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Abstract Liposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have undergone prior gemcitabine-based therapies. This randomized, double-blind, parallel-controlled, multicenter phase 3 study (NCT05074589) assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil (5-FU) and leucovorin (LV) in this patient population. Patients with unresectable, locally advanced, or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1:1 to receive either HR070803 (60 mg/m2 anhydrous irinotecan hydrochloride, equal to 56.5 mg/m2 free base) or placebo, both in combination with 5-FU (2000 mg/m2) and LV (200 mg/m2), all given intravenously every two weeks. The primary endpoint of the study was overall survival (OS). A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV (HR070803 group, n = 149) or placebo plus 5-FU/LV (placebo group, n = 149). Median OS was significantly improved in the HR070803 group compared to the placebo group (7.4 months [95% CI 6.1–8.4] versus 5.0 months [95% CI 4.3–6.0]; HR 0.63 [95% CI 0.48–0.84]; two-sided p = 0.0019). The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase (19.0% versus 11.6% in placebo group) and decreased neutrophil count (12.9% versus 0 in placebo group). No treatment-related deaths occurred in the HR070803 group, while the placebo group reported one treatment-related death (abdominal infection). HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting, representing a potential option in this patient population.

Abstract Background Mecapegfilgrastim, a long‐acting granulocyte‐colony stimulating factor has been approved for reducing the incidence of infection, particularly febrile neutropenia (FN), in China. Objective We conducted a multicenter prospective observational study to examine the safety and effectiveness of mecapegfilgrastim in preventing neutropenia in gastrointestinal patients receiving the chemotherapy, including S‐1/capecitabine‐based regimens or the fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) regimens. Method Five hundred and sixty‐one gastrointestinal patients from 40 sites across China, between May 2019 and November 2021, were included. The administration of mecapegfilgrastim was prescribed at the discretion of local physicians. Results The most common adverse drug reactions (ADRs) of any grade for all patients was increased white blood cells (2.9%). Grade 3/4 ADRs were observed for anemia (0.2%), decreased white blood cells (0.2%), and decreased neutrophil count (0.2%). Among the 116 patients who received S‐1/capecitabine‐based chemotherapy throughout all cycles, ADRs of any grade included anemia (1.7%), myalgia (0.9%), and increased alanine aminotransferase (0.9%). No grade 3/4 ADRs were observed. In 414 cycles of patients who underwent S‐1/capecitabine‐based regimens, only one (0.2%) cycle experienced grade 4 neutropenia. In the FOLFIRINOX, FOLFOXIRI, and FOLFOX chemotherapy regimens, grade 4 neutropenia occurred in one (2.7%) of 37 cycles, four (4.7%) of 85 cycles, and two (1.2%) of 167 cycles, respectively. Conclusion In a real‐world setting, mecapegfilgrastim has proven effective in preventing severe neutropenia in gastrointestinal patients following chemotherapy. This includes commonly used moderate or high‐risk FN regimens or regimens containing S1/capecitabine, all of which have demonstrated favorable efficacy and safety profiles.

Background: Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. Objectives: This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. Design: A multicenter, randomized, double-blind, placebo-controlled, phase II study. Methods: Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count

Background: Skin toxicities are the most common adverse events related to immunotherapy, such as reactive cutaneous capillary endothelial proliferation (RCCEP) following treatment with the anti-programmed cell death-1 antibody camrelizumab. Objective: This study aimed to comprehensively analyze the clinical features and prognostic value of RCCEP in patients with malignancies who received camrelizumab alone (Camre) or in combination with the angiogenesis-targeted agent apatinib (Camre-Apa) or chemotherapy (Camre-Chemo). Design: A large-scale pooled analysis. Methods: Individual patient-level data were derived from 10 clinical trials of camrelizumab monotherapy, camrelizumab plus apatinib, or camrelizumab plus chemotherapy ( n = 1305). Results: RCCEP occurred in 77.0% (516/670) of patients with Camre, 23.6% (70/296) with Camre-Apa, and 67.8% (230/339) with Camre-Chemo. Most RCCEP lesions were grade 1 or 2 in severity. The median time to onset was 0.8 months [interquartile range (IQR), 0.6–1.2] with Camre, 5.0 months (IQR, 2.7–8.0) with Camre-Apa, and 1.6 months (IQR, 1.0–4.2) with Camre-Chemo; and the median duration was 4.8 months (IQR, 2.6–8.8), 4.4 months (IQR, 1.7–8.9), and 7.2 months (IQR, 4.1–14.3), respectively. In all the three groups, patients with RCCEP showed significantly better clinical outcomes compared with those without [objective response rate: 23.8% versus 1.9% with Camre, 48.6% versus 21.2% with Camre-Apa, and 78.7% versus 54.1% with Camre-Chemo; median progression-free survival: 3.2 versus 1.7 months (hazard ratio (HR) = 0.36), 10.2 versus 4.5 months (HR = 0.39), and 12.7 versus 7.3 months (HR = 0.38); median overall survival: 13.3 versus 3.8 months (HR = 0.34), 29.2 versus 13.5 months (HR = 0.46), and not reached versus 12.8 months (HR = 0.19); all p

Introduction: In REFLECT, lenvatinib was noninferior to sorafenib in terms of overall survival (OS) in patients with unresectable hepatocellular carcinoma (uHCC; median 13.6 vs 12.3 months; HR 0.92, 95% CI 0.79-1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per Response Evaluation Criteria in Solid tumors version 1.1 (RECIST v1.1); per modified RECIST (mRECIST), the ORR was 40.6%. We sought to further characterize these tumor responses and explore ORR’s importance among outcomes for patients with HCC. Methods: Efficacy assessments included all patients randomized to receive lenvatinib treatment (body weight ≥60 kg, 12 mg/day;

