Regorafenib with immunotherapy versus regorafenib alone as second-line treatment for hepatocellular carcinoma: A multicenter real-world study.

INTRODUCTION: Regorafenib remains the standard and widely used second-line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large-scale multicenter real-world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second-line therapy for advanced HCC under real-world circumstances. PATIENTS AND METHODS: The study included 208 patients from five medical facilities. One hundred forty-three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. RESULTS: The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p < 0.001) compared to the regorafenib monotherapy group based on mRECIST criteria. Median progression-free survival (7.9 vs. 3.2 months, after PSM, p < 0.001) and overall survival (25.6 vs. 16.4 months, p = 0.010, after PSM) were also considerably longer in the regorafenib plus ICI group. The incidence of Grades 3-4 treatment-related adverse events (TRAEs) was marginally greater in the regorafenib plus ICI group than in the regorafenib group (23.8% vs. 20.0%, p = 0.546). Notably, there were no instances of treatment-related mortality or emergence of new TRAEs in any treatment group. CONCLUSION: The combination of regorafenib and ICI shows potential as a viable second-line treatment for advanced HCC, exhibiting favorable efficacy while maintaining a tolerable safety profile in contrast to regorafenib monotherapy.

Adjuvant Transarterial Chemoembolization With Sorafenib for Portal Vein Tumor Thrombus: A Randomized Clinical Trial.

Importance: Certain patients with hepatocellular carcinoma with portal vein tumor thrombus could benefit from surgical resection, and postoperative adjuvant therapy may lower the incidence of tumor recurrence. Objective: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization vs sorafenib alone as postoperative adjuvant therapy for patients with hepatocellular carcinoma with portal vein tumor thrombus. Design, Setting, and Participants: This was a phase 3, multicenter, randomized clinical trial conducted in 5 hospitals in China. A total of 158 patients were enrolled and randomized from October 2019 to March 2022, with a median follow-up of 28.4 months. Portal vein tumor thrombus was graded by the Cheng classification. Eligible patients with hepatocellular carcinoma with Cheng grade I to III portal vein tumor thrombus (ie, involving segmental or sectoral branches, right- or left-side branch, or main trunk of portal vein) were included. Interventions: Patients were randomly assigned 1:1 to receive transarterial chemoembolization with sorafenib or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400 mg orally twice a day. In the transarterial chemoembolization with sorafenib group, transarterial chemoembolization was performed 1 day after the first administration of sorafenib. Main Outcomes and Measures: The primary end point was recurrence-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least 1 dose of study treatment. Results: Of 158 patients included, the median (IQR) age was 54 (43-61) years, and 140 (88.6%) patients were male. The median (IQR) recurrence-free survival was significantly longer in the transarterial chemoembolization with sorafenib group (16.8 [12.0-NA] vs 12.6 [7.8-18.1] months; hazard ratio [HR], 0.57; 95% CI, 0.39-0.83; P = .002). The median (IQR) overall survival was also significantly longer with transarterial chemoembolization with sorafenib than with sorafenib alone (30.4 [20.6-NA] vs 22.5 [15.4-NA] months; HR, 0.57; 95% CI, 0.36-0.91; P = .02). The most common grade 3/4 adverse event was hand-foot syndrome (23 of 79 patients in the transarterial chemoembolization with sorafenib group [29.1%] vs 24 of 79 patients in the sorafenib alone group [30.4%]). There were no treatment-related deaths in either group. The transarterial chemoembolization with sorafenib group did not show additional toxicity compared with the sorafenib monotherapy group. Conclusion and Relevance: In this study, the combination of sorafenib and transarterial chemoembolization as postoperative adjuvant therapy in patients with hepatocellular carcinoma with portal vein tumor thrombus resulted in longer recurrence-free survival and overall survival than sorafenib alone and was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04143191.

An unresectable and metastatic intrahepatic cholangiocarcinoma with EML4-ALK rearrangement achieving partial response after first-line treatment with ensartinib: a case report.

