Publications by authors named "Yuankai Shi"

227 Publications

polymorphism predicts response to oxaliplatin-based adjuvant chemotherapy in patients with colon cancer.

Am J Cancer Res 2021 15;11(4):1522-1539. Epub 2021 Apr 15.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing 100021, China.

Response to oxaliplatin-based adjuvant chemotherapy varies among patients with stage II and III colon cancer; however, genetic alterations associated with this response remain incompletely characterized. A three-stage analytical framework, including the discovery, validation, and replication stages, was designed to explore genetic alterations modulating response to oxaliplatin-based chemotherapy in adjuvant setting among patients with stage II and III colon cancer receiving complete resection of tumor. Except for several somatic mutated genes, such as and , showing less definitive associations with response to oxaliplatin-based adjuvant chemotherapy, we found stable associations of rs6891545C > A polymorphism in gene, a key component of DNA damage response system, with the response across all three stages. Patients with rs6891545 A allele had significantly lower risk of poor responsiveness to oxaliplatin-based adjuvant chemotherapy at both discovery and validation stages, compared with ones possessing wild homozygous genotype CC (discovery stage: odds ratio, 0; 95% CI, 0-0.48; = .005; validation stage: odds ratio, 0.33; 95% CI, 0.11-0.99; = .048). In the replication cohort, rs6891545 A allele was confirmed to be strongly associated with improved DFS (hazard ratio, 0.43; 95% CI, 0.23-0.81; = .007). Notably, the improvement persisted after controlling for sex, age, tumor location, differentiation, and stage (hazard ratio, 0.42; 95% CI, 0.22-0.80; = .009). Moreover, in silico analysis unraveled strong impact of rs6891545 A allele on local secondary structure of mRNA, possibly leading to low SLF1 protein expression. We conclude that the rs6891545C > A polymorphism may serve as an independent marker of response to oxaliplatin-based adjuvant chemotherapy in patients with stage II and III colon cancer, with improved clinical benefit observed in patients with the A allele possibly attributable to low expression of SLF1 protein resulting in deficient DNA repair capacity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085871PMC
April 2021

A Remarkable and Durable Response to Sintilimab and Anlotinib in the First-Line Treatment of an Anaplastic Thyroid Carcinoma without Targetable Genomic Alterations: A Case Report.

Onco Targets Ther 2021 20;14:2741-2746. Epub 2021 Apr 20.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China.

Anaplastic thyroid carcinoma (ATC) is a rare and highly aggressive fatal tumor. Most ATC patients using traditional surgery or radio-chemotherapy have poor prognosis and experience recurrence in a very short time. There is no optimal therapy for ATC, and the median survival time is about 5 months. We report a 67-year-old ATC patient, who experienced rapid local recurrence after radical thyroidectomy. The resected tumor tissue was sent for immunohistochemistry analysis and targeted next-generation sequencing. The results indicated high PD-L1 expression, a tumor mutation burden of 0.48 muts/Mb, microsatellite stable, and somatic mutations of promoter, and . However, none of the mutations indicated corresponding target therapy. An immediate operation was unsuitable because of rapid recurrence after surgery. The patient was also not in a condition to tolerate chemotherapy. Based on the high expression of PD-L1, an optimum strategy was used, combining immunotherapeutic agent, sintilimab, with an anti-angiogenesis drug, anlotinib. The patient obtained remarkable tumor shrinkage and an 18.3-month-sustained remission period. This is an effective case of using immunotherapy and anti-angiogenesis agent in the first-line treatment of ATC. It demonstrates a feasible and novel therapeutic option for future treatment of ATC patients.
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http://dx.doi.org/10.2147/OTT.S305196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068508PMC
April 2021

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2021 05 10;22(5):678-689. Epub 2021 Apr 10.

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.

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 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<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group.

Interpretation: Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

Funding: Bayer.
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http://dx.doi.org/10.1016/S1470-2045(21)00145-5DOI Listing
May 2021

Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.

Lancet Respir Med 2021 Mar 26. Epub 2021 Mar 26.

Shanghai Allist Pharmaceutical Technology, Shanghai, China.

Background: Furmonertinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both sensitising EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to assess the efficacy and safety of furmonertinib in patients with EGFR T790M mutated advanced non-small-cell lung cancer (NSCLC).

Methods: This study was a single-arm, open-label, phase 2b study at 46 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumour tissue who progressed after first or second generation EGFR TKIs or with primary EGFR T790M mutations received furmonertinib 80 mg orally once daily. The primary endpoint was objective response rate. Efficacy was assessed by blinded independent central review as per the Response Evaluation Criteria in Solid Tumors (version 1.1) in all patients who had measurable disease at baseline and received at least one dose of furmonertinib. Safety was assessed as per the Common Terminology Criteria for Adverse Events (version 4.03) in all patients who received at least one dose of furmonertinib with at least one safety assessment during follow-up. This study is registered with ClinicalTrials.gov (NCT03452592) and is ongoing for survival follow-up.

Findings: From Jun 4, 2018, to Dec 8, 2018, 220 patients received furmonertinib treatment. All 220 patients were included in the efficacy and safety analyses. At the data cutoff point of Jan 29, 2020, 71 (32%) patients remained on treatment. The median duration of follow-up was 9·6 months (range 0·7-19·4). The objective response rate was 74% (163 of 220 [95% CI 68-80]). Grade 3 or higher adverse events occurred in 58 (26%) patients and treatment-related grade 3 or higher adverse events occurred in 25 (11%) patients. The most common all-cause grade 3 or higher adverse events were increased γ-glutamyltransferase (five; 2%), increased aspartate aminotransferase, increased alanine aminotransferase, hyponatraemia, hypertension, pulmonary infection, hypermagnesaemia, and pericardial effusion (three each; 1%). Treatment-related diarrhoea was reported in ten (5%) patients and rashes were reported in 16 (7%) patients, all grade 1-2. Serious adverse events were reported in 52 (24%) patients, of which 12 (5%) were possibly treatment-related as evaluated by the investigator.