Introduction: RATIONALE-301 (NCT03412773) was a global, phase 3 study comparing the efficacy and safety of tislelizumab with sorafenib as first-line (1L) treatment in adult patients with unresectable hepatocellular carcinoma (HCC) that met its primary endpoint of noninferiority in overall survival (OS). This analysis compared health-related quality-of-life (HRQOL) outcomes between the arms. Methods: Systemic therapy–naive adults with HCC were randomized 1:1 to receive tislelizumab n = 342) or sorafenib (n = 332). HRQOL was assessed using EORTC QLQ-C30, QLQ-HCC18, and EQ-5D-5L. At cycles 4 and 6, a mixed model for repeated measures was performed using key prespecified patient-reported outcome (PRO) endpoints of the QLQ-C30 and the QLQ-HCC18. Time to deterioration was analyzed with the Kaplan-Meier method using the PRO endpoints. Results: At cycles 4 and 6, patients in the tislelizumab arm had better HRQOL outcomes than the patients in the sorafenib arm per mean-change differences in GHS/QOL, QLQ-C30 physical functioning and fatigue, and QLQ-HCC18 symptom index; however, no differences for pain were observed. Patients in the tislelizumab arm had lower risk of deterioration in GHS/QOL (HR, 0.68; 95% CI, 0.49-0.94), QLQ-C30 physical functioning (HR, 0.46; 95% CI, 0.33-0.64) and fatigue (HR, 0.48; 95% CI, 0.37-0.63), QLQ-HCC18 symptom index (HR, 0.53; 95% CI, 0.34-0.81), and HCC-specific fatigue (HR, 0.60; 95% CI, 0.46-0.80). For pain, both arms had similar risk of deterioration (HR, 0.78; 95% CI, 0.56-1.09). At cycle 4 and 6, patients in the tislelizumab arm maintained in EQ-5D-5L visual analog scale, whereas scores decreased for the patients in the sorafenib arm. Conclusion: Patients with 1L HCC treated with tislelizumab had better HRQOL outcomes compared with patients treated with sorafenib, particularly in fatigue and physical functioning. These results, along with favorable safety profile, better response rate, and OS noninferiority, support tislelizumab as a potential 1L treatment option for unresectable HCC.

Objective: AST-3424 is a novel specific aldo-keto reductase 1C3 (AKR1C3) prodrug that releases a DNA alkylating reagent upon reduction by AKR1C3. This study aimed to evaluate the efficacy and safety of AST-3424 in patient-derived tumor xenograft (PDTX) model and orthotopic model against hepatocellular carcinoma (HCC). Materials and method: PDTX models derived from three HCC patients and orthotopic mice models using HepG2 cells were developed. The mice were treated with AST-3424 alone or combined with other drugs (oxaliplatin, apatinib, sorafenib and elemene in PDTX models, oxaliplatin and 5- fluorouracil in orthotopic models). The tumor volume and weight, as well as the mice weight were assessed. The liver tumor and transplanted tumor were removed for histological, immunohistochemical and Western blot detection in orthotopic model experiments. Results: AST-3424 could inhibit tumor growth in HCC PDTX models and orthotopic models, with no difference in safety compared with other marketed drugs, and the drug combination did not increase toxicity. The inhibitory effect of combination treatment was more obvious than which used alone. The reduction of AKR1C3 expression was negatively correlated with AST-3424 dose. Conclusion: AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety.

Abstract Background Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. Methods Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan–Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. Results Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6–5.4%), and DCR was 35.8% (95% CI, 33.7–38.0%). The median PFS was 2.7 months (95% CI 2.2–2.8), and the median OS was 5.8 months (95% CI 5.4–6.1). Conclusions The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. Trial registration This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

Introduction KEYNOTE-394 showed pembrolizumab significantly improved overall survival, progression-free survival, and objective response rate with manageable safety versus placebo for patients from Asia with previously treated advanced hepatocellular carcinoma. We present results on health-related quality of life (HRQoL). Methods HRQoL was evaluated using the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EuroQol-5D-3L (EQ-5D-3L) questionnaires. Key HRQoL endpoints were least squares mean (LSM) score changes from baseline to week 12 and time to deterioration (TTD) for EORTC QLQ-C30 global health status (GHS)/QoL. p values were one-sided and nominal without adjustment for multiplicity. Results The HRQoL population included patients randomly assigned to pembrolizumab (n = 298) and placebo (n = 152). From baseline to week 12, a greater decline in EORTC QLQ-C30 GHS/QoL score was observed with placebo (LSM, −8.4; 95% CI: −11.7 to −5.1) versus pembrolizumab (−4.0; 95% CI: −6.4 to −1.6; difference vs placebo: 4.4; 95% CI: 0.5–8.4; nominal p = 0.0142). Similarly, a greater decline in EQ-5D-3L visual analog scale score was observed with placebo (−6.9; 95% CI: −9.4 to −4.5) versus pembrolizumab (−2.7; 95% CI: −4.5 to −1.0; difference vs placebo: 4.2; 95% CI: 1.2–7.2; nominal p = 0.0030). TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (hazard ratio, 0.85; 95% CI: 0.58–1.25; nominal p = 0.1993). Conclusion Patients receiving placebo showed greater decline in HRQoL than those receiving pembrolizumab. Combined with efficacy and safety data from KEYNOTE-394 and the global KEYNOTE-240 and KEYNOTE-224 trials, our data support the clinically meaningful benefit and manageable tolerability of pembrolizumab as second-line therapy for patients with advanced hepatocellular carcinoma.

Abstract Background Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies. Methods This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1. Results A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4–8.3), 11.6 months (95% CI 8.3–13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. Conclusions Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC. Trial registration Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.