Systemic chemotherapies are the primary treatment options for patients with unresectable and metastatic intrahepatic cholangiocarcinoma (ICC), but the effectiveness of current systemic therapies is limited. The development of targeted-therapy has changed the treatment landscape of ICC, and comprehensive genome sequencing of advanced cholangiocarcinoma patients could be beneficial to identify potential targets to guide individualized treatment. Herein, we reported an unresectable and metastatic ICC patient who detected EML4-ALK rearrangement in peripheral blood, which was later confirmed on tissue-based testing, and achieved partial response (PR) after first-line treatment with ensartinib. This case suggests that the liquid biopsy is of clinical value for unresectable or metastatic ICC, and the discovery of rare molecular targets provides new therapeutically approaches for advanced ICC patients.

Identifying optimal candidates for post-TIPS patients with HCC undergoing TACE: a multicenter observational study.

OBJECTIVE: To develop a prognostic model for post-transjugular intrahepatic portosystemic shunt (TIPS) patients with hepatocellular carcinoma (HCC) beyond the Milan criteria treated by transarterial chemoembolization (TACE). DESIGN: Between January 2013 and January 2020, 512 patients with HCC beyond the Milan criteria who underwent TACE after TIPS were retrospectively recruited from 15 tertiary centers. Patients were randomly sorted into a training set (n = 382) and a validation set (n = 130). Medical data and overall survival were assessed. A prediction model was developed using multivariate Cox regression analyses. Predictive performance and discrimination were evaluated and compared with other prognostic models. RESULTS: Vascular invasion, log10(AFP), 1/creatinine, extrahepatic spread, and log10(ALT) were the most significant prognostic factors of survival. These five parameters were included in a new VACEA score. This score was able to stratify patients in the training set into four distinct risk grades whose median overall survival were 25.2, 15.1, 8.9, and 6.2 months, respectively. The 6-month, 1-year, 2-year, and 3-year AUROC values and C-index of the VACEA model were 0.819, 0.806, 0.779, 0.825, and 0.735, respectively, and higher than those of other seven currently available models in both the training and validation sets, as well as in different subgroups. CONCLUSION: The VACEA score could stratify post-TIPS patients with HCC beyond the Milan criteria treated by TACE and help to identify candidates who benefit from this treatment. KEY POINTS: • Vascular invasion, AFP, creatinine, extrahepatic spread, and ALT were independent significant prognostic factors of survival for HCC patients who underwent TACE after TIPS. • Our new model, named VACEA score, can accurately predict prognosis at the individual level and stratify patients into four distinct risk grades. • The VACEA model showed better prognostic discrimination and calibration than other current TACE-/TIPS-specific models Graphical abstract.

Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH).

PURPOSE: Lenvatinib (LEN) is a first-line therapy for patients with advanced hepatocellular carcinoma (HCC); however, it has shown modest survival benefits. Therefore, we aimed to compare clinical outcomes of LEN combined with transarterial chemoembolization (LEN-TACE) versus LEN monotherapy in patients with advanced HCC. MATERIALS AND METHODS: This was a multicenter, randomized, open-label, parallel group, phase III trial. Patients with primary treatment-naive or initial recurrent advanced HCC after surgery were randomly assigned (1:1) to receive LEN plus on-demand TACE (LEN-TACE) or LEN monotherapy. LEN was initiated within 3 days after random assignment (initial dose: 12 mg once daily for patients ≥ 60 kg; 8 mg once daily for patients < 60 kg). TACE was initiated one day after LEN initiation. The primary end point was overall survival (OS). RESULTS: Between June 2019 and July 2021, a total of 338 patients underwent random assignment at 12 centers in China: 170 to LEN-TACE and 168 to LEN. At a prespecified event-driven interim analysis after a median follow-up of 17.0 months, the median OS was significantly longer in the LEN-TACE group (17.8 v 11.5 months; hazard ratio, 0.45; P < .001). The median progression-free survival was 10.6 months in the LEN-TACE group and 6.4 months in the LEN group (hazard ratio, 0.43; P < .001). Patients in the LEN-TACE group had a higher objective response rate according to the modified RECIST (54.1% v 25.0%, P < .001). Multivariable analysis revealed that portal vein tumor thrombus and treatment allocation were independent risk factors for OS. CONCLUSION: The addition of TACE to LEN improves clinical outcomes and is a potential first-line treatment for patients with advanced HCC.

