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Background Collagen fibers play an important role in tumor initiation, progression, and invasion. Our previous research has already shown that large-scale tumor-associated collagen signatures (TACS) are powerful prognostic biomarkers independent of clinicopathological factors in invasive breast cancer. However, they are observed on a macroscale and are more suitable for identifying high-risk patients. It is necessary to investigate the effect of the corresponding microscopic features of TACS so as to more accurately and comprehensively predict the prognosis of breast cancer patients. Methods In this retrospective and multicenter study, we included 942 invasive breast cancer patients in both a training cohort (n = 355) and an internal validation cohort (n = 334) from one clinical center and in an external validation cohort (n = 253) from a different clinical center. TACS corresponding microscopic features (TCMFs) were firstly extracted from multiphoton images for each patient, and then least absolute shrinkage and selection operator (LASSO) regression was applied to select the most robust features to build a TCMF-score. Finally, the Cox proportional hazard regression analysis was used to evaluate the association of TCMF-score with disease-free survival (DFS). Results TCMF-score is significantly associated with DFS in univariate Cox proportional hazard regression analysis. After adjusting for clinical variables by multivariate Cox regression analysis, the TCMF-score remains an independent prognostic indicator. Remarkably, the TCMF model performs better than the clinical (CLI) model in the three cohorts and is particularly outstanding in the ER-positive and lower-risk subgroups. By contrast, the TACS model is more suitable for the ER-negative and higher-risk subgroups. When the TACS and TCMF are combined, they could complement each other and perform well in all patients. As expected, the full model (CLI+TCMF+TACS) achieves the best performance (AUC 0.905, [0.873–0.938]; 0.896, [0.860–0.931]; 0.882, [0.840–0.925] in the three cohorts). Conclusion These results demonstrate that the TCMF-score is an independent prognostic factor for breast cancer, and the increased prognostic performance (TCMF+TACS-score) may help us develop more appropriate treatment protocols.

Background The EXTREME regimen (chemotherapy [CT; cisplatin/carboplatin and 5-fluorouracil]) plus cetuximab is a standard-of-care first-line (1L) treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), as supported by international guidelines. The phase III CHANGE-2 trial assessed the efficacy and safety of a modified CT regimen (with a reduced dose of both components) and cetuximab versus CT for the 1L treatment of Chinese patients with R/M SCCHN. Methods Patients were randomised to receive up to six cycles of CT plus cetuximab followed by cetuximab maintenance until progressive disease or CT alone. The primary end-point was the progression-free survival (PFS) time assessed by the independent review committee (IRC). Results Overall, 243 patients were randomised (164 to CT plus cetuximab; 79 to CT). The hazard ratios for PFS by IRC and overall survival (OS) were 0.57 (95% CI: 0.40–0.80; median: 5.5 versus 4.2 months) and 0.69 (95% CI: 0.50–0.93; median: 11.1 versus 8.9 months), respectively, in favour of CT plus cetuximab. The objective response rates (ORR) by IRC were 50.0% and 26.6% with CT plus cetuximab and CT treatment, respectively. Treatment-emergent adverse events of maximum grade 3 or 4 occurred in 61.3% (CT plus cetuximab) and 48.7% (CT) of patients. Conclusions CHANGE-2 showed an improved median PFS, median OS and ORR with the addition of cetuximab to a modified platinum/5-fluorouracil regimen, with no new or unexpected safety findings, thereby confirming CT plus cetuximab as an effective and safe 1L treatment for Chinese patients with R/M SCCHN. Clinical trial registration number NCT02383966.

GALLIUM is a global phase III study that demonstrated significant improvements in progression-free survival (PFS) for obinutuzumab plus chemotherapy (G-chemo) vs. rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). This study aimed to report the results of a subgroup of patients in China.Patients were randomized to G-chemo or R-chemo. Responders received maintenance therapy for 2 years or until disease progression. The primary endpoint was investigator (INV)-assessed PFS. Secondary endpoints included the overall response rate (ORR) and complete response rate (CRR) at the end of induction chemotherapy, overall survival (OS), and safety.Overall, 58 patients with FL were randomized to the G-chemo (n = 25) and R-chemo arms (n = 33). The INV-assessed PFS rate at 3 years was 81.8% in the G-chemo arm, vs. 70.2% in the R-chemo arm (hazard ratio 0.35; 95% confidence interval: 0.09-1.34; P = 0.1120). The INV-assessed CRRs (without positron emission tomography [PET]) in these arms were 24.0% and 21.2%, respectively, whereas the ORRs were 80.0% and 90.9%, respectively. INV-assessed CRR-PET was 52.6% in the G-chemo, vs. 60.9% in the R-chemo. Median OS was not reached in either arm. Grade 3 to 5 adverse events were more frequent in the R-chemo arm (97.0% vs. 88.0%).The results of this subgroup analysis were consistent with those of the global population, and they suggest that G-chemo has a positive benefit-risk profile in patients from China with FL.ClinicalTrials.gov, No. NCT01332968.

Background Previous clinical trials have demonstrated that entinostat in combination with exemestane had good tolerability and significant clinical efficacy in patients with advanced hormone receptor positive (HR+) and HER2 negative (HER2−) metastatic breast cancer (MBC) in the USA. However, no clinical trials have been conducted in Chinese populations. Objective To investigate the safety, pharmacokinetics, and pilot efficacy of entinostat with or without exemestane in Chinese postmenopausal patients with locally advanced or metastatic HR+ /HER2− MBC. Patients and methods Nineteen patients received entinostat for 4 weeks (dose-limiting toxicity (DLT) observation stage) at 3, 5, or 7 mg/week, with a “3+3” dose-escalation design and in combination with exemestane thereafter (extended treatment stage: entinostat, 3 or 5 mg/week; exemestane, 25 mg/day). An additional 21 patients were enrolled to assess the entinostat (5 mg) plus exemestane (25 mg) pharmacokinetic profile and potential efficacy. Results The peak entinostat serum concentration and area under the curve increased dose proportionally, without significant interaction between entinostat and exemestane. Entinostat was well tolerated at all doses. The most common grade 3/4 adverse effects (AEs) included neutropenia (31.6%) and thrombocytopenia (15.8%). In the DLT observation stage, grade 3/4 AEs accounted for 16.7% in the 5 mg group with one suspicious DLT (G3 ventricular tachycardia) and 33.3% in the 7 mg group. In the extended treatment stage, 2/16 patients achieved partial response and three patients experienced stable disease (> 12 weeks). The median progression-free survival was 9.41 months for the additional 21 patients, who experienced grade 3/4 AEs of neutropenia (38%), thrombocytopenia (9.5%), anemia (9.5%), and fatigue (9.5%). Conclusion Entinostat with exemestane showed reasonable safety, tolerability, and encouraging efficacy in Chinese patients with HR+/HER2− MBC. These results support further evaluation in a randomized, double-blind Phase III study with a weekly 5 mg entinostat dose in a Chinese population. Trial Registration NCT02833155.

This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China. Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments. By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUCτ was 1217 and 2501 ng∙h/mL, and t½ was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed. Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile. NCT02499146

Background HLX02 is an approved biosimilar of trastuzumab. Objective This study aimed to evaluated the efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. Patients and Methods This randomized, double-blind, phase III study was conducted at 89 centers in China, the Philippines, Poland, and Ukraine. Eligible patients were randomized (1:1) to receive HLX02 or European Union (EU)-sourced trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months) in combination with docetaxel intravenously. The primary endpoint was overall response rate up to week 24 (ORR24). Equivalence was declared if the 95% confidence interval (CI) of difference was within ± 13.5%. Safety and immunogenicity were evaluated in patients who received at least one dose of study medication. Results Between 11 November 2016 and 10 July 2019, a total of 649 patients were enrolled. The ORR24 was 71.3 and 71.4% in the HLX02 (n = 324) and EU-trastuzumab (n = 325) groups, with a difference of − 0.1% (95% CI − 7 to 6.9), which fell entirely in the predefined equivalence margins. No statistically significant differences were observed in all secondary efficacy analyses. Safety profiles and immunogenicity were comparable in HLX02 and EU-trastuzumab groups. In total, 98.8% of patients in each group experienced at least one treatment-emergent adverse event (TEAE), 23.8 and 24.9% experienced serious TEAEs, and 0.6% in each group had antidrug antibodies. Conclusions Among patients with HER2-positive recurrent or metastatic breast cancer, HLX02 demonstrated equivalent efficacy and similar safety and immunogenicity to reference trastuzumab. Clinical Trial Registration Chinadrugtrials.org CTR20160526 (12 September 2016), ClinicalTrials.gov NCT03084237 (20 March 2017), EudraCT 2016-000206-10 (27 April 2017). Supplementary Information The online version contains supplementary material available at 10.1007/s40259-021-00475-w., Plain Language Summary Trastuzumab is a biologic drug used to treat patients with certain types of breast cancer and stomach cancer. Biosimilars are medications that are almost identical to and indistinguishable from original biologic drugs but usually less expensive and more accessible. The main purpose of this study was to evaluate the efficacy (treatment effects) of HLX02 (trastuzumab biosimilar) compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. Other objectives were to evaluate the safety of HLX02 by monitoring adverse events and assessing its potential to induce antibody production (which can prevent a drug from being effective). Patients with HER2-positive recurrent or metastatic breast cancer were randomly allocated to receive HLX02 (n = 324) or European Union (EU)-sourced trastuzumab (n = 325). Study drugs (HLX02 or EU-trastuzumab) were given intravenously, with an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months. Statistical analyses showed that HLX02 was equivalent to trastuzumab in efficacy evaluations. Adverse events observed in the HLX02 treatment group were consistent with those seen with trastuzumab in the current and previous clinical studies. Additionally, no statistically significant differences were seen in the tendency to stimulate antibody production between the two study drugs. To conclude, HLX02 and reference trastuzumab had similar efficacy and safety profiles. These data support the approval of HLX02 as a trastuzumab biosimilar. Supplementary Information The online version contains supplementary material available at 10.1007/s40259-021-00475-w.