Pancreatic cancer is one of the leading causes of cancer-related mortality in both developed and developing countries. The incidence of pancreatic cancer in China accounts for about a quater of the global incidence, and the epidemiological characteristics and therapeutic strategies differ due to social, economic, cultural, environmental, and public health factors. Non-domestic guidelines do not reflect the clinicopathologic characteristics and treatment patterns of Chinese patients. Thus, in 2018, the Chinese Society of Clinical Oncology (CSCO) organized a panel of senior experts from all sub-specialties within the field of pancreatic oncology to compile the Chinese guidelines for the diagnosis and treatment of pancreatic cancer. The guidelines were made based on both the Western and Eastern clinical evidence and updated every one or two years. The experts made consensus judgments and classified evidence-based recommendations into various grades according to the regional differences, the accessibility of diagnostic and treatment resources, and health economic indexes in China. Here we present the latest version of the guidelines, which covers the diagnosis, treatment, and follow-up of pancreatic cancer. The guidelines might standardize the diagnosis and treatment of pancreatic cancer in China and will encourage oncologists to design and conduct more clinical trials about pancreatic cancer.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4 have shown significantly durable clinical benefits and tolerable toxicities and have improved the survival of patients with various types of cancer. Since 2018, the National Medical Products Administration of China has approved 17 ICIs as the standard treatment for certain advanced or metastatic solid tumors. As ICIs represent a broad-spectrum antitumor strategy, the populations eligible for cancer immunotherapy are rapidly expanding. However, the clinical applications of ICIs in cancer patient populations with special issues, a term that refers to complex subgroups of patients with comorbidities, special clinical conditions, or concomitant medications who are routinely excluded from prospective clinical trials of ICIs or are underrepresented in these trials, represent a great real-world challenge. Although the Chinese Society of Clinical Oncology (CSCO) has provided recommendations for screening before the use of ICIs in special populations, the recommendations for full-course management remain insufficient. The CSCO Expert Committee on Immunotherapy organized leading medical oncology and multidisciplinary experts to develop a consensus that will serve as an important reference for clinicians to guide the proper application of ICIs in special patient populations. This article is a translation of a study first published in Chinese in The Chinese Clinical Oncology (ISSN 1009-0460, CN 32-1577/R) in May 2022 (27(5):442–454). The publisher of the original paper has provided written confirmation of permission to publish this translation in Therapeutic Advances in Medical Oncology .

Abstract Background Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab. Methods Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC. Results Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR. Conclusions At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted. Trial registration NCT02325739 .

Background: Primary liver cancer, around 75%–85% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China, but also may re-shape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice, and improve the national average five-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

Introduction Intratumoral administration of pexa-vec (Pexastimogene Devacirepvec), an oncolytic and immunotherapeutic vaccinia virus. given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥ 1 dose of study treatment. Results The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib 234, sorafenib: 225). At the interim analysis the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Discussion/Conclusion Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.

Summary: Background: In the global REACH-2 study, ramucirumab significantly improved overall survival (OS) compared with placebo in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). REACH-2 China study aimed to evaluate the efficacy and safety of ramucirumab in Chinese patients with advanced HCC (NCT02435433). Methods: REACH-2 China was a randomised, double-blind, placebo-controlled, phase 3 study done at 31 centres in China between Sep 16, 2015, and March 15, 2021. Patients with advanced HCC and AFP ≥400 ng/mL after first-line sorafenib were randomly assigned (2:1) to receive ramucirumab 8 mg/kg intravenously or placebo Q2W, until disease progression or unacceptable toxicity. The primary endpoint was OS. Efficacy was assessed per intention-to-treat, and safety in patients who received any treatment. Findings: Of 104 Chinese patients enrolled (44 in the global study and 60 in the China extension study), 70 received ramucirumab and 34 received placebo. Median OS was 9·1 months in the ramucirumab group and 6·2 months in the placebo group (HR = 0·854 [95% CI: 0·536, 1·359]). The most common grade 3 or worse treatment-emergent adverse event were hypertension (5 [7·1%] of 70 patients in the ramucirumab group vs 1 [2.9%] of 34 in the placebo group), pneumonia (5 [7·1%] vs 1 [2·9%]), and hyponatraemia (4 [5·7%] vs 0 [0%]). Interpretation: Ramucirumab demonstrated clinically meaningful improvement in OS compared to placebo for Chinese patients with advanced HCC and elevated AFP, although lacking statistical superiority. Ramucirumab was well tolerated, with a manageable safety profile. The results are consistent with those of the global REACH-2 study, supporting a favourable risk-benefit profile for ramucirumab in this population. Funding: Eli Lilly and Company, USA.

ObjectiveThe objective of this study was to assess the comparative efficacy in third-line setting for metastatic CRC (mCRC) patients using matched population of FRESCO trial with fruquintinib and real-world data with other TKIs.Materials and methodsThe arm of fruquintinib from the FRESCO phase III trial (NCT02314819) included the data of patients with metastatic CRC that progressed after at least two lines of chemotherapy and received fruquintinib treatment. An external control arm was constructed using real-world data (RWD) of patients who received other TKIs based on key eligibility criteria of FRESCO. The baseline characteristics of two arms was balanced by propensity score matching (PSM). The Kaplan–Meier method and Cox proportional hazard model was used to evaluate progression free survival (PFS) and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), respectively.ResultsOverall, 128 patients were successfully matched by PSM in each, fruquintinib and other TKIs group. The patients in fruquintinib group showed significant increase in median PFS than other TKIs (3.71 vs. 2.49 months, HR = 0.67, 95%CI, 0.48-0.94, p = 0.019). In the subgroup analysis, fruquintinib showed a significant benefit in PFS compared with other TKIs among patients undergoing two or three previous chemotherapy regimens (HR 0.58, 95%CI 0.40-0.84; p=0.004), with rectum as primary disease site (HR 0.52, 95%CI 0.31-0.87; p=0.013), with left sided primary tumor location (HR 0.62, 95%CI 0.42-0.90; p=0.011), with multiple metastasis sites (HR 0.68, 95%CI 0.48-0.97; p=0.034) and with lung metastasis (HR 0.65, 95%CI 0.43-0.98; p=0.042).ConclusionWith the approach of establishing the external control arm from RWD, this study has demonstrated that treatment with fruquintinib significantly prolonged PFS as compared to other TKIs in patients as third-line mCRC treatment.