Interpretation: Furmonertinib has promising efficacy and an acceptable safety profile for the treatment of patients with EGFR T790M mutated NSCLC. Furmonertinib is expected to become a new treatment option after first or second generation EGFR TKIs in the Chinese population.

Funding: Shanghai Allist Pharmaceutical Technology, Ministry of Science and Technology of the People's Republic of China, and Chinese Academy of Medical Sciences.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2213-2600(20)30455-0DOI Listing
March 2021

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

Future Oncol 2021 May 17;17(14):1825-1838. Epub 2021 Mar 17.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs. No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.

This meta-analysis explored the prognostic and clinical value of serum 25-hydroxyvitamin D, 25(OH)D, levels in previously untreated lymphoma. 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. 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). Low level of serum 25(OH)D is a prognostic risk factor for newly diagnosed lymphoma.
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http://dx.doi.org/10.2217/fon-2020-0914DOI Listing
May 2021

End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA.

Blood Adv 2021 03;5(5):1283-1290

1st Department of Medicine, 1st Faculty of Medicine, Charles University General Hospital, Prague, Czech Republic.

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)-based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose-PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee-assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.
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http://dx.doi.org/10.1182/bloodadvances.2020002690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948296PMC
March 2021

Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study.

J Hematol Oncol 2021 Feb 15;14(1):25. Epub 2021 Feb 15.

Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, 81 Irwon-ro, Irwon-dong, Gangnam-gu, Seoul, 06351, South Korea.

Background: Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL.

Methods: This phase 2 study with Simon's two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification).

Results: In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5-43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29-339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43-106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94-438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab.

Conclusions: In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.
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http://dx.doi.org/10.1186/s13045-020-01020-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885403PMC
February 2021

Development and Validation of a Novel Risk Stratification Model for Cancer-Specific Survival in Diffuse Large B-Cell Lymphoma.

Front Oncol 2020 14;10:582567. Epub 2021 Jan 14.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease. Identifying more precise and individual survival prognostic models are still needed. This study aimed to develop a predictive nomogram and a web-based survival rate calculator that can dynamically predict the long-term cancer-specific survival (CSS) of DLBCL patients. A total of 3,573 eligible patients with DLBCL from 2004 to 2015 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. The entire group was randomly divided into the training (n = 2,504) and validation (n = 1,069) cohorts. We identified six independent predictors for survival including age, sex, marital status, Ann Arbor stage, B symptom, and chemotherapy, which were used to construct the nomogram and the web-based survival rate calculator. The C-index of the nomogram was 0.709 (95% CI, 0.692-0.726) in the training cohort and 0.700 (95% CI, 0.671-0.729) in the validation cohort. The AUC values of the nomogram for predicting the 1-, 5-, and 10- year CSS rates ranged from 0.704 to 0.765 in both cohorts. All calibration curves revealed optimal consistency between predicted and actual survival. A risk stratification model generated based on the nomogram showed a favorable level of predictive accuracy compared with the IPI, R-IPI, and Ann Arbor stage in both cohorts according to the AUC values (training cohort: 0.715 0.676, 0.652, and 0.648; validation cohort: 0.695 0.692, 0.657, and 0.624) and K-M survival curves. In conclusion, we have established and validated a novel nomogram risk stratification model and a web-based survival rate calculator that can dynamically predict the long-term CSS in DLBCL, which revealed more discriminative and predictive accuracy than the IPI, R-IPI, and Ann Arbor stage in the rituximab era.
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http://dx.doi.org/10.3389/fonc.2020.582567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841349PMC
January 2021

Investigation on the potential of circulating tumor DNA methylation patterns as prognostic biomarkers for lung squamous cell carcinoma.

Transl Lung Cancer Res 2020 Dec;9(6):2356-2366

Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Background: Aberrant epigenetic modifications play a key role in lung tumorigenesis. In our study, we aimed to explore the clinical implications of baseline circulating tumor DNA (ctDNA) somatic and methylation profiles in patients with lung squamous cell carcinoma (LUSC).

Methods: A total of 26 patients with LUSC of various stages were included in this study. Somatic mutations and methylation levels were profiled from the plasma-derived ctDNA obtained at the time of diagnosis using unique molecular identifier (UMI)-based targeted sequencing and bisulfite sequencing, respectively. The correlation between baseline ctDNA mutation and methylation profile, and overall survival (OS), were analyzed.

Results: Somatic mutations were detected in 80.8% (20/26) of the patients. Patients harboring somatic mutations with maximum allelic fraction (maxAF) of >5% had significantly shorter OS compared to those with maxAF ≤5% (7.1 54.6 months; P=0.020). ctDNA methylation level was found to be strongly correlated with maxAF (Pearson correlation =0.934; P<0.001). Consistent with maxAF, higher methylation levels were also associated with poorer OS (hazard ratio =2.377; 95% CI: 1.283-4.405; P=0.006). Moreover, a total of 1,956 ctDNA methylation blocks were differentially methylated in patients with maxAF >0 (P<0.05). Least absolute shrinkage and selection operator (LASSO) regression analysis revealed a significant correlation between methylation signatures from 5 methylation blocks and OS (hazard ratio =183.20, 95% CI: 2.74-12,243.32; P=0.015). These 5 methylation blocks could serve as an alternative to maxAF and can be explored as prognostic biomarkers.

Conclusions: Our study identified several ctDNA methylation blocks that can potentially predict the prognosis of LUSC at the time of diagnosis.
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http://dx.doi.org/10.21037/tlcr-20-1070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815356PMC
December 2020

Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002).

J Hematol Oncol 2021 01 12;14(1):12. Epub 2021 Jan 12.

Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, China.

Background: Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients.

Methods: We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed PTCL entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria.