PURPOSEAs yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy.PATIENTS AND METHODSIn this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).RESULTSAmong all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1− patients, respectively ( P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7% ( P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab.CONCLUSIONThe POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response.

Background: Our study measured the body composition of Diffuse large B-cell lymphoma (DLBCL) patients receiving rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen by computed tomographic (CT) and assessed their correlation with treatment-related toxicity and other adverse outcomes. Methods: We retrospectively analyzed 201 DLBCL patients who underwent pre-treatment abdominal CT examination. CT images were used to assess body composition metrics at the third lumbar vertebrae including fat tissues and muscle. Based on the skeletal muscle area (SMA) and density (SMD), skeletal muscle index (SMI), skeletal muscle gauge (SMG = SMI × SMD) and lean body mass (LBM) were calculated. Also analyzed were the toxicity, adverse events and survival. Results: We found that SMG, SMD, SMI and LBM were correlated with any grade 3–4 toxicity, dose reduction, hospitalization or termination of the treatment due to immunochemotherapy and worse survival. However, multivariate analysis demonstrated SMG [progression-free survival (PFS): hazard ratio (HR), 2.889, 95% CI, 1.401–5.959, p = 0.004, overall survival (OS): HR, 2.655, 95% CI, 1.218–5.787, p = 0.014] was the best predictor of poor prognosis. Conclusions: SMG, SMD, SMI and LBM were identified as predictors of adverse reactions and poor survival. SMG was an innovative and valuable indicator of immunochemotherapy toxicity and other adverse outcomes. Additionally, it can be used to individualize antineoplastic drug dosing.

Summary Background Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. Methods This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. Findings Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p Interpretation Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. Funding Jiangsu Hengrui Medicine and National Key R&D Program of China. Translations For the Chinese translation of the abstract see Supplementary Materials section.

Background The addition of pertuzumab to trastuzumab plus standard chemotherapy as adjuvant therapy following surgery significantly improved invasive disease-free survival (IDFS) in patients with HER2-positive early breast cancer in the multinational randomized APHINITY trial (NCT01358877, BIG 4–11/BO25126/TOC4939G). We analyzed clinical outcomes in the subgroup of patients recruited at Chinese sites. Methods Patients were randomized to standard adjuvant chemotherapy plus 1 year of trastuzumab with pertuzumab or placebo. Patients recruited in mainland China, Hong Kong and Taiwan are included in this descriptive analysis. Results Chinese patients had similar demographic characteristics to the global population, but a higher proportion had nodal involvement. Although this subgroup analysis was not powered to detect statistical significance, a numerical improvement in IDFS was observed with the addition of pertuzumab to trastuzumab in Chinese patients (hazard ratio, 0.69; 95% confidence interval: 0.39–1.19; 3-year IDFS event-free estimates 92.5% [pertuzumab] and 91.7% [placebo]), which was consistent with the primary analysis of the global population. Further subgroup analyses showed numerical improvements in the Chinese node-positive, hormone receptor-negative and -positive subgroups, although confidence intervals were wide due to the low number of events. The incidence of diarrhea was higher in the pertuzumab arm, and no primary cardiac events occurred in Chinese patients in either arm. Conclusions Pertuzumab, used in combination with trastuzumab and chemotherapy in APHINITY, is effective as an adjuvant treatment regimen for Chinese patients with HER2-positive early breast cancer in a setting with curative intent. The safety profile in Chinese patients was consistent with that of the global population.

Background: In the phase III MONARCH plus study (NCT02763566) the cyclin-dependent kinase (CDK) 4&6 inhibitor abemaciclib in combination with non-steroidal aromatase inhibitors (NSAI) or with fulvestrant compared with placebo demonstrated its efficacy and acceptable safety profile at interim analysis in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locoregionally recurrent or metastatic breast cancer. One of the most common treatment-emergent adverse event (TEAE) was diarrhea, typically low grade and of early onset. We will further characterize abemaciclib-associated diarrhea and describe its management in MONARCH plus trial. Methods: MONARCH plus study included two cohorts of patients. Cohort A enrolled patients with initial treatment of endocrine therapy, received abemaciclib or placebo plus NSAI (anastrozole or letrozole); Cohort B enrolled patients who progressed on prior endocrine therapy, receiving abemaciclib or placebo plus fulvestrant. The relative dose intensity was defined as the percentage of actual dose received relative to the planned dose. The severity of diarrhea was reported by investigators and graded according to Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). Further analysis on diarrhea included time to onset, duration, supportive medication and dose modifications. Progression-free survival (PFS) was defined as time from randomization to death or progression (RECIST v1.1), and a stratified Cox proportional hazard model was used to estimate the hazard ratio (HR) between study intervention arm and placebo arm. Results: The median relative dose intensity of abemaciclib in abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm were 96.77% and 96.30% respectively. In abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm, the median time to onset of first reported diarrhea was 7 and 6 days and majority of diarrhea events occurred early (66.3% and 71.2% of patients reported diarrhea in Cycle 1 respectively). Diarrhea was typically of low grade (3.9% and 1.9% of patients reported Grade 3 in abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm, no Grade 4 diarrhea was reported in either arm). Median duration of grade ≥ 3 diarrhea was 2.5 and 3.5 days. Diarrhea was managed by dose adjustments and/or supportive medication (Table 1). Dose reductions were present in 2.0% and 2.9% of patients, and anti-diarrhea therapy was received in 30.2% and 32.7% of patients with abemaciclib plus NSAI and abemaciclib plus fulvestrant arm, respectively. As data cutoff, most diarrhea events were reported as resolved, and the incidence dropped below 10% (Grade 2) and 1% (Grade 3) by Cycle 2 in both arms and kept low incidence over time. Compared to the placebo arm, patients treated with abemaciclib combination who reported diarrhea within the first 7 days (abemaciclib + NSAI, HR [95% CI]: 0.289 [0.166, 0.502]; abemaciclib + fulvestrant, HR [95% CI]: 0.371 [0.213, 0.647]) had significant improvement in PFS. Conclusion: Majority of diarrhea events were of low grade in severity and well managed by anti-diarrheal medications, dose omissions or/and dose reductions in MONARCH plus patients. Table 1. Summary of dose adjustments and supportive medications in patients experiencing diarrheaCohort ACohort BAbemaciclib + NSAIAbemaciclib + FulvestrantN = 205N = 104Diarrhea (any grade), n (%)164 (80.0)82 (78.8)1105 (51.2)52 (50.0)251 (24.9)28 (26.9)38 (3.9)2 (1.9)Outcome, number of events, n796333Recovered/resolved, n (%)757 (95.1)318 (95.5)Not recovered/resolved, n (%)17 (2.1)7 (2.1)Treatment change, n (%)Dose reduction4 (2.0)3 (2.9)Dose omission3 (1.5)3 (2.9)Treatment discontinuation00Anti-diarrhea therapies, n (%)62 (30.2)34 (32.7)loperamide48 (23.4)21 (20.2)berberine6 (2.9)6 (5.8) Citation Format: Zefei Jiang, Xichun Hu, Qingyuan Zhang, Tao Sun, Yongmei Yin, Huiping Li, Min Yan, Zhongsheng Tong, Christina Pimentel Oppermann, Yunpeng Liu, Romulo Costa, Man Li, Xi Chen, Ying Cheng, Quchang Ouyang, Ning Liao, Xiaojia Wang, Xinhong Wu, Jifeng Feng, Roberto Hegg, Govindbabu Kanaka Setty, Amit Agarwal, Jyoti Bajpai, Jing Cheng, Gustavo Girotto, Chanchal Goswami, Wenjing Hu, Jian Huang, MA Coccia Portugal, Jin Yang, Rongsheng Zheng, Fabio Andre Franke, Qiang Liu, Yunjiang Liu, Yongkui Lu, Cristiano Souza, Shiying Yu, Nalini Kilara, Harsha Panchal, Ashish Singh, Shona Nag, Jian Liu, Bernardo Rapoport, Neonyana Keorapetse Rebecca Tabane, Hongxia Wang, Ning Wang, Rubing Han, Wanli Zhang. Management of abemaciclib associated diarrhea in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Analysis of the MONARCH plus study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-25.

