcinoma (HCC). However, the clinical development of Telomelysin may be hindered by human antiviral immunity and tumor resistance. Combining oncolytic and epigenetic therapies is a viable approach for treating various cancers. This study investigated the potential synergism of Telomelysin and AR42 and the relevant underlying mechanisms. Telomelysin and AR42 exhibited synergistic antiproliferative effects in human HCC models in vitro and in vivo. Apoptosis induced by Telomelysin was significantly enhanced by AR42 in both PLC5 and Hep3B HCC cells. AR42 treatment unexpectedly attenuated the expression of the coxsackievirus and adenovirus receptor and the mRNA levels of human telomerase reverse transcriptase, which may be positively associated with the cytotoxicity of Telomelysin. Meanwhile, the cellular antiviral interferon response was not altered by AR42 treatment. Further, we found that Telomelysin enhanced Akt phosphorylation in HCC cells. AR42 reduced Telomelysin-induced phospho-Akt activation and enhanced Telomelysin-induced apoptosis. The correlation of Akt phosphorylation with drug-induced apoptosis was validated in HCC cells with upregulated or downregulated Akt signaling. Combination therapy with Telomelysin and AR42 demonstrated synergistic anti-HCC efficacy. Clinical trials investigating this new combination regimen are warranted.

Sarcopenia and myosteatosis are associated with survival in patients receiving immunotherapy for advanced hepatocellular carcinoma.

OBJECTIVES: To investigate the association of sarcopenia, myosteatosis, and sarcopenic obesity with survival outcomes among patients who underwent immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective analysis, patients who initiated immunotherapy for advanced HCC were enrolled. Sarcopenia and myosteatosis were evaluated on pretreatment CT at L3 level by skeletal muscle index and mean muscle attenuation using predefined cutoff values. Sarcopenic obesity was defined as concurrent sarcopenia and body mass index > 25 kg/m2. The log-rank test and the Cox proportional hazards model were used to compare overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 138 patients was included (discovery cohort n = 111, validation cohort n = 27). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p = 0.048) and OS (p = 0.002) than patients without sarcopenia. Patients with myosteatosis exhibited significantly poorer PFS (p < 0.001) and OS (p < 0.001) than patients without myosteatosis. Patients with sarcopenic obesity compared to patients without sarcopenic obesity exhibited significantly poorer OS (p = 0.006) but not PFS (p = 0.31). In multivariate analysis adjusting for patient demographics, tumor extent, and liver function reserve, myosteatosis remained an independent predictor of poor PFS (p = 0.014) and OS (p = 0.007); sarcopenia remained an independent predictor for poor OS (p = 0.007). The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort. CONCLUSIONS: Sarcopenia and myosteatosis are independent prognostic factors in patients who received immunotherapy for advanced HCC. KEY POINTS: • Sarcopenia and myosteatosis can be evaluated by CT at L3 level. • Sarcopenia, myosteatosis, and sarcopenic obesity were associated with poor survival outcomes in patients who underwent immunotherapy for advanced HCC. • Myosteatosis was an independent predictor of PFS and OS, and sarcopenia was independent for OS in these patients.

