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Kai Li



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    OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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      OA13.03 - Anlotinib as Third-Line or Further-Line Treatment in Relapsed SCLC: A Multicentre, Randomized, Double-Blind Phase 2 Trial (ID 12102)

      10:50 - 11:00  |  Author(s): Kai Li

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment for patients with relapsed small cell lung cancer (SCLC) who failed ≥ 2 lines of chemotherapy have high unmet needs. Anlotinib is a novel TKI with highly selective inhibition effects on multi-targets, especially on VEGFR, c-Kit, PDGFR, FGFR. Here we report results of a phase 2 study of anlotinib for the third-line and further-line treatment of SCLC. (ALTER1202, NCT03059797).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible either limited- or extensive-stage SCLC patients with disease progression after ≥ 2 lines of chemotherapy were randomized 2:1 to anlotinib or placebo (12 mg PO QD from day 1 to 14, every 3 weeks). The primary endpoint was PFS and secondary endpoints was OS, ORR, DCR, quality of life and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Between March 2017 and May 2018, 120 patients from 11 centers were randomized to either anlotinib arm (n=82) or placebo arm (n=38). Until the data cutoff date (30 Jun 2018), median PFS was 4.1 months (95%CI, 2.8 to 4.2 months) in anlotinib arm and 0.7 months (95% CI, 0.7 to 0.8 months) in placebo arm (HR, 0.19; 95% CI, 0.12 to 0.32, p<0.0001). OS data were not sufficiently mature for analysis. Although ORR was similar, considerable improvement in DCR was observed in anlotinib arm (71.6% vs 13.2%, p<0.0001). Treatment-related adverse events (TRAEs) occurred more frequently in anlotinib arm than that in placebo (87.7% and 74.4%). The most common TRAEs were hypertension, anorexia, fatigue, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 29 (35.8%) of patients in anlotinib arm and 6 (15.4%) in placebo arm, respectively.

      figure 1 kaplan-meier estimates of progression-free survival.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      ALTER 1202 study demonstrates anlotinib should be considered a treatment option for patients with relapsed SCLC who have experienced treatment failure with two lines of chemotherapy. The safety profile was consistent with the previous report and no newly adverse events were identified.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-107 - The Impact of Anlotinib on Quality of Life in Patients with Advance NSCLC: Post-Hoc Analysis of a Phase III Randomized Control Trial (ALTER0303) (ID 12249)

      16:45 - 18:00  |  Author(s): Kai Li

      • Abstract
      • Slides

      Background

      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.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      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.

      4c3880bb027f159e801041b1021e88e8 Result

      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 (at cycle 2), social functioning (at cycle 4), dyspnea (at cycle 2, 4), insomnia (at cycle 6), constipation (at cycle 2) and financial problems (at cycle 2). Only sore mouth or tongue symptom was worse in the anlotinib arm (at cycle 2, 4, 6) than in the placebo arm.

      8eea62084ca7e541d918e823422bd82e Conclusion

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-108 - Management of Anlotinib-Related Adverse Events: Data From ALTER 0303 (ID 12054)

      16:45 - 18:00  |  Author(s): Kai Li

      • Abstract
      • Slides

      Background

      Anlotinib is an oral tyrosine kinase inhibitor targeting VEGFR, FGFR, PDGFR and c-kit. 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 summarized adverse event management in this trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 4.0) and managed by investigators. Adverse events and key strategies for preventing and managing the most common adverse events were described. Proportions were compared using the χ2 test or Fisher’s exact test, as appropriate. Two-sided values of P <0.05 were considered statistically significant. Analyses were calculated by SAS 9.4.

      4c3880bb027f159e801041b1021e88e8 Result

      Between February 2015, and August 2016, a total of 437 patients were randomized to anlotinib group (n=294) and placebo group (n=143). The most common anlotinb related adverse events were hypertension (64.6%), fatigue (46.3%), TSH elevation (44.6%), hand-foot syndrome (HFS) (43.2%), hypertriglyceridemia (38.8%), anorexia (38.4%). The most common anlotinib related grade ≥3 adverse events were hypertension (13.3%), HFS (3.7%), and hypertriglyceridemia (2.4%). The median onset time of hypertension, HFS, and hypertriglyceridemia were 6 days, 30 days, and 22 days respectively.