The notion of personalized medicine demands proper prognostic biomarkers to guide the optimal therapy for an invasive breast cancer patient. However, various risk prediction models based on conventional clinicopathological factors and emergent molecular assays have been frequently limited by either a low strength of prognosis or restricted applicability to specific types of patients. Therefore, there is a critical need to develop a strong and general prognosticator. Methods: We observed five large-scale tumor-associated collagen signatures (TACS4-8) obtained by multiphoton microscopy at the invasion front of the breast primary tumor, which contrasted with the three tumor-associated collagen signatures (TACS1-3) discovered by Keely and coworkers at a smaller scale. Highly concordant TACS1-8 classifications were obtained by three independent observers. Using the ridge regression analysis, we obtained a TACS-score for each patient based on the combined TACS1-8 and established a risk prediction model based on the TACS-score. In a blind fashion, consistent retrospective prognosis was obtained from 995 breast cancer patients in both a training cohort (n= 431) and an internal validation cohort (n = 300) collected from one clinical center, and in an external validation cohort (n = 264) collected from a different clinical center. Results: TACS1-8 model alone competed favorably with all reported models in predicting disease-free survival (AUC: 0.838, [0.800-0.872]; 0.827, [0.779-0.868]; 0.807, [0.754-0.853] in the three cohorts) and stratifying low- and high-risk patients (HR 7.032, [4.869-10.158]; 6.846, [4.370-10.726], 4.423, [2.917-6.708]). The combination of these factors with the TACS-score into a nomogram model further improved the prognosis (AUC: 0.865, [0.829-0.896]; 0.861, [0.816-0.898]; 0.854, [0.805-0.894]; HR 7.882, [5.487-11.323]; 9.176, [5.683-14.816], and 5.548, [3.705-8.307]). The nomogram identified 72 of 357 (~20%) patients with unsuccessful 5-year disease-free survival that might have been undertreated postoperatively. Conclusions: The risk prediction model based on TACS1-8 considerably outperforms the contextual clinical model and may thus convince pathologists to pursue a TACS-based breast cancer prognosis. Our methodology identifies a significant portion of patients susceptible to undertreatment (high-risk patients), in contrast to the multigene assays that often strive to mitigate overtreatment. The compatibility of our methodology with standard histology using traditional (non-tissue-microarray) formalin-fixed paraffin-embedded (FFPE) tissue sections could simplify subsequent clinical translation.

Chemotherapy-induced neutropenia (CIN) is a potentially fatal and common complication in myelosuppressive chemotherapy. The timing and grade of CIN may play prognostic and predictive roles in cancer therapy. CIN is associated with older age, poor functional and nutritional status, the presence of significant comorbidities, the type of cancer, previous chemotherapy cycles, the stage of the disease, specific chemotherapy regimens, and combined therapies. There are many key points and new challenges in the management of CIN in adults including: (1) Genetic risk factors to evaluate the patient's risk for CIN remain unclear. However, these risk factors urgently need to be identified. (2) Febrile neutropenia (FN) remains one of the most common reasons for oncological emergency. No consensus nomogram for FN risk assessment has been established. (3) Different assessment tools [e.g., Multinational Association for Supportive Care in Cancer (MASCC), the Clinical Index of Stable Febrile Neutropenia (CISNE) score model, and other tools] have been suggested to help stratify the risk of complications in patients with FN. However, current tools have limitations. The CISNE score model is useful to support decision-making, especially for patients with stable FN. (4) There are still some challenges, including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN. In view of the current reports, our group discusses the key points, new challenges, and management of CIN.

Patients with primary central nervous system lymphoma (PCNSL) have a prognosis poorer than that of systemic lymphoma patients. In patients with this condition, TLR4/STAT3 pathway alterations and the MYD88 L265P mutation may be viable targets for therapeutic intervention. The present study was, therefore, designed to identify clinicopathologic correlates of MYD88 mutations and TLR4/STAT3 pathway alterations in PCNSL. We detected TLR4 and p-STAT3 in 41.5% (22/53) and 43.4% (23/53) of PCNSL patients, respectively, while 60.4% of these patients (32/53) were found to harbor the MYD88 L265P mutation. TLR4 expression was found to be significantly associated with the presence of multiple brain lesions, while p-STAT3 expression was significantly linked to advanced age, the presence of multiple brain lesions, non-GCB histological findings, and non-CR status. The presence of the MYD88 L265P mutation was significantly linked to advanced age, the presence of multiple brain lesions, and DLBCL molecular subtype. Multivariate analyses additionally confirmed that elevated TLR4 and p-STAT3 expression levels are associated with a poorer PCNSL patient prognosis. Based on these findings, we hypothesize that signaling through the TLR4/MYD88/STAT3 pathway plays a key role in the pathogenesis of PCNSL.

Background Molecular subtyping of triple-negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. Materials and methods By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC-based classifier, and applied it to another two cohorts (n = 183 and 214). Results We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC-based luminal androgen receptor (IHC-LAR; AR-positive [+]), (b) IHC-based immunomodulatory (IHC-IM; AR-negative [-], CD8+), (c) IHC-based basal-like immune-suppressed (IHC-BLIS; AR-, CD8-, FOXC1+), (d) IHC-based mesenchymal (IHC-MES; AR-, CD8-, FOXC1-, DCLK1+), and (e) IHC-based unclassifiable (AR-, CD8-, FOXC1-, DCLK1-). The κ statistic indicated substantial agreement between the IHC-based classification and mRNA-based classification. Multivariate survival analysis suggested that our IHC-based classification was an independent prognostic factor for relapse-free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC-LAR subtype showed relative activation of HER2 pathway. The IHC-IM subtype tended to exhibit an immune-inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC-BLIS subtype showed high expression of a VEGF signature. The IHC-MES subtype displayed activation of JAK/STAT3 signaling pathway. Conclusion We developed an IHC-based approach to classify TNBCs into molecular subtypes. This IHC-based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes. Implications for practice An immunohistochemistry (IHC)-based classification approach was developed for triple-negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression-based classification. This IHC-based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype-specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.

Purpose In clinical practice, the risk factors for pegylated liposomal doxorubicin-related hand-foot syndrome remain unclear. The purpose of this study was to determine the risk factors associated with hand-foot syndrome in patients with lymphoma using pegylated liposomal doxorubicin. Methods This retrospective descriptive analysis included patients with lymphoma who received PLD treatment (≥ 2 cycles of chemotherapy) at our cancer centre and had complete follow-up data from January 2016 to February 2020. Clinical, laboratory data, as well as the occurrence of hand-foot syndrome (incidence, location, severity, impact on follow-up chemotherapy) were obtained. The primary end point was the incidence of hand-foot syndrome, which was classified according to the “Common Terminology Criteria for Adverse Events” (Version 4.0). A multivariate logistic regression analysis was used to identify risk factors for hand-foot syndrome in patients with lymphoma using doxorubicin liposomes. Findings A total of 167 patients met the inclusion criteria. 58 developed HFS, of which 45 occurred after the second course of chemotherapy. The multivariate logistic regression analysis revealed that a dose increase of pegylated liposomal doxorubicin and hepatobiliary dysfunction were significantly associated with an increased risk for hand-foot syndrome(dose intensity, OR = 6.479; 95% CI, 1.431–29.331 [P = 0.015]; history of gallstones, OR = 14.144, 95% CI, 1.512–132.346 [P = 0.020]; alanine aminotransferase, OR = 1.194, 95% CI, 1.056–1.350 [P = 0.005]; aspartate aminotransferase, OR = 1.162, 95% CI, 1.010–1.336 [P = 0.035]; and glutamine transpeptidase, OR = 1.092, 95% CI, 1.016–1.174 [P = 0.018]). Implications These findings contribute to the risk assessment of patients with lymphoma before using pegylated liposomal doxorubicin. For patients with the above risk factors, preventive measures should be taken in advance to reduce the incidence of HFS.

BackgroundGastric diffuse large B-cell lymphoma (gDLBCL) related to Helicobacter pylori infection exhibits a wide spectrum of prognosis, and the tumor immune microenvironment (TIME) affects tumor progression. However, there are few studies on the correlation between prognosis and changes of TIME induced by H. pylori infection in de novo gDLBCL.MethodsA retrospective study was performed to determine the prognostic value of TIME related to H. pylori infection in de novo gDLBCL. A total of 252 patients were included and have been treated with standard rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy or other similar regimens in addition to H. pylori eradication (HPE). All patients were stratified by H. pylori infection, HPE efficacy, and preliminary TIME evaluation using conventional criteria. Statistical analyses were conducted. To assess the mechanism, 30 subjects were assessed for H. pylori infection. The components and spatial distributions of TIME were analyzed.ResultsThe median follow-up of the 252 patients was 66.6 months (range 0.7–119.2), and the 5-year overall survival (OS) was 78.0%. A total of 109 H. pylori-positive cases with pathological complete remission and high tumor-infiltrating T lymphocytes (cohort 1) had significantly higher 5-year progression-free survival (88.1% vs 70.5%, pConclusionH. pylori-evoked inflammatory responses disturb the TIME, causing a differential prognosis in de novo gDLBCL, which can be used to identify patients who could benefit from HPE and immunochemotherapy.

