Publications by authors named "Shaodong Hong"

99 Publications

First-in-human phase I study of TQ-B3139 (CT-711) in advanced non-small cell lung cancer patients with ALK and ROS1 rearrangements.

Authors:
Yuxiang Ma Hongyun Zhao Jinhui Xue Li Liu Nong Yang Yang Zhang Haiyan Yang Shaodong Hong Yi Xiong Zhonghan Zhang Liang Zeng Hui Pan Chunhua Zhou Yongchang Zhang Xunqiang Wang Xi Han Xiaojing Wan Yang Shao Jingwen Liu Yunpeng Yang Yan Huang Yuanyuan Zhao Wenfeng Fang Su Li Li Zhang

Eur J Cancer 2022 Aug 5;173:238-249. Epub 2022 Aug 5.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address:

Background: TQ-B3139 is a novel ALK tyrosine kinase inhibitor (TKI) against a broad range of ALK mutations. The aim of this first-in-human phase I trial was to investigate the safety, tolerability, pharmacokinetics, and clinical efficacy of TQ-B3139 in ALK or ROS1 positive advanced NSCLC patients.

Methods: Following a 3 + 3 design, patients received escalating daily dose of TQ-B3139 (50-800 mg) continuously in 28-day cycles. Expansion stage started at dose of 200 mg twice daily (BID). The primary objectives were the safety, dose-limited toxicities (DLT) and recommended phase II dose (RP2D); secondary objectives included pharmacokinetics and antitumor activity. Non-obligatory tumor samples at baseline were collected and sequenced.

Results: The study enrolled 63 patients. Fifty-nine (93.4%) patients experienced treatment-related adverse events (TRAEs), mostly grade 1-2 vomiting (79.3%), diarrhea (76.1%) or nausea (68.2%). 1 (1/6) DLT occurred at 600 mg BID and 1 (1/3) at 800 mg BID. Based on safety and pharmacokinetics data, the RP2D was selected as 600 mg BID. At a dose level ≥200 mg BID, the overall response rate (ORR) was 76.7% (33/43), and the median progression free survival (mPFS) was 25.2 months (95%CI 11.9-NR) for TKI-naive patients. For TKI-treated patients, the ORR was 37.5% (6/16), and the mPFS was 5.4 months (95%CI 3.6-9.1). The ORR was 66.7% (2/3) in patients with ROS1 fusion at dose level ≥200 mg BID. In patients with measurable brain metastases, the intracranial ORR was 70% (7/10), with median intracranial PFS of 15.9 months. In TKI-treated patients, variant 3 and TP53 alteration were associated with poor PFS.

Conclusions: TQ-B3139 was well-tolerated and exhibited promising anti-tumor activities in patients with ALK and ROS1 positive advanced NSCLC.

Clinical Trial Number: NCT03099330.
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http://dx.doi.org/10.1016/j.ejca.2022.06.037DOI Listing
August 2022

Paclitaxel exposure-toxicity analysis reveals a pharmacokinetic determinant for dose-limiting neutropenia in East-Asian solid tumor patients: results from two prospective, phase II studies.

Authors:
Jinhui Xue Haipeng He Zuan Lin Yuehan Wu Yuehao Lin Hongyun Zhao Salvatore J Salamone Yan Huang Yunpeng Yang Wenfeng Fang Yang Zhang Shaodong Hong Yuxiang Ma Li Zhang

Cancer Chemother Pharmacol 2022 Aug 3. Epub 2022 Aug 3.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No. 651 East Dongfeng Road, Guangzhou, 510060, China.

Purpose: The time of a paclitaxel (PTX) concentration remains above 0.05 μM (Tc > 0.05) has been associated with PTX-induced adverse effects in Caucasians, while limited studies were reported in Asians. This study was aimed to explore the characteristics of Tc > 0.05 and the relationship between PTX exposure and toxicity in East-Asian patients.

Methods: This study was based on two prospective phase II clinical trials and patients with advanced nasopharyngeal cancer (NPC) and non-small cell lung cancer (NSCLC) who were naïve to PTX were included independently. Eligible patients receive PTX (175 mg/m) and carboplatin (AUC = 5) treatment every 3 weeks. PTX pharmacokinetic analysis was accessed. The relationship between PTX exposure and toxicities after first cycle as well as clinical efficacy was evaluated.

Results: A total of 93 NPC and 40 NSCLC patients were enrolled. PTX exposure was consistent in two trials with average Tc > 0.05 duration of 38.8 h and 38.4 h, respectively. Average Tc > 0.05 in patients with grade 3/4 neutropenia was significantly higher than those without severe neutropenia in NPC patients (P = 0.003) and NSCLC patients (P = 0.007). Cut-off value of Tc > 0.05 were identified from the NPC cohort and then verified in the NSCLC cohort, dividing patients into high exposure Tc > 0.05 group (> 39 h) and low exposure group (≤ 39 h). Incidence of grade 3/4 neutropenia were significantly higher in the high exposure group in NPC cohort (43.3% vs 10.0%, P < 0.001) and NSCLC cohort (42.1% vs 9.5%, P = 0.028). No significant relationship between Tc > 0.05 and efficacy were observed.

Conclusion: Patients with PTX Tc > 0.05 duration above 39 h experience more severe neutropenia than those under 39 h. Prospective studies are needed to verify this threshold.
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http://dx.doi.org/10.1007/s00280-022-04456-wDOI Listing
August 2022

Adverse Event Reporting Quality in Cancer Clinical Trials Evaluating Immune Checkpoint Inhibitor Therapy: A Systematic Review.

Authors:
Yuhong Wang Chen Chen Wei Du Yixin Zhou Lina He Shaodong Hong Li Zhang

Front Immunol 2022 7;13:874829. Epub 2022 Jul 7.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: Immunotherapy has become one of the most important breakthroughs in cancer treatment. Consequently, there have been more immuno-oncology (IO) clinical trials for various cancers in recent decades. However, the quality of such trials in reporting adverse events (AE), especially immune-related AE (irAE), has not been comprehensively evaluated.

Methods: We evaluated the harm reporting quality of IO trials. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify all head-to-head phase II and III clinical trials assessing cancer immunotherapy published between January 1, 2010, and December 31, 2021. Publications were assessed using a 16-point harm reporting quality score (HRQS) derived from the 2004 Consolidated Standards of Reporting Trials (CONSORT) extension. The characteristics associated with improved reporting quality were identified with linear regression.

Results: A total of 123 publications were included. The mean HRQS was 11.1 (range, 5-14). The most common poorly reported items were harms addressed in the title (2%), AE collection methodology (3%), the statistical approach for analyzing harms (11%), and the irAE onset patterns and management (adequately reported in 14% and 33% of publications, respectively). The harm information was well described in the publications' Results and Discussion sections (89-99%). The multivariable regression model revealed that higher impact factor (IF) (30
Conclusion: Our findings show that AE reporting in IO randomized trials is suboptimal. Efforts should be made to improve harm reporting and to standardize reporting practices. Improvements in AE reporting would permit more balanced assessment of interventions and would enhance evidence-based IO practice.
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http://dx.doi.org/10.3389/fimmu.2022.874829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301013PMC
July 2022

A CT-based radiomics model to predict subsequent brain metastasis in patients with ALK-rearranged non-small cell lung cancer undergoing crizotinib treatment.

