Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study.

BACKGROUND: Furmonertinib (AST2818) is an irreversible, selective, third-generation EGFR tyrosine-kinase inhibitor. We aimed to investigate the efficacy and safety of furmonertinib versus the first-generation EGFR tyrosine-kinase inhibitor gefitinib as first-line treatment in patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: The FURLONG study is a multicentre, double-blind, randomised, phase 3 study done in 55 hospitals across mainland China. We enrolled patients who were aged 18 years or older and had histologically confirmed, locally advanced or metastatic, stage IIIB, IIIC, or IV unresectable NSCLC with EGFR exon 19 deletions or exon 21 Leu858Arg mutation on tissue biopsy confirmed by a central laboratory. Eligible patients were stratified according to EGFR mutation (exon 19 deletions or exon 21 Leu858Arg) and CNS metastases (with or without) and randomly assigned (1:1) to receive either oral furmonertinib (80 mg/day) or oral gefitinib (250 mg/day) in 21-day cycles until disease progression, the occurrence of intolerable toxicities, withdrawal of consent, or other discontinuation reasons judged by the investigators. Investigators, clinicians, participants, independent review centre (IRC) members, the sponsor, and those analysing the data were all masked to treatment allocation. The primary endpoint was IRC-assessed progression-free survival and, along with safety, was analysed in the full analysis set, which comprised all randomly assigned patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03787992, and is ongoing for survival follow-up. FINDINGS: Between May 30, 2019, and Dec 5, 2019, 750 patients were screened, of whom 358 were randomly assigned to receive either furmonertinib and gefitinib-matching placebo (n=178) or gefitinib and furmonertinib-matching placebo (n=180). 178 patients randomly assigned to furmonertinib and 179 patients randomly assigned to gefitinib were treated and were included in the full analysis set. Median follow-up was 21·0 months (IQR 18·0-23·5) in the furmonertinib group and 21·0 months (18·0-23·5) in the gefitinib group. Median IRC-assessed progression-free survival was 20·8 months (95% CI 17·8-23·5) in the furmonertinib group and 11·1 months (9·7-12·5) in the gefitinib group (hazard ratio 0·44, 95% CI 0·34-0·58; p<0·0001). Treatment-related adverse events of a grade 3 or more occurred in 20 (11%) of 178 patients in the furmonertinib group and in 32 (18%) of 179 patients in the gefitinib group. Treatment-related serious adverse events were reported in ten (6%) patients in the furmonertinib group and in 11 (6%) patients in the gefitinib group. Ten (6%) patients in the furmonertinib group and three (2%) patients in the gefitinib group died due to adverse events, which were all judged to be possibly unrelated to study treatment by the investigators. INTERPRETATION: Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in Chinese patients with EGFR mutation-positive NSCLC, along with an acceptable safety profile without new signals. Furmonertinib is a new potential treatment option for this population. FUNDING: Shanghai Allist Pharmaceuticals and the China National Major Project for New Drug Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Enhancement of the International prognostic index with ß2-microglobulin, platelet count and red blood cell distribution width: a new prognostic model for diffuse large B-cell lymphoma in the rituximab era.

BACKGROUND: This study aimed to propose a new user-friendly, cost effective and robust risk model to facilitate risk stratification for diffuse large B-cell lymphoma (DLBCL) treated with frontline R-CHOP regimens. METHODS: Data on 998 patients with de novo DLBCL diagnosed between Jan 1st, 2005 and Dec 31st, 2018 at our center, who received frontline R-CHOP or R-CHOP-like regimens, were retrospectively collected. Patients were randomly divided into the training cohort (n = 701) and the validation cohort (n = 297). A new prognostic model for overall survival (OS) was built based on the training cohort. The performance of the new model was compared with International prognostic index (IPI), revised IPI (R-IPI) and National Comprehensive Cancer Network (NCCN)-IPI (NCCN-IPI). The new model was validated in the validation cohort. RESULTS: The multivariate analysis of the training cohort showed that the IPI, ß2-microglobulin, platelet count and red blood cell distribution width were independent factors for OS, which were incorporated into the new prognostic model. Patients were stratified into low risk, low-intermediate risk, high-intermediate risk, high risk and very high risk groups, with distinct survival outcomes. The new model achieved good C-indexes for 5-year OS prediction of 0.750 (95%CI 0.719-0.781) and 0.733 (95%CI 0.682-0.784) in the training and validation cohorts, respectively, and displayed well-fitted calibration curves. The C-index and the time-dependent ROC analysis demonstrated better performance of the new model than the IPI, R-IPI and NCCN-IPI in both training and validation cohorts. The integrated Brier score for predicting 5-year OS of the new model was lower than that of the IPI, R-IPI and NCCN-IPI in both cohorts, and decision curve analysis also showed a higher net benefit, indicating the superiority of the new model over the conventional models. CONCLUSION: The new prognostic model might be a useful predictive tool for DLBCL treated with R-CHOP regimens. Further external validation is warranted.