Introduction: In the Phase 3 IMbrave150 trial (NCT03434379), atezolizumab + bevacizumab demonstrated a clinically meaningful survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (HCC), including those with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. We used IMbrave150 data to investigate the safety and risk of viral reactivation or flare in infected patients treated with atezolizumab + bevacizumab or sorafenib. Methods: Patients with unresectable HCC not previously treated with systemic therapy were randomized 2:1 to atezolizumab + bevacizumab or sorafenib. In this exploratory analysis, safety was continually evaluated, including for hepatic adverse events. Patients were monitored for HBV and HCV reactivation and flare at screening, the beginning of Cycles 5 and 9, and at treatment discontinuation. Results: Of 501 enrolled patients, 485 were included in the safety population; 329 (68%) received atezolizumab + bevacizumab and 156 (32%) sorafenib. Overall, 150 (31%) and 58 (12%) patients had HBV and HCV infection, respectively. The safety profiles of atezolizumab + bevacizumab and sorafenib were consistent across patients regardless of viral infection. Overall, hepatic serious adverse events occurred in 11% of patients receiving atezolizumab + bevacizumab and 8% receiving sorafenib. HBV or HCV reactivation occurred in 2% or 16% of atezolizumab + bevacizumab–treated patients, respectively, vs 7% or 14% with sorafenib. There were no instances of hepatitis flare with atezolizumab + bevacizumab. Conclusions: Atezolizumab + bevacizumab had a similar hepatic safety profile in patients with and without HBV or HCV infection. Viral reactivation rates were similar between arms. Overall, these data support the use of atezolizumab + bevacizumab in patients with HCC and HBV or HCV infection without any special precaution.

Abstract Background Monoclonal antibodies targeting programmed death ligand 1 (PD-L1) signaling currently approved for defective mismatch repair (dMMR)/microsatellite instability high (MSI-H) tumors must be delivered by intravenous infusion. Envafolimab, a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment, represents a potential advance because it can be conveniently administered subcutaneously. Methods This open-label, single-arm, phase 2 study evaluated the efficacy and safety of envafolimab in patients with previously treated advanced dMMR/MSI-H tumors from 25 clinical sites across China. Adults with histologically confirmed locally advanced or metastatic malignant dMMR/MSI-H solid tumors received weekly 150 mg subcutaneous envafolimab injections in a 28-day treatment cycle. The primary efficacy endpoint was the objective response rate (assessed by a blinded independent review committee). Secondary efficacy outcomes were disease control rate, duration of response, progression-free survival, and overall survival. Results One hundred and three patients (65 with colorectal cancer, 18 with gastric cancer, and 20 with other solid tumors) were enrolled. Median follow-up was 11.5 months. The objective response rate was 42.7% (95% confidence interval [CI] 33.0–52.8), and the disease control rate was 66.0% (95% CI 56.0–75.1). Median duration of response was not reached; the duration of response rate at 12 months was 92.2% (95% CI 77.5–97.4). Median progression-free survival was 11.1 months (95% CI 5.5 to not evaluable). Overall survival at 12 months was 74.6% (95% CI 64.7–82.1). Sixteen patients (16%) had at least one grade 3 or 4 related treatment-emergent adverse event. No grade 5 treatment-emergent adverse events related to envafolimab were reported. Injection site reactions, all grade 1–2, were reported in nine patients (9%), but there were no infusion reactions. Eight patients (8%) had grade 3 or 4 immune-related adverse events. Conclusions This is the first pivotal phase 2 study to examine the efficacy and safety of a single-domain immune checkpoint antibody in the treatment of cancer. Envafolimab was effective and had acceptable safety in the treatment of previously treated advanced dMMR/MSI-H solid tumors. As the first single-domain PD-L1-targeting antibody administered by rapid subcutaneous injection, envafolimab has the potential to be a significant advance in the treatment of cancer. Trial registration ClinicalTrials.gov, NCT03667170. Registered 10 September 2018—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03667170 .

Introduction: In a multicenter, open-label, parallel-group, randomized, phase 2 study for pretreated advanced hepatocellular carcinoma (HCC), camrelizumab showed potent antitumor activity and acceptable safety profile. The aim of this report was to provide long-term data and evaluate potential benefit of treatment with camrelizumab beyond progression. Methods: From November 15, 2016, to November 16, 2017, 217 patients received camrelizumab 3 mg/kg intravenously every 2 or 3 weeks. Treatment beyond first Response Evaluation Criteria in Solid Tumors (RECIST)-defined progression (TBP) with camrelizumab was allowed. Results: At data cutoff of December 16, 2019 (>2 years after the last patient enrollment; median duration of follow-up, 13.2 months [IQR 5.7–25.8]), 14 (43.8%) of the 32 responses per blinded independent central review were ongoing. The median duration of response was not reached (range 2.5–30.5 + months). The ongoing response rates at 12, 18, and 24 months were 68.3% (95% confidence interval [CI] 47.7–82.2), 59.8% (95% CI 38.8–75.6), and 53.1% (95% CI 31.0–71.0), respectively. The median overall survival (OS) was 14.2 months (95% CI 11.5–16.3). The 18- and 24-month OS rates were 41.3% (95% CI 34.6–47.9) and 33.7% (95% CI 27.3–40.2), respectively. Of the 172 patients who experienced RECIST-defined progression per investigator, 102 received TBP, while 70 did not (non-TBP). The median OS was 16.9 months (95% CI 13.3–22.6) in the TBP group versus 9.4 months (95% CI 5.8–14.8) in the non-TBP group, and the 18- and 24-month OS rates were 47.5% (95% CI 37.3–56.9) versus 33.1% (95% CI 22.3–44.3) and 38.8% (95% CI 29.2–48.4) versus 23.2% (95% CI 13.8–34.1), respectively. No new safety signals of camrelizumab were observed. Conclusions: With prolonged follow-up, camrelizumab continues to demonstrate the durable response and long survival in pretreated advanced HCC patients with manageable toxicities, especially in those who continued the treatment beyond first RECIST-defined progression.

