Baolan Li

A multicenter, open-label, randomized phase II controlled study of rh-endostatin (Endostar) in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer

Background: Based on promising efficacy in a single-arm study, a randomized phase II trial was designed to compare the efficacy and safety of adding rh-endostatin (Endostar) to first-line standard etoposide and carboplatin (EC) chemotherapy for treatment of extensive-stage small-cell lung cancer. Methods: One hundred forty Chinese patients with pathologically confirmed, extensive-stage small-cell lung cancer were randomly assigned to EC alone or rh-endostatin + EC for 4–6 cycles, followed by single-agent rh-endostatin until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, Objective response rate (ORR), and quality of life. Results: Median PFS was 6.4 months with rh-endostatin + EC (n = 69) and 5.9 months with EC (n = 69) (hazard ratio 0.8 [95% confidence interval 0.6–1.1]). PFS was significantly higher with rh-endostatin + EC than with EC (hazard ratio 0.4 [0.2–0.9; p = 0.020]) in female. Median overall survival was similar in both groups (12.1 versus 12.4 months, respectively [p = 0.82]). ORR was higher in the rh-endostatin + EC group (75.4%) than in the EC group (66.7%) (p = 0.348). The efficacy of rh-endostatin + EC relative to that of EC was reflected by greater improvements in patient-assessed quality of life scores after 4 and 6 weeks of treatment. There was no difference between each regimen in the incidence of nonhematological or Grade III–IV hematological toxicities. Conclusions: Addition of rh-endostatin to EC for the treatment of extensive-stage small-cell lung cancer had an acceptable toxicity profile, but did not improve overall survival, PFS, and ORR.

Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302).

Background:Anlotinib (AL3818) is a novel multitarget tyrosine kinase inhibitor, inhibiting tumour angiogenesis and proliferative signalling. The objective of this study was to assess the safety and efficacy of third-line anlotinib for patients with refractory advanced non-small-cell lung cancer (RA-NSCLC).Methods:Eligible patients were randomised 1 : 1 to receive anlotinib (12 mg per day, per os; days 1–14; 21 days per cycle) or a placebo. The primary end point was progression-free survival (PFS).Results:A total of 117 eligible patients enrolled from 13 clinical centres in China were analysed in the full analysis set. No patients received immune check-point inhibitors and epidermal growth factor receptor status was unknown in 60.7% of the population. PFS was better with anlotinib compared with the placebo (4.8 vs 1.2 months; hazard ratio (HR)=0.32; 95% confidence interval (CI), 0.20–0.51; P<0.0001), as well as overall response rate (ORR) (10.0%; 95% CI, 2.4–17.6% vs 0%; 95% CI, 0–6.27%; P=0.028). The median overall survival (OS) was 9.3 months (95% CI, 6.8–15.1) for the anlotinib group and 6.3 months (95% CI, 4.3–10.5) for the placebo group (HR=0.78; 95% CI, 0.51–1.18; P=0.2316). Adverse events were more frequent in the anlotinib than the placebo group. The percentage of grade 3–4 treatment-related adverse events was 21.67% in the anlotinib group.Conclusions:Anlotinib as a third-line treatment provided significant PFS benefits to patients with RA-NSCLC when compared with the placebo, and the toxicity profiles showed good tolerance.

Efficacy and safety of third-line treatment with anlotinib in patients with refractory advanced non-small-cell lung cancer (ALTER-0303): a randomised, double-blind, placebo-controlled phase 3 study

Abstract Background Anlotinib hydrochloride, an oral tyrosine kinase inhibitor targeting VEGFR, FGFR, PDGFR, and c-kit, showed promising efficacy in a phase 2 study. Here, we evaluated the efficacy and safety of anlotinib as third-line treatment for advanced non-small-cell lung cancer. Methods We did a randomised, double-blind, placebo-controlled phase 3 trial (ALTER-0303) at 31 sites. Eligible patients with stage 3B/4 non-small-cell lung cancer who progressed after at least two lines of previous therapies were randomly assigned (2:1) to receive anlotinib (12 mg once a day from day 1 to 14 of a 21-day cycle) or placebo until progression or intolerable toxicity. Enrolled patients harbouring EGFR or ALK mutations must have failed in previous match-targeted therapies. The primary endpoint was overall survival. This trial is registered with ClinicalTrials, number NCT02388919. Findings Between February, 2015, and August, 2016, we randomly assigned 437 patients. The baseline characteristics of the anlotinib group (n=294) and placebo group (n=143) were well balanced in age, gender, ECOG performance status, and gene status. With 292 overall survival events (67%), a significant improvement in overall survival was observed in the anlotinib group compared with the placebo group (hazard ratio 0·68, 95% CI 0·54–0·87 p=0·0018), according to investigator-assessed results (table). Interpretation The ALTER-0303 trial met its primary endpoint; anlotinib significantly improved overall survival in advanced non-small-cell lung cancer with a manageable safety profile. The results strongly suggest that anlotinib should be considered as a candidate for the third-line treatment or beyond in advanced non-small-cell lung cancer. Funding Chia-tai Tianqing Pharmaceutical Co Ltd.