Purpose To assist in the selection of a suitable combination of an irradiation technique and jaw condition in intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc radiotherapy (VMAT) for lung cancer treatment plans. Materials and methods Thirty patients with lung cancer who underwent radiotherapy were enrolled retrospectively. They were categorized as having central lung cancer, peripheral lung cancer with mediastinal lymph node metastasis (peripheral E lung cancer), and peripheral lung cancer without mediastinal lymph node metastasis (peripheral N lung cancer). Four treatment plans were designed for each patient: fixed jaw and adaptive jaw IMRT technique (FJ-IMRT and JA-IMRT), and fixed jaw and jaw tracking VMAT technique (FJ-VMAT and JT-VMAT). The dose parameters of the four group plans were compared and analyzed. Results Compared to FJ-IMRT, JA-IMRT significantly reduced the mean dose (Dmean ) and volume percentage of 5 Gy (V5Gy ) of the total lung in central and peripheral N lung cancer. Similarly, compared to FJ-VMAT, JT-VMAT provided better protection to most organs at risk (OARs), particularly for total lung and heart. In comparison with IMRT, VMAT significantly improved the conformity index (CI) of the planning target volume for the three lung cancer classifications, and it reduced the dose of almost all OARs except V5Gy and Dmean of the total lung. Moreover, the mean monitor units of the VMAT groups were far lower than the IMRT groups. Conclusion Based on the dosimetric findings and considering clinical data published on lung and heart side effects, we propose recommendations on the preferred treatment technique based on tumor location and pulmonary function. For central lung cancer with normal pulmonary function, we advise JT-VMAT techniques. Conversely, for central lung cancer with poor pulmonary function, we recommend JA-IMRT techniques. We advocate JA-IMRT for peripheral E lung cancer. For peripheral N lung cancer, JT-VMAT techniques are strongly recommended.

Background. Chronic heart failure is the main critical illness and cause of death in the later stages of cardiovascular disease, and it is one of the two major challenges in the field of cardiovascular research. The clinical application of traditional Chinese medicine in the prevention and treatment of chronic heart failure has been relatively common in China, and the “Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine” has been published in China. Combining the literature in this field, the authors found that Zhigancao Decoction has been used in the treatment of chronic heart failure with more clinical research reports and higher frequency (this article refers to it as a high-frequency prescription for short). However, Zhigancao Decoction was not included in the recommended prescriptions in the “Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine,” and there was no relevant systematic review and meta-analysis. For this reason, this article has carried out two parts of work, including systematically organizing the literature in this research field and carrying out systematic review and meta-analysis. This can provide stronger evidence support for Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure and provide a new option for the improvement and update of the “Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine.” Methods. This article used the bibliometric method to investigate the research articles on the treatment of chronic heart failure with integrated traditional Chinese and Western medicine and analyzed the high-frequency prescriptions which are used and reported frequently. In addition, we also used manual and computer-aided search methods, the search scope includes CNKI, WANFANG, VIP, SinoMed, Web of Science, PubMed, and Cochrane Library, and the search content is the clinical randomized control of Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure trials (RCTs). The search period is from the establishment of the database to January 29, 2021. The literature was managed and screened by EndNote software; the quality of the included literature was evaluated according to the modified Jadad scale, and the risk bias was assessed using the Cochrane tool; the results of the included studies were analyzed using the Review Manager 5.3 software; the sources of heterogeneity between the studies were analyzed using Stata16.0 software for sensitivity analysis. Results. According to the bibliometric analysis, the maximum number of research reports is 553, which are arranged in descending order of 21 prescriptions, including Zhenwu Decoction, Zhigancao, and powder of five drugs containing poria. The second most frequently used prescription is Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure, but its systematic review and meta-analysis still need further research. A total of 17 clinical randomized controlled trials of Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure were included in the search, with a total of 1752 subjects. Meta-analysis results show that Zhigancao combined with conventional Western medicine is more effective than conventional Western medicine in the treatment of chronic heart failure. The advantages are the following 5 outcome indicators: total clinical effective rate, left ventricular ejection fraction, left ventricular end-diastolic diameter, B-type natriuretic peptide, and 6-minute walk test. Conclusions. There are many prescriptions combined with Western medicine to treat chronic heart failure, among which Zhigancao Decoction is the second most frequently used prescription. There are many original studies on Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure. The quality of the evaluation research shows that the overall standard is scientific, and a few experimental designs are slightly irregular. Meta-analysis shows that Zhigancao Decoction combined with conventional Western medicine has better therapeutic effects and safety than conventional Western medicine. This shows the characteristics and advantages of integrated Chinese and Western medicine in the treatment of cardiovascular diseases and is worth recommending.

Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We report the interim results of DAWNA-1 ( NCT03927456 ), a double-blind, randomized, phase 3 trial of dalpiciclib (a new cyclin-dependent kinase 4 and 6 inhibitor) plus fulvestrant in hormone receptor-positive, HER2-negative ABC with disease progression after endocrine therapy. A total of 361 patients were randomized 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary end point, showing significantly prolonged investigator-assessed progression-free survival with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (median = 15.7, 95% confidence interval (CI) = 11.1–not reached versus 7.2, 95% CI = 5.6–9.2 months; hazard ratio = 0.42, 95% CI = 0.31–0.58; one-sided P

Purpose: For classical Hodgkin lymphoma (cHL), programmed death-l (PD-1) is a well-recognized attractive target. This multicenter, single-arm, phase II study evaluated the efficacy and safety of camrelizumab, a humanized high-affinity IgG4 mAb against PD-1, in Chinese patients with relapsed or refractory cHL. Patients and Methods: Patients who had failed to achieve a remission or experienced progression after autologous stem cell transplantation or had received at least two lines of systemic chemotherapies were given camrelizumab 200 mg every 2 weeks. The primary endpoint was objective response rate per independent review committee (IRC) assessment. This study is registered with ClinicalTrials.gov (NCT03155425). Results: Between June 9, 2017 and September 18, 2017, 75 patients were enrolled and treated. At a median follow-up of 12.9 months, 57 of 75 (76.0%; 95% CI, 64.7–85.1) patients achieved an IRC-assessed objective response, including 21 (28.0%) and 36 (48.0%) patients who had complete and partial remission, respectively. Median duration of response was not reached (range, 0.0+–12.8+ months). Treatment-related adverse events (AE) occurred in all patients. The most common ones included cutaneous reactive capillary endothelial proliferation (97.3%, 73/75) and pyrexia (42.7%, 32/75). Grade 3 or 4 treatment-related AEs occurred in 20 patients (26.7%); the most common AE was decreased white blood cell count (4.0%, 3/75). There were no grade 5 treatment-related AEs. Conclusions: Camrelizumab demonstrated a high response rate, durable response and controllable safety in Chinese patients with relapsed or refractory cHL, becoming a new safe and effective treatment option in this setting.

Author(s): Guo, Y; Ahn, M-J; Chan, A; Wang, C-H; Kang, J-H; Kim, S-B; Bello, M; Arora, RS; Zhang, Q; He, X; Li, P; Dechaphunkul, A; Kumar, V; Kamble, K; Li, W; Kandil, A; Cohen, EEW; Geng, Y; Zografos, E; Tang, PZ | Abstract: BackgroundTreatment options are limited for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) following progression after first-line platinum-based therapy, particularly in Asian countries.Patients and methodsIn this randomised, open-label, phase III trial, we enrolled Asian patients aged ≥18 years, with histologically or cytologically confirmed recurrent/metastatic HNSCC following first-line platinum-based therapy who were not amenable for salvage surgery or radiotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1. Patients were randomised (2 : 1) to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week), stratified by ECOG performance status and prior EGFR-targeted antibody therapy. The primary end point was progression-free survival (PFS) assessed by an independent central review committee blinded to treatment allocation.ResultsA total of 340 patients were randomised (228 afatinib; 112 methotrexate). After a median follow-up of 6.4 months, afatinib significantly decreased the risk of progression/death by 37% versus methotrexate (hazard ratio 0.63; 95% confidence interval 0.48-0.82; P = 0.0005; median 2.9 versus 2.6 months; landmark analysis at 12 and 24 weeks, 58% versus 41%, 21% versus 9%). Improved PFS was complemented by quality of life benefits. Objective response rate was 28% with afatinib and 13% with methotrexate. There was no significant difference in overall survival. The most common grade ≥3 drug-related adverse events were rash/acne (4% with afatinib versus 0% with methotrexate), diarrhoea (4% versus 0%), fatigue (1% versus 5%), anaemia (l1% versus 5%) and leukopenia (0% versus 5%).ConclusionsConsistent with the phase III LUX-Head a Neck 1 trial, afatinib significantly improved PFS versus methotrexate, with a manageable safety profile. These results demonstrate the efficacy and feasibility of afatinib as a second-line treatment option for certain patients with recurrent or metastatic HNSCC.Clinical trial registrationClinicalTrials.gov identifier: NCT01856478.

