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Robert Pirker

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    JICC01 - Joint IASLC-CAALC-CSCO Session: The Truth and Myth of Oral Anti-VEGFR Inhibitors for Advance NSCLC (ID 276)

    • Event: WCLC 2020
    • Type: Workshop
    • Track: N.A.
    • Presentations: 1
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      JICC01.07 - Oral VEGFR Inhibitor Monotherapy for Lung Cancer: Should We or Should We Not? (ID 4266)

      07:00 - 09:00  |  Presenting Author(s): Robert Pirker

      • Abstract


      The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are involved in activation of angiogenesis during tumor progression. Therefore, blockade of VEGF or VEGFR has been studied as a therapeutic strategy in advanced non-small-cell lung cancer (NSCLC) (1). Carboplatin plus paclitaxel combined with bevacizumab has been established as a first-line therapy for patients with advanced non-squamous NSCLC. Docetaxel plus ramucirumab has been established as a second-line treatment for patients with advanced NSCLC. VEGFR tyrosine kinase inhibitors (TKIs) were studied in combination with chemotherapy or as single agents. Docetaxel plus nintedanib has become a second-line treatment for patients with adenocarcinomas. When added to first-line chemotherapy, neither sorafenib nor motesanib improved overall survival of patients. Based on meta-analyses, chemotherapy plus VEGFR TKIs improved response rates and progression-free survival but did not prolong overall survival in patients with advanced NSCLC (2) and was also associated with increased toxicity compared to chemotherapy alone (3). Results of trials with VEGFR TKIs as single agents with focus on phase 3 trials are summarized here.

      Vandetanib failed to improve overall survival compared to placebo in patients with advanced NSCLC who had been pretreated with an EGFR tyrosine kinase inhibitor and one or two chemotherapy regimens (4). The MISSION phase 3 trial also failed to show a survival benefit for sorafenib compared to placebo in patients with advanced predominantly nonsquamous NSCLC who had been pretreated with two or three treatment regimens (5). The hazard ratio was 0.99 and median survival times were 8.2 and 8.3 months, respectively. Sorafenib improved progression-free survival (hazard ratio 0.61). Among 89 patients with epidermal growth factor receptor mutations, sorafenib improved overall survival (hazard ratio 0.48) and progression-free survival (hazard ratio 0.27). Side effects of sorafenib were rash, diarrhea and fatigue. Sunitinib as maintenance therapy improved progression-free survival but had no impact on survival of patients with advanced NSCLC (6).

      The phase 3 ALTER 0303 trial evaluated anlotinib compared to placebo in Chinese patients with advanced NSCLC (7). Anlotinib targets VEGFR 1-3, endothelial growth factor receptor, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor α and β, and stem cell factor receptor. Patients were randomized 2:1 to anlotinib at 12 mg daily (n=296) or placebo (n=143). The primary endpoint was overall survival. Anlotinib improved overall survival compared to placebo. The hazard ratio was 0.68 (95% CI 0.54-0.87; p=0.002) and median survival times were 9.6 and 6.3 months, respectively. Progression-free survival was also increased with anlotinib. The hazard ratio was 0.25 (95% CI 0.19-0.31; p< 0.001) and median progression-free survival times were 5.4 and 1.4 months, respectively. Grade 3 or higher adverse events with anlotinib arm were hypertension and hyponatremia. Other side effects more common with anlotinib were fatigue, anorexia, hand-foot syndrome, hyperlipidemia and thyroid-stimulating hormone elevation. The authors concluded that anlotinib is a potential third-line or further therapy for Chinese patients with advanced NSCLC.

      Apatinib, an inhibitor of VEGFR-2, has also shown efficacy in patients with advanced NSCLC that failed prior chemotherapy or EGFR-TKIs (8). The multikinase inhibitor lenvatinib is directed against VEGFR 1-3, fibroblast growth factor receptors 1-4, RET and other targets (9). Lenvatinib resulted in a response rate of 16% and a median progression-free survival of 7.3 months among 25 patients with RET fusion-positive lung cancer (10). Lenvatinib has been studied in combination with pembrolizumab in patients with advanced NSCLC. In a phase 1b/2 trial, pembrolizumab plus lenvatinib resulted in a response rate of 33% among patients with advanced NSCLC who had progressed after one or two lines of therapy (11). The LEAP-006 phase 3 trial (NCT03829319) evaluates chemotherapy plus pembrolizumab with and without lenvatinib as first-line therapy in patients with non-squamous NSCLC. The LEAP-007 phase 3 trial (NCT03829332) compares pembrolizumab plus lenvatinib to pembrolizumab plus placebo in treatment-naïve patients with advanced PD-L1-positive NSCLC.

      In summary, anlotinib as single agent is a treatment option for pretreated patients with advanced NSCLC. Monotherapy with other VEGFR TKIs is not recommended.


      1. Villaruz LC, Socinski MA. The role of anti-angiogenesis in non-small-cell lung cancer: an update. Curr Oncol Rep. 2015;17:26.

      2. Liu L, Zhang Y, Wie J, et al. VEGFR-TKIs combined with chemotherapy for advanced non-small cell lung cancer: A systematic review. Journal of Cancer. 2019;10:799-809.

      3. Lv WW, Zhang JJ, Zhou XL, et al. Safety of combining vascular endothelial growth factor receptor tyrosine-kinase inhibitors with chemotherapy in patients with advanced non-small-cell lung cancer. A PRISMA-compliant meta-analysis. Medicine. 2019; 98:23(e15806).

      4. Lee JS, Hirsh V, Park K, et al. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012;30:1114-1121.

      5. Paz-Ares L, Hirsh V, Zhang L, et al. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: a phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015;10:1745-1753.

      6. Baggstrom MQ, Socinski MA, Wang XF, et al. Maintenance sunitinib following initial platinum-based combination chemotherapy in advanced-stage IIIB/IV non-small cell lung cancer: a randomized, double-blind, placebo-controlled phase III study - CALGB 30607 (Alliance). J Thorac Oncol. 2017;12:843-849.

      7. Han B, Li K, Wang Q , et al. 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. JAMA Oncol. 2018;4:1569-1575.

      8. Ma JT, Sun J, Sun L, et al. Efficacy and safety of apatinib in patients with advanced nonsmall cell lung cancer that failed prior chemotherapy or EGFR-TKIs. A pooled analysis. Medicine. 2018; 97:e12083.

      9. Hao Z, Wang P. Lenvatinib in management of solid tumors. Oncologist. 2020;25:e302-e310.

      10. Hida T, Velcheti V, Reckamp KL, et al. A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma. Lung Cancer. 2019;138:124-130.

      11. Brose MS, Vogelzang NJ, DiSimone C, et al. A phase Ib/II trial of lenvatinib plus pembrolizumab in non-small cell lung cancer. Journal of Clinical Oncology. 2019;37:8 (suppl, 16-16).