Quality of life results from a randomized, double-blinded, placebo-controlled, multi-center phase III trial of anlotinib in patients with advanced non-small cell lung cancer

OBJECTIVES Anlotinib is a novel multi-target tyrosine Kinase inhibitor that inhibits VEGFR2/3, FGFR1-4, PDGFD α/β, c-Kit and Ret. In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small-cell lung cancer (NSCLC) patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study assessed quality of life (QoL) in these patients. METHODS Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. The QoL were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the associated EORTC Quality of Life Lung Cancer Specific Module (QLQ-LC13) at baseline, end of cycle 1, end of every two cycles, and at the final visit. The analyses were conducted in the first 6 cycles. Differences in scores of 10 points or more between two arms or from baseline were considered clinically meaningful. RESULTS A total of 437 patients were assigned to anlotinib (n = 294) and placebo (n = 143). The completion rates of the QoL questionnaires were from 69.9% to 97.0%. Mean scores of QLQ-C30 and QLQ-LC13 subscales were similar in the anlotinib and placebo arms at baseline. Compared to placebo, anlotinib improved role functioning, social functioning, dyspnea, insomnia, constipation and financial problems. Only sore mouth or tongue symptom was worse in the anlotinib arm than in the placebo arm. CONCLUSIONS Anlotinib improved quality of life versus placebo in advanced NSCLC patients who had received at least two previous chemotherapies. The QoL analyses provided evidence that anlotinib should be a choice for the third-line treatment or beyond in advanced NSCLC.

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

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 < .001). Considerable improvement in objective response rate and disease control rate was observed in the anlotinib group over the placebo group. The most common grade 3 or higher adverse events in the anlotinib arm were hypertension and hyponatremia. 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

A Randomized Multicenter Phase III Study of Single Administration of Mecapegfilgrastim (HHPG-19K), a Pegfilgrastim Biosimilar, for Prophylaxis of Chemotherapy-Induced Neutropenia in Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC)

BACKGROUND Mecapegfilgrastim (code name HHPG-19K) is a biosimilar to pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF). The efficacy and safety of mecapegfilgrastim, using a regimen of once-per-cycle injection of 100-μg/kg or a fixed 6-mg dose, were evaluated for the prophylactic therapy for neutropenia in patients with advanced non-small-cell lung cancer (NSCLC) who were treated with myelosuppressive chemotherapy. MATERIALS AND METHODS Patients were randomized (1:1:1) blindly to 3 treatment arms to receive a single injection of mecapegfilgrastim 100 μg/kg, a 6-mg fixed dose of mecapegfilgrastim, or saline (control) in cycle 1. In cycles 2 to 4 following unblinding at the end of cycle 1, patients in the control arm received daily injections of short-acting rhG-CSF at a dose of 5 μg/kg, whereas patients in the 2 mecapegfilgrastim arms continued the same treatment as in cycle 1. All patients received 4 chemotherapy cycles of docetaxel combined with cisplatin or carboplatin every 21 days. The primary endpoint was the incidence of grade ≥ 3 neutropenia in cycle 1. RESULTS A single dose of 100 μg/kg or a fixed 6-mg dose of mecapegfilgrastim per cycle effectively reduced chemotherapy-induced neutropenia and was comparable to daily rhG-CSF with regard to all efficacy endpoints, including incidence of grade ≥ 3 neutropenia, incidence of febrile neutropenia, duration of grade ≥ 3 neutropenia, and time to neutrophil recovery. No difference in efficacy parameters was observed between the 2-dose regimens of mecapegfilgrastim across all cycles. Mecapegfilgrastim was well-tolerated and was as safe as daily rhG-CSF. CONCLUSION Once-per-cycle injection of mecapegfilgrastim is as effective and safe as daily rhG-CSF for prophylaxis of chemotherapy-induced neutropenia in patients with NSCLC. Mecapegfilgrastim (fixed 6-mg dose) is recommended in clinical practice for its convenient dose management.