Authors:
Yongluo Jiang Yixing Wang Sha Fu Tao Chen Yixin Zhou Xuanye Zhang Chen Chen Li-Na He Wei Du Haifeng Li Zuan Lin Yuanyuan Zhao Yunpeng Yang Hongyun Zhao Wenfeng Fang Yan Huang Shaodong Hong Li Zhang

Thorac Cancer 2022 06 18;13(11):1558-1569. Epub 2022 Apr 18.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)-based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies.

Methods: A total of 75 eligible patients were enrolled from Sun Yat-sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis-free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log-rank test was performed to describe the difference of BMFS risk.

Results: Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C-index], 0.762; 95% confidence interval [CI], 0.663-0.861) and validation cohort (C-index, 0.724; 95% CI, 0.601-0.847).

Conclusion: We have developed a CT-based radiomics model to predict subsequent BM in patients with non-brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM.
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http://dx.doi.org/10.1111/1759-7714.14386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9161316PMC
June 2022

Optimizing the tumor shrinkage threshold for evaluating immunotherapy efficacy for advanced non-small-cell lung cancer.

Authors:
Wei Du Chen Chen Lin-Feng Luo Li-Na He Yixing Wang Xuanye Zhang Yixin Zhou Zuan Lin Shaodong Hong

J Cancer Res Clin Oncol 2022 Mar 18. Epub 2022 Mar 18.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Purpose: The rise of immune checkpoint inhibitors (ICIs) in recent years has coincided with unusual clinical response patterns. Modification of the sum of longest diameters (SLD)-based threshold that reflecting dynamic change of the tumor burden and predicting response to ICIs, may markedly improve current treatment regimens.

Methods: The baseline and post-treatment SLD of target lesion was recorded and the maximum percent change of the SLD from baseline was designated as SLD-change score. The optimal cut-off value was obtained using the X-tile program. The relationship between SLD-change score and survival outcome (PFS, OS) was evaluated.

Results: 10% cut-off value of SLD-change score was found to be most distinctive for PFS. Responders defined according to this cut-off value showed a significant improvement for PFS and OS. Bone metastasis and brain metastasis were also two independent prognostic factors of PFS and OS, respectively.

Conclusions: 10% SLD change score could discriminate for ICIs treatment response, which holds great promise in promoting the development of precise immunotherapeutic strategy.
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http://dx.doi.org/10.1007/s00432-022-03978-3DOI Listing
March 2022

Assessment of sarcopenia as a predictor of poor overall survival for advanced non-small-cell lung cancer patients receiving salvage anti-PD-1 immunotherapy.

Authors:
Yixing Wang Ping Chen Jinsheng Huang Minghui Liu Dingsheng Peng Zichun Li Tao Chen Shaodong Hong Yixin Zhou

Ann Transl Med 2021 Dec;9(24):1801

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: Sarcopenia, which is defined as the loss of skeletal muscle mass, has been identified as a poor prognostic factor for cancer patients. This study sought to elucidate the effects of sarcopenia on the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving salvage anti-programmed death-1 (PD-1) immunotherapy.

Methods: In total, 105 NSCLC patients receiving second-line anti-PD-1 immunotherapy at the Sun Yat-sen University Cancer Center between January 2015 and December 2017 were enrolled in this study, and detailed patient data were collected. Available lumbar computed tomography images of the patients were analyzed to determine the total skeletal muscle cross-section area. The efficacy of the predictive and prognostic role of sarcopenia in progression-free survival (PFS) and overall survival (OS) was analyzed using the Kaplan-Meier method, and the risk factors were analyzed using Cox analyses.

Results: We found that patients with sarcopenia receiving salvage anti-PD-1 immunotherapy had significantly worse PFS (2.67 . 7.96 months; P<0.001) and OS (9.08 . 21.84 months; P<0.001) than their non-sarcopenic counterparts. We also found that sarcopenia was associated with the neutrophil-to-lymphocyte ratio (NLR) (P=0.041), and that the NLR acts as a predictor of OS.

Conclusions: Sarcopenia was associated with a poor prognosis in advanced NSCLC patients receiving salvage anti-PD-1 immunotherapy. Further research needs to be conducted to identify more biomarkers and the patients most likely to benefit from immunotherapy.
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http://dx.doi.org/10.21037/atm-21-6578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756219PMC
December 2021

Reducing number of target lesions for RECIST1.1 to predict survivals in patients with advanced non-small-cell lung cancer undergoing anti-PD1/PD-L1 monotherapy.

Authors:
Li-Na He Tao Chen Sha Fu Chen Chen Yongluo Jiang Xuanye Zhang Wei Du Haifeng Li Yixing Wang Wael Abdullah Sultan Ali Yixin Zhou Zuan Lin Yunpeng Yang Yan Huang Hongyun Zhao Wenfeng Fang Li Zhang Shaodong Hong

Lung Cancer 2021 Dec 31;165:10-17. Epub 2021 Dec 31.

State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Objectives: The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 provides conventional and standardized response assessment for multiple solid tumors. We investigated the smallest number of target lesions that can be measured without compromising response categorization and survival prediction in patients with advanced non-small-cell lung cancer (aNSCLC) undergoing anti-PD-1/PD-L1 monotherapy.

Material And Methods: 125 aNSCLC patients with at least two measurable lesions undergoing PD-1/PD-L1 inhibitor treatment were retrospectively studied. Tumor measurements allowing up to two lesions per organ and five lesions in total were reviewed. Inter-individual agreement and κ values for inter-method concordance on response status were evaluated based on up to five target lesions versus the largest one through four lesions. C-index was calculated to evaluate the prognostic accuracy of response categorization based on the selected number of target lesions for predicting overall survival (OS). Cox regression analysis was conducted for survival analysis.

Results: The highly consistent response assignment (99.2%) could be obtained when measuring the largest two lesions versus up to five lesions. Using the largest two through four lesions produced κ values of 0.986, 1.000 and 1.000 for response assessment, values significantly higher than those obtained when measuring the largest single lesion (κ = 0.850). C-index for overall survival (OS) was similar when assessing the largest one through five lesions, ranging from 0.646 to 0.654. Cox regression analyses showed that radiological response significantly predicted OS, irrespective of the number of target lesions selected.

Conclusions: Reducing the number of target lesions does not affect OS prediction in aNSCLC patients treated with anti-PD-1/PD-L1 therapy. Considering the high intra-individual and inter-method concordance, using the largest two lesions in total is proposed to assess response.
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http://dx.doi.org/10.1016/j.lungcan.2021.12.015DOI Listing
December 2021

Determinants of survival in advanced non-small cell lung cancer patients treated with anti-PD-1/PD-L1 therapy.