Association of annexin A10 expression with poor prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND: Annexin A10 expression influences the prognosis of several gastrointestinal cancers. We explored the association of annexin A10 expression with the overall survival (OS) of patients who underwent curative surgery for cholangiocarcinoma. METHODS: Patients who underwent curative surgery for cholangiocarcinoma (except gallbladder cancer) and had pathological stage T1-3N0M0 disease were enrolled. Annexin A10 expression was examined by performing immunohistochemical staining. Patient demographics and survival outcome data were retrieved from medical records. RESULTS: In total, 185 patients were enrolled. The primary tumor location was intrahepatic and extrahepatic (including the perihilar region) for 89% and 11% of patients, respectively. Positive annexin A10 staining was detected for 61 (33%) patients and associated with extrahepatic or perihilar cholangiocarcinoma (p = 0.001) and lower histological grade (p < 0.001). Patients with positive annexin A10 staining exhibited significantly poorer survival relative to patients with negative staining results (median OS, 2.5 vs. 4.9 years, p = 0.025). In the multivariate analysis adjusting for age, sex, tumor location, tumor grade, hepatitis infection, and disease stage, positive annexin A10 remained an independent predictor of poor OS (hazard ratio 1.572, p = 0.034). In the subgroup analysis, the association between annexin A10 and prognosis was restricted to intrahepatic cholangiocarcinoma. Among patients with intrahepatic cholangiocarcinoma, patients with positive annexin A10 staining exhibited significantly poorer survival compared with patients with negative annexin A10 staining (median OS, 2.3 vs. 4.9 years, p = 0.008). CONCLUSION: Positive annexin A10 expression was associated with poor prognosis of intrahepatic cholangiocarcinoma.

Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade.

BACKGROUND: Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial (NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC. METHODS: Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as ≤ -2.60 score and a grade of 2 as a score of > -2.60 to ≤ -1.39. RESULTS: Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46-0.86] and 0.42 [0.32-0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66-1.06] and 0.46 [0.37-0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup. DISCUSSION: These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01908426.

Revisiting Hepatic Artery Infusion Chemotherapy in the Treatment of Advanced Hepatocellular Carcinoma.

Hepatic artery infusion chemotherapy (HAIC) is a well-established and common treatment for advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, HAIC is not recognized internationally. Although several trials have demonstrated the safety and efficacy of HAIC, evidence corroborating its overall survival (OS) benefits compared with standard treatments is insufficient. Nevertheless, HAIC may provide prominent benefits in selected patients such as patients with portal vein thrombosis or high intrahepatic tumor burden. Moreover, HAIC has been combined with several therapeutic agents and modalities, including interferon-alpha, multikinase inhibitors, radiation therapy, and immunotherapy, to augment its treatment efficacy. Most of these combinations appeared to increase overall response rates compared with HAIC alone, but results regarding OS are inconclusive. Two prospective randomized controlled trials comparing HAIC plus sorafenib with sorafenib alone have reported conflicting results, necessitating further research. As immunotherapy-based combinations became the mainstream treatments for advanced HCC, HAIC plus immunotherapy-based treatments also showed encouraging preliminary results. The trials of HAIC were heterogeneous in terms of patient selection, chemotherapy regimens and doses, HAIC combination agent selections, and HAIC technical protocols. These heterogeneities may contribute to differences in treatment efficacy, thus increasing the difficulty of interpreting trial results. We propose that future trials of HAIC standardize these key factors to reveal the clinical value of HAIC-based treatments for HCC.

Early Changes in DCE-MRI Biomarkers May Predict Survival Outcomes in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: Two Prospective Phase II Trials.

In this paper, our main objective was to predict survival outcomes using DCE-MRI biomarkers in patients with advanced hepatocellular carcinoma (HCC) after progression from 1st-line sorafenib treatment in two prospective phase II trials. This study included 74 participants (men/women = 64/10, mean age 60 ± 11.8 years) with advanced HCC who received 2nd-line targeted therapy (n = 41 with lenalidomide in one clinical trial; n = 33 with axitinib in another clinical trial) after sorafenib failure from two prospective phase II studies. Among them, all patients underwent DCE-MRI at baseline, and on days 3 and 14 of treatment. The relative changes (Δ) in the DCE-MRI parameters, including ΔPeak, ΔAUC, and ΔKtrans, were derived from the largest hepatic tumor. The treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The Cox model was used to investigate the associations of the clinical variables and DCE-MRI biomarkers with progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was 10.8% (8/74) and the disease control rate (DCR) was 58.1% (43/74). The median PFS and OS values were 1.9 and 7.8 months, respectively. On day 3 (D3), participants with high reductions in ΔPeak_D3 (hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.17-0.93, p = 0.017) or ΔAUC_D3 (HR 0.51, 95% CI 0.25-1.04, p = 0.043) were associated with better PFS. On day 14, participants with high reductions in ΔPeak_D14 (HR 0.51, 95% CI 0.26-1.01, p = 0.032), ΔAUC_D14 (HR 0.54, 95% CI 0.33-0.9, p = 0.009), or ΔKtrans_D14 (HR 0.26, 95% CI 0.12-0.56, p < 0.001) had a higher PFS than those with lower reduction values. In addition, high reductions in ΔAUC_D14 (HR 0.53, 95% CI 0.32-0.9, p = 0.016) or ΔKtrans_D14 (HR 0.47, 95% CI 0.23-0.98, p = 0.038) were associated with a better OS. Among the clinical variables, ORR was associated with both PFS (p = 0.001) and OS (p = 0.005). DCR was associated with PFS (p = 0.002), but not OS (p = 0.089). Cox multivariable analysis revealed that ΔKtrans_D14 (p = 0.002) remained an independent predictor of PFS after controlling for ORR and DCR. An early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict favorable survival outcomes in participants with HCC receiving 2nd-line targeted therapy after sorafenib failure.