The changing landscape of anti-lung cancer drug clinical trials in mainland China from 2005 to 2020.

BACKGROUND: In recent years, new drug development on lung cancer is in full swing in China. The aim of this study was to overview the changing landscape of anti-lung cancer drug clinical trials in mainland China from 2005 to 2020. METHODS: We analysed anti-lung cancer drug clinical trials registered on three websites including the China National Medical Products Administration Centre for Drug Evaluation platform, the Chinese Clinical Trial Registry and ClinicalTrials.gov. FINDINGS: A total of 1595 anti-lung cancer drug clinical trials from Jan 1st, 2005 to Dec 31st, 2020 were extracted, which included 630 (39•5%) investigator-initiated trials (IITs), 698 (43•8%) domestic industry-sponsored trials (ISTs), and 267 (16•7%) international ISTs. During the past 16 years, the number of anti-lung cancer clinical trials including IITs and domestic ISTs had a remarkable growth, however, the number of international ISTs increased slowly. The number of principal clinical trial units also increased significantly over time. Of the 1595 trials, the largest growth was observed in phase I trials during 2013-2020, with an average annual growth rate of 38•6%. 278 trials were led by principal investigators (PI) from Guangdong, followed by Beijing (n=273) and Shanghai (n=257). Among the 965 ISTs, clinical trials involving targeted drugs (588, 60•9%) accounted for the largest proportion, followed by immunotherapeutic drugs (284, 29•4%), cytotoxic drugs (75, 7•8%), and traditional Chinese medicine (18, 1•9%). In terms of targeted drugs, EGFR-TKIs remained the most studied drugs (225/588, 38•27%). As for immunotherapy, 125 out of 284 (44•01%) trials involved PD-1 inhibitors, 60 (21•13%) trials involved PD-L1 inhibitors, and seven (2•46%) trials involved CTLA-4 inhibitors. INTERPRETATION: In the past 16 years, the development of anti-lung cancer drug clinical trials has achieved much progress in mainland China. The most progress lied in targeted therapy and immunotherapy. FUNDING: This work was financially supported in part by China National Major Project for New Drug Innovation (2017ZX09304015) and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001).

Meta-analysis of the prognostic and clinical value of serum 25-hydroxyvitamin D levels in previously untreated lymphoma.

Background: This meta-analysis explored the prognostic and clinical value of serum 25-hydroxyvitamin D, 25(OH)D, levels in previously untreated lymphoma. Materials & methods: PubMed, Web of Science, Embase and the Cochrane Central Register of Controlled Trials databases were searched for eligible studies. Summary effect estimates and 95% CIs were pooled using random-effects or fixed-effects models. Results: Twelve studies with 4139 patients were included. Low level of serum 25(OH)D was associated with inferior progression-free survival (hazard ratio [HR]: 2.06; 95% CI: 1.82-2.32) and overall survival (HR: 1.94; 95% CI: 1.71-2.19), advanced disease (odds ratio [OR]: 1.52; 95% CI: 1.09-2.13) and elevated lactate dehydrogenase (OR: 1.84; 95% CI: 1.08-3.15). Conclusions: Low level of serum 25(OH)D is a prognostic risk factor for newly diagnosed lymphoma.

Lay abstract Vitamin D is a nutrient. Vitamin D deficiency is common in lymphoma patients. Serum level of 25-hydroxyvitamin D, 25(OH)D, reflects vitamin D status. Aim: We studied whether low levels of 25(OH)D are related with poor survival for newly diagnosed lymphoma. Materials & methods: We researched four databases for eligible studies. We then extracted data from the studies. Finally, we pooled the effect sizes based on the data. Results: Twelve studies with 4139 patients were included in the study. Results showed that low levels of serum 25(OH)D were associated with greater lymphoma progression and death. Patients with low serum 25(OH)D were likely to have poor clinical features as well. Conclusions: Low serum 25(OH)D is a risk factor for lymphoma survival. Assessment of vitamin D status should be considered in clinical practice. Further research is needed to assess the effect of vitamin D supplementation therapy.

Prognostic Nomogram for Overall Survival in Patients with Diffuse Large B-Cell Lymphoma.