Authors:
Wael Abdullah Sultan Ali Pan Hui Yuxiang Ma Yuehan Wu Yang Zhang Yukun Chen Shaodong Hong Yunpeng Yang Yan Huang Yuanyuan Zhao Wenfeng Fang Hongyun Zhao Li Zhang

Ann Transl Med 2021 Nov;9(22):1639

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: The present study aimed to investigate the determinant factors of survival in patients with pretreated advanced stage non-small cell lung cancer (NSCLC) who received anti-PD-1/PD-L1 therapy.

Methods: In this observational retrospective study, the clinical profiles and laboratory parameters of patients with NSCLC treated with anti-PD-1/PD-L1 therapy were consecutively collected. Lung Immune Prognostic Index (LIPI) was calculated based on the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase level (LDH). Modified Glasgow Prognostic Score (mGPS) was calculated based on serum C reactive protein and albumin, and tumor mutation burden (TMB) was calculated using a targeted next-generation sequencing panel based on 422 cancer-relevant genes. The primary and secondary end points were overall survival (OS) and progression-free survival (PFS), respectively. The Cox regression model was used to identify the potential determinant factors of survival benefit. Trained oncologists at Sun Yat-sen University Cancer Center followed all of the participants through visits to doctors' offices or via telephone calls to determine their clinical status.

Results: Seventy-three patients were included in our study. With a median follow up time of 637 days, there was a significant difference in PFS between patients with high TMB compared to those with low TMB (3.7 2.1 months; P=0.004), while no significant difference was found in OS (14.0 16.4 months; P=0.972). Patients with a good LIPI score had a significantly longer OS compared to patients with a poor LIPI score (19.2 12.6 months; P=0.010). The median OS in patients with a good and a poor mGPS was 16.8 and 4.3 months, respectively (P=0.029). In multivariate analysis, TMB was found to be significantly associated with PFS (HR, 0.38; 95% CI: 0.21-0.69; P=0.002), while LIPI score was found to be significantly associated with OS (HR, 0.50; 95% CI: 0.28-0.89; P=0.012).

Conclusions: In the present study, LIPI score was a significant determinant of OS in patients with advanced NSCLC who received ICIs; however, TMB was only associated with PFS and not associated with OS.
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http://dx.doi.org/10.21037/atm-21-1702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667098PMC
November 2021

Correction to: Hepatotoxicity associated with PD-1 blockade antibodies in cancer patients co-infected with hepatitis B virus.

Authors:
Zuan Lin Xuanye Zhang Yixin Zhou Chen Chen Li-Na He Haifeng Li Yuhong Wang Tao Chen Shaodong Hong Li Zhang

Cancer Immunol Immunother 2022 May;71(5):1257

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

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http://dx.doi.org/10.1007/s00262-021-03112-1DOI Listing
May 2022

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis.

Authors:
Ling Peng Dafeng Lu Yang Xia Shaodong Hong Giovanni Selvaggi Justin Stebbing Yilan Sun Fei Liang

Front Oncol 2021 8;11:754768. Epub 2021 Nov 8.

Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: Targeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.

Methods: PubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration's tool.

Results: Nine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs.

Conclusions: Lorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly.
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http://dx.doi.org/10.3389/fonc.2021.754768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606689PMC
November 2021

Incidence and risk factors of second primary cancer after the initial primary human papillomavirus related neoplasms.

Authors:
Jiayi Shen Huaqiang Zhou Jiaqing Liu Zhonghan Zhang Wenfeng Fang Yunpeng Yang Shaodong Hong Wei Xian Yuxiang Ma Ting Zhou Yaxiong Zhang Hongyun Zhao Yan Huang Li Zhang

MedComm (2020) 2020 Dec 3;1(3):400-409. Epub 2020 Dec 3.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China.

Comprehensive studies in second primary cancer (SPC) after the initial primary human papillomavirus (HPV)-related cancer still remain warranted. We aimed to analyze the incidence and risk factors of SPC after HPV-related cancer. We identified 86 790 patients diagnosed with initial primary HPV-related cancer between 1973 and 2010 in the SEER database. Standardized incidence ratio (SIR) and cumulative incidence were calculated to assess the risk of SPC after HPV-related cancer. The SIR of SPC after HPV-related cancer was 1.60 (95% confidence interval [CI], 1.55-1.65) for male and 1.25 (95% CI, 1.22-1.28) for female. SIR of second primary HPV-related cancer (7.39 [95% CI, 6.26-8.68] male and 4.35 [95% CI, 4.04-4.67] female) was significantly higher than that of HPV-unrelated cancer (1.54 [95% CI, 1.49-1.60] male and 1.16 [95% CI, 1.13-1.19] female). The 5-year cumulative incidence of SPC was 7.22% (95% CI, 6.89-7.55%) for male and 3.72% (95% CI, 3.58-3.88%) for female. Risk factors for SPC included being married and having initial primary cancer (IPC) diagnosed at earlier stage for both genders, and IPC diagnosed at older age as well as surgery performed for female. Patients diagnosed with HPV-related cancer are more likely to develop another primary cancer, compared with the age-specific reference population.
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http://dx.doi.org/10.1002/mco2.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491207PMC
December 2020

PD-1/PD-L1 inhibitor plus chemotherapy versus bevacizumab plus chemotherapy in first-line treatment for non-squamous non-small-cell lung cancer.

Authors:
Hui Yu Ping Chen Liangping Xia Sha Fu Chen Chen Xuanye Zhang Lina He Bei Zhang Yixin Zhou Shaodong Hong

J Immunother Cancer 2021 11;9(11)

State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China

Anti-PD-1)/programmed cell death-ligand 1 (PD-L1) antibody plus platinum-based chemotherapy (PBC) has replaced PBC as first-line treatment for patients with non-squamous (sq) non-small cell lung cancer (NSCLC) lacking targetable driver mutations. However, few studies have directly compared immune checkpoint inhibitor (ICI) plus chemotherapy with bevacizumab plus chemotherapy (beva +chemo) in this setting. Herein, we conducted an indirect comparison for anti-PD-1/PD-L1 antibody plus chemotherapy (ICI +chemo) versus beva +chemo in non-sq NSCLC using the frequentist methods. The main outcomes analyzed include progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Data were subtracted from randomized trials comparing ICI +chemo or beva +chemo against PBC. Fourteen trials involving 6165 patients were included. Direct meta-analyses showed that both ICI +chemo (PFS: HR 0.58, OS: HR 0.73, ORR: relative risk (RR) 1.66) and beva +chemo (PFS: HR 0.74, OS: HR 0.89, ORR: RR 1.62) improved clinical outcomes compared with PBC. Indirect comparison showed that ICI +chemo reduced the risk of disease progression (HR 0.78, 95% CI 0.60 to 1.00) and death (HR 0.82, 95% CI 0.71 to 0.94) compared with beva +chemo. The PFS benefits with ICI +chemo over beva +chemo were non-significant in those with negative PD-L1 expression and non-smokers. In conclusion, ICI +chemo is superior to beva +chemo in first-line treatment for non-sq NSCLC.
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http://dx.doi.org/10.1136/jitc-2021-003431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576478PMC
November 2021

Unsatisfied Reporting Quality of Clinical Trials Evaluating Immune Checkpoint Inhibitor Therapy in Cancer.