      To monitor blood pressure, every patient had an electronic manometer. One hundred and eight (36.7%) patients received dihydropyridine calcium channel blockers, 79 (26.9%) patients received converting enzyme inhibitors of angiotensin /angiotensin receptor blockers, 57 (19.4%) patients received diuretics, 35 (11.9%) patients received beta-blockers. Only 3 (1.0%) patients need dose modification due to hypertension.

      Prophylactic measures of HFS were recommended. Frequent emollients should be used on hands and feet to maintain skin hydration, manicure or pedicure to control calluses, protect pressure points and tender areas of feet with insole cushions, shock-absorbing soles, comfortable shoes. Seven (2.3%) patients required dose reduction due to hand-foot skin syndrome. Eleven (3.7%) patients received cortisone cream for topical therapy.

      Twenty-four patients received fibrates to reduce plasma triglyceride level. Two (0.7%) patients required dose reduction due to hypertriglyceridemia.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Anlotinb-related adverse events could be controlled by prophylactic measures, and early intervention.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.03 - Biology (Not CME Accredited Session) (ID 935)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.03-16 - Anlotinib Inhibits Angiogenesis of Refractory Advanced Non-Small Cell Lung Cancer via Blocking CCL2 Expression (ID 12406)

      16:45 - 18:00  |  Author(s): Kai Li

      • Abstract
      • Slides

      Background

      Anlotinib has been demonstrated to be effective in prolonging progression free survival (PFS; Anlotinib: 5.37 months vs Placebo: 1.40 months) and overall survival (OS; Anlotinib: 9.63 months vs Placebo: 6.30 months) of refractory advanced Non-Small Cell Lung Cancer (NSCLC) patients in clinical trials. Clinical evidences suggested that Anlotinib-induced anti-tumor efficacy could be attributed to anti-angiogenesis. However, the underlying molecular mechanisms and predictive biomarker of Anlotinib are still unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      437 patients with advanced NSCLC enrolled in clinical study, and 294 patients received Anlotinib therapy. Retrospectively analysis of the Anlotinib-administrated 294 NSCLC patients was performed to screen out underlying biomarker for Anlotinib-responsive patients. Transcriptome and functional assays were performed to understand the anti-tumor molecular mechanism of Anlotinib in vitro. CCL2 levels and their roles in angiogenesis were evaluated by ELISA detection, RT-qPCR quantification, and immunofluorescence assay, in vivo. Changes in serum CCL2 levels were analyzed to reveal the correlation of Anlotinib response between responders and non-responders.

      4c3880bb027f159e801041b1021e88e8 Result

      Anlotinib therapy is more beneficial to prolong OS for NSCLC patients harboring positive driver gene mutations, especially for patients harboring EGFRT790M mutation. Moreover, our data indicated that Anlotinib-induced cell viability downregulation, cell apoptosis induction, cell invasion inhibition, cell cycle arrest, and cell migration inhibition are associated with CCL2 levels in vitro. We demonstrated that Anlotinib inhibits angiogenesis of NCI-H1975 derived xenografts model via inhibiting CCL2 in vivo. Lastly, we found that Anlotinib-induced serum CCL2 level decreases are associated with the benefits of PFS and OS, in refractory advanced NSCLC patients (n = 28).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study reports a novel anti-angiogenesis mechanism of Anlotinib via inhibiting CCL2 in NCI-H1975 derived xenografts model, and suggests the changes in serum CCL2 levels may be used to monitor and predict clinical outcome in Anlotinib-administered refractory advanced NSCLC patients. The biomarker of serum CCL2 alteration may guide precision therapy of Anlotinib for NSCLC patients at third-line or over third-line.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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