Importance Prevention of primary breast cancer (BCa) in women is of great public health importance. The existing results from observational epidemiologic studies focused on the association between bisphosphonates and primary BCa risk have been inconsistent. Objective To update this systematic review and meta-analysis to assess the effect of bisphosphonates on primary BCa risk. Data sources We comprehensively searched MEDLINE, EMBASE, Cochrane libraries, ProQuest, and Web of Science through June 25, 2018 for relevant studies. Study selection Epidemiological studies that assessed the effect of bisphosphonates on the risk of primary BCa in women. Data extraction and synthesis We reported this meta-analysis according to the PRISMA guidelines. Available multivariable-adjusted effect estimates and corresponding 95% CIs were pooled with a random-effects model. Main outcomes and measures The prespecified main outcome was the risk of primary BCa. Results In total, five cohort studies involving 657,558 women and 12,991 primary BCa patients, three population-based case-control studies involving 54,701 primary BCa cases and 237,962 healthy controls and two randomized controlled trials (RCTs) involving 13,774 women and 165 primary BCa patients were included in this meta-analysis. Bisphosphonates were associated with a 12% decreased risk of primary BCa (RR, 0.88; 95% CI, 0.83-0.94). However, when we analyzed study designs separately, the pooled results from observational studies were inconsistent with that from RCTs. The observed association of primary BCa risk with long-term use (≥1 year) of bisphosphonates seemed to be more robust and stronger than that of short-term use (

Introduction The objective of this study was to evaluate the efficacy and safety of eribulin monotherapy, relative to vinorelbine, in Chinese women with locally recurrent/metastatic breast cancer (MBC). Methods This phase III open-label, randomised, parallel-group, multicentre clinical trial enrolled patients with locally recurrent or MBC who had had 2–5 prior chemotherapy regimens, including an anthracycline and taxane) from September 26, 2013, to May 19, 2015. Women were randomised 1:1 to receive eribulin (1.4 mg/m2, intravenously, on day 1 and day 8) or vinorelbine (25 mg/m2, intravenously, on day 1, day 8 and day 15) every 21 days. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), duration of response and overall survival (OS). Results Five hundred thirty women were randomised to receive eribulin (n = 264) or vinorelbine (n = 266). Improvement in PFS was observed with eribulin compared with vinorelbine (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.65–0.98, P = 0.036); median PFS was 2.8 months in both treatment arms. The median OS was 13.4 months with eribulin and 12.5 months with vinorelbine (HR: 1.03, 95% CI: 0.80–1.31, P = 0.838). The ORR was 30.7% (95% CI: 25.2%–36.6%) with eribulin and 16.9% (95% CI: 12.6%–22.0%) with vinorelbine (P Conclusions Eribulin achieved statistically significantly superior PFS (and response rate) compared with vinorelbine in previously treated women with locally recurrent or MBC. Eribulin appeared to be better tolerated than vinorelbine, with no new safety signals observed. Trial registration National Institutes of Health ClinicalTrials.gov registry, NCT02225470. Registered 05 August 2014- Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT02225470?term=NCT02225470&rank=1 .

Next-generation sequencing (NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously. Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology (CSCO) and the China Actionable Genome Consortium (CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians, pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure (SOP), data analysis, report, and NGS platform certification and validation.

Background This survey aims to investigate the incidence of chemotherapy-induced nausea and vomiting (CINV) in Chinese real clinical setting and evaluate the effect of guideline-consistent CINV prophylaxis (GCCP) and guideline-inconsistent CINV prophylaxis (GICP) on incidence of complete response (CR) of CINV.Materials and Methods A cross-sectional nationwide multicenter study assessing the guideline consistency and CINV incidence of patients was conducted at a total of 32 large medical centers from 26 provinces across the west,east༌northeast and middle part of China between April and May 2021.Result Data for 2964 patients were analyzed. Patients treated with moderately emetogenic chemotherapy (MEC) were more prone to experience CINV during the acute phase compared to those receiving highly emetogenic chemotherapy (HEC); patients receiving low or minimally emetogenic chemotherapy (L/mEC) were least likely to experience CINV during the overall phase among the whole study population. The prevalence of GCCP was 29.2% in the whole study population, and 13.6%, 35.7% and 45.1% for the patients receiving HEC, MEC and L/mEC, respectively. For patients receiving HEC and MEC, GCCP increased incidence of CR during both delayed and overall phases. For those receiving L/mEC and GICP, incidence of CR was not higher than that of patients receiving L/mEC and GCCP.Conclusion This study revealed Chinese CINV status, the prevalence of GCCP in the real clinical setting and the association between GCCP and CR rate for the first time. The findings indicate that prescribing antiemetics in compliance with guidelines for all patients receiving chemotherapy is strongly suggested.

Background Hand-foot syndrome (HFS) is a side effect of skin related to pegylated liposomal doxorubicin (PLD) application. Moderate to severe hand-foot syndrome (MSHFS) might have a serious impact on patients’ quality of life and treatment. However, information on risk factors for the development of MSHFS is still limited. To analyze the risk factors for PLD-induced MSHFS in breast cancer patients and constructed a logistic regression prediction model. Methods We conducted a retrospective analysis of breast cancer patients who were treated with a PLD regimen in the Tumor Hospital of Harbin Medical University from January 2017 to August 2019. A total of 26 factors were collected from electronic medical records. Patients were divided into MSHFS (HFS > grade 1) and NMHFS (HFS ≤ grade 1) groups according to the NCI classification. Statistical analysis of these factors and the construction of a logistic regression prediction model based on risk factors. Results A total of 44.7% (206/461) of patients developed MSHFS. The BMI, dose intensity, and baseline Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) levels in the MSHFS group, as well as good peripheral blood circulation, excessive sweat excretion, history of gallstones, and tumour- and HER2-positive percentages, were all higher than those in the NMHFS group (P P = 1/1 + exp. (11.138–0.110*BMI-0.234*dose intensity-0.018*baseline ALT+ 0.025*baseline AST-1.225*gallstone history-0.681* peripheral blood circulation-1.073*sweat excretion-0.364*with or without tumor-0.680*HER-2). The accuracy of the model was 72.5%, AUC = 0.791, and Hosmer-Lemeshow fit test P = 0.114 > 0.05. Conclusions Nearly half of the patients developed MSHFS. The constructed prediction model may be valuable for predicting the occurrence of MSHFS in patients.

Background To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents. Methods The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 μg, 2100 μg, and 2400 μg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 μg and rhG-CSF 5 μg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 μg, 1500 μg, and continuous rhG-CSF 5 μg/kg. Results Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 μg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 μg to 2400 μg, while the double delivery of HSA/G-CSF 2400 μg failed to meet the noninferiority in comparison with rhG-CSF. Conclusion The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 μg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial. Trial registration ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).

Breast cancer is the leading cause of cancer death in women. Hormone‐receptor‐positive breast cancer (HR + BC) is the most common pathological type of breast cancer, of which the main treatment method is endocrine therapy. Unfortunately, primary or acquired drug resistance greatly limits its efficacy. In recent years, the newly launched CDK4/6 inhibitors could effectively reverse endocrine resistance in breast cancer. However, considering their expensive price and side effects, it is particularly important to find out effective biomarkers and screen sensitive patients. Here, we found through bioinformatics analysis that high mobility group box 1 (HMGB1) expression increased in endocrine‐resistant HR + BC. In clinical specimens, the higher expression of HMGB1 was associated with shorter progression‐free survival (PFS) for HR + BC patients with endocrine therapy after surgery. For endocrine‐resistant breast cancer, compared with HMGB1‐negative patients, HMGB1‐positive patients who received CDK4/6 inhibitors treatment benefited more in PFS. Moreover, we demonstrated that HMGB1 promoted tamoxifen resistance by combining with the Toll‐like receptor 4 (TLR4) and activating nuclear factor kappa B (NF‐κB) pathway. CDK4/6 inhibitors could downregulate the expression of HMGB1 and suppress the TLR4‐NF‐κB pathway, and in turn reverse tamoxifen resistance. These results illuminated the critical role of HMGB1 in the process of tamoxifen resistance, explained the mechanism of CDK4/6 inhibitors reversing tamoxifen resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors., This article illustrated the critical role of HMGB1 in the process of endocrine therapy resistance, explained one of the mechanisms of CDK4/6 inhibitors reverse endocrine therapy resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors.

Background Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Methods CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m(2) given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. Findings Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19.2 months (IQR 7.4-28.8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21.5 months (95% CI 17.8-33.0) versus 13.8 months (10.2-17.5; hazard ratio 0.52 [95% CI 0.39-0.69]; p, Bayer, Bayer.

Background: Accurate identification of axillary lymph node (ALN) status is crucial for tumour staging procedure and decision making. The aim of this study is to evaluate the diagnostic performance of clinical parameters combined with collagen signatures (tumour-associated collagen signatures (TACS) and the TACS corresponding microscopic features (TCMF)) in predicting the probability of ALN metastasis in patients with breast cancer. Methods: This retrospective study of 898 participants from two institutions was conducted. Collagen signatures (TACS and TCMF) were generated by multiphoton microscopy (MPM) imaging and feature extraction. Logistic analysis was used to determine the association of clinical parameters, TACS and TCMF with ALN metastasis. Findings: TACS and TCMF were significant predictors of ALN status. A nomogram based on independent clinical parameters combined with TACS and TCMF was developed to predict the probability of ALN metastasis with an area under the receiver operating curve (AUC) of 0.783 in the training cohort, 0.747 in the internal validation cohort, and 0.746 in the external validation cohort. Interpretation: These findings suggest that TACS and TCMF in the breast tumour microenvironment are both novel and independent biomarkers for the estimation of ALN metastasis. The nomogram yields good diagnostic performance in predicting ALN status. Funding: Fujian Major Scientific and Technological Special Project for “Social Development” (No. 2020YZ016002), Special Funds of the Central Government Guiding Local Science and Technology Development (No. 2020L3008), Natural Science Foundation of China (Nos. 81901787, 81700576), Natural Science Foundation of Fujian Province (Nos. 2019J01269, 2020J011008, 2020J01154). Declaration of Interest: The authors declare no competing interests. Ethical Approval: This retrospective study used anonymous data which was approved by the Institutional Review Board of Fujian Medical University Union Hospital (Fuzhou, China) and Harbin Medical University Cancer Hospital (Harbin, China).