Authors:
Chen Chen Yixin Zhou Xuanye Zhang Yuhong Wang Li-Na He Zuan Lin Tao Chen Yongluo Jiang Shaodong Hong Li Zhang

Front Immunol 2021 5;12:736943. Epub 2021 Oct 5.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Background: More and more immune-oncology trials have been conducted for treating various cancers, yet it is unclear what the reporting quality of immune-oncology trials is,and characteristics associated with higher reporting quality.

Objective: This study aims to evaluate the reporting quality of immune-oncology trials.

Methods: The PubMed and Cochrane library were searched to identify all English publications of clinical trials assessing immunotherapy for cancer. Reporting quality of immune-oncology trials was evaluated by a quality score with 11 points derived from the Trial Reporting in Immuno-Oncology (TRIO) statement, which contained two parts: an efficacy score of 6 points and toxicity score of 5 point. Linear regression was used to identify characteristics associated with higher scores.

Results: Of the 10,169 studies screened, 298 immune-oncology trial reports were enrolled. The mean quality score, efficacy score, and toxicity score were 6.46, 3.61, and 2.85, respectively. The most common well-reported items were response evaluation criteria (96.0%) and toxicity grade (98.7%), followed by Kaplan-Meier survival analyses (80.5%). Treatment details beyond progression (12.8%) and toxicity onset time and duration (7.7%) were poorly reported. Multivariate regression revealed that higher impact factor (IF) (IF >20 vs. IF <5, < 0.001), specific tumor type ( = 0.018 for lung, = 0.021 for urinary system, vs. pan cancer), and a certain kind of immune checkpoint blocking agent ( < 0.001 for anti-PD-1 or multiagents, vs. anti-CTLA-4) were independent predictors of higher-quality score. Similar independent predictive characteristics were revealed for high-efficacy score. Only IF >20 had a significant high-toxicity score ( < 0.001).

Conclusion: Immune-oncology trial reports presented an unsatisfied quality score, especially in the reporting of treatment details beyond progression and toxicity onset time and duration. High IF journals have better reporting quality. Future improvement of trial reporting was warranted to the benefit-risk assessment of immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.736943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524036PMC
December 2021

Hepatotoxicity associated with PD-1 blockade antibodies in cancer patients co-infected with hepatitis B virus.

Authors:
Zuan Lin Xuanye Zhang Yixin Zhou Chen Chen Li-Na He Haifeng Li Yuhong Wang Tao Chen Shaodong Hong Li Zhang

Cancer Immunol Immunother 2022 May 14;71(5):1247-1255. Epub 2021 Oct 14.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

The use of anti-programmed cell death-1 (PD-1) antibodies in treating malignancies is increasing; however, most registered clinical trials on anti-PD-1 antibodies exclude patients infected with hepatitis B virus (HBV). This retrospective study aimed to assess hepatotoxicity in cancer patients infected with HBV undergoing anti-PD1 antibody therapy and identify the associated risk factors. A total of 301 cancer patients positive for hepatitis B core antibodies (HbcAb) (negative or positive hepatitis B surface antigen [HBsAg]) who received PD-1 inhibitors were enrolled. The primary and secondary endpoints were the incidence rate of hepatotoxicity related to PD-1 inhibitor treatment, and risk factors associated with hepatic toxicity, respectively. Of the enrolled analyzed, 16.9% (n = 51) developed any grade and 4.7% (n = 14) developed grade 3-4 hepatotoxicity, respectively. Higher risk for any-grade hepatotoxicity development was associated with sero-positive HBsAg (OR = 6.30; P = 0.020), existence of liver involvement (OR = 2.10; P = 0.030), and detectable baseline HBV DNA levels (OR = 2.39; P = 0.012). Patients with prophylactic antiviral therapy decreased hazard for the incidence of grade 3-4 hepatotoxicity (OR = 0.10; P = 0.016). Our results suggested chronic (HBsAg-positive)/resolved (HBsAg-negative and HBcAb-positive) HBV-infected cancer patients are at an increased risk of hepatotoxicity following PD-1 inhibitor therapy. Cancer patients should be tested for HBsAg/HBcAb prior to the commencement of immune checkpoint inhibitor therapy. For patients with chronic/resolved HBV infection, ALT/AST and HBV DNA should be closely monitored during the whole immunotherapy period.
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http://dx.doi.org/10.1007/s00262-021-03082-4DOI Listing
May 2022

Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer.

Authors:
Huaqiang Zhou Yi Hu Rongzhen Luo Yuanyuan Zhao Hui Pan Liyan Ji Ting Zhou Lanjun Zhang Hao Long Jianhua Fu Zhesheng Wen Siyu Wang Xin Wang Peng Lin Haoxian Yang Junye Wang Mengmeng Song Xin Yi Ling Yang Xuefang Xia Yanfang Guan Wenfeng Fang Yunpeng Yang Shaodong Hong Yan Huang Pansong Li Yaxiong Zhang Ningning Zhou

Nat Commun 2021 09 14;12(1):5431. Epub 2021 Sep 14.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.
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http://dx.doi.org/10.1038/s41467-021-25787-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440529PMC
September 2021

Association of hepatitis B virus infection status with outcomes of non-small cell lung cancer patients undergoing anti-PD-1/PD-L1 therapy.

Authors:
Xuanye Zhang Dan Tian Yue Chen Chen Chen Li-Na He Yixin Zhou Haifeng Li Zuan Lin Tao Chen Yuhong Wang Alessandro Russo Ernest Nadal Francesco Passiglia Ross Andrew Soo Satoshi Watanabe Teresa Moran In-Jae Oh Sha Fu Shaodong Hong Li Zhang

Transl Lung Cancer Res 2021 Jul;10(7):3191-3202

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: The aim of this study was to evaluate the safety and survival outcomes of anti-programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) monotherapy in patients with advanced non-small cell lung cancer (NSCLC) and different hepatitis B virus (HBV) infection status.

Methods: Patients with advanced NSCLC and both chronic and/or resolved HBV infection who were treated with anti-PD-(L)1 monotherapy were retrospectively enrolled. The primary endpoint was the safety of PD-1/PD-L1 monotherapy, while the secondary endpoints included the survival outcomes.

Results: Of the 62 eligible patients, 10 (16.1%) were hepatitis B surface antigen (HBsAg) positive [chronic hepatitis B (CHB) infection] and 52 (83.9%) were HBsAg negative and HBcAb positive [resolved hepatitis B (RHB) infection]; 42 (67.7%) patients had at least 1 treatment-related adverse event (AE), with 4 patients (6.5%) developing grade 3 AEs and 6 (9.7%) developing hepatic AEs. One CHB patient experienced HBV reactivation during anti-PD-1 immunotherapy due to the interruption of antiviral prophylaxis. The objective response rate and durable clinical benefit (DCB) rate were 17.7% and 29.0%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 23.6 months [95% confidence interval (CI): 14.4-32.8] and 2.1 months (95% CI: 1.2-3.0), respectively. The DCB rate was significantly higher in the CHB group than in the RHB group (60% 23.1%; P=0.048). Patients with CHB experienced a longer PFS (8.3 2.0 months; P=0.103) and OS (35.0 18.2 months, P=0.119) than did RHB patients.

