Jianhua Shi

Bio: Jianhua Shi is an academic researcher from Southeast University. The author has contributed to research in topics: Clinical endpoint & Placebo. The author has an hindex of 11, co-authored 35 publications receiving 390 citations.

Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non–Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial

Abstract: Importance Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug’s efficacy in advanced non–small cell lung cancer (NSCLC). Objective To investigate the efficacy of anlotinib on overall survival of patients with advanced NSCLC progressing after second-line or further treatment. Design, Setting, and Participants The ALTER 0303 trial was a multicenter, double-blind, phase 3 randomized clinical trial designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC. Patients from 31 grade-A tertiary hospitals in China were enrolled between March 1, 2015, and August 31, 2016. Those aged 18 to 75 years who had histologically or cytologically confirmed NSCLC were eligible (n = 606), and those who had centrally located squamous cell carcinoma with cavitary features or brain metastases that were uncontrolled or controlled for less than 2 months were excluded. Patients (n = 440) were randomly assigned in a 2-to-1 ratio to receive either 12 mg/d of anlotinib or a matched placebo. All cases were treated with study drugs at least once in accordance with the intention-to-treat principle. Main Outcomes and Measures The primary end point was overall survival. The secondary end points were progression-free survival, objective response rate, disease control rate, quality of life, and safety. Results In total, 439 patients were randomized, 296 to the anlotinib group (106 [36.1%] were female and 188 [64.0%] were male, with a mean [SD] age of 57.9 [9.1] years) and 143 to the placebo group (46 [32.2%] were female and 97 [67.8%] were male, with a mean [SD] age of 56.8 [9.1] years). Overall survival was significantly longer in the anlotinib group (median, 9.6 months; 95% CI, 8.2-10.6) than the placebo group (median, 6.3 months; 95% CI, 5.0-8.1), with a hazard ratio (HR) of 0.68 (95% CI, 0.54-0.87;P = .002). A substantial increase in progression-free survival was noted in the anlotinib group compared with the placebo group (median, 5.4 months [95% CI, 4.4-5.6] vs 1.4 months [95% CI, 1.1-1.5]; HR, 0.25 [95% CI, 0.19-0.31];P Conclusions and Relevance Among the Chinese patients in this trial, anlotinib appears to lead to prolonged overall survival and progression-free survival. This finding suggests that anlotinib is well tolerated and is a potential third-line or further therapy for patients with advanced NSCLC. Trial Registration ClinicalTrials.gov identifier:NCT02388919

Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02).

Abstract: PURPOSEAs yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a n...

Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled Phase 2 study.

Abstract: This study aimed to evaluate the efficacy and safety of anlotinib as a third-line and subsequent treatment for patients with small cell lung cancer (SCLC). We conducted this Phase 2 trial at 11 institutions in China. Patients with pathologically confirmed SCLC who failed at least two lines of chemotherapy were enrolled. Subjects were randomly assigned in a 2:1 ratio to receive either anlotinib 12 mg orally once daily for 14 days every 3 weeks or placebo. The primary endpoint was progression-free survival (PFS). Between March 30, 2017 and June 8, 2018, a total of 82 and 38 patients were randomly assigned to receive anlotinib and placebo. The median PFS was significantly longer in the anlotinib group compared with the placebo group (4.1 months [95% confidence interval (CI), 2.8–4.2] vs 0.7 months [95% CI, 0.7–0.8]; hazard ratio (HR) 0.19 [95% CI, 0.12–0.32], p < 0.0001). Overall survival (OS) was significantly longer with anlotinib than placebo (7.3 months [95% CI, 6.1–10.3] vs 4.9 months [95% CI, 2.7–6.0]; HR 0.53 [95% CI, 0.34–0.81], p = 0.0029). Anlotinib as a third-line or subsequent treatment for Chinese patients with SCLC showed improved PFS and OS than placebo with favourable safety profile. ClinicalTrials.gov, number NCT03059797.

Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+).

Abstract: 9519Background: There are unmet medical needs for pts with METex14+ NSCLC. PSC is a rare type of NSCLC with high incidence of MET exon 14 mutations and poor prognosis. Savolitinib (AZD6094, HMPL-50...

Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study.