Current Smoking has a Detrimental Effect on Survival for Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) negative Advanced non-squamous Non-small Cell Lung Cancer (NSCLC) Patients Treated with Pemetrexed Continuation Maintenance.

Objectives: The aim of this study is to investigate the predictive value of smoking history on treatment outcomes of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC patients without EGFR mutations and ALK rearrangements. Methods: 71 consecutive EGFR and ALK negative advanced non-squamous NSCLC patients who had received pemetrexed continuation maintenance therapy at least two cycles were retrospectively analyzed in our single center. The enrolled patients were categorized into two groups as never-/former light smokers and current smokers according to their smoking history. Results: In the 71 non-squamous NSCLC patients, 30 (42.3%) were never-/former light smokers and 41 (57.7%) were current smokers. The objective response rate (ORR) of never-/former light smokers was significantly higher than that of current smokers (26.7% vs. 7.3%, p = 0.026). Never-/former light smokers showed significantly longer progression free survival (PFS) (6.6 [95% CI 5.3-7.9] months vs. 5.1 [95% CI 3.5-6.7] months; HR: 0.557, 95% CI 0.339-0.915, p = 0.021) and overall survival (OS) (17.3 [95% CI 14.4-20.2] months vs. 15.7 [95% CI 12.0-19.4] months; HR: 0.578, 95% CI 0.338-0.986, p = 0.044) than current smokers. Multivariate analysis identified smoking history was an independent predictive factor for PFS and OS. Conclusions: Current smoking is an independent negative predictive factor of outcomes for pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC patients without EGFR mutations and ALK rearrangements.

Impact of Weight Loss at Presentation on Survival in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI) Sensitive Mutant Advanced Non-small Cell Lung Cancer (NSCLC) Treated with First-line EGFR-TKI.

Purpose The aim of this study is to evaluate the impact of weight loss at presentation on treatment outcomes of first-line EGFR-tyrosine kinase inhibitors (EGFR-TKI) in EGFR-TKI sensitive mutant NSCLC patients. Methods We retrospectively analyzed the clinical outcomes of 75 consecutive advanced NSCLC patients with EGFR-TKI sensitive mutations (exon 19 deletion or exon 21 L858R) received first-line gefitinib or erlotinib therapy according to weight loss status at presentation in our single center. Results Of 75 EGFR-TKI sensitive mutant NSCLC patients, 49 (65.3%) patients had no weight loss and 26 (34.7%) had weight loss at presentation, the objective response rate (ORR) to EGFR-TKI treatment were similar between the two groups (79.6% vs. 76.9%, p = 0.533). Patients without weight loss at presentation had significantly longer median progression free survival (PFS) (12.4 months vs. 7.6 months; hazard ratio [HR] 0.356, 95% confidence interval [CI] 0.212-0.596, p < 0.001) and overall survival (OS) (28.5 months vs. 20.7 months; HR 0.408, 95% CI 0.215-0.776, p = 0.006) than those with weight loss at presentation; moreover, the stratified analysis by EGFR-TKI sensitive mutation types also found similar trend between these two groups except for OS in EGFR exon 21 L858R mutation patients. Multivariate analysis identified weight loss at presentation and EGFR-TKI sensitive mutation types were independent predictive factors for PFS and OS. Conclusions Weight loss at presentation had a detrimental impact on PFS and OS in EGFR-TKI sensitive mutant advanced NSCLC patients treated with first-line EGFR-TKI. It should be considered as an important factor in the treatment decision or designing of EGFR-TKI clinical trials.

Anaplastic lymphoma kinase (ALK)-rearranged pulmonary pleomorphic carcinoma successfully treated with crizotinib.