Conclusions: Anti-PD-(L)1 monotherapy was safe and effective in patients with NSCLC and HBV infection. This population should not be excluded from receiving immunotherapy in routine clinical practice or within clinical trials if HBV biomarkers are monitored and antiviral prophylaxis is properly used.
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http://dx.doi.org/10.21037/tlcr-21-455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350074PMC
July 2021

Gemcitabine Plus Cisplatin Versus Fluorouracil Plus Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: Final Overall Survival Analysis of GEM20110714 Phase III Study.

Authors:
Shaodong Hong Yaxiong Zhang Gengsheng Yu Peijian Peng Jiewen Peng Jun Jia Xuan Wu Yan Huang Yunpeng Yang Qing Lin Xuping Xi Mingjun Xu Dongping Chen Xiaojun Lu Rensheng Wang Xiaolong Cao Xiaozhong Chen Zhixiong Lin Jianping Xiong Qin Lin Conghua Xie Zhihua Li Jianji Pan Jingao Li Shixiu Wu Yingni Lian Quanlie Yang Chong Zhao Wenfeng Fang Li Zhang

J Clin Oncol 2021 10 11;39(29):3273-3282. Epub 2021 Aug 11.

Department of Medical Oncology of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University, Guangzhou, China.

Purpose: GEM20110714 (ClinicalTrials.gov identifier: NCT01528618), the first randomized, phase III study of systemic chemotherapy in recurrent or metastatic nasopharyngeal carcinoma (NPC), reported significant progression-free survival improvement with gemcitabine plus cisplatin (GP) versus fluorouracil plus cisplatin (FP; hazard ratio, 0.55; 95% CI, 0.44 to 0.68; < .001). Data from the final analysis of overall survival (OS) are presented here.

Methods: From February 2012 to October 2015, 362 patients were randomly assigned to receive either GP (gemcitabine 1 g/m once daily on days 1 and 8 and cisplatin 80 mg/m once daily on day 1; n = 181) or FP (fluorouracil 4 g/m in continuous intravenous infusion over 96 hours and cisplatin 80 mg/m once daily on day 1; n = 181) once every 21 days. The primary end point was progression-free survival, which has been previously reported; OS was a secondary end point.

Results: After a median follow-up time of 69.5 months with GP and 69.7 months with FP, 148 (81.8%) and 166 (91.7%) deaths occurred in the GP and FP arms, respectively. The estimated hazard ratio for OS was 0.72 (95% CI, 0.58 to 0.90; two-sided = .004). The median OS was 22.1 months (95% CI, 19.2 to 25.0 months) with GP versus 18.6 months (95% CI, 15.4 to 21.7 months) with FP. The OS probabilities at 1, 3, and 5 years were 79.9% versus 71.8%, 31.0% versus 20.4%, and 19.2% versus 7.8%, respectively. Poststudy therapy was administered in 51.9% and 55.2% of patients in the GP and FP arms, respectively.

Conclusion: Among patients with previously untreated advanced nasopharyngeal carcinoma, those who receive GP have longer OS than those receive FP. Gemcitabine plus cisplatin should be considered a preferred front-line option for these patients.
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http://dx.doi.org/10.1200/JCO.21.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500603PMC
October 2021

Efficacy and safety of PD-L1 inhibitors versus PD-1 inhibitors in first-line treatment with chemotherapy for extensive-stage small-cell lung cancer.

Authors:
Hui Yu Ping Chen Xiuyu Cai Chen Chen Xuanye Zhang Lina He Yixin Zhou Shaodong Hong Bei Zhang

Cancer Immunol Immunother 2022 Mar 23;71(3):637-644. Epub 2021 Jul 23.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Objectives: Programmed cell death-ligand 1 inhibitors plus chemotherapy (PD-L1 + Chemo) have achieved substantial progress in extensive-stage small-cell lung cancer (ES-SCLC). However, evidence about programmed cell death 1 inhibitors plus chemotherapy (PD-1 + Chemo) in SCLC is relatively lacking. Whether PD-1 inhibitors differ from PD-L1 inhibitors in their clinical outcomes remains controversial.

Materials And Methods: We performed a meta-analysis to compare efficacy and safety of PD-L1 + Chemo vs PD-1 + Chemo in ES-SCLC by searching PubMed, Embase, the Cochrane Library, and major oncology conferences. We examined overall survival (OS) as the primary outcome. Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs).

Results: We included four randomized trials (IMpower133, CASPIAN, KEYNOTE-604, and EA5161) with a total of 1553 patients. Direct comparison showed that PD-L1 + Chemo (PFS: hazard ratio [HR] 0.79; OS: HR 0.75) and PD-1 + Chemo (PFS: HR 0.72; OS: HR 0.77) significantly prolonged survival time compared with chemotherapy alone. But PD-L1 + Chemo (relative risk [RR]: 1.07) and PD-1 + Chemo (RR: 1.13) were not superior to chemotherapy alone in terms of ORR. Indirect comparison showed no significant difference in clinical efficacy between PD-L1 + Chemo and PD-1 + Chemo (OS: HR 0.99; PFS: HR 1.10; ORR: RR 0.95). We further stratified patients according to subgroups in terms of OS. In the subgroup of patients with brain metastasis, PD-L1 + Chemo tended to prolong OS (HR: 0.61, 0.28 to 1.32). There were no significant differences between PD-L1 + Chemo and PD-1 + Chemo regarding safety analyses. However, PD-L1 + Chemo exhibited a better safety profile in reducing the risk of treatment discontinuation due to AEs (RR: 0.43, 0.19 to 0.95) and pneumonia (pneumonia of any grade, RR: 0.59, 0.24 to 1.42; pneumonia of grade ≥ 3, RR: 0.37, 0.10 to 1.39).

Conclusions: PD-L1 + Chemo and PD-1 + Chemo provided a significant survival benefit relative to chemotherapy alone for ES-SCLC. The efficacy and safety of PD-L1 + Chemo and PD-1 + Chemo were similar based on current evidence.
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http://dx.doi.org/10.1007/s00262-021-03017-zDOI Listing
March 2022

Baseline and early changes in circulating Serum Amyloid A (SAA) predict survival outcomes in advanced non-small cell lung cancer patients treated with Anti-PD-1/PD-L1 monotherapy.

Authors:
Li-Na He Sha Fu Xuanye Zhang Qiaozhen Hu Wei Du Haifeng Li Tao Chen Chen Chen Yongluo Jiang Yixin Zhou Zuan Lin Yunpeng Yang Yan Huang Hongyun Zhao Wenfeng Fang Li Zhang Shaodong Hong

Lung Cancer 2021 08 28;158:1-8. Epub 2021 May 28.

