Asian Pacific Journal of Cancer Prevention

  • 제16권11호
  • /
  • Pages.4759-4768
  • /
  • 2015
  • /
  • 1513-7368(pISSN)
  • /
  • 2476-762X(eISSN)
아시아태평양암예방학회 (Asian Pacific Journal of Cancer Prevention)
권호 표지
DOI QR코드

DOI QR Code

Predictive and Prognostic Biomarkers for Patients Treated with Anti-EGFR Agents in Lung Cancer: A Systemic Review and Meta-Analysis

  • Wang, Ying (Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Qu, Xiao (Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Shen, Hong-Chang (Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Wang, Kai (Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Liu, Qi (Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Du, Jia-Jun (Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University)
  • 발행 : 2015.06.26
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Background: Several studies have investigated predictive and prognostic biomarkers for patients treated with anti-epidermal growth factor receptor (EGFR) agents in lung cancer. However, the conclusion is controversial. Materials and Methods: A meta-analysis was conducted to evaluate the associations of mutant K-ras, PIK3CA and PTEN deficiency with the efficacy of anti-EGFR agents in lung cancer. The primary endpoint was objective response rate (ORR). The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results: A total of 61 studies were included in the final meta-analysis. The result showed that K-ras mutation was a good predictor for ORR (RR=0.42, 95%CI, 0.33-0.55, p=0.000) and an effective prognostic marker for OS (HR=1.37, 95%CI, 1.15-1.65, p=0.001) and PFS (HR=1.33, 95%CI, 1.05-1.69, p=0.019). However, PTEN deficiency or PIK3CA mutation did not show any significance predictive value for ORR (PTEN, RR=0.82, 95%CI, 0.56-1.19, p=0.286; PIK3CA, RR=1.08, 95%CI, 0.17-6.66, P=0.938). And PTEN deficiency or expression of PIK3CA did not show significance prognostic value for OS (PTEN, HR=0.88, 95%CI, 0.31-2.46,P=0.805; PIK3CA, HR=0.79, 95%CI: 0.23-2.68, P=0.706). Conclusions: Our meta-analysis showed that K-ras mutation may be an effective predictor in lung cancer patients treated with anti-EGFR agents. Whereas, the predictive and prognostic value of PTEN deficiency and PIK3CA mutation need to be further investigated.