BackgroundPrimary liver cancer (PLC) is a common and highly lethal malignancy in the world. Approximately 85% of PLC is hepatocellular carcinoma (HCC), and this study mainly focuses on HCC. The onset of liver cancer is insidious and often complicated with basic liver disease. Meanwhile, its clinical symptoms are atypical, and the degree of malignancy is high. What is worse is that its treatment is difficult, and the prognosis is poor. All these factors make its mortality close to its incidence. AST-3424 is a prodrug of a potent nitrogen mustard, which targets the tumor by its specific and selective mode of activation and results in the concentration of the drug in the tumor and plays a higher intensity of antitumor effect with reduced side effects. The purpose of this study was to explore the in-vitro antitumor activity and mechanism of AST-3424 monotherapy and combination therapy with oxaliplatin (OXA) or 5-fluorouracil (5-Fu). Moreover, it can provide an experimental basis for further studies.MethodsTumor growth of HCC cells was examined by using the Cell Counting Kit-8 (CCK-8), flow cytometry, and clone formation assays. Tumor migration of HCC cells was examined by using the Transwell assay. The in-vitro antitumor activity of AST-3424 monotherapy and combination therapy with OXA and 5-Fu was quantified by growth and metastasis inhibition rate. The underlying molecular mechanism was investigated by using Western blotting.ResultsThe inhibiting effects of AST-3424 were significant in both HepG2 cells and PLC/PRF/5 cells. Moreover, HepG2 cells showed higher sensitivity to AST-3424. With increasing AST-3424 concentration, AKR1C3 protein expression level was downregulated significantly. The inhibition of AST-3424 was significantly higher than OXA, 5-Fu, Sor (sorafenib), and Apa (apatinib) in both HCC cells. AST-3424 monotherapy and combination therapy with OXA or 5-Fu all strongly inhibited the proliferation of HCC cells, blocked HCC cells in the S phase, promoted apoptosis induction, and suppressed the migration of HCC cells. Among them, the antitumor effect of AST-3424 in combination with OXA was obviously enhanced. Western blotting analysis demonstrated the regulation of P21, Bax, Caspase3, PARP, MMP-2, MMP-9, and p-Smad proteins in the presence of AST-3424 monotherapy and combination therapy with OXA or 5-Fu, indicating that its antitumor mechanisms may be associated with the regulation of the TGF-β signaling cascade.ConclusionThe in-vitro studies revealed that AST-3424 in combination with both OXA and 5-Fu showed an increased antitumor effect, and the combination with OXA resulted in a synergistic effect. Together with the in-vitro results, additional in-vitro and in-vivo studies are warranted to further certify its antitumor effects and explore more potential antitumor mechanisms.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts’ discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported. Methods: IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population. Results: Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25–0.76) and for PFS was 0.60 (95% CI, 0.40–0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2–8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6–4.8) with sorafenib. Grade 3–4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3–4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent. Conclusion: Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC.

Background: Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2017 Edition) in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition (2019 Edition) was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years. Key Messages: Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People’s Republic of China in December 2019.

Aim: To investigate the mechanisms employed by PS-T (polysaccharides of Trametes, PS-T), the main active ingredient of Huaier granules, to improve the susceptibility of hepatoma cells to oxaliplatin (OXA). Methods: Cell proliferation in response to PS-T was determined both in vitro and in vivo. The effects of PS-T on miRNAs were analyzed with the use of a microarray. MiRNAs were screened under specific conditions (P ABS [1.5]) and further silenced or overexpressed by liposome transfection. Levels of ABCB1 mRNA and P-gp were detected by qRT-PCR and western blot analysis, respectively. A dual fluorescence assay was performed to determine whether miRNA directly targets ABCB1. Results: PS-T enhanced the inhibitory effect of OXA in human hepatoma cells and xenografts. Among 5 up-regulated miRNAs, overexpression of only miR-224-5p inhibited the expression of ABCB1 mRNA and P-gp, while silencing of miR-224-5p had an opposite effect. Moreover, miR-224-5p can directly target the 3′-UTR of ABCB1. Conclusion: PS-T increases the sensitivity of human hepatoma cells to OXA via the miR-224-5p/ABCB1/P-gp axis.

Abstract Background Association of immune-related adverse events with tumor response has been reported. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event related to camrelizumab, an immune checkpoint inhibitor, but lack of comprehensive analyses. In this study, we conducted comprehensive analyses on RCCEP in advanced hepatocellular carcinoma (HCC) patients treated with camrelizumab monotherapy. Methods Data were derived from a Chinese nationwide, multicenter phase 2 trial of camrelizumab in pre-treated advanced HCC. The occurrence, clinicopathological characteristics, and prognostic value of RCCEP were analyzed. Results With a median follow-up of 12.5 months, 145 of the 217 camrelizumab-treated patients (66.8%) experienced RCCEP (all grade 1 or 2). RCCEP occurred on the skin surface, mainly on the skin surface of head, face, and trunk. RCCEP could be divided into 5 types including “red-nevus-like,” “pearl-like,” “mulberry-like,” “patch-like,” and “tumor-like,” according to the morphological features. RCCEP biopsy and pathology showed capillary endothelial hyperplasia and capillary hyperplasia in dermis. Significant association between RCCEP occurrence with higher objective response rate was observed (19.3% vs. 5.6%; one-sided p = 0.0044). Compared with those without RCCEP, patients with RCCEP had prolonged progression-free survival (median PFS; 3.2 months vs. 1.9 months; one-sided p < 0.0001) and overall survival (median OS; 17.0 months vs. 5.8 months; one-sided p < 0.0001). In multivariable analyses, the development of RCCEP was significantly associated with prolonged PFS and OS after adjusting for baseline covariates. In addition, the landmark analyses of PFS and OS were consistent with the unadjusted analysis. Conclusions RCCEP occurred on the skin surface and was an immune response of skin capillary endothelial cells. RCCEP occurrence positively associated with outcomes of camrelizumab in advanced HCC.