Results: Between July 12, 2018, and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At the data cutoff date (August 15, 2020), the median follow-up was 4.06 (range 0.30-22.9) months. For 89 patients in FAS, 36 achieved objective response (40.4%, 95% CI 30.2-51.4), of which 13 (14.6%) were complete response and 23 (25.8%) had partial response assessed by IRRC. The median duration of response (DOR) was 11.4 (95% CI 4.8 to not reached) months per IRRC. Patients with PD-L1 expression ≥ 50% derived more benefit from geptanolimab treatment compared to < 50% ones (ORR, 53.3% vs. 25.0%, p = 0.013; median PFS 6.2 vs. 1.5 months, p = 0.002). Grade ≥ 3 treatment-related adverse events occurred in 26 (25.5%) patients, and the most commonly observed were lymphocyte count decreased (n = 4) and platelet count decreased (n = 3). Serious adverse events were observed in 45 (44.1%) patients and 19 (18.6%) were treatment related.

Conclusions: In this study, geptanolimab showed promising activity and manageable safety profile in patients with r/r PTCL. Anti-PD-1 antibody could be a new treatment approach for this patient population.

Trial Registration: This clinical trial was registered at the ClinicalTrials.gov (NCT03502629) on April 18, 2018.
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http://dx.doi.org/10.1186/s13045-021-01033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802130PMC
January 2021

Potential predictive value of serum targeted metabolites and concurrently mutated genes for EGFR-TKI therapeutic efficacy in lung adenocarcinoma patients with sensitizing mutations.

Am J Cancer Res 2020 1;10(12):4266-4286. Epub 2020 Dec 1.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.

There is a discrepancy in the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment for advanced lung adenocarcinoma (LUAD) patients with sensitizing mutations (). Molecular markers other than remain to be investigated to better predict EGFR-TKI efficacy. Here, 49 LUAD patients with (19 deletions or 21 L858R mutations) who received the first-generation EGFR-TKI icotinib therapy were included and stratified into 25 good-responders with a progression-free survival (PFS) longer than 11 months and 24 poor-responders with a PFS shorter than 11 months. We conducted targeted metabolomic detection and next-generation sequencing on serum and tissue samples, respectively. Subsequently, two metabolomic profiling-based discriminant models were constructed for icotinib efficacy prediction, 10 metabolites overlapped in both models ensured high credibility for distinguishing good- and poor-responders. Seven of the 10 metabolites displayed significant differences between the two groups, which belong to lipids including ceramides (Cers), lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), sphingomyelins (SMs), and free fatty acids (FAs). Briefly, LPC 16:1, LPC 22:5-1, and LPE 18:2 decreased in poor-responders, while Cer 36:1-3, Cer 38:1-3, SM 36:1-2 and SM 42:2 increased in poor-responders. In parallel, we identified 6 co-mutated genes (, , , , , and ) which were significantly correlated with a shorter PFS. Additionally, 4 efficacy-related metabolites (Cer 36:1-3, Cer 38:1-3, SM 36:1-2, and LPC 16:1) showed significant differences between the mutant and wild-type of 4 efficacy-related genes (, , , and ). SM 36:1-2 elevated while LPC 16:1 decreased in , , and mutant groups compared to the wild-type groups. Cer 36:1-3 increased in the and mutant groups, and Cer 38:1-3 only rose in the mutant group. Furthermore, we observed a causal-mediator-network-based interrelation between the 4 concurrently mutated genes and the 4 metabolites related metabolic genes in glycerophospholipid metabolism and sphingolipid metabolism pathways. This study demonstrated that lipids metabolism and concurrently mutated genes with were associated with the icotinib efficacy, which provides novel perspectives in classifying clinical responses of LUAD patients and reveals the potential of non-invasive pretreatment serum metabolites in predicting EGFR-TKI efficacy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783757PMC
December 2020

Minimal Residual Disease and Survival Outcomes in Patients with Mantle Cell Lymphoma: a systematic review and meta-analysis.

J Cancer 2021 1;12(2):553-561. Epub 2021 Jan 1.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, 100021, China.

Minimal residual disease (MRD) has shown the prognostic value in mantle cell lymphoma (MCL). To quantify the relationships between progression free survival (PFS) and overall survival (OS) with MRD status in MCL, we conducted this meta-analysis. We searched databases including Pubmed, Embase, Web of Science and the Cochrane Library up to July 15, 2020. Data of patients' characteristics, MRD assessment and survival outcomes were extracted and analyzed. Ten articles were included. For the impact of post-induction MRD status on survival outcomes, MRD positive status was associated with worse PFS (HR=1.44; 95%CI 1.27-1.62; <0.00001) and OS (HR=1.30; 95%CI 1.03-1.64; =0.03) compared with MRD negative status. Regarding the impact of post-consolidation MRD status on survival outcomes, MRD positivity predicted shorter PFS (HR=1.84; 95%CI 1.49-2.26; <0.00001) and OS (HR=2.38; 95%CI 1.85-3.06; <0.00001) than MRD negativity. This study indicated that MRD positivity after induction and consolidation treatments was associated with worse PFS and OS for MCL. MRD-based treatment strategies should be further explored in clinical trials and real-world practice.
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http://dx.doi.org/10.7150/jca.51959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738989PMC
January 2021

Development of an LC-MS/MS method for quantifying ASK120067, a novel mutant-selective inhibitor of the epidermal growth factor receptor (EGFR) as well as its main metabolite in human plasma and its application in a pharmacokinetic study.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jan 7;1162:122488. Epub 2020 Dec 7.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Beijing 100032, China. Electronic address:

ASK120067, an oral irreversible tyrosine kinase inhibitor (TKI) targeting the epidermal growth factor receptor (EGFR), is formulated for the management of patients with non-small cell lung cancer (NSCLC) who harbor T790M resistant and EGFR active mutations. Two rapid and high-throughput methods based on liquid chromatography-tandem mass spectrometry to detect ASK120067 and its primary metabolite CCB4580030 in human plasma were developed and applied in the clinical trials. A protein precipitation method using acetonitrile coupled with a gradient elution separation in a BEH C18 column (1.7 µm, 2.1 × 50 mm) was used to process plasma and separation analytes. The chromatographic separation was performed on the mobile phase of 5 mM ammonium acetate in water with 0.1% formic acid (A) and acetonitrile (B), and the flow rate was 0.4 mL/min. The multiple reaction monitoring (MRM) mode was selected to monitor the precursor-to-product ion transitions of m/z 546.2 → m/z 431.2 for ASK120067 and m/z 532.1 → m/z 420.2 for CCB4580030 at the positive ionization mode. The precision and accuracy of the two methods for ASK1200067 and CCB4580030 were within acceptable range for the linear range in 5.00-5000 ng/mL and 0.500-500 ng/mL, respectively. Further stabilities for the two analytes and internal standard were also investigated covered the entire experimental process beginning from harvesting whole blood to plasma extraction and analysis. ASK120067 was then administered without issue onto a dose-escalation, the first-in-human Phase I clinical trial in Chinese NSCLC patients to determine the pharmacokinetics of oral ASK120067 administration.
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http://dx.doi.org/10.1016/j.jchromb.2020.122488DOI Listing
January 2021

Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer: 2-year follow-up from a randomized, open-label, phase 3 study (CheckMate 078).

Lung Cancer 2021 02 24;152:7-14. Epub 2020 Nov 24.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, 106 Zhongshan Second Road, Guangzhou 510080, China. Electronic address:

Background: In the phase 3 CheckMate 078 study, nivolumab showed significant overall survival (OS) benefit and superior tolerability versus docetaxel in a predominantly Chinese patient population with non-small cell lung cancer (NSCLC). However, data on long-term outcomes with immunotherapy in Asian patients are limited. We report 2-year efficacy and safety data.

Methods: Patients with advanced/metastatic NSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks; n = 338) or docetaxel (75 mg/m every 3 weeks; n = 166) until progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was OS; secondary endpoints included progression-free survival, objective response rate, and safety.

Results: After 25.9 months minimum follow-up, 21 patients (6 %) remained on nivolumab versus 0 on docetaxel. Median OS was 11.9 months with nivolumab versus 9.5 months with docetaxel (HR: 0.75; 95 % CI: 0.61-0.93); 2-year OS rates were 28 % versus 18 %, respectively. Survival benefits were observed across a variety of predefined subgroups. At 2 years, 39 % and 0 % of responders had ongoing responses with nivolumab and docetaxel, respectively. Grade 3-4 treatment-related adverse events occurred in 12 % of patients with nivolumab versus 47 % with docetaxel, leading to discontinuation in 4 % and 5 % of patients, respectively. No new treatment-related deaths occurred.

Conclusion: At 2 years, nivolumab maintained a favorable safety profile and continued to demonstrate superior OS versus docetaxel in this predominantly Chinese patient population with previously treated NSCLC. These data are consistent with long-term outcomes from the global CheckMate 017/057 studies.
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http://dx.doi.org/10.1016/j.lungcan.2020.11.013DOI Listing
February 2021

Current management of chemotherapy-induced neutropenia in adults: key points and new challenges: Committee of Neoplastic Supportive-Care (CONS), China Anti-Cancer Association Committee of Clinical Chemotherapy, China Anti-Cancer Association.

Cancer Biol Med 2020 11 15;17(4):896-909. Epub 2020 Dec 15.

Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832000, China.

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.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721096PMC
November 2020

Phase 1/2 study of ceritinib in Chinese patients with advanced anaplastic lymphoma kinase-rearranged non-small cell lung cancer previously treated with crizotinib: Results from ASCEND-6.

Lung Cancer 2020 12 5;150:240-246. Epub 2020 Nov 5.

Sun Yat-Sen University Cancer Center, Guangzhou, China.

Background: Patients with anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC) treated with crizotinib inevitably relapse, with brain as common site of progression.

Patients And Methods: ASCEND-6, a phase 1/2, single-arm study, included adult Chinese patients with stage IIIB or IV ALK+ NSCLC pretreated with crizotinib as the last therapy (irrespective of prior chemotherapies [≤2]). Primary endpoints were pharmacokinetics (PK), safety, and tolerability. Key secondary endpoint was overall response rate (ORR; investigator assessed).

Results: Of the 103 enrolled patients, all received prior crizotinib, 70 % received ≥1 prior chemotherapy regimen, and 63.1 % had brain metastases at baseline. In the phase 1 component, 20 patients completed a 5-day PK run-in period. Median T (n = 16) was ∼6 h; geometric means of AUC (n = 16) and C (n = 16) at steady state were 22,000 ng*h/mL and 1080 ng/mL, respectively. In the final analysis, median follow-up time was 34 months (range: 27.8-40.6). The ORR was 41.7 % (95 % confidence interval [CI]: 32.1-51.9), and median progression-free survival was 7.2 months (95 % CI: 4.1-7.5). Median overall survival was 17.5 months (95 % CI: 10.8-24.3). Most frequent adverse events, regardless of study drug relationship (mostly grade 1/2), were diarrhea (74.8 %), vomiting (62.1 %), alanine transaminase increased (59.2 %), aspartate transaminase increased (58.3 %), and nausea (58.3 %).

Conclusions: Ceritinib PK in Chinese patients is consistent with those observed in the global ASCEND-1 study. Ceritinib was well tolerated and showed durable responses in Chinese patients with ALK+ NSCLC who progressed after crizotinib and ≤2 prior lines of chemotherapy.
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http://dx.doi.org/10.1016/j.lungcan.2020.10.024DOI Listing
December 2020

Characteristics and Management of -Mutated Diffuse Large B-Cell Lymphoma Patients.

Cancer Manag Res 2020 10;12:11515-11522. Epub 2020 Nov 10.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China.