Limited Predictive or Prognostic Role of Tumor-Infiltrating Tissue-Resident Memory CD8 T Cells in Patients with Hepatocellular Carcinoma Receiving Immunotherapy.

PURPOSE: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 TRM; CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 TRM and their subsets with the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Consecutive HCC patients who received ICB in prospective trials were analyzed. Formalin-fixed paraffin-embedded tumor sections were stained for DAPI, CD8, CD103, CD39, programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1) using a multiplex immunohistochemical method. The densities of CD8 T cells, CD8 TRM, and CD39+ or PD-L1+ subsets of CD8 TRM were correlated with tumor response and overall survival (OS). RESULTS: A total of 73 patients were identified, and 48 patients with adequate pretreatment tumor specimens and complete follow-up were analyzed. A median of 32.7% (range: 0-92.6%) of tumor-infiltrating CD8 T cells were TRM. In subset analyses, 66.6% ± 34.2%, 69.8% ± 33.4%, and 0% of CD8 TRM cells coexpressed CD39, PD-L1, and PD-1, respectively. The objective response rates for CD8 T cell-high, CD8 TRM-high, CD39+ CD8 TRM-high, and PD-L1+ CD8 TRM-high groups were 41.7%, 37.5%, 37.5%, and 29.2%, respectively. Patients with CD8 T cell-high, but not those with CD8 TRM-high, CD39+ CD8 TRM-high, or PD-L1+ CD8 TRM-high, tumors, had significantly prolonged OS (p = 0.0429). CONCLUSIONS: Compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 TRM or their subsets failed to provide additional advantages in predicting the efficacy of immunotherapy for HCC.

An Exploratory Study for the Association of Gut Microbiome with Efficacy of Immune Checkpoint Inhibitor in Patients with Hepatocellular Carcinoma.

BACKGROUND: Gut microbiome has been associated with the efficacy of immune checkpoint inhibitors (ICI) in patients with various types of cancers but not yet in hepatocellular carcinoma (HCC). AIMS: To investigate the association between gut microbiome and efficacy of ICI in patients with HCC. METHODS: Patients with HCC who were scheduled to receive ICI were prospectively enrolled. Fecal samples were collected within 7 days before initiation of ICI (baseline) and 8 weeks later. Gut microbiome was assessed using 16S rRNA sequencing and shotgun whole-genome sequencing and correlated with objective response (complete or partial response), disease control (objective response or stable disease for ≥16 weeks), and overall survival. RESULTS: Thirty-six patients with HCC were enrolled, and 20 of them provided both baseline and 8-week feces. Alpha diversity, richness, and compositions of baseline gut microbiome indicated no difference between responders and nonresponders or between disease control and nondisease control groups. For the 20 paired feces, immunotherapy did not change any of the major microbiome features. No specific taxa were enriched in patients with objective response. Three taxa-Bifidobacterium, Coprococcus, and Acidaminococcus-were enriched in patients with disease control. However, the baseline abundance of these three taxa did not predict overall survival benefit. CONCLUSIONS: In this exploratory study, we failed to disclose any overt association of gut microbiome with the efficacy of ICI in patients with HCC. A larger prospective study is warranted for definite conclusion.