Abstract: Summary Background Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients. Methods ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or irinotecan (180 mg/m2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov , NCT03099382 , and is closed to new participants. Findings From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1–12·8) in the camrelizumab group and 6·2 months (3·6–10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8–9·7) in the camrelizumab group and 6·2 months (5·7–6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57–0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [ Interpretation Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China. Funding Jiangsu Hengrui Medicine.

Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development.

Abstract: Anlotinib is a new, orally administered tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit Compared to the effect of placebo, it improved both progression-free survival (PFS) and overall survival (OS) in a phase III trial in patients with advanced non-small-cell lung cancer (NSCLC), despite progression of the cancer after two lines of prior treatments Recently, the China Food and Drug Administration (CFDA) approved single agent anlotinib as a third-line treatment for patients with advanced NSCLC Moreover, a randomized phase IIB trial demonstrated that anlotinib significantly prolonged the median PFS in patients with advanced soft tissue sarcoma (STS) Anlotinib also showed promising efficacy in patients with advanced medullary thyroid carcinoma and metastatic renal cell carcinoma (mRCC) The tolerability profile of anlotinib is similar to that of other tyrosine kinase inhibitors that target VEGFR and other tyrosine kinase-mediated pathways; however, anlotinib has a significantly lower incidence of grade 3 or higher side effects compared to that of sunitinib We review the rationale, clinical evidence, and future perspectives of anlotinib for the treatment of multiple cancers

Emerging therapies for small cell lung cancer.

Abstract: Currently, chemotherapy remains the standard treatment for first- and second-line management of small cell lung cancer (SCLC). Immunotherapy has made progress in the treatment of SCLC, and nivolumab, pembrolizumab, atezolizumab, and durvalumab have led to significant improvements in clinical outcomes of SCLC. Regarding options in other classes of therapy, the cytotoxic drug lurbinectedin was granted orphan drug status based on a remarkable objective response rate of 39.3%. In addition, an increase in progression-free survival (PFS) was achieved in a phase II study of anlotinib (ALTER 1202). Future prospects for even better outcomes in SCLC lie in novel ways to integrate immunotherapy and small-molecule TKI drugs. Innovative clinical trial designs are needed to efficiently explore the increasing number of options with new drugs and new combinations thereof for SCLC.

Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor.

Abstract: Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase show unexpected adverse effects and limited anticancer efficacy. In the present study, we detailed the pharmacological properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP-binding pocket of VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC50 <1 nmol/L) for VEGFR2 relative to other tyrosine kinases. Concordant with this activity, anlotinib inhibited VEGF-induced signaling and cell proliferation in HUVEC with picomolar IC50 values. However, micromolar concentrations of anlotinib were required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibited HUVEC migration and tube formation; it also inhibited microvessel growth from explants of rat aorta in vitro and decreased vascular density in tumor tissue in vivo. Compared with the well-known tyrosine kinase inhibitor sunitinib, once-daily oral dose of anlotinib showed broader and stronger in vivo antitumor efficacy and, in some models, caused tumor regression in nude mice. Collectively, these results indicate that anlotinib is a well-tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in tumor growth, and support ongoing clinical evaluation of anlotinib for a variety of malignancies.

Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy

Abstract: Angiogenesis has always been the topic of major scientific interest in the field of malignant tumors. Nowadays, targeting angiogenesis has achieved success in various carcinomas by several mechanisms, including the use of anti-angiogenic small molecule receptor tyrosine kinase inhibitors (TKIs). The development of TKIs targeting pro-angiogenic receptors, mainly vascular endothelial growth factor receptor (VEGFR) family, have significantly improved the outcome of certain types of cancers, like renal cell carcinoma, hepatocellular carcinoma, and colorectal carcinoma. However, the general response rate is not very satisfactory. The particular toxicity profile and resistance to anti-angiogenic targeted agents are unavoidable, and no specific marker is available to screen responsive patients to TKIs for precision therapy. To date, about 11 anti-angiogenic TKIs with different binding capacities to angiogenic receptor tyrosine kinase have been approved for the treatment of patients with advanced cancers. This review presents all approved anti-angiogenic small molecule receptor TKIs so far with an emphasis on their indications and clinical efficacy. We also discuss the combination between TKIs and immune checkpoint blockade inhibitors based on the most recent exciting outcome in immunotherapy.