State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Background: Systemic inflammation plays an important role in carcinogenesis and is associated with overall survival in patients with different cancer types, including those treated with immune checkpoint blockade (ICB). Serum Amyloid A (SAA) is an acute-phase protein and a marker of persistent inflammation. We hypothesized that circulating SAA may predict outcomes in advanced non-small cell lung (aNSCLC) patients treated with PD-1/PD-L1 ICB.

Materials And Methods: This retrospective study included 91 aNSCLC patients who received anti-PD-(L)1 monotherapy in Sun Yat-sen University Cancer Center (Guangzhou, China) between August 2016 and June 2018. We examined the impact of circulating SAA at baseline and 8 (±2) weeks later on overall survival (OS). X-tile program was used to determine the cut-off values which optimized the significance of the split between Kaplan-Meier survival curves. Kaplan-Meier methodology and Cox regression analyses were conducted for survival analyses.

Results: The optimal cut-off value of baseline SAA for OS stratification was 137.6 mg/L. In univariate analysis, both high level of baseline SAA (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.47-5.18; P = 0.002) and lack of early SAA descent (HR, 1.51; 95% CI, 1.11-2.06; P = 0.009) were significantly associated with inferior OS. In multivariate analysis, gender, smoking status, performance status, liver metastasis, neutrophil-to-lymphocyte ratio, baseline SAA and early changes in SAA independently predicted OS (all with P < 0.05). A combined baseline SAA ≥ 137.6 mg/L and without early SAA descent identified a small cohort with remarkably worse OS (median, 3.2 months).

Conclusions: Both high baseline and lack of early decline in circulating SAA are significantly associated with inferior outcomes in aNSCLC patients treated with PD-1/PD-L1 ICB. Combined these two SAA indexes provided improved risk stratification. The prognostic value of this simple, readily-available, and cost-effective biomarker warrants larger, prospective validation before definitive recommendation can be made.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.030DOI Listing
August 2021

Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma.

Authors:
Yuxiang Ma Xi Chen Ao Wang Hongyun Zhao Qingguang Lin Hua Bao Yang Zhang Shaodong Hong Wanxiangfu Tang Yan Huang Yunpeng Yang Xue Wu Yang Shao Wenfeng Fang Li Zhang

J Immunother Cancer 2021 03;9(3)

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

Background: Anti-programmed death (PD)-1 therapy has recently been used in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The long-term survival and its biomarkers responding to anti-PD-1 treatment in patients with R/M NPC remain unclear.

Methods: Patients with R/M NPC were enrolled between March 2016 and January 2018 from two phase I clinical trials. The median follow-up period was 24.7 months. Eligible patients progressed on standard chemotherapy had measurable disease by Response Evaluation Criteria in Solid Tumor V.1.1. Non-obligatory contemporaneous tumor samples were collected for whole-exome sequencing. The primary outcome was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were secondary outcomes assessed in all patients.

Results: Among 124 evaluable patients, anti-PD-1 therapy achieved an ORR of 29.8% and a durable clinical benefit rate of 60.5%. The median OS (mOS) was 17.1 months (95% CI 14.2 to 24.7), median PFS (mPFS) was 3.8 months (95% CI 3.4 to 6.0), and median DOR was 9.5 months. Significant OS benefit from treatment was observed in patients without liver metastasis (23.8 vs 13.3 months, p=0.006). Copy number deletion in genes encoding granzyme B or granzyme H () was associated with poor treatment outcome (mPFS altered vs wildtype: 1.7 vs 3.6 months, p=0.03; mOS altered vs wildtype: 10.1 vs 18 months, p=0.012).

Conclusions: Anti-PD-1 treatment provided promising clinical benefit in pretreated patients with R/M NPC. Copy number loss in either or genes was associated with reduced survival.
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http://dx.doi.org/10.1136/jitc-2020-002014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978327PMC
March 2021

Intratumoral heterogeneity as a predictive biomarker in anti-PD-(L)1 therapies for non-small cell lung cancer.

Authors:
Wenfeng Fang Haoxuan Jin Huaqiang Zhou Shaodong Hong Yuxiang Ma Yaxiong Zhang Xiaofan Su Longyun Chen Yunpeng Yang Shengqiang Xu Yuwei Liao Yuming He Hongyun Zhao Yan Huang Zhibo Gao Li Zhang

Mol Cancer 2021 02 23;20(1):37. Epub 2021 Feb 23.

Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangzhou Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China.

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http://dx.doi.org/10.1186/s12943-021-01331-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901210PMC
February 2021

Pre-Treatment Tumor Growth Rate Predicts Clinical Outcomes of Patients With Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD-1/PD-L1 Therapy.

Authors:
Li-Na He Xuanye Zhang Haifeng Li Tao Chen Chen Chen Yixin Zhou Zuan Lin Wei Du Wenfeng Fang Yunpeng Yang Yan Huang Hongyun Zhao Shaodong Hong Li Zhang

Front Oncol 2020 19;10:621329. Epub 2021 Jan 19.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Tumor growth rate (TGR; percent size change per month [%/m]) is postulated as an early radio-graphic predictor of response to anti-cancer treatment to overcome limitations of RECIST. We aimed to evaluate the predictive value of pre-treatment TGR (TGR) for outcomes of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1/PD-L1 monotherapy. We retrospectively screened all aNSCLC patients who received PD-1 axis inhibitors in Sun Yat-Sen University Cancer Center between August 2016 and June 2018. TGR was calculated as the percentage change in tumor size per month (%/m) derived from two computed tomography (CT) scans during a "wash-out" period before the initiation of PD-1 axis inhibition. Final follow-up date was August 28, 2019. The X-tile program was used to identify the cut-off value of TGR based on maximum progression-free survival (PFS) stratification. Patients were divided into two groups per the selected TGR cut-off. The primary outcome was the difference of PFS between the two groups. The Kaplan-Meier methods and Cox regression models were performed for survival analysis. A total of 80 eligible patients were included (54 [67.5%] male; median [range] age, 55 [30-74] years). Median (range) TGR was 21.1 (-33.7-246.0)%/m. The optimal cut-off value of TGR was 25.3%/m. Patients with high TGR had shorter median PFS (1.8 months; 95% CI, 1.6 - 2.1 months) than those with low TGR (2.7 months; 95% CI, 0.5 - 4.9 months) ( = 0.005). Multivariate Cox regression analysis revealed that higher TGR independently predicted inferior PFS (hazard ratio [HR] 1.97; 95% CI, 1.08-3.60; = 0.026). Higher TGR was also significantly associated with less durable clinical benefit rate (34.8% vs. 8.8%, = 0.007). High pre-treatment TGR was a reliable predictor of inferior PFS and clinical benefit in aNSCLC patients undergoing anti-PD-1/PD-L1 monotherapy. The findings highlight the role of TGR as an early biomarker to predict benefit from immunotherapy and could allow tailoring patient's follow-up.
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http://dx.doi.org/10.3389/fonc.2020.621329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863973PMC
January 2021

MDM2/4 amplification predicts poor response to immune checkpoint inhibitors: a pan-cancer analysis.