Background/aim: TP53 mutation is recognized as a negative prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL). Here, we present the characteristics of DLBCL patients following investigation of the effect of a treatment approach on survival of DLBCL patients.

Methods: A total of 44 DLBCL patients with and treated with an R-CHOP regimen were included for analysis. Patients who failed to achieve a complete response (CR) to initial treatment or relapsed in the first 6 months after initial CR were deemed to have primary refractory disease.

Results: Among 44 patients harboring mutations who underwent upfront R-CHOP or R-CHOP-like treatment, 21 (47.7%) had limited-stage and 23 (52.3%) presented advanced-stage disease. Apart from the seven patients receiving upfront surgical resection, 37 had measurable disease under the R-CHOP regimen, with 59.1% (n=26) developing primary refractory disease. Seven limited-stage patients after early complete resection and one with residue resection remained event-free at median follow-up of 37 months. Multivariate analysis revealed that elevated baseline lactate dehydrogenase (LDH), extranodal involvement (two or more), Ann Arbor stage, and locoregional treatment (surgery or radiation therapy) were independent indicators for progression-free survival (PFS). After adjustment for baseline LDH and extranodal involvement, adding locoregional treatment including surgery and radiation to the R-CHOP regimen significantly improved PFS (=0.008) and overall survival (=0.017) in limited-stage DLBCL patients compared to R-CHOP-only treatment.

Conclusion: This study presents the characteristics of -mutated DLBCL and implies a potential benefit of locoregional treatment in limited-stage DLBCL patients with mutations.
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http://dx.doi.org/10.2147/CMAR.S269624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666999PMC
November 2020

[Advances in Drug Resistance Mechanisms and Prognostic Markers of Targeted Therapy in ALK-positive Non-small Cell Lung Cancer].

Zhongguo Fei Ai Za Zhi 2020 Nov;23(11):1014-1022

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, China.

Echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion accounts for 3%-5% of non-small cell lung cancer (NSCLC) patients. With the in-depth study of the EML4-ALK driver gene, ALK inhibitors represented by crizotinib have been gradually developed and applied in the clinic. However, the response to ALK-targeted therapy is heterogeneous among different patients. Most patients with ALK-targeted therapy will inevitably develop drug resistance, leading to tumor progression. Monitoring the efficacy of patients with prognostic markers to change the treatment in time, and selecting individualized follow-up treatment according to the mechanism of drug resistance, can effectively improve the prognosis of patients. This article will review the mechanism of ALK tyrosine kinase inhibitor (ALK-TKI) resistance and related prognostic markers to discuss the prediction for ALK-targeted therapy and the choice of subsequent treatment for drug-resistant patients.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.101.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679215PMC
November 2020

Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advances.

Leukemia 2021 02 29;35(2):312-332. Epub 2020 Oct 29.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.

Bruton's tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.
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http://dx.doi.org/10.1038/s41375-020-01072-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862069PMC
February 2021

Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001-2020).

J Hematol Oncol 2020 10 27;13(1):143. Epub 2020 Oct 27.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.

Tyrosine kinases are implicated in tumorigenesis and progression, and have emerged as major targets for drug discovery. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Over the past 20 years, multiple robust and well-tolerated TKIs with single or multiple targets including EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT have been developed, contributing to the realization of precision cancer medicine based on individual patient's genetic alteration features. TKIs have dramatically improved patients' survival and quality of life, and shifted treatment paradigm of various solid tumors. In this article, we summarized the developing history of TKIs for treatment of solid tumors, aiming to provide up-to-date evidence for clinical decision-making and insight for future studies.
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http://dx.doi.org/10.1186/s13045-020-00977-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590700PMC
October 2020

Activity and Safety of Geptanolimab (GB226) for Patients with Unresectable, Recurrent, or Metastatic Alveolar Soft Part Sarcoma: A Phase II, Single-arm Study.

Clin Cancer Res 2020 12 12;26(24):6445-6452. Epub 2020 Oct 12.

Department of Medical Science, Genor Biopharma Co, Ltd, Shanghai, China.

Purpose: Patients with alveolar soft part sarcoma (ASPS) are rare and have few treatment options. We assessed the activity of geptanolimab (GB226), a fully humanized programmed cell death protein 1 antibody, for patients with unresectable, recurrent, or metastatic ASPS.

Patients And Methods: We conducted this multicenter, single-arm, phase II study (Gxplore-005, NCT03623581) in patients aged 18-75 years who had unresectable, recurrent, or metastatic ASPS at 11 sites in China. Patients received intravenous geptanolimab (3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by independent review committee (IRC) per RECIST 1.1 in the full analysis set population.

Results: Between September 6, 2018 and March 6, 2019, we enrolled and treated 37 patients with 23 (62.2%) having received prior systemic treatment. Fourteen [37.8%; 95% confidence interval (CI), 22.5-55.2] of 37 patients had an objective response assessed by IRC with a 6-month duration of response rate of 91.7%. Median progression-free survival was 6.9 months (95% CI, 5.0-not reached) and disease control was achieved in 32 (86.5%; 95% CI, 71.2-95.5) patients. Three of 37 patients reported grade 3 treatment-related adverse events (TRAEs), including anemia, hypophysitis, and proteinuria [one each (2.7%)]. No grade 4 TRAEs were observed. Two (5.4%) patients discontinued treatment due to TRAEs (one with hypophysitis and one with Mobitz type I atrioventricular block). The baseline percentage of CD4 T cells was adversely associated with patient response ( = 0.031).

Conclusions: Geptanolimab has clinically meaningful activity and a manageable safety profile in unresectable, recurrent, or metastatic ASPS.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2819DOI Listing
December 2020

Nimotuzumab plus platinum-based chemotherapy platinum-based chemotherapy alone in patients with recurrent or metastatic nasopharyngeal carcinoma.

Ther Adv Med Oncol 2020 16;12:1758835920953738. Epub 2020 Sep 16.

Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.