PURPOSE: This study aimed to develop a prognostic nomogram in diffuse large B-cell lymphoma (DLBCL) and compare it with traditional prognostic systems. MATERIALS AND METHODS: We included 1,070 consecutive and nonselected patients with DLBCL in the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, between 2006 and 2012. A nomogram based on the Cox proportional hazards model was developed. RESULTS: The entire group were divided into the primary (n = 748) and validation (n = 322) cohorts. The 5-year overall survival (OS) rate was 64.1% for the entire group. Based on a multivariate analysis of the primary cohort, seven independent prognostic factors including age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status score, lactate dehydrogenase, ß2-microglobulin, CD5 expression, and Ki-67 index were identified and entered the nomogram. The calibration curve showed the optimal agreement between nomogram prediction and actual observation. In addition, the concordance index (C-index) of the nomogram for OS prediction was 0.77 (95% confidence interval [CI], 0.73-0.81) in the primary cohort and 0.76 (95% CI, 0.70-0.81) in the validation, superior to that of the international prognostic index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network (NCCN)-IPI (range, 0.69-0.74, p<.0001). Moreover, in patients receiving rituximab plus CHOP (R-CHOP) or R-CHOP-like regimens, compared with IPI (C-index, 0.73; 95% CI, 0.69-0.77), R-IPI (C-index, 0.70; 95% CI, 0.66-0.74), or NCCN-IPI (C-index, 0.71; 95% CI, 0.66-0.75), the DLBCL-specific nomogram showed a better discrimination capability (p < .0001). CONCLUSIONS: The proposed nomogram provided an accurate estimate of survival of patients with DLBCL, especially for those receiving R-CHOP or R-CHOP-like regimens, allowing clinicians to optimized treatment plan based on individualized risk prediction. IMPLICATIONS FOR PRACTICE: A diffuse large B-cell lymphoma (DLBCL)-specific prognostic nomogram was developed based on Chinese patients with DLBCL. As a tertiary hospital, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences is the number 1 ranked cancer center in China, with more than 800,000 outpatients in 2018. Patients included in this study were nonselected and came from 29 different provinces, municipalities, and autonomous regions in China. Thus, the data is believed to be representative to an extent.

Medical management of lung cancer: Experience in China.

Lung cancer is the leading cause of death from cancer worldwide, as well as in China. A multidisciplinary treatment strategy for lung cancer, which includes medical and radiation oncology, surgery, and pathology is used in clinical practice in China. Chinese lung cancer patients are treated according to different pathologic and genetic types of the disease. For those with active epidermal growth factor receptor (EGFR) mutation, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are used in first-, second- or third-line and maintenance treatment of non-small cell lung cancer (NSCLC). For patients with anaplastic lymphoma kinase (ALK) gene rearrangement, Crizotinib is a promising treatment in advanced NSCLC patients. A platinum-based regimen remains the mainstay of first-line systemic therapy for advanced NSCLC patients who are negative for EGFR mutation or ALK gene rearrangement. For patients with non-squamous NSCLC, Pemetrexed plus Cisplatin is recommended in first-line systemic therapy. An Endostatin combination with chemotherapy is used in first- and second-line advanced NSCLC patients. S-1 presents a new option of chemotherapy in advanced NSCLC cases. Cisplatin-based doublet chemotherapy is commonly used in NSCLC patients after surgery as adjuvant therapy. EGFR-TKIs are now being assessed in the adjuvant setting. The standard first-line chemotherapy regimen of small cell lung cancer (SCLC) is platinum with Etoposide (PE). Amrubicin provides similar survival compared with the PE regimen with an acceptable toxicity profile in extensive stage SCLC patients. Supportive care, such as traditional Chinese medicine and pegylated filgrastim, play an important role in improving patients' quality of life.

Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer.

Advanced non-small-cell lung cancer (NSCLC) is the main cause for cancer-related mortality. Treatments for advanced NSCLC are largely palliative and a benefit plateau appears to have reached with the platinum-based chemotherapy regimens. EGF receptor (EGFR) tyrosine kinase inhibitors gefitinib, erlotinib and afatinib came up with prolonged progression-free survival and improved quality of life, especially in EGFR-mutated patients. Icotinib is an oral selective EGFR tyrosine kinase, which was approved by China Food and Drug administration in June 2011 for treating advanced NSCLC. Its approval was based on the registered Phase III trial (ICOGEN), which showed icotinib is noninferior to gefitinib. This review will discuss the role of icotinib in NSCLC, and its potential application and ongoing investigations.

Platinum-based chemotherapy plus cetuximab first-line for Asian patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Results of an open-label, single-arm, multicenter trial.