Eg5 as a Prognostic Biomarker and Potential Therapeutic Target for Hepatocellular Carcinoma.

BACKGROUND: The kinesin Eg5, a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of Eg5 in hepatocellular carcinoma (HCC). METHODS: HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. Eg5 expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific Eg5 inhibitor, was tested in HCC cell lines. In vivo efficacy of Eg5 inhibition was investigated in a xenograft model. RESULTS: A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low Eg5 expression levels. OS of patients with low Eg5 expression was better than that of patients with medium and high Eg5 expression (median, 155.6 vs. 75.3 vs. 57.7 months, p = 0.002). DFS of patients with low Eg5 expression was also better than that of patients with medium and high Eg5 expression (median, 126.3 vs. 46.2 vs. 39.4 months, p = 0.001). In multivariate analyses, the associations between Eg5 expression and OS (p < 0.001) or DFS remained (p < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than under the control. CONCLUSION: High Eg5 expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that Eg5 may be a reasonable therapeutic target for HCC.

Dynamic Contrast-Enhanced and Intravoxel Incoherent Motion MRI Biomarkers Are Correlated to Survival Outcome in Advanced Hepatocellular Carcinoma.

OBJECTIVE: This study assessed dynamic contrast-enhanced (DCE)-MRI and intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI) parameters to prospectively predict survival outcomes in participants with advanced hepatocellular carcinoma (HCC) who received lenalidomide, a dual antiangiogenic and immunomodulatory agent, as second-line therapy in a Phase II clinical trial. MATERIALS AND METHODS: Forty-four participants with advanced HCC who had progression after sorafenib as first-line treatment were prospectively enrolled. Pretreatment MRI parameters-obtained from DCE-MRI (peak, slope, AUC, Ktrans, Kep, and Ve), apparent diffusion coefficient (ADC), and IVIM DWI (pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f))-were derived from the largest hepatic tumor. The Cox model was used to investigate the associations of the parameters with progression-free survival (PFS) and overall survival (OS). RESULTS: Median PFS and OS were 2.3 and 8.0 months, respectively. Univariate analysis showed that participants with a high slope (p = 0.024), Kep (p < 0.001), and ADC (p = 0.018) values had longer PFS than those with low values; participants with a small tumor size (p = 0.006), high slope (p = 0.01), ADC (p = 0.015), and f (p = 0.012) values had longer OS than those with low values did. Cox multivariable analysis revealed that Kep (p < 0.001) and ADC (p = 0.009) remained independent predictors of PFS; slope (p = 0.003) and ADC (p = 0.009) remained independent predictors of OS. Moreover, Kep and slope were still significant after Bonferroni correction was performed (p < 0.005). CONCLUSION: Both pretreatment DCE-MRI and IVIM DWI parameters, especially slope and ADC, may predict PFS and OS in participants with HCC receiving lenalidomide as second-line therapy.

The Short- and Long-term Causal Relationships Between Self-compassion, Trait Mindfulness, Caregiver Stress, and Depressive Symptoms in Family Caregivers of Patients with Lung Cancer.