Background: Palliative chemotherapy has been the mainstay treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). However, little is known about the efficacy and toxicity of nimotuzumab (NTZ) - a monoclonal antibody drug targeting epidermal growth factor receptor - plus chemotherapy (CT) CT alone for these patients.

Methods: The database at Cancer Hospital of Chinese Academy of Medical Sciences was queried for patients diagnosed with NPC who received CT with or without NTZ between 2004 and 2018. Treatment compliance, survival outcomes, and adverse effects were compared among these groups.

Results: Records of 70 patients with R/M-NPC were reviewed: 21 (30%) received NTZ plus CT (NTZ+CT) and 49 (70%) received CT. CT regimens included gemcitabine plus platinum, taxane plus platinum (TP), and fluorouracil plus platinum. Comparing the CT group with NTZ+CT group, the median follow up was 62 months (range = 3-133) 59 months (range = 9-117); median progression free survival was 7.5 [95% confidence interval (CI) 6.552-8.381] months 8.5 (95% CI 6.091-10.976) months,  = 0.424; median overall survival (OS) was 25.6 (95% CI 18.888-32.379) months 48.6 (95% CI 35.619-61.581) months,  = 0.017, respectively. Multivariable analysis established treatment group (CT NTZ+CT) as an independent prognostic factor for OS (hazard ratio, 0.5; 95% CI 0.255-0.979;  = 0.043). No significant difference with regard to toxicities was observed between the two groups. Among them, a subgroup analysis was performed in 53 (75.7%) patients who received TP with or without NTZ, which showed similar results.

Conclusion: Our findings suggested that NTZ+CT provides a novel treatment option and prolongs survival significantly for R/M-NPC.
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http://dx.doi.org/10.1177/1758835920953738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498835PMC
September 2020

Long-term survival and prognostic analysis of advanced stage follicular lymphoma in the rituximab era: A China single-center retrospective study.

Asia Pac J Clin Oncol 2020 Sep 24. Epub 2020 Sep 24.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.

Aim: The prognosis and treatment options for follicular lymphoma (FL) remain heterogenous. This study aimed to analyze the prognostic impact of rituximab maintenance and evaluate the prognostic models in Chinese FL patients.

Methods: We retrospectively evaluated patients with treatment-naïve advanced stage FL who were treated in Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College between January 2008 and December 2018. We compared the baseline characteristics, long-term survival outcomes, prognostic factors and the performance of four common prognostic models (i.e., FLIPI, FLIPI2, PRIMA-PI and LDH+β2M) between them.

Results: A total of 158 patients were included (rituximab maintenance group, 77 patients; observation group, 81 patients). The median follow-up time was 61.0 months. The rituximab maintenance group showed significantly higher 5-year progression-free survival (PFS; 83.3% vs 52.7%, P < 0.001) and overall survival (OS; 97.8% vs 84.1%, P = 0.032) than the observation group. FLIPI2 showed a more discriminating C index than the other three models.

Conclusion: This study showed that rituximab maintenance after chemoimmunotherapy induction can prolong both PFS and OS in patients with advanced-stage FL, and FLIPI2 is a promising prognostic model.
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http://dx.doi.org/10.1111/ajco.13463DOI Listing
September 2020

Prognostic value of pretreatment smoking status for small cell lung cancer: A meta-analysis.

Thorac Cancer 2020 11 22;11(11):3252-3259. Epub 2020 Sep 22.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.

Background: Although tobacco exposure remains the most important risk factor of tumorigenesis of small cell lung cancer (SCLC), its prognostic value has failed to reach a consensus until now. Accordingly, we conducted a meta-analysis to investigate the prognostic value of pretreatment smoking status (smokers vs. never-smokers) in SCLC.

Methods: The four databases PubMed, Medline, Embase, and Cochrane library were searched to identify the relevant literature from the inception dates to 24 June 2020. The primary outcome was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). The hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to assess the relationship between pretreatment smoking status and patient survival. Sensitivity analysis was performed to assess the stability of the pooled results. Begg's funnel plot and Egger's test were applied to detect the publication bias. All statistical analyses were performed using RevMan V.5.3 and STATA version 15.0 software.

Results: A total of 27 studies involving 12 047 patients with SCLC (9137 smokers and 2910 never-smokers) were included in this meta-analysis. The results showed that smoking history was closely related to poorer survival outcome (OS: HR = 1.17, 95% CI: 1.12-1.23, P < 0.00001; I = 0%; PFS: HR = 1.20, 95% CI: 1.06-1.35, P = 0.004; I = 0%).

Conclusions: Smoking history should be considered as an independent poor prognostic factor for patients with SCLC. More large-scale prospective studies are warranted to testify the prognostic value of pretreatment smoking status.
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http://dx.doi.org/10.1111/1759-7714.13661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605986PMC
November 2020

Refined Stratification Based on Baseline Concomitant Mutations and Longitudinal Circulating Tumor DNA Monitoring in Advanced EGFR-Mutant Lung Adenocarcinoma Under Gefitinib Treatment.

J Thorac Oncol 2020 12 9;15(12):1857-1870. Epub 2020 Sep 9.

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China. Electronic address:

Introduction: The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking.

Methods: ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel.

Results: Three subgroups categorized by baseline comutations-EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)-exhibited distinct progression-free survival (13.2 [11.3-15.2] versus 9.3 [7.6-10.5] versus 4.0 [2.4-9.3] months) and overall survival (32.0 [29.2-41.5] versus 21.7 [19.3-27.0] versus 15.5 [10.5-33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher's exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9-13.2] versus 7.4 [5.6-9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p < 0.001, Fisher's exact test), giving clues to postline treatment.

Conclusions: The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.
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http://dx.doi.org/10.1016/j.jtho.2020.08.020DOI Listing
December 2020

Association of MUC16 Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors.

JAMA Netw Open 2020 08 3;3(8):e2013201. Epub 2020 Aug 3.

Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Department of Medical Oncology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Importance: As the third most frequently mutated gene in cancers, the association between MUC16 mutation and response to immune checkpoint inhibitors (ICIs) in solid tumors remains unclear.

Objective: To examine whether MUC16 mutation is associated with genomic factors in ICI response in solid tumors and with outcomes in ICI-treated patients.

Design, Setting, And Participants: This cohort study used multidimensional genomic data of 10 195 patients from The Cancer Genome Atlas (TCGA) across 30 solid tumor types, 56 patients from a non-small cell lung cancer (NSCLC) cohort, and 145 patients from a melanoma cohort. Genomic factors associated with ICI response covered tumor mutational burden, neoantigens, immune-related gene signatures, and tumor immune microenvironment. Both NSCLC and melanoma cohorts included ICI-treated patients. The TCGA cohort was used to examine the association of MUC16 mutation with genomic factors. Two ICI-treated cohorts were used to explore the significance of outcomes associated with MUC16 mutation, using Kaplan-Meier curves and Cox models with adjusting for potential confounders. Gene set enrichment analysis was used to identify MUC16 mutation-associated biological processes. Data were obtained from October 1 through October 10, 2019, and were analyzed from October 11 through December 31, 2019.

Main Outcomes And Measures: Genomic factors associated with ICI response, overall survival, and clinical response.

Results: Of the 10 195 patients, 4821 (47.6%) were men (median [interquartile range {IQR}] age, 60 [50-70] years). MUC16 was mutated in 2006 of 10 195 patients (19.68%). In this pan-cancer data set, patients with MUC16 mutation had higher tumor mutational burden (median [IQR], 230 [93-595] mutations vs 48 [25-92] mutations; difference, 182 mutations; 95% CI, 164-199 mutations; P < .001) and neoantigen load (median [IQR], 179 [74-394.5] neoantigens vs 48 [24-89] neoantigens; difference, 131 antigens; 95% CI, 116.5-145 neoantigens; P < .001) than those without mutations. The tumor immune microenvironment with dual-positive CD8A and PD-L1 was overrepresented in MUC16-mutated tumors compared with wild-type ones (43.8% vs 32.4%; odds ratio, 1.63; 95% CI, 1.46-1.80; P < .001). Of the 40 immune-related genes, 37 (92.5%) exhibited differential expression between 2 states. MUC16 mutation was associated with improved overall survival in both the NSCLC (hazard ratio, 0.34; 95% CI, 0.12-0.99; P = .04) and melanoma (hazard ratio, 0.57; 95% CI, 0.36-0.90; P = .02) cohorts. The improvement persisted after adjusting for age, sex, and dominant mutational signatures in the melanoma cohort (hazard ratio, 0.57; 95% CI, 0.33-0.96; P = .04). MUC16 mutation was associated with greater response rates in the NSCLC cohort (odds ratio, 4.03; 95% CI, 1.06-16.43; P = .03) and the melanoma cohort (odds ratio, 3.38; 95% CI, 1.07-14.25; P = .03). Gene set enrichment analysis revealed that gene sets regarding cell proliferation and immune response were enriched in MUC16-mutated tumors (false discovery rate, <.001).

Conclusions And Relevance: MUC16 mutation appears to be associated with reported genomic factors associated with response to and improved outcomes for ICI treatment in solid tumors. It may hold promise as a marker for guiding immunotherapeutic responsiveness.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.13201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450349PMC
August 2020

Biomarkers of Osimertinib Response in Patients with Refractory, EGFR-T790M-positive Non-Small Cell Lung Cancer and Central Nervous System Metastases: The APOLLO Study.

Clin Cancer Res 2020 12 17;26(23):6168-6175. Epub 2020 Aug 17.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China.

Purpose: Dynamic biomarker monitoring may inform pathways for treating -T790M-positive non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases with osimertinib. This study aimed to determine the efficacy and safety of osimertinib for real-world patients with -T790M NSCLC and CNS metastases and to explore potential circulating biomarkers of therapeutic response.

Patients And Methods: APOLLO (ClinicalTrials.gov registration: NCT02972333) was a prospective, single-arm, open-label trial which ran from January 2017 to April 2019. Eligible patients had confirmed -T790M-positive NSCLC, prior treatment with an EGFR-tyrosine kinase inhibitor, and CNS metastases. All enrolled patients received oral osimertinib 80 mg once daily until disease progression or intolerable toxicity. Primary outcome was overall progression-free survival (PFSo) and secondary outcomes included objective response rate (ORR) and adverse events (AE). Exploratory biomarker analysis involved collection of plasma and cerebrospinal fluid (CSF) samples for next-generation sequencing and drug penetration analysis.

Results: From January to September 2017, 38 patients were enrolled. After a median follow-up of 8.2 months (range, 0.07-15.6), 23 (60.5%) of 38 patients had disease progression or death. Median PFSo was 8.4 months [95% confidence interval (CI), 5.8-10.9]. Overall ORR was 39.4%. Twelve (31.6%) of 38 patients had ≥1 grade 3-4 AE. Median osimertinib CSF penetration rate was 31.7%. Patients with undetectable plasma mutations at week 6 had improved PFSo compared with those with detectable mutations (not reached vs. 4.5 months; 95% CI, 0.0-1.1; < 0.05).

Conclusions: Osimertinib had potent activity against -T790M-positive NSCLC with CNS metastases. Dynamic monitoring of plasma may suffice for predicting clinical responses, mitigating the need for repeat CSF biopsy..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2081DOI Listing
December 2020

R-CHOP immunochemotherapy plus surgery is associated with a superior prognosis in Chinese primary intestinal diffuse large B-cell lymphoma.

Asia Pac J Clin Oncol 2020 Dec 10;16(6):385-391. Epub 2020 Aug 10.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.

Aim: The aim of the study was to compare the therapeutic strategies and prognostic factors of patients with primary intestinal diffuse large B-cell lymphoma (PI-DLBCL).