BACKGROUND: The ability to predict high risk factors for recurrence after neoadjuvant chemotherapy (NAC) is controversial. The purpose of the present study was to investigate the prognostic significance of tumor location, tumor-infiltrating lymphocyte (TIL) level, and pretreatment lymphocyte-to-monocyte ratio (LMR) in determining the survival of patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer after treatment with NAC. METHODS: The clinical data of 285 ER-positive, HER2-negative patients with clinical stage II–III breast cancer were analyzed from January 2009 to January 2015. To explore the prognostic factors for ER-positive, HER2-negative patients, we combined the conventional clinicopathological prognostic factors with tumor location, pretreatment LMR, and TIL. In addition, samples from 79 patients, who did not achieve pathological complete response (pCR) testing after NAC, were selected for hematoxylin-eosin (HE) staining to analyze the effect of TIL on prognosis. RESULTS: An LMR >5.2 was correlated with better 5-year disease-free survival (DFS) and overall survival (OS; P10%, and pretreatment LMR level ≤5.2 were correlated with a poor prognosis. More aggressive NAC and/or endocrine therapy with internal mammary node radiotherapy (IMN-RT) should be administered to address the relatively poor prognosis of patients with breast carcinoma presenting the aforementioned adverse factors.

T lymphocyte are a strong indicator of treatment immune response. This study was aimed to determine the utility of T lymphocyte subsets, cytokines and inflammatory biomarkers in predicting the immunological benefits of Ganoderma spore powder (G. lucidum) in post-operative patients with breast and lung cancer. We prospectively evaluated 120 breast and lung cancer patients with or without G. lucidum. T lymphocyte subsets with relative cytokines were detected using flow cytometry and PCR and assessed by Spearman correlation analysis. The relationships between albumin-to-globulin ratio (AGR) and neutrophil–to-lymphocyte ratio (NLR) with G. lucidum treatment and prognosis were analyzed using Kaplan–Meier and Cox regression methods. The prevalence of CD3 + CD4 + , CD3 + HLADR- types was higher in G. lucidum group compared to control, whilst CD4 + CD25 + Treg, CD3 + HLADR + cell types was lower. IL-12 levels were significantly higher during the treatment period which negatively impacted levels of IL-10. Other immunosuppressive factors such as COX2 and TGF-β1 had lower prevalence in treated patients. Correlation analysis showed a positive relationship between IL-10 and CD28. IL-2 was positively related to TGF-β1, whilst it was negatively related to CD3. Kaplan–Meier analysis suggested that low AGR/high NLR was related to poor progression free survival (PFS) and overall survival (OS). A combination of high AGR and low NLR may predicted treatment benefits associated with PFS and OS. Our findings show that T lymphocyte subsets combined with relevant cytokines and AGR/NLR inflammatory predictors may help to identify patients most likely to benefit from the immunological enhancements from G. lucidum treatment.

Background Penpulimab is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1. Penpulimab was engineered to eliminate Fc?R binding and ADCC/ADCP completely, as compared to majority of marketed IgG4 PD-1 antibodies with ADCC/ADCP activity. ADCC/ADCP effects can induce T-cell apoptosis and clearance and then compromise anti-tumor activity. The removal of Fc?R binding eliminates Fc receptor mediated immune-cell recruitment and activation and could potentially reduce immune-related adverse reactions. Penpulimab demonstrated a slower PD-1 antigen binding off-rate than marketed PD-1 antibodies, which result in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1 which could be an advantage to facilitate interaction of PD-1 antibody and may contribute to slower binding off-rate. These structural differentiations offer more robust biological effect and enhance anti-tumor activity of penpulimab. Methods AK105-201 (NCT03722147) is a multicenter, single-arm, open-label study of penpulimab in R/R cHL. All pts received penpulimab 200 mg q2w until progression or unacceptable toxicity. Eligible pts had R/R cHL after ASCT, or at least 2 lines of prior chemotherapy. The primary endpoint was ORR based on the Lugano 2014 criteria as assessed by an independent review committee (IRC). Key secondary endpoints included CR rate, DCR, PFS, duration of response (DoR), safety, and tolerability. Results As of 10 January, 2020, the median follow-up was 6.3 months (range, 3.5 to 17.0). The anti-tumor activity of penpulimab in the 73 pts evaluable for efficacy (defined as pts who had an opportunity to be followed for at least 16 weeks) is shown in the table 1. At data cutoff, 91.8% of responders remained ongoing and still on treatment. Treatment-related adverse events (TRAEs) occurred in 93.6% of pts (G3 in 13.8% [13/94], no G4 or G5, treatment discontinuation in 2.1% [2/94]). Treatment-related SAEs occurred in 3.2%. Most frequent TRAEs (≥15%) were fever (24.5%), hypothyroidism (21.3%), upper respiratory tract infection (18.1%), and ALT elevations (17.0%). Grade ≥3 TRAEs reported in ≥2 pts were platelet count decreased (2.1%). Immune-related AEs were reported in 42.6% of pts (G3 in 2.1%: psoriasis [n=1], IgA nephropathy [n=1]). Conclusions Penpulimab was shown to be highly active resulting in a high CR rate in pts with R/R cHL. With longer follow-up, CR rate for penpulimab in R/R cHL could be further increased. Penpulimab demonstrated notably lower rates of SAE, TRAE leading to discontinuation, and Grade Grade ≥3 immune-related AEs in pts with R/R cHL. Trial Registration NCT03722147

Patients with diffuse large B-cell lymphoma (DLBCL) have limited access to rituximab. IBI301 is a recombinant chimeric murine/human anti-CD20 monoclonal antibody and is a candidate biosimilar to rituximab. This study aimed to assess the therapeutic equivalence of IBI301 and rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). This multicenter, randomized, double-blind, parallel-group, phase 3 trial compared IBI301 and rituximab, both plus the chemotherapy of doxorubicin, cyclophosphamide, vindesine, and prednisone (CHOP), was conducted in 68 centers across China. Eligible patients with untreated CD20 positive (CD20+) DLBCL randomly received IBI301 (375 mg/m2) plus the standard CHOP or rituximab (375 mg/m2) plus the standard CHOP for six cycles of a 21-day cycle. The primary end point was the overall remission rate (ORR). Efficacy equivalence was defined if 95% CIs for the ORR difference between the two groups were within a ± 12.0% margin. Between August 22, 2016, and September 5, 2018, 419 patients were randomly allocated into the IBI301 group (N = 209) and rituximab group (N = 210). In the full analysis set, the ORR was 89.9% and 93.8% in the IBI301 and rituximab groups, respectively, and the ORR difference was -3.9% (95% CI − 9.1%–1.3%), falling within a ± 12.0% margin. The occurrences of treatment-emergent adverse events (TEAEs) (100% vs. 99.0%) and AEs of grade ≥ 3 (87.1% vs. 83.3%) were similar in the two groups (P > 0.05). IBI301 had a non-inferiority efficacy and a comparable safety compared with rituximab. IBI301 plus CHOP could be suggested as a candidate treatment regimen for untreated patients with CD20+ DLBCL. This trial is registered on ClinicalTrials.gov (NCT02867566).

IMPORTANCE: Plinabulin is a novel, non–granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects. OBJECTIVE: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non–small lung cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non–small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020. INTERVENTIONS: All patients received docetaxel 75 mg/m(2) on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m(2)) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles. MAIN OUTCOMES AND MEASURES: The primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1. RESULTS: Of the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m(2) (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected. CONCLUSIONS AND RELEVANCE: Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m(2), will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03102606

Background: T lymphocyte subsets with correlative cytokines, albumin to globulin ratio (AGR) and neutrophil to lymphocyte ratio (NLR), have been linked to inflammatory indicators of immune response and prognosis in various cancer types. The aim of this study was to determine the utility of these biomarkers in predicting the immunological benefits of Ganoderma spore powder in post-operative patients with breast and lung cancer. Methods: We prospectively evaluated 120 consecutive breast and lung cancer patients with or without Ganoderma spore powder. T lymphocyte subsets, as well as relative cytokines were detected and assessed by Pearson correlation analysis. The relationships between AGR and NLR with ganoderma spore powder treatment and prognosis were analyzed using Kaplan–Meier and Cox regression methods.Results: The prevalence of CD3+, CD4+ and CD4+/CD8+, CD3+HLADR-, CD4+HLADR- and CD8+HLADR- cell types was higher in the ganderma spore treated group compared to untreated controls. In addition, the percentage of CD4+CD25+Treg, CD3+HLADR+, CD4+HLADR+ and CD8+HLADR+ cell types was lower in the treated group. IL-2 and IL-12 frequencies were significantly higher during the treatment period which negatively impacted levels of IL-10. Other immunosuppressive factors such as COX2, TGF- 1 and HIF-1A had higher prevalence in non-treated patients. Correlation analysis showed several correlations between the biomarkers, specifically between IL-6 and TGF- 1, CD28 and IL-12R, TGF- 1 and Foxp3, IL-10 and IL-12R with COX2, Foxp3 and CD8, IL-10 and CD28 with IL-12R, COX2 and CD8, IL-12R with COX2, CD3 with CD4 and CD8. A positive relationship was also observed between IL-2 and TGF- 1. Conversely, IL-2 was negatively related to CD3, and HIF-1 negatively related with CD4, CD28 and CD3. Kaplan–Meier analysis suggested that low AGR/high NLR was related to poor progression free survival (PFS, HR=1.572, P=0.038/HR=2.064, P=0.042). A combination of high AGR and low NLR that predicted treatment benefits was also associated with PFS (HR=0.661, P=0.033/HR=1.044, P=0.048).Conclusions: Our findings show that T lymphocyte subsets predominately combined with relevant cytokines and AGR/NLR inflammatory predictors may help to identify patients most likely to benefit from the immunological enhancements from Ganoderma spore powder treatment.