Authors:
Wenfeng Fang Huaqiang Zhou Jiayi Shen Jianwen Li Yaxiong Zhang Shaodong Hong Li Zhang

ESMO Open 2020 30;5(1):e000614. Epub 2020 Sep 30.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address:

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http://dx.doi.org/10.1136/esmoopen-2019-000614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046406PMC
July 2021

Efficacy and Tolerability of Erlotinib 100 mg/d vs. Gefitinib 250 mg/d in EGFR-Mutated Advanced Non-small Cell Lung Cancer (E100VG250): An Open-Label, Randomized, Phase 2 Study.

Authors:
Shen Zhao Zhen Zhang Wenfeng Fang Yaxiong Zhang Zhonghan Zhang Shaodong Hong Yuxiang Ma Ting Zhou Yunpeng Yang Yan Huang Hongyun Zhao Li Zhang

Front Oncol 2020 10;10:587849. Epub 2020 Nov 10.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.

Erlotinib-based combination therapy leads to increased efficacy but also toxicity for EGFR-mutated NSCLC. Reducing the dose of erlotinib could improve treatment tolerability, but few evidences are available regarding its efficacy at reduced dose. This randomized phase-2 study intends to compare the efficacy and tolerability between lower dose erlotinib (100 mg/d) and standard dose gefitinib (250 mg/d) in EGFR-mutated NSCLC. Patients with EGFR-mutated advanced NSCLC were randomized at 1:1 ratio to receive erlotinib 100 mg/d or gefitinib 250 mg/d until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). Between April 2013 and September 2018, 171 patients were randomized to receive erlotinib ( = 85) and gefitinib ( = 86); 74 in the erlotinib group and 83 in the gefitinib group were include in analysis. DCR with erlotinib and gefitinib were 91% [95% CI 81.7-95.3] and 93% [85.1-96.6], respectively ( = 0.613). Response rate was 62% [50.8-72.4] in the erlotinib group and 53% [42.4-63.4] in the gefitinib group ( = 0.247). No significant difference was observed between erlotinib and gefitinib in median progression-free survival [10.1 vs. 11.3 months, HR = 1.295 [0.893-1.879], = 0.171] and median overall survival [26.6 vs. 28.7 months, HR = 0.999 [0.637-1.569], = 0.998]. Subgroup analyses by line of treatment, EGFR subtypes and status of central nervous system (CNS) metastasis found similar results. More toxicity [any-grade, 80 [96%] vs. 66 [89]; grade 3-4, 11 [13%] vs. 4 [5%]] and toxicity-related discontinuation [10 [12%] vs. 3 [4%]] occurred with gefitinib compared with erlotinib. But no significant difference was observed. Lower dose erlotinib (100 mg/d) achieved comparable efficacy compared with standard dose gefitinib (250 mg/d) in EGFR-mutated NSCLC. https://clinicaltrials.gov, identifier: NCT01955421.
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http://dx.doi.org/10.3389/fonc.2020.587849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683781PMC
November 2020

Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma by Targeting the Epidermal Growth Factor Receptor Combined with Gemcitabine Plus Platinum.

Authors:
Chen Chen Xuanye Zhang Yixin Zhou Sha Fu Zuan Lin Shaodong Hong Li Zhang

Cancer Manag Res 2020 20;12:10353-10360. Epub 2020 Oct 20.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China.

Purpose: The purpose of this study was to evaluate the anti-tumor activity and safety of anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with gemcitabine plus platinum (GP) as a first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC).

Patients And Methods: This retrospective study analyzed RM-NPC patients at Sun Yat-sen University Cancer Center who received anti-EGFR antibody plus GP as a first-line treatment between July 2007 and November 2018. Survival analyses were performed using the Kaplan-Meier method with Log rank test. Cox proportional hazards model was used for the multivariate analysis.

Results: A total of 84 patients were enrolled. The median progression-free survival (PFS) was 10.3 months (95% CI, 6.9-13.6 months), and the median overall survival (OS) was 42.8 months (95% CI, 24.6-60.9 months). The objective response rate and disease control rate were 67.9% and 92.9%, respectively. The multivariate analysis identified a higher baseline EBV DNA level as a risk factor for both PFS (P=0.025) and OS (P=0.013). Additionally, age≥44 years (P =0.003), non-cisplatin (P= 0.009), and poor KPS (≤80) (P =0.034) were other risk factors for OS. The most common adverse events were leukopenia (n=73, 86.9%). The most common grade 3-4 AEs were leukopenia (n=30, 35.7%) and thrombocytopenia (n=22, 26.2%).

Conclusion: Anti-EGFR monoclonal antibody plus GP achieved promising antitumor activity with a tolerable toxicity profile in RM-NPC as a first-line treatment. Randomized clinical trials are warranted to compare the efficacy of GP with or without anti-EGFR antibody in these patients.
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http://dx.doi.org/10.2147/CMAR.S275947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585779PMC
October 2020

Mendelian randomization study indicates lack of causal relationship between physical activity and lung cancer.

Authors:
Wei Xian Jiayi Shen Huaqiang Zhou Jiaqing Liu Yaxiong Zhang Zhonghan Zhang Ting Zhou Shaodong Hong Yunpeng Yang Wenfeng Fang Hongyun Zhao Yan Huang Li Zhang

J Cancer Res Clin Oncol 2021 Jan 28;147(1):177-181. Epub 2020 Sep 28.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China.

Background: Previous researches have indicated physical activity (PA) may be associated with lower risk of lung cancer. However, causal relationship between PA and risk of lung cancer is not clear. We aimed to inspect the causal effect of PA on lung cancer.

Methods: We analyzed summary data of accelerator-measured PA and lung cancer from the genome-wide association study (GWAS) using two-sample Mendelian randomization (MR) method. We obtained summary data of accelerator-measured PA from UK Biobank, data of lung cancer patients from Consortium and International Lung Cancer Consortium (ILCCO) to investigate possible causal effect of PA on lung cancer.

Results: According to result of MR using inverse variance weighted method (IVW), we found that genetically predicted higher PA level did not causally decrease risk of lung cancer (OR 0.95, 95% CI 0.88-1.03, p = 0.238). Results of MR-Egger and weighted median method were consistent with IVW method.

Conclusion: Our mendelian randomization study showed that genetically higher PA is not causally associated with risk of lung cancer. More researches are needed to investigate relationship between PA and lung cancer.
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http://dx.doi.org/10.1007/s00432-020-03409-1DOI Listing
January 2021

The perception gap of chemotherapy-induced adverse events between doctors and cancer patients: an observational study in China.

Authors:
Juan Yu Zhen Zhang Huaqiang Zhou Xia Liu Yan Huang Wenfeng Fang Yunpeng Yang Shaodong Hong Ting Zhou Yaxiong Zhang Gang Chen Shen Zhao Zhonghan Zhang Yuxiang Ma Hongyun Zhao Ruizhen Gao Li Zhang

Support Care Cancer 2021 Mar 29;29(3):1543-1548. Epub 2020 Jul 29.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China.