Methods: A total of 50 PI-DLBCL patients who accepted standard first-line treatment at National Cancer Center in China were included in this retrospective study. Survival analysis was performed to evaluate the prognostic risk factors.

Results: The 3-year overall survival (OS) and 3-year progression-free survival (PFS) for the entire group were 76.0% and 65.9%, respectively. Univariate analysis showed that B symptom, advanced Lugano stage, elevated LDH status, poor ECOG PS and immunochemotherapy alone were significantly correlated with a poor PFS. Elevated LDH status, poor ECOG PS, advanced Lugano stage, high IPI score and immunochemotherapy alone were significantly correlated with a poor OS. Multivariate analysis revealed that ECOG PS (P= 0.035; HR = 0.233; 95% CI, 0.060-0.905), LDH level (P = 0.010; HR = 0.223; 95% CI, 0.072-0.693) and surgery (P = 0.002; HR = 5.584; 95% CI, 1.883-16.563) were independent prognostic factors for OS. LDH level (P = 0.035; HR = 0.210; 95% CI, 0.049-0.894) and surgery (P = 0.003; HR = 6.410; 95% CI, 1.903-21.593) were independent risk factors for PFS in PI-DLBCL. R-CHOP immunochemotherapy combined surgery treatment was also associated with a lower rate of refractory/relapsed (R/R) disease (P = 0.004). Furthermore, stratified analysis revealed that partial resection or radical resection combined with immunochemotherapy had no significantly difference which affect OS (P = 0.338) and PFS (P = 0.207).

Conclusion: R-CHOP immunochemotherapy plus surgery was associated with a superior prognosis compared with R-CHOP alone in Chinese PI-DLBCL population.
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http://dx.doi.org/10.1111/ajco.13396DOI Listing
December 2020

Pretreatment body mass index and clinical outcomes in cancer patients following immune checkpoint inhibitors: a systematic review and meta-analysis.

Cancer Immunol Immunother 2020 Dec 4;69(12):2413-2424. Epub 2020 Aug 4.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.

Background: This systematic review and meta-analysis aimed to evaluate the association between pretreatment body mass index (BMI) and clinical outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs).

Methods: Systematical searches of PubMed, Embase, and the Cochrane Library databases were carried out. Studies reporting on the association between BMI and outcomes of ICIs were included. The intended outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and immune-related adverse events (irAEs). Quantitative analyses and dose-response meta-analyses were performed under random effect models.

Results: Twenty-two eligible studies involving 5686 cancer patients treated with ICIs were identified. Compared to those with lower BMI, patients with higher BMI obtained a significant benefit on OS (HR = 0.698, 95% CI 0.614-0.794, P < 0.001; I = 45.9%) and PFS (HR = 0.760, 95% CI 0.672-0.861, P < 0.001; I = 37.9%). Most stratified analyses for OS and PFS also showed similar pooled risk estimates. For an increment of every 5 kg/m in BMI, the risk for death reduced by approximately 15.6% (HR = 0.844, 95% CI 0.752-0.945, P = 0.003). Moreover, patients with higher BMI had a remarkably better ORR (OR = 0.468, 95% CI 0.263-0.833, P = 0.010; I = 73.6%) than that of those with lower BMI. However, no statistically significant differences were found in the incidence of any grade irAEs (P = 0.073) and ≥ 3 grade irAEs (P = 0.105) between higher and lower BMI.

Conclusion: Higher BMI is significantly associated with improved outcomes in patients treated with ICIs. Further large-scale prospective research is warranted to better illuminate the association between BMI and outcomes from ICIs.
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http://dx.doi.org/10.1007/s00262-020-02680-yDOI Listing
December 2020

Event-free survival at 24 months is a robust surrogate endpoint for long-term survival in pediatric, adolescent, and adult T cell lymphoblastic lymphoma.

Ann Hematol 2020 Dec 25;99(12):2847-2857. Epub 2020 Jul 25.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.

T cell lymphoblastic lymphoma (T-LBL) has an aggressive clinical behavior. To date, powerful and consistent prognostic factors have not been established for T-LBL. In this study, we first evaluated the association of event-free survival (EFS) at 24 months (EFS24) with overall survival (OS) in T-LBL patients. Besides, we sought to identify clinical factors of prognostic importance in this rare entity. Between January 2006 and December 2017, ninety-one patients with newly diagnosed T-LBL were retrospectively analyzed. EFS was defined as the time from diagnosis to relapse or progression, unplanned retreatment, death from any cause, or to the last follow-up. In total, 91 patients with a median age of 24 years were enrolled. At a median follow-up of 40.4 months (range, 1.4 to 163.3 months), the 5-year OS and EFS was 47.9% and 43.2%, respectively. Of all patients, 45 (49.5%) achieved EFS24 and 46 (50.5%) did not. Patients who achieved EFS24 showed a markedly superior outcome, compared with those who failed to achieve EFS24 (5-year OS, 90.5% vs 3%, P < 0.001). Univariate analysis indicated bone marrow involvement, response to induction treatment, and stem cell transplantation (SCT) consolidation to be prognostic factors for EFS and OS. In addition, compared with the patients receiving non-Hodgkin's lymphoma (NHL)-like treatment protocols, patients treated with hyper-CVAD showed significantly improved EFS and OS. Such survival advantage in terms of EFS and OS was also observed of BMF-90 regimens over NHL-like therapy, despite that the difference in EFS did not reach statistical significance (P = 0.056). Multivariate analysis demonstrated that achievement of complete remission (CR) after induction therapy and SCT consolidation were independent prognostic indicators for both EFS and OS. We confirm that EFS24 is a strong surrogate endpoint for long-term survival in T-LBL, which is clinically useful for individualized risk reassessment, future clinical trial design, and biomarker discovery validation. Further validation in the context of directed prospective clinical trials is warranted.
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http://dx.doi.org/10.1007/s00277-020-04195-zDOI Listing
December 2020