Pulmonary pleomorphic carcinoma (PPC) is rare, and the response of patients to conventional chemotherapy is very poor. Here we present a patient with anaplastic lymphoma kinase (ALK)-rearranged advanced PPC treated with crizotinib. Computed tomography revealed a mass in the left upper lung of a nonsmoking 60-year-old woman. Pathological findings using resected tissue were consistent with PPC stage 1A, T1bN0M0. Although the patient received adjuvant radiotherapy, the disease relapsed, quickly progressed, and remained PPC according to analysis of biopsied tissue. Although negative for epidermal growth factor receptor mutations, ALK rearrangements were detected in adenocarcinoma and spindle-cell components. The patient received crizotinib therapy and achieved a partial response for 7 months. This case indicates that patients with PPC, particularly those with adenocarcinoma, may harbor an epithelial component with the ALK rearrangement. Although the progression-free survival of patients treated with crizotinib is limited, they may obtain more benefit compared with conventional chemotherapy.

Meta-analysis of the incidence and risks of interstitial lung disease and QTc prolongation in non-small-cell lung cancer patients treated with ALK inhibitors.

BACKGROUND: To conduct a systematic review and meta-analysis to assess the overall incidence and risk of interstitial lung disease (ILD) and QTc prolongation associated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (-TKIs) in non-small-cell lung cancer (NSCLC) patients. RESULTS: A total of 1,770 patients from 8 clinical trials were included. The incidences of high-grade ILD and QTc prolongation was 2.5% (95% CI 1.7-3.6%), and 2.8% (95% CI 1.8-4.3%), respectively. Meta-analysis demonstrated that the use of ALK-TKIs in NSCLC patients significantly increased the risk of developing high-grade ILD (Peto OR, 3.27, 95%CI: 1.18-9.08, p = 0.023) and QTc prolongation (Peto OR 7.51, 95% CI, 2.16-26.15; p = 0.002) in comparison with chemotherapy alone. MATERIALS AND METHODS: A systematic literature search was performed to identify related citations up to January 31, 2017. Data were extracted, and summary incidence rates, Peto odds ratios (Peto ORs), and 95% confidence intervals (CIs) were calculated. CONCLUSIONS: The use of ALK-TKIs significantly increases the risk of developing high-grade ILD and QTc prolongation in lung cancer patients. Clinicians should pay attention to the risks of severe ILD and QTc prolongation with the administration of these drugs.

Comparison of the efficacy and tolerability of gefitinib with pemetrexed maintenance after first-line platinum-based doublet chemotherapy in advanced lung adenocarcinoma: single-center experience.

PURPOSE: Both gefitinib and pemetrexed maintenance were effective therapies for advanced lung adenocarcinoma, but which is better is unclear. For patients with advanced lung adenocarcinoma, we have no idea whether we should choose gefitinib or pemetrexed maintenance in clinical practice. Here, we assessed the efficacy and tolerability of gefitinib versus pemetrexed maintenance in these patients. PATIENTS AND METHODS: A total of 101 patients were identified and divided into gefitinib (n=53) or pemetrexed (n=48) maintenance. Epidermal growth factor receptor (EGFR) status of tumors was analyzed in 67 patients. Disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. RESULTS: The results showed that DCR (79.2% vs 75%, P=0.642) was similar between gefitinib and pemetrexed groups. The PFS of gefitinib was significantly longer than that of pemetrexed (8 months vs 5.4 months, hazard ratio [HR]: 0.520, 95% confidence interval [CI]: 0.341-0.791, P=0.002); however, the OS was similar (19.9 months vs 18.8 months, HR: 1.006, 95% CI: 0.664-1.525, P=0.977). In EGFR mutation-positive patients, PFS was significantly longer in gefitinib (12 months vs 5.4 months; HR: 0.158, 95% CI: 0.074-0.333, P<0.001), whereas in EGFR wild-type subgroup gefitinib had a significantly shorter PFS than that by pemetrexed (2.5 months vs 5 months; HR: 2.822, 95% CI: 1.137-7.005, P=0.025). Cox multivariate regression analysis of PFS for overall population showed that smoking status (P=0.001) and maintenance regimens (P=0.013) were independent prognostic factors for PFS. Both gefitinib and pemetrexed were well tolerated. CONCLUSION: Gefitinib compared with pemetrexed as maintenance therapy had a significantly longer PFS and a similar OS with good tolerability in patients with advanced lung adenocarcinoma. Moreover, for EGFR mutation-positive patients, gefitinib maintenance had a significantly longer PFS; however, pemetrexed maintenance was considered more effective for EGFR wild-type patients.