This multicenter, randomized, double-blind, parallel-controlled trial aimed to compare the pharmacokinetics (PK) of IBI301 with rituximab in patients with CD20-positive (CD20+) B-cell lymphoma, who achieved a complete response/unconfirmed complete response after standard treatments. Patients were randomized (1:1) to receive IBI301 or rituximab (375 mg/m2, IV). Patients who continuously benefitted from the trial after the PK phase underwent the extension phase to receive up to three cycles of 3-month-cycle of rituximab/IBI301 maintenance therapy. PK was described using the area under the serum concentration–time curve from time zero to infinity (AUC0-inf), AUC from time zero to last quantifiable concentration (AUC0-t), and maximum serum concentration (Cmax). Pharmacodynamics (PD), incidence of adverse events and immunogenicity were evaluated. PK was defined equivalent, if 90% confidence intervals (CIs) for geometric mean ratios of PK endpoints fell within the margin of 0.8–1.25. Overall, 181 patients were enrolled in IBI301 (n = 89) and rituximab (n = 92) groups. Geometric mean ratios of AUC0-inf, AUC0-t, and Cmax were 0.91 (90% CI 0.85, 0.97), 0.91 (90% CI 0.86, 0.97), and 0.96 (90% CI 0.92, 1.01) between treatment groups, all within the bioequivalence range. Peripheral CD19+ and CD20+ B-cell counts were similar at each prespecified time point between the groups. No difference in immunogenicity was observed. The incidences of treatment-emergent adverse events (84.3% vs. 83.5%) and treatment-related AEs (56.2% vs. 61.5%) were comparable (IBI301 vs. rituximab). IBI301 was PK bioequivalent to rituximab in patients with CD20+ B-cell lymphoma. The PD, safety, and immunogenicity profiles of IBI301 were similar to those of rituximab.

BackgroundTislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.MethodsThe purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.ResultsAs of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.ConclusionsTislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.Trial registration numberCTR20160872.

Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

While combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) cures most patients with diffuse large B-cell lymphoma (DLBCL), those with high-risk international prognostic index disease have inferior survival. Enzastaurin as a potent inhibitor of PKC-β and PI3K/AKT pathway suppressor has been tested in many clinical trials including two key studies in DLBCL: Phase III maintenance study (Preventing Relapse in Lymphoma Using Daily Enzastaurin [PRELUDE]) and a first-line Phase II study (S028). DNA extracted from PRELUDE patients’ blood samples was retrospectively genotyped identifying a novel genetic biomarker, DGM1 that showed high correlation with response to enzastaurin. A similar finding observed in the S028 study suggested that addition of enzastaurin to R-CHOP may significantly improve outcomes as frontline therapy for high-risk DGM1 positive DLBCL patients. ENGINE is a global, multicenter, placebo-controlled and randomized study to compare the effect of R-CHOP/enzastaurin as frontline treatment in high-risk DLBCL patients. The primary end point for this study is overall survival in patients who are DGM1 positive. Clinical Trial Registration Identifier: NCT03263026

Purpose The Chinese bridging study PUFFIN (NCT02896855) aimed to assess consistency of efficacy with CLEOPATRA (NCT00567190), investigating pertuzumab with trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer. Methods Patients were randomized 1:1, stratified by visceral/non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (in patients with measurable baseline disease), overall survival, and safety. The consistency threshold for PFS (hazard ratio [HR] n = 240). Results Two hundred forty-three patients were randomized. Median PFS was 14.5 months in the pertuzumab arm (95% confidence interval [CI] 12.5, 18.6) and 12.4 months in the placebo arm (95% CI 10.4, 12.7) in the intention-to-treat population (HR: 0.69 [95% CI 0.49, 0.99]). Objective responses were recorded in 83/105 (79.0%) and 67/97 (69.1%) patients, respectively. Grade ≥ 3 adverse events (70.5% and 69.2%, respectively) and serious adverse events (19.7% and 19.2%, respectively) were similar across both arms. No heart failure cases or symptomatic left ventricular ejection fraction declines were reported. Conclusions PUFFIN met its primary objective. Overall, efficacy data were consistent with CLEOPATRA. Safety was consistent with the known pertuzumab safety profile. PUFFIN adds to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit–risk profile of pertuzumab in Chinese patients Trial registration ClinicalTrials.gov, NCT02896855, registered 7 September 2016

Background The elevated risk for recurrence in breast cancer patients after receiving neoadjuvant chemotherapy (NAC) is still controversial. The purpose of this paper was to investigate the prognostic significance of tumor location concerning the survival of patients with breast cancer treated with NAC. Methods The clinical information of 676 patients with stage II-III breast carcinoma who were being treated with NAC between March 2009 and 2014 was investigated. The primary tumor sites were categorized into three groups: outer quadrant, upper-inner quadrant, and lower-inner/central quadrant. Results According to the results of multivariate analyses, the number of tumor locations, nuclear grade, and the initial clinical stage was associated with disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS). When stratified into subgroups, tumors in the lower-inner/central quadrant were associated with a significantly worse prognosis in patients not treated with postmastectomy radiation therapy (PMRT) and in patients in the human epidermal growth factor receptor 2 (HER-2)-enriched and triple-negative subgroups. Conclusions The primary tumor site is likely to be a critical feature that affects the prognosis of breast cancer tumors treated with NAC. To address the poor prognosis related to inner-quadrant participation in breast carcinoma, more aggressive NAC with internal mammary node radiotherapy (IMN-RT) should be conducted.

Background: We assessed the effect of bisphosphonates (BPs) on breast cancer (BCa) patient survival and explored how long the effect can persist after treatment. Methods: We performed a meta-analysis and trial sequential analysis (TSA) of prospective studies including randomized controlled trials (RCTs) and cohort studies and reported effect estimates with 95% confidence intervals (CIs). We performed extensive sensitivity analyses to assess the robustness of the findings.\ Results: Seventeen RCTs and eight cohorts with 81508 BCa patients were identified. A significant beneficial effect of BPs on BCa survival was found (RR, 0·725; 95%CI, 0·627-0·839), and TSA results also suggested firm evidence for this beneficial effect. Both summarized results from RCTs and cohorts provides firm evidence for this effect, though the effect estimates were stronger from cohorts than RCTs (RR, 0·892; 95%CI, 0·829-0·961; 0·570; 95%CI, 0·436-0·745; respectively). This beneficial effect was confirmed for bone-metastases (RR, 0·713; 95%CI, 0·602-0·843) and postmenopausal women (RR, 0·737; 95%CI, 0·640-0·850). Importantly, our results demonstrated that this beneficial effect retained at least 1-2 years after treatment completion (RR, 0·780; 95%CI, 0·638-0·954) and could persist for up to more than 4 years after treatment completion (RR, 0·906; 95%CI, 0·832-0·987). Extensive sensitivity analyses showed the robustness of our results. The GRADE quality of evidence was generally judged to be moderate to high. Conclusions: The present study provides firm evidence for a significant beneficial effect of BPs on BCa survival in patients with early-stage BCa, particularly for bone metastases and postmenopausal patients; and this effect retained at least 1-2 years after BP treatment completion. Systematic Review Registration: PROSPERO CRD42014014699. Funding Statement: This work was supported by the China Postdoctoral Science Foundation (grant number 2018M641875 to YPL); the Natural Science Foundation of Heilongjiang Province (grant number YQ2019H021to YPL); the National Key Research and Development Program of China (grant number 2017YFC0108602 to XDL). Declaration of Interests: None.

The goal of this study was to assess the antitumor efficacy and safety of lobaplatin-based regimens as the second line of treatment in patients with metastatic breast cancer (MBC) resistant to anthracyclines and taxanes, compared with that of cisplatin-based regimens. During August 2012 to April 2015, 87 patients who received lobaplatin-based regimens or cisplatin-based regimens were included. Medical records of the patients noted that lobaplatin (30 mg/m2) or cisplatin (25 mg/m2), combined with another chemotherapeutic agent such as Gemcitabine (1000 mg/m2) or Vinorelbine (25 mg/m2), was intravenously given to the patients on a basis of twenty-one days as one treatment cycle. All the patients were followed until August 2017. The endpoint of this study was progression-free survival (PFS), overall survival (OS), and estimated objective response rate (RR). Safety and drug tolerability data were also obtained. Lobaplatin-based regimens prolonged PFS compared to cisplatin-based regimens (median 13.2 vs 4.7 months, hazard ratio = 0.37, 95% confidence intervals: 0.21–0.67, P = .0007), while OS was not significantly different between the two groups (hazard ratio = 0.72, 95% confidence intervals: 0.40–1.30, P = .2767), as was objective RR (37.8% vs 33.4%, x2 = 0.19, P = .6653). Nausea/vomiting and renal injury were more frequent with cisplatin-based regimens. Our results show that lobaplatin-based regimens are superior to cisplatin in terms of efficacy and are better tolerated. Keywords: Lobaplatin, Metastatic, Breast cancer, Resistant, Cisplatin

Objective The recurrence or progression under endocrine therapy in hormone receptor-positive (HR+) advanced breast cancer (ABC) remained a critical clinical challenge. Chidamide is an oral subtype-selective histone deacetylase (HDAC) inhibitor with multiple functions in tumor growth inhibition and microenvironment modulation via epigenetic reprogramming. The purpose of this study was to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of chidamide in combination with exemestane in HR+ ABC patients. Methods Eligible patients were postmenopausal women with HR+ ABC recurrent or progressed to at least one endocrine therapy. Blood samples were obtained in the run-in period and the first day of combination treatment for PK analysis. In combination treatment, patients were given exemestane 25 mg daily and chidamide 30 mg twice a week (BIW) until progression of disease or intolerable toxicities. A treatment cycle was defined as 4 weeks. Safety, PK parameters, and preliminary efficacy were evaluated. Results A total of 20 patients were enrolled between July and December, 2015. The median number of treatments cycle was 5.2 (20.8 weeks) with 2 patients still on treatment at the data cut-off date of October, 2017. The treatment-related adverse events (AE) ≥ grade 3 in more than 2 patients were neutropenia (35%), thrombocytopenia (30%), and leucopenia (20%). The plasma exposure of exemestane was consistent in the presence or absence of chidamide. A slight increase in chidamide exposure was noted in the presence of exemestane, probably due to the inter- and intra-patient variations. The best response in 16 evaluable patients was assessed by Response Evaluation Criteria in Solid Tumors (RECIST), including 4 patients with partial response, 10 patients with stable disease. The median progression-free survival (PFS) was 7.6 months. Conclusions The combination of chidamide with exemestane was generally well tolerated with promising preliminary efficacy in HR+ ABC patients. The overall results from this study encourage further pivotal trial in this patient population.