Abstract Background We performed a pooled analysis of the COMPARZ study assessing efficacy and safety of pazopanib versus sunitinib in treatment-naïve Chinese patients with locally advanced and/or metastatic renal cell carcinoma (a/mRCC). Methods In the COMPARZ study, patients were randomized (1:1) to receive pazopanib 800 mg once daily (QD) continuously or sunitinib 50 mg QD in 6-week cycles (4 weeks on, 2 weeks off). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. PFS and ORR were assessed by independent review committee (IRC) and local investigators. Results Of the 209 Chinese patients (pazopanib, [n = 109] and sunitinib, [n = 100]), 155 (74%) were males and median age was 57 years (range, 18–79). Median PFS was 13.9 months for pazopanib versus 14.3 months for sunitinib per investigator assessment and 8.3 months in both arms per IRC assessment; PFS hazard ratio was 1.17 (investigator) and 0.99 (IRC). Median OS was not reached in pazopanib arm and was 29.5 months in sunitinib arm. ORR was significantly higher in pazopanib arm versus sunitinib arm (investigator: 41% versus 23% [P = 0.0052]; IRC: 35% versus 20% [P = 0.0203]). Pazopanib was generally well tolerated in Chinese patients with a/mRCC. Most frequent AEs in the pazopanib arm were diarrhea and hair color changes whereas the most frequent AEs in the sunitinib arm were decreased platelets, decreased neutrophil count, and thrombocytopenia. Conclusion The results of the pooled analysis were consistent with the overall population in the COMPARZ study, and confirmed similar PFS and OS of pazopanib and sunitinib in the Chinese patients. Trial registration clinical trials.gov, NCT00720941 (August 14, 2008) and NCT01147822 (May 19, 2010).

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, most NSCLC patients are at advanced stage at the time of diagnosis. For patients without sensitive driven-oncogene mutations, chemotherapy is still the main treatment at present, the overall prognosis is poor. Improving outcomes and obtaining long-term survival are the most urgent needs of patients with advanced NSCLC. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs), especially targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), have made a breakthrough in the treatment of NSCLC, beneficial to patients’ survival and changed the treatment pattern for NSCLC. It shows more and more important role in the treatment of NSCLC. Led by NSCLC expert committee of Chinese society of clinical oncology (CSCO), relevant experts in this field were organized. On the basis of referring to domestic and foreign literature, systematically evaluating the results of Chinese and foreign clinical trials, and combining the experiences of the experts, the experts group reached an agreement to develop this consensus. It will guide domestic counterparts for better application of ICIs to treat NSCLC.

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and causes many cancer-related deaths worldwide; in China it is the second most prevalent cause of cancer deaths. Most patients are diagnosed clinically with advanced stage disease. Summary: For more than a decade, sorafenib, a small molecular weight tyrosine kinase-inhibitor (SMW TKI) was the only molecular targeted drug available with a survival benefit for the treatment of advanced HCC. With the development of novel TKIs and immune checkpoint inhibitors (ICIs) for advanced HCC, the management of patients has been greatly improved. However, though angiogenic-based targeted therapy remains the backbone for the systemic treatment of HCC, to date no Chinese guidelines for novel molecular targeted therapies to treat advanced HCC have been established. Our interdisciplinary panel on the treatment of advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists，radiologists，pathologists, orthopedic surgeons, traditional Chinese medicine physicians and interventional radiologists have reviewed the literature in order to develop updated treatment regimens. Key Messages: Panel consensus statements for the appropriate use of new molecular targeted drugs including doses, combination therapies, adverse reaction management as well as efficacy evaluation and predictions for treatment of advanced HCC with evidence levels based on published data are presented, thereby providing an overview of molecular targeted therapies for healthcare professionals.

Icaritin is a potential treatment option for hepatocellular carcinoma (HCC) based on the results of its phase 2 stage trial. Glucose transporter 1 (GLUT1), a critical gene in regulating glycolysis, has been recognized as a promising target in HCC treatment. Previous studies have reported that FAM99A, a new long noncoding (lncRNA), is associated with HCC metastasis. It has also been demonstrated that the JAK2/STAT3 pathway is related to HCC and is the target of icaritin treatment. However, whether FAM99A participates in icaritin treatment and regulates GLUT1-mediated glycolysis via the JAK2/STAT3 pathway in HCC cells remains to be explored. Our study aimed to clarify the mechanisms underlying glycolysis and understand the regulating effects of the FAM99A and JAK2/STAT3 pathway in HCC cells in icaritin treatment. Molecular mechanism studies were conducted to verify whether FAM99A could bind to the JAK2/STAT3 pathway and to identify the regulatory mechanisms in the HCC cells. It was revealed that icaritin inhibited proliferation, GLUT1 level, and the glycolysis of the HCC cells. FAM99A in HCC cells was upregulated after a high concentration treatment of icaritin. FAM99A inhibited GLUT1 by blocking the JAK2/STAT3 pathway. Mechanically, FAM99A interacted with EIF4B to inhibit gp130 and gp80 translation, which then interacted with miR-299-5p to upregulate SOCS3, causing the JAK2 pathway to inhibit STAT3 phosphorylation, so that JAK2/STAT3 was blocked in HCC cells. Overall, our study proved that icaritin-induced FAM99A can inhibit HCC cell viability and GLUT1-mediated glycolysis via blocking the JAK2/STAT3 pathway.

Aims: This post hoc analysis evaluated albumin/bilirubin (ALBI) score, an objective measure of liver function, in patients receiving pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC in the KEYNOTE-240 study. Methods: Patients with confirmed hepatocellular carcinoma (HCC) and progression after/intolerance to sorafenib, Child–Pugh class A liver function, and Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned 2:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks plus BSC for ⩽35 cycles or until confirmed progression/unacceptable toxicity. Outcomes were assessed by ALBI grade. Results: Of 413 patients, at baseline 116 had an ALBI grade 1 score (pembrolizumab, n = 74; placebo, n = 42) and 279 had an ALBI grade 2 score ( n = 193; n = 86). Change from baseline in ALBI score to the end of treatment was similar in both arms [difference in least squares mean, −0.039; 95% confidence interval (CI): −0.169 to 0.091]. Time to ALBI grade increase was similar in both arms [median for pembrolizumab versus placebo: 7.8 versus 6.9 months; hazard ratio (HR) = 0.863 (95% CI: 0.625–1.192)]. Regardless of baseline ALBI grade, a trend toward improved overall survival was observed with pembrolizumab [grade 1: HR = 0.725 (95% CI: 0.454–1.158); grade 2: HR = 0.827 (95% CI: 0.612–1.119)]. Conclusion: Pembrolizumab did not adversely impact liver function compared with placebo in patients with HCC, as measured by changes in ALBI scores. A trend toward improved overall survival was observed with pembrolizumab in both ALBI grade groups. ClinicalTrials.gov identifier : NCT02702401.