OBJECTIVES: Using a prospective longitudinal design, this paper examines a serial mediation model of the associations between self-compassion, trait mindfulness, caregiver stress, and depressive symptoms among the family caregivers of patients with lung cancer. METHODS: A four-wave design was used, with initial assessment (T1) and three follow-ups, at the 2nd month (T2), the 5th month (T3), and the 8th month (T4). A total of 123 family caregivers completed the baseline measurements, including caregiver stress, self-compassion, trait mindfulness, and depressive symptoms. Data were analyzed by serial mediation models to determine the causal ordering of these variables. RESULTS: Nearly one-quarter of the family caregivers suffered from clinically significant depressive symptoms and the severity of their depression remained unchanged throughout the 8-month follow-up period. Both cross-sectional and longitudinal path analyses revealed that the relationship between self-compassion and depressive symptoms was mediated sequentially by trait mindfulness and caregiver stress. The subscale analysis indicated that the association of higher compassionate action with fewer depressive symptoms was through chain-mediating effects of higher mindful awareness and lower caregiver stress. CONCLUSIONS: Family caregivers who have higher levels of self-compassion tend to have more mindfulness; greater mindfulness leads to lower levels of perceived caregiving stress which, in turn, links to fewer symptoms of depression. Both self-compassion and mindfulness could be regarded as protective factors for caregivers to reduce caregiving stress and depression.

Trait mindfulness and depressive symptoms in non-small cell lung cancer patients: the mediating roles of quality of life and meaning in life.

OBJECTIVE: The present study examined the potential mediating influences of meaning in life and quality of life in the relationship of trait mindfulness and depressive symptoms in lung cancer patients. Design: We adopted a cross-sectional design studying a sample of patients with non-small cell lung cancer, aged 20-65 years, and receiving cancer treatments or follow-up care. Main Outcome Measures: The outcome measures included Beck Depression Inventory-II, European Organisation for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and lung cancer specific complementary measure (EORTC QLQ-LC13), Five Facet Mindfulness Questionnaire, and the meaning in life questionnaire. Results: Among 116 lung cancer patients, 26.72% of them had clinically significant depressive symptoms. The presence of meaning, quality of life (QOL) functioning and symptom distress mediated the relationship of trait mindfulness and depressive symptoms. Multiple mediation analyses found that the presence of meaning in life was the main mediator. Conclusion: The reductions of depressive symptoms might be related to trait mindfulness enhancing lung cancer patients' perceptions of meaning in life. A mindfulness program has the potential to improve depressive symptoms in people with lung cancer.

Clinical outcomes and toxicity predictors of thoracic re-irradiation for locoregionally recurrent lung cancer.

BACKGROUND AND PURPOSE: Thoracic re-irradiation may be an alternative treatment for lung cancer patients who develop intrathoracic locoregional recurrence without systemic progression. This study aimed to retrospectively assess locoregional control, clinical outcomes, and toxicities in lung cancer patients who received thoracic re-irradiation. MATERIALS AND METHODS: We retrospectively reviewed 50 lung cancer patients who received thoracic re-irradiation using conventional photon radiotherapy (RT) and stereotactic body radiotherapy (SBRT) between 2009 and 2017. The correlations of clinicopathologic factors, treatment factors, and dosimetric factors of RT with time to local progression (TTLP), progression-free survival (PFS), and overall survival (OS) after starting thoracic re-irradiation were calculated using log-rank tests and Cox regression models. RESULTS: The median re-irradiation dose in equivalent dose in 2-Gy fractions was 51.1 Gy, and the mean re-irradiation planning target volume was 201.58 ml. The median mean lung dose (MLD) was 4.18 Gy, and the total lung volumes receiving a dose of 5 Gy (lung V5) and of 20 Gy (V20) were 19.8% and 5.85%, respectively. The TTLP, PFS, and OS were 18.0, 5.9, and 25.1 months, respectively. Lung V5 (p < 0.001), V20 (p = 0.011), and MLD (p = 0.002) were significantly associated with grade ≥2 lung toxicity. Seven (14%) patients developed lethal lung events. Subsequent chemotherapy following thoracic re-irradiation was significantly correlated with lethal lung events (p = 0.009). CONCLUSION: Promising local control can be achieved with thoracic re-irradiation in lung cancer patients with locoregional recurrence. However, unexpected lethal lung events may occur, especially in patients receiving systemic therapy following thoracic re-irradiation.

A Multicenter Phase II Study of Second-Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First-Line Sorafenib Monotherapy.