Background: Follicular lymphoma (FL) is a common subtype of indolent lymphomas, and accounts for about 10% of all non-Hodgkin lymphoma(NHL) cases. FL patients generally respond well to the 1 st line therapy, but most patients would then relapse, and duration of response gradually decreases as treatment line escalates. For FL patients of 3 rd line and beyond, treatment options are limited, and recurrent chemotherapy also greatly impact their quality of life. Four PI3Kδ inhibitors have been approved in the US for adult patients with relapsed or refractory FL. Currently, multiple trials investigating PI3K inhibitors in R/R FL are on-going in China, yet none has been approved. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor, has shown promising efficacy and tolerance in patients with previously treated B-cell malignancies. Here, we report interim result of CIBI376A201 (NCT04298879), a multicenter, open-label phase 2 study of parsaclisib in 3 rd line FL patients in China. Methods: Key eligibility included, age ≥18 years, histologically confirmed FL grade 1, 2, or 3a, ≥2 prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and ineligible for hematopoietic stem cell transplantation (HSCT). Patients were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by 2.5 mg QD, till disease progression, intolerable AE or withdrawal from study due to other reasons. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Primary end point was objective response rate (ORR) evaluated by independent review committee (IRC), secondary end points included: ORR by investigator, duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetic characteristics and safety and tolerability. Results: From April, 2020 to 11 th, April 2021 (data cut-off), 36 patients were treated. Enrollment is ongoing. At cut-off date, 5 (13.9%) patients had discontinued treatment due to PD (progressive disease)/PMD (progressive metabolic disease). The median exposure (range) was 104 days (5-354 days). The median age was 51 years, and 52.8% of the patients were male. The median time since initial diagnosis was 3.3 years. At enrollment, most patients (88.9%) had an ECOG PS ≤1, and 55.6% had a Follicular Lymphoma International Prognostic Index score ≥3 (high risk). All patients had ≥2 lines of prior systemic therapy, in which 22.2% had 3 or more prior lines. At the data cut-off date, 24 patients were evaluable for response. According to the investigator's evaluation, the ORR and CRR were 91.7% (95% confidence interval [CI]: 73%−99%) and 16.7% (95% confidence interval [CI]: 4.7%-37.4%) respectively, in all evaluable patients. The median DOR was not reached among responders overall. Among the 36 patients evaluable for safety, the most common treatment-emergent adverse events (TEAE) were neutrophil count decrease (36.1%), white blood cell count decrease (16.7%), platelet count decrease (16.7%), anemia (13.9%), upper respiratory tract infection (11.1%), ALT elevation (11.1%) and diarrhea (11.1%). The most common grade ≥3 TEAEs were neutrophil count decrease (8.3%), platelet count decrease (2.8%), upper respiratory tract infection (2.8%) and anemia (2.8%). 22.2% of patients had dose interruption due to TEAE, no dose reduction occurred due to TEAE. No treatment discontinuation occurred due to TEAE. Serious TEAEs included upper respiratory tract infection (2.8%), organ dysfunction (2.8%), dizziness (2.8%) and nasal cavity mass (2.8%), all unrelated to the study drug. One patient (2.2%) died during the trial, considered unrelated to studied drug by investigator. Conclusion: Parsaclisib demonstrated promising efficacy, and was generally well tolerated. These results demonstrate parsaclisib could bring substantial benefit for 3 rd line FL patient. Updated data will be presented in the future. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

BackgroundStudies have demonstrated correlation of GA and TMB with clinical efficacy of an anti-programmed cell death protein-1 (PD-1) therapy, but this correlation has not yet been demonstrated in Chinese patients treated with tislelizumab (anti-PD-1 antibody). We report the association between TMB, GA, and the clinical efficacy of tislelizumab in Chinese patients with different tumor types from a Phase 1/2 study (NCT04068519).MethodsChinese patients with advanced solid tumors who received tislelizumab monotherapy and had available tissues for genomic testing (BurningRock OncoScreen Plus 520 NGS panel) were eligible. Patients were classified as having hyper-amplification (HA) if their genome harbored ≥1 amplified gene with a copy number >5. Logistic regression was used to analyze the association of TMB with objective response rate (ORR) and Cox proportional hazard was used to determine the association of TMB with progression-free survival (PFS) and overall survival (OS).ResultsA total of 156 patients were evaluable. TMB was higher in responders (R) versus non-responders (NR) (median [m] TMB: 9.3 vs 6.2 mut/Mb, p=0.003). TMB-H was defined as ≥8 mut/Mb according to the receiver operating characteristic curve. Patients in the TMB-H group showed superior clinical benefit compared with the TMB-L group (table 1). Further GA analysis showed a trend toward a higher frequency of HA in NR (40.00%; 16/40) compared with R (28.78%; 5/18), in the TMB-H group. A total of 33.33% (10/30) of these amplified genes in NR belonged to the RTK-RAS-PI3K signaling pathway. When TMB-H patients with HA in this pathway were excluded, ORR reached 37.78%.Abstract 372 Table 1Median study follow-up and clinical efficacy dataNE, non-estimableConclusionsTMB-H status was associated with improved clinical efficacy of tislelizumab in Chinese patients with advanced solid tumors, consistent with other PD-1 inhibitors. These observations support TMB-H as a potential predictive biomarker for response to tislelizumab in this patient population. HA in the RTK-RAS-PI3K pathway may be associated with resistance mechanisms to anti-PD-1 therapy, even in patients with TMB-H tumors.AcknowledgementsEditorial writing support for the development of this abstract, under direction of the authors, was provided by Louise Oakes, PhD, of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene Ltd.Trial RegistrationNCT04068519Ethics ApprovalThis study was conducted according to the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, the principles of informed consent and the requirements of the public registration of clinical trials. Written informed consent was obtained from each patient prior to screening. The protocol was approved by the institutional ethics committee and was monitored by the investigators and study sponsor.

Importance The effectiveness of the mammalian target of rapamycin (mTOR) inhibitor everolimus in premenopausal women with hormone receptor (HR)-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving selective estrogen receptor modulators (SERMs) is unknown. Objective To compare the effectiveness of everolimus plus letrozole vs letrozole alone in premenopausal women with HR-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs. Design, setting, and participants The Everolimus Trial for Advanced Premenopausal Breast Cancer (MIRACLE) was a multicenter, open-label phase 2 randomized clinical trial of everolimus plus letrozole vs letrozole alone as first-line treatment conducted from December 8, 2014, to September 26, 2018. Participants included premenopausal women with HR-positive, ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs. Analysis was performed on an intent-to-treat basis from January 5, 2015, to December 30, 2019. Exposures Patients were randomly assigned in a 1:1 ratio to receive everolimus (10 mg orally once daily) plus letrozole (2.5 mg orally once daily) (n = 101) or letrozole alone (2.5 mg orally once daily) (n = 98). Both groups received goserelin, 3.6 mg, subcutaneously on day 1 of each 28-day cycle. Patients in the letrozole group were permitted to cross over to receive everolimus with letrozole if disease progression occurred. Main outcomes and measures The primary end point was progression-free survival (PFS), defined as the time from randomization to confirmed disease progression or death due to any cause. Results A total of 199 women (mean [SD] age, 44.3 [6.3] years) were randomized. Patients receiving everolimus plus letrozole achieved a significantly longer median PFS compared with those receiving letrozole alone (19.4 months [95% CI, 16.3-22.0 months] vs 12.9 months [95% CI, 7.6-15.7 months]; hazard ratio, 0.64 [95% CI, 0.46-0.89]; P = .008). A total of 56 of the 98 patients in the letrozole group (57.1%) were crossed over to also receive everolimus. The median PFS after crossover was 5.5 months (95% CI, 3.8-8.2 months). Conclusions and relevance In this randomized clinical trial, PFS was significantly longer among premenopausal patients with HR-positive/ERBB2-negative advanced breast cancer who received everolimus plus letrozole than among those who received letrozole alone. The results revealed that everolimus was effective even among patients receiving treatment with the same endocrine agent after disease progression. Trial registration ClinicalTrials.gov Identifier: NCT02313051.