Abstract Background The JACOB trial (NCT01774786) was a double-blinded, placebo-controlled, randomized, multicenter, international, phase III trial evaluating the efficacy and safety of adding pertuzumab to trastuzumab and chemotherapy in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer/gastroesophageal junction cancer (GEJC). The aim of this analysis was to investigate efficacy and safety outcomes in the Chinese subpopulation from the JACOB trial. Methods This post hoc subpopulation analysis included all patients recruited in mainland China (n = 163; 20.9%) between June 2013 and January 2016. The patients were randomly assigned in a 1:1 ratio to receive pertuzumab plus trastuzumab and chemotherapy (pertuzumab group; n = 82) or placebo plus trastuzumab and chemotherapy (control group; n = 81). Intravenous pertuzumab (840 mg) and trastuzumab (8 mg/kg loading and 6 mg/kg maintenance doses) were given every 3 weeks until disease progression or unacceptable toxicity. Chemotherapy was given as per standard regimens/doses of capecitabine or 5-fluorouracil plus cisplatin. The primary endpoint was overall survival (OS); secondary efficacy endpoints included progression-free survival (PFS), and overall objective response rate (ORR). Results The median OS was 18.7 months in the pertuzumab group and 16.1 months in the control group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.49 to 1.14). The median PFS was 10.5 and 8.6 months in the pertuzumab and control groups, respectively (HR 0.85; 95% CI 0.60 to 1.21), and the median ORRs were 68.9% and 55.7%, respectively. The treatment effect in this Chinese subpopulation showed consistency with that in the global ITT population with numerically lower HR for OS and PFS compared with the control group. The safety profiles of the pertuzumab and control groups in this Chinese subpopulation analysis were generally comparable. The most common grade 3–5 adverse events were neutropenia, anemia, and leukopenia. However, due to the nature of being a post hoc subgroup analysis, the results presented here are descriptive only and need to be interpreted with caution. Conclusions OS and PFS were numerically improved by adding pertuzumab to trastuzumab and chemotherapy as first-line treatment in Chinese HER2-positive gastric cancer/GEJC patients, and this regimen demonstrated an acceptable safety profile. Trial registration ClinicalTrials.gov. NCT01774786. Registered on 24 January 2013, https://clinicaltrials.gov/ct2/show/NCT01774786

Abstract Background The 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) regimen is the standard first-line treatment for metastatic colorectal cancer (mCRC), however, the optimal second-line regimen for KRAS wild-type mCRC patients is still investigational. In this study, we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan-only as a second-line regimen for treating KRAS wild-type mCRC patients. Methods Patients with KRAS wild-type mCRC who had previously failed to respond to FOLFOX treatment were randomly assigned in a 2:1 ratio, to receive CMAB009 plus irinotecan or irinotecan-only. Patients receiving irinotecan-only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential-CMAB009 arm. The primary endpoints were overall response rate (ORR) and median progression-free survival (PFS). The secondary endpoints were median overall survival (OS), disease control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR). Results The CMAB009 plus irinotecan arm demonstrated significantly improved ORR (33.2% vs. 12.8%; P

Background Emerging clinical data suggest that an immune checkpoint inhibitor in combination with an antiangiogenic agent is a reasonable strategy for multiple malignancies. We assessed the combination of camrelizumab with apatinib in pretreated advanced primary liver cancer (PLC, cohort A) from a multicohort phase Ib/II trial.Methods Patients with PLC after prior systemic treatment(s) were administered camrelizumab (3 mg/kg, once every 2 weeks) plus apatinib (125, 250, 375, or 500 mg; once per day) in a 3+3 dose-escalation stage and subsequent expansion stage. The primary endpoints were tolerability and safety of study treatment.Results From April 2017 to July 2019, 28 patients (21 with hepatocellular carcinoma and 7 with intrahepatic cholangiocarcinoma) received camrelizumab plus apatinib. Two dose-limiting toxicities (both grade 3 diarrhea) were reported in the 500 mg cohort. Therefore, the 375 mg cohort was expanded. Of the 19 patients in the 375 mg cohort, dose reduction to 250 mg occurred in 8 patients within 2 months after treatment initiation. Of the 28 patients with PLC, 26 had grade ≥3 treatment-related adverse events, with hypertension being the most common (9/28). One treatment-related death occurred. The objective response rate was 10.7% (95% CI 2.3% to 28.2%). Median progression-free survival and overall survival were 3.7 months (95% CI 2.0 to 5.8) and 13.2 months (95% CI 8.9 to not reached), respectively.Conclusion The combination of camrelizumab with apatinib had a manageable toxicity and promising antitumor activity in patients with advanced PLC. Apatinib at a dose of 250 mg is recommended as a combination therapy for further studies of advanced PLC treatment.Trial registration numbers NCT03092895.

Introduction: Sequential therapy with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) is effective in some patients with metastatic renal cell carcinoma (mRCC) progressed from or were intolerant to a prior TKIs. Anlotinib is a multi-kinase inhibitor targeting VEGFR1/2/3, PDGFR and FGFR, which has demonstrated efficacy and safety in first-line treatment of mRCC. This study assessed the potential of anloitnib as second-line treatment for patients with mRCC after prior one VEGFR-TKI.Methods: This is a single-arm, open-label, phase 2 study. Patients progressed after or were intolerant to sorafenib or sunitinib were enrolled. Anlotinib was administrated orally 12 mg once daily for 14 days every 3 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), safety and quality of life (QoL).Results: Forty three patients were enrolled and 42 received anlotinib, of whom 32 progressed after and 10 were intolerant to sorafenib or sunitinib. Median PFS were 14.0 months (95% CI 8.3–20.3) and 8.5 months (95% CI 5.6–16.6) for overall population and patients progressed after a previous VEGFR-TKI, respectively. Median OS was 21.4 months (95% CI 16.0–34.5), confirmed ORR and DCR were 16.7 and 83.3% in overall population. The most common adverse events included diarrhea (47.6%), hypertension (45.2%), hand and foot syndrome (42.9%), and fatigue (40.5%). Grade 3 hematological adverse events occurred in four cases, while no grade 4 hematological adverse events was observed.Conclusions: Anlotinib showed promising efficacy as well as favorable safety as second-line treatment for patients with mRCC.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02072044.