LESSONS LEARNED: For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers. BACKGROUND: Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC. METHODS: Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control. RESULTS: From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib. CONCLUSION: Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.

A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma.

BACKGROUND: The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response. METHODS: This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC. RESULTS: A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules (n = 8), and in the expansion, patients received 600 mg BID capsules (n = 28) or 400 mg BID tablets (n = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses [1 durable (>600 days)]. CONCLUSIONS: Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01737827. https://clinicaltrials.gov/ct2/show/NCT01737827.

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.

Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma.

BACKGROUND: Post-treatment decline in serum alpha-foetoprotein (AFP) levels has been shown to predict the treatment efficacy of antiangiogenic therapy for advanced hepatocellular carcinoma (HCC). We explored whether a decline in AFP levels was also associated with treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with advanced HCC. METHODS: We reviewed all patients who received ICI therapy for advanced HCC. AFP response was evaluated in patients with the pretreatment AFP level of >20 ng/mL. We defined early AFP response as a >20% decline in serum AFP levels within the first 4 weeks of treatment initiation relative to pretreatment levels. We then studied whether early AFP response was associated with treatment outcomes. RESULTS: Sixty patients were enrolled in this study; 43 of them were evaluable for early AFP response. The objective response rate of early AFP responders was significantly higher than that of early AFP nonresponders (73% vs. 14%, P < .001). Early AFP responders, compared with early AFP nonresponders, exhibited significantly longer overall survival (OS) (median, 28.0 vs 11.2 months, P = .048) and progression-free survival (PFS) (median, 15.2 vs 2.7 months, P = .002). After adjusting for other clinicopathological variables and treatments, early AFP response remained an independent predictor for longer OS (hazard ratio [HR] = 0.089, 95% confidence interval [CI] = 0.018-0.441; P = .003) and PFS (HR = 0.128, 95% CI = 0.041-0.399; P < .001). CONCLUSION: Early AFP response was associated with higher treatment efficacy of ICIs for advanced HCC. Additional validation studies are nonetheless warranted.

Development and validation of nomograms for predicting survival probability of patients with advanced adenocarcinoma in different EGFR mutation status.

INTRODUCTION: Molecular markers are important variables in the selection of treatment for cancer patients and highly associated with their survival. Therefore, a nomogram that can predict survival probability by incorporating epidermal growth factor receptor mutation status and treatments for patients with advanced adenocarcinoma would be highly valuable. The aim of the study is to develop and validate a novel nomogram, incorporating epidermal growth factor receptor mutation status and treatments, for predicting 1-year and 2-year survival probability of patients with advanced adenocarcinoma. MATERIAL AND METHODS: Data on 13,043 patients between June 1, 2011, and December 31, 2014 were collected. Seventy percent of them were randomly assigned to the training cohort for nomogram development, and the remaining 30% assigned to the validation cohort. The most important factors for constructing the nomogram were identified using multivariable Cox regression analysis. The discriminative ability and calibration of the nomograms were tested using C-statistics, calibration plots, and Kaplan-Meier curves. RESULTS: In the training cohort, 1-year and 2-year OS were 52.8% and 28.5% in EGFR(-) patients, and 73.9% and 44.1% in EGFR(+) patients, respectively. In EGFR(+) group, factors selected were age, gender, congestive heart failure, renal disease, number of lymph node examined, tumor stage, surgical intervention, radiotherapy, first-line chemotherapy, ECOG performance status, malignant pleural effusion, and smoking. In EGFR(-) group, factors selected were age, gender, myocardial infarction, cerebrovascular disease, chronic pulmonary disease, number of lymph node examined, tumor stage, surgical intervention, radiotherapy, ECOG performance status, malignant pleural effusion, and a history of smoking. Two nomograms show good accuracy in predicting OS, with a concordance index of 0.83 in EGFR(+) and of 0.88 in EGFR(-). CONCLUSIONS: The survival prediction models can be used to make individualized predictions with different EGFR mutation status and a useful tool for selecting regimens for treating advanced adenocarcinoma.