Introduction: Patient-reported outcomes (PROs) have been widely accepted in western countries. However, limited attention has been given to PROs in China due to a lack of research on the agreement between doctors' and patients' reports of adverse events. This study aims to reveal the perception gap of chemotherapy-induced adverse events between doctors and cancer patients in China.

Methods: An observational study was administered at Sun Yat-Sen University Cancer Center (SYSUCC). Totally, 200 adult cancer patients undergoing chemotherapy participated. Patient reports were collected by nurses via telephone. Doctor reports were collected by nurses based on their medical records. The agreement between doctors and patients was analyzed by Cohen's κ.

Results: Agreement between doctors and patients varied among different symptoms: 0.26 for nausea/vomiting, 0.49 for constipation, 0.63 for diarrhea, 0.65 for general pain, and 0.76 for rash. Doctors' underreporting rates were 70% for nausea/vomiting, 50% for diarrhea, 38% for rash, 33% for constipation, and 29% for general pain.

Conclusions: The perception gap of chemotherapy-induced adverse events between doctors and patients exists in China, especially regarding subjective symptoms. Introduction of PROs in both clinical trials and routine clinical practice should be considered in China.
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http://dx.doi.org/10.1007/s00520-020-05649-wDOI Listing
March 2021

mutation genotypes affect efficacy and resistance mechanisms of osimertinib in T790M-positive NSCLC patients.

Authors:
Qiufan Zheng Yan Huang Hongyun Zhao Yunpeng Yang Shaodong Hong Xue Hou Yuanyuan Zhao Yuxiang Ma Ting Zhou Yaxiong Zhang Wenfeng Fang Li Zhang

Transl Lung Cancer Res 2020 Jun;9(3):471-483

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.

Background: Osimertinib is a potent third-generation tyrosine kinase inhibitor (TKI) with robust activity in advanced -mutant non-small cell lung cancer (NSCLC), including those with T790M resistance mutation. However, a broad interpatient variability was observed. This study aimed to evaluate whether -mutant genotypes affect the clinical outcomes and resistance mechanisms in T790M-positive NSCLC patients receiving osimertinib therapy.

Methods: All NSCLC patients treated with osimertinib in our institute were screened. We included those with known -mutant genotypes and T790M positivity. Clinical outcomes including objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS), were evaluated and compared between different genotypes. Patients with next-generation sequencing testing or tumor rebiopsy after osimertinib treatment were analyzed for resistance mechanisms.

Results: ORR, CBR, PFS, and OS were all non-significantly different among patients harboring exon 19 deletion (19Del, n=136), L858R (n=93), and uncommon mutations (n=6). However, a subset of tumors with deletion starting at E746 (ΔE746, n=98), but not non-ΔE746 tumors (n=38), had better clinical outcomes than L858R tumors (n=93). Frequencies of T790M loss and C797S acquisition after osimertinib treatment were similar between 19Del (n=56) and L858R tumors (n=33). However, compared with L858R tumors (n=33), those with 19Del ΔE746 subtype (n=40) had a higher whereas non-ΔE746 subtype (n=16) had a similar frequency of acquired C797S mutation. Combined analysis of our cohort and public cohort confirmed these findings.

Conclusions: Our findings indicate that the 19Del subtypes affect the clinical outcomes and resistance mechanisms to osimertinib in T790M-positive patients. Identifying patients with relatively worse treatment outcomes may be informative for establishing new therapies for these patients.
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http://dx.doi.org/10.21037/tlcr.2020.03.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354104PMC
June 2020

Combinatorial assessment of ctDNA release and mutational burden predicts anti-PD(L)1 therapy outcome in nonsmall-cell lung cancer.

Authors:
Wenfeng Fang Yuxiang Ma Jiani C Yin Huaqiang Zhou Fufeng Wang Hua Bao Ao Wang Xue Wu Shaodong Hong Yunpeng Yang Yan Huang Hongyun Zhao Yang W Shao Li Zhang

Clin Transl Med 2020 Jan;10(1):331-336

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

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http://dx.doi.org/10.1002/ctm2.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240844PMC
January 2020

Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer.

Authors:
Zhonghan Zhang Yang Zhang Fan Luo Yuxiang Ma Wenfeng Fang Jing Zhan Su Li Yunpeng Yang Yuanyuan Zhao Shaodong Hong Ting Zhou Yaxiong Zhang Shen Zhao Yan Huang Hongyun Zhao Li Zhang

Clin Transl Med 2020 Jun 4;10(2):e33. Epub 2020 Jun 4.

Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.

Background: Dual blockade of both EGFR and VEGFR pathways in EGFR-mutant NSCLC have shown enhanced antitumor efficacy versus EGFR-TKIs alone. Apatinib is an orally effective VEGFR-2 tyrosine kinase inhibitor (TKI). This pilot study aims to evaluate the tolerability, pharmacokinetic profile, and antitumor activity of apatinib plus gefitinib as a therapy for EGFR-mutant advanced NSCLC.

Methods: Advanced non-squamous NSCLC participants harbored with the EGFR 19 deletion or the 21 L858R point mutation were included. There were two cohorts: Cohort A: apatinib 500 mg + gefitinib 250 mg. Cohort B: apatinib 250 mg + gefitinib 250 mg. The primary endpoint was safety profile. Other endpoints consisted of PK analysis, objective response rate (ORR), and progression-free survival (PFS). Exploratory analysis was conducted using next-generation sequencing of plasma circulating-tumor DNA.

Results: Between July 2016 and April 2017, 13 of NSCLC patients were recruited. Six patients were pooled in Cohort A, while seven patients were in Cohort B. Adverse events (AEs) were tolerable (mostly grade 1-2) and the treatment-related AEs were similar in both cohorts: rash (100% vs 71.4%), diarrhea (66.7% vs 71.4%), hypertension (66.7% vs 71.4%), proteinuria (66.7% vs 42.9%), and hand-foot skin reaction (33.3% vs 28.6%). The area under plasma concentration-time curve for the steady state of apatinib was 2864.73 ± 2605.54 ng mL h in Cohort A and 2445.09 ± 1550.89 ng mL h in Cohort B. Of the 11 patients evaluable for efficacy, Cohort A achieved an ORR of 80.0% and reached a median PFS of 19.2 months, while it was 83.3% and 13.4 months in Cohort B. Patients without a concomitant mutation at baseline had a prolonged PFS tendency (20.99 months v 13.21 months, P = .0624). The EGFR-T790M mutation remained the dominant resistance mechanism.

Conclusion: Apatinib (500 mg) plus gefitinib (250 mg) showed a tolerable safety profile and encouraging antitumor activity for advanced EGFR-mutant NSCLC in the first-line setting. Phase III trials of apatinib (500 mg) plus gefitinib (250 mg) are warranted.

Trial Registration: Clinicaltrials.gov, NCT02824458, date of registration June 23, 2016.
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http://dx.doi.org/10.1002/ctm2.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403827PMC
June 2020
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