Abstract Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed malignancies worldwide with poor prognosis and tends to be hypervascular. Aberrant expression of the vascular endothelial growth factor 2 (VEGFR‐2) has been implicated in the progression of HCC and represents a valid target for anticancer therapy. Apatinib, a small molecule inhibitor of VEGFR‐2 tyrosine kinase, shows strong antitumor activity in various tumors. This study is designed to evaluate the activity of apatinib on both human umbilical vein vascular endothelial cells (HUVECs) and HCC cell lines (in vitro and in vivo), and also to investigate the characteristics and possible mechanisms underlying these effects by molecular biology methods. Following the results in our study, apatinib inhibited phosphorylation of VEGFR‐2 in HUVECs and blocked in vitro endothelial cell migration and tube formation. Concentration‐dependent antiproliferative effects of apatinib were also observed in all 6 HCC cell lines including SK‐Hep‐1, HepG2, Hep3B, Huh‐7, PLC/PRF/5, SMMC‐7721. Moreover, response to apatinib of HCC cell lines was significantly correlated with VEGFR‐2 expression level. Additionally, apatinib significantly inhibit VEGF‐triggered VEGFR‐2 phosphorylation and activation of downstream signaling molecules such as Akt and ERK1/2 in HCCs. Apatinib can also induce a cell cycle arrest at G2/M phase and promote HCC apoptosis tested in vitro. In vivo data showed that apatinib can effectively inhibit tumor growth, decreased angiogenesis, as well as induced HCC apoptosis (in some tumors), and thus prolonged animal survival in a mouse xenograft model of human HCC. Our findings suggested that apatinib is a highly potent, oral active anti‐angiogenic, and anti‐HCC agent. The results from current study provide a clear biological rationale to evaluate apatinib as a new agent in HCC in clinical setting, especially for the VEGFR‐2 overexpression ones.

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

Abstract Objectives Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. In China, sorafenib and oxaliplatin plus infusional-fluorouracil/leucovorin (FOLFOX4) are approved for the systemic treatment of advanced HCC. This study compared the cost-effectiveness of these therapies from a healthcare system perspective and a patient perspectives. Methods A Markov model was constructed using overall and progression-free survival rates and adverse event (AE) rate from two randomized controlled studies of advanced HCC patients from Asia: EACH for FOLFOX4 and ORIENTAL for sorafenib. The patients in the Markov model were followed until death, the length of each Markov cycle was 1 month, and the survival was adjusted for quality-adjusted life years (QALYs). Direct medical costs included costs of therapies, AE treatment, general ward and tests. Costs were derived from published sources, interviews with oncologists and hospital data from China. One-way and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the results. Results From the healthcare system perspective, FOLFOX4 dominated sorafenib with lower therapy costs (FOLFOX4: US$ 6972; sorafenib: US$ 12,289), lower direct medical costs (FOLFOX4: US$ 8428; sorafenib: US$ 12,798), and higher QALYs (FOLFOX4: 0.42; sorafenib: 0.38) per patient. This result was robust according to comprehensive one-way sensitivity analyses. According to the PSA, at the cost-effectiveness threshold for China (3 × GDP, US$ 22,073), FOLFOX4 should be chosen in 63.9% of simulations. From the patient perspective, FOLFOX4 also dominated sorafenib. Conclusions The study results indicate that FOLFOX4 dominates sorafenib because it appears to provide higher effectiveness with significantly lower costs in treating Chinese advanced HCC patients.

Abstract Background Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. Patients and methods We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan–Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. Results Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64–0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53–0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p

Abstract Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) are standard treatment for advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. However, EGFR mutation testing is not attainable in approximately 20% of patients. The current study examined intercalating and maintaining gefitinib treatment in stage IIIB/IV non-squamous NSCLC, never or former light smoking patients with unknown EGFR mutation status. Briefly, 219 patients who achieved stable disease (SD) with gemcitabine (1250 mg/m2) plus carboplatin (5 AUC) were randomized at 1:1 ratio to continue chemotherapy (n = 110) or intercalating gefitinib (250 mg/day on days 15–25 of each cycle until disease progress (n = 109). Progression-free survival (PFS) was 9.7 vs. 4.2 month in the gefitinib vs. control arm (HR: 0.41, 95% CI: 0.31–0.56; P

Abstarct The original article [1] contains two errors in Table 2

Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125 mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety.From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9-6.6 m) and 5.4 months (95%CI 3.1-7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127).In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy.ClinicalTrials.gov NCT02486354.

To investigate the effect of endostar on specific angiogenesis induced by human hepatocellular carcinoma, this research systematically elucidated the inhibitory effect on HepG2-induced angiogenesis by endostar from 50 ng/mL to 50000 ng/mL. We employed fluorescence quantitative Boyden chamber analysis, wound-healing assay, flow cytometry examination using a coculture system, quantitative analysis of tube formation, and in vivo Matrigel plug assay induced by HCC conditioned media (HCM) and HepG2 compared with normal hepatocyte conditioned media (NCM) and L02. Then, we found that endostar as a tumor angiogenesis inhibitor could potently inhibit human umbilical vein endothelial cell (HUVEC) migration in response to HCM after four- to six-hour action, inhibit HCM-induced HUVEC migration to the lesion part in a dose-dependent manner between 50 ng/mL and 5000 ng/mL at 24 hours, and reduce HUVEC proliferation in a dose-dependent fashion. Endostar inhibited HepG2-induced tube formation of HUVECs which peaked at 50 ng/mL. In vivo Matrigel plug formation was also significantly reduced by endostar in HepG2 inducing system rather than in L02 inducing system. It could be concluded that, at cell level, endostar inhibited the angiogenesis-related biological behaviors of HUVEC in response to HCC, including migration, adhesion proliferation, and tube formation. At animal level, endostar inhibited the angiogenesis in response to HCC in Matrigel matrix.