BACKGROUND: The purpose of this study was to assess the efficacy, safety, and pharmacokinetics of cisplatin-based chemotherapy plus cetuximab as first-line treatment in Chinese and Korean patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients (n = 68) received cetuximab weekly plus 3-week cycles of cisplatin/5-fluorouracil (5-FU) chemotherapy for up to 6 cycles. The primary endpoint was overall response rate. RESULTS: The overall response rate was 55.9%, including 2 complete responses (CRs). Median overall survival (OS) was 12.6 months and median progression-free survival (PFS) was 6.6 months. Grade 3/4 adverse events (AEs) were reported in 41 (60.3%) patients. The safety profile was in line with previous clinical experience. The pharmacokinetic profile was in line with that observed with cetuximab in white and Japanese patients. CONCLUSION: The efficacy, safety, and pharmacokinetic findings from this study support the use of first-line platinum-based chemotherapy plus cetuximab in Chinese and Korean patients with recurrent and/or metastatic SCCHN (ClinicalTrials.gov NCT01177956).

[Randomize trial of cisplatin plus gemcitabine with either sorafenib or placebo as first-line therapy for non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. METHODS: Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. RESULTS: Overall demographics were balanced between experimental group (sorafenib+chemotherapy) and controlled group (chemotherapy only). Overall response (OS) rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905). Median progressive-free survival (PFS) and median overall survival were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68). Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. CONCLUSIONS: No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.

[Effect of immunomagnetic selection in purging autologous peripheral blood progenitor cell of breast cancer patients].

OBJECTIVE: To evaluate the effect of immunomagnetic technique in purging of peripheral blood progenitor cell (PBPC) of breast cancer patients. METHODS: A sample of APBSC from non-breast cancer patients mixed with 1% MCF-7 cell lines and 10 samples of APBSC from breast cancer patients were subjected to positive purging, negative purging, and positive/positive purging. The CD34 + cell purity, CD34 + cell recovery rate and the enrichment of colony form units were compared. The number of tumor cells before and after immunochemistry (ICC) and flow detected purging procedure cytometry (FCM). The influence of refrigeration on the effect of purging was analyzed. RESULTS: The TC depletion in 10 samples of PBPC of breast cancer patients after positive purging was 2.1 (1.1 approximately 2.7) log steps, the CD34 + cell purity was 55.1 (25.9 approximately 99.5)%, and the CD34 + cell recovery was 39.4 (34.0 approximately 80.0)%. After the 6 samples of ICC positive PBPC from breast cancer patients were subjected to negative selection and subsequent positive purging, the mean CD34 cell purity was 64.3 (34.0 approximately 86.4)%, the mean CD34 + cell recovery was 35.0 (24.0 approximately 52.5)%, the purging efficiency was 3.0 (1.8 approximately 3.9) log, and the enrichment of colony-forming units-granulocyte macrophage (CFU-GM) and burst-forming unit-erythrocyte (BFU-E) were 2.2 and 3.1 respectively. TCs were detectable in all 6 cases prior to the purging procedure by ICC and FCM. After the -/+ purging procedure, only one case was tumor cell positive by ICC and residual tumor cells could be detected by FCM, however the number of TCs was evidently decreased. Along with the extension of refrigeration time, the CD34 cell purity, CD34 cell recovery, and tumor cell clearance rate decreased. CONCLUSION: Immunomagnetic double negative/positive selections an effective, rapid and simple purging method.

[Results of combined therapy for 1260 patients with small cell lung cancer].

OBJECTIVE: To evaluate the efficacy of combined modality treatment and determine the prognostic factors for small cell lung cancer (SCLC). METHODS: From January 1974 to December 1995, 1260 patients with SCLC treated were retrospectively evaluated, with limited lesions in 732 patients, extensive lesions in 500 and stage unrecorded in 28. 553 patients were alloted into chemotherapy + radiotherapy (C + R) group, 355 into C + R + C group, 97 into R + C group, 126 into C group, 64 into R group and 65 into surgery (S + C + R) group. Patients with limited lesions received 2 - 4 cycles of chemotherapy including COMC, COMP, COMVP and CE-CAP. Radiotherapy was given to a dose of 40 - 70 Gy/4 - 7 w. Radiation portals for patients with limited lesions encompassed the primary tumor, hilar lymphatic drainage areas, partial mediastinum and bilateral supraclavicular regions. Patients with extensive lesions mainly received chemotherapy with or without palliative irradiation. RESULTS: The overall CR and PR rates were 26.7% and 52.3%. Local recurrence and distant metastasis rates were 58.8% and 61.5%. The 1-, 3- and 5-year survival rates were 50.2%, 14.7% and 11.7%, with median survival time of 12 months. The era, sex, age, tumor stage and treatment modality were all significant prognostic factors by both uni-variate and multi-variate analyses (P < 0.05). The result of S + C + R rated the best among these modalities and the result of C + R + C was superior to C + R, though the difference of which was not significant. CONCLUSION: Surgical resection should be considered as one part of comprehensive therapy for small cell lung cancer patients with limited lesions whenever possible. On top of routine chemotherapy early administration of radiotherapy is advisable.