키워드

참고문헌

  1. Boldrini L, Ali G, Gisfredi S, et al (2009). Epidermal growth factor receptor and K-RAS mutations in 411 lung adenocarcinoma: a population-based prospective study. Oncol Rep, 22, 683-91.
  2. Brugger W, Triller N, Blasinska-Morawiec M, et al (2011). Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol, 29, 4113-20. https://doi.org/10.1200/JCO.2010.31.8162
  3. Cadranel J, Mauguen A, Faller M, et al (2012). Impact of systematic EGFR and KRAS mutation evaluation on progression-free survival and overall survival in patients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC project--part 2). J Thorac Oncol, 7, 1490-502. https://doi.org/10.1097/JTO.0b013e318265b2b5
  4. Cappuzzo F, Ligorio C, Janne PA, et al (2007). Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial. J Clin Oncol, 25, 2248-55. https://doi.org/10.1200/JCO.2006.09.4300
  5. Chaft JE, Arcila ME, Paik PK, et al (2012). Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther, 11, 485-91. https://doi.org/10.1158/1535-7163.MCT-11-0692
  6. Chang JW, Liu HP, Hsieh MH, et al (2008). Increased epidermal growth factor receptor (EGFR) gene copy number is strongly associated with EGFR mutations and adenocarcinoma in non-small cell lung cancers: a chromogenic in situ hybridization study of 182 patients. Lung Cancer, 61, 328-39. https://doi.org/10.1016/j.lungcan.2008.01.009
  7. D'Addario G, Rauch D, Stupp R, et al (2008). Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03. Ann Oncol, 19, 739-45.
  8. Dahabreh IJ, Linardou H, Kosmidis P, et al (2011). EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer. Ann Oncol, 22, 545-52. https://doi.org/10.1093/annonc/mdq432
  9. De Roock W, Claes B, Bernasconi D, et al (2010). Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol, 11, 753-62. https://doi.org/10.1016/S1470-2045(10)70130-3
  10. Dingemans AM, de Langen AJ, van den Boogaart V, et al (2011). First-line erlotinib and bevacizumab in patients with locally advanced and/or metastatic non-small-cell lung cancer: a phase II study including molecular imaging. Ann Oncol, 22, 559-66. https://doi.org/10.1093/annonc/mdq391
  11. Douillard JY, Shepherd FA, Hirsh V, et al (2010). Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol, 28, 744-52. https://doi.org/10.1200/JCO.2009.24.3030
  12. Eberhard DA, Johnson BE, Amler LC, et al (2005). Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol, 23, 5900-9. https://doi.org/10.1200/JCO.2005.02.857
  13. Endoh H, Yatabe Y, Kosaka T, et al (2006). PTEN and PIK3CA expression is associated with prolonged survival after gefitinib treatment in EGFR-mutated lung cancer patients. J Thorac Oncol, 1, 629-34.
  14. Fang H, Lin RY, Sun MX, et al (2014). Efficacy and Survival-associated Factors with Gefitinib Combined with Cisplatin and Gemcitabine for Advanced Non- small Cell Lung Cancer. Asian Pac J Cancer Prev, 15, 10967-70.
  15. Felip E, Rojo F, Reck M, et al (2008). A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. Clin Cancer Res, 14, 3867-74. https://doi.org/10.1158/1078-0432.CCR-07-5186
  16. Fidler MJ, Morrison LE, Basu S, et al (2011). PTEN and PIK3CA gene copy numbers and poor outcomes in non-small cell lung cancer patients with gefitinib therapy. Br J Cancer, 105, 1920-6. https://doi.org/10.1038/bjc.2011.494
  17. Fujimoto N, Wislez M, Zhang J, et al (2005). High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res, 65, 11478-85. https://doi.org/10.1158/0008-5472.CAN-05-1977
  18. Giaccone G, Gallegos Ruiz M, Le Chevalier T, et al (2006). Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res, 12, 6049-55. https://doi.org/10.1158/1078-0432.CCR-06-0260
  19. Guan JL, Zhong WZ, An SJ, et al (2013). KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann Surg Oncol, 20, 1381-8. https://doi.org/10.1245/s10434-012-2754-z
  20. Han SW, Kim TY, Jeon YK, et al (2006). Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res, 12, 2538-44. https://doi.org/10.1158/1078-0432.CCR-05-2845
  21. Hirsch FR, Kabbinavar F, Eisen T, et al (2011). A randomized, phase II, biomarker-selected study comparing erlotinib to erlotinib intercalated with chemotherapy in first-line therapy for advanced non-small-cell lung cancer. J Clin Oncol, 29, 3567-73. https://doi.org/10.1200/JCO.2010.34.4929
  22. Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al (2006). Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol, 24, 5034-42. https://doi.org/10.1200/JCO.2006.06.3958
  23. Hirsch FR, Varella-Garcia M, Cappuzzo F, et al (2007). Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol, 18, 752-60.
  24. Ichihara S, Toyooka S, Fujiwara Y, et al (2007). The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. Int J Cancer, 120, 1239-47. https://doi.org/10.1002/ijc.22513
  25. Jackman DM, Miller VA, Cioffredi LA, et al (2009). Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res, 15, 5267-73. https://doi.org/10.1158/1078-0432.CCR-09-0888
  26. Jackman DM, Yeap BY, Lindeman NI, et al (2007). Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol, 25, 760-6. https://doi.org/10.1200/JCO.2006.07.5754
  27. Johnson ML, Sima CS, Chaft J, et al (2013). Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas. Cancer, 119, 356-62. https://doi.org/10.1002/cncr.27730
  28. JP H, SG T, JJ D, et al (2003). Measuring inconsistency in meta-analyses. BMJ, 327, 557-60. https://doi.org/10.1136/bmj.327.7414.557
  29. Kalikaki A, Koutsopoulos A, Trypaki M, et al (2008). Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC. Br J Cancer, 99, 923-9. https://doi.org/10.1038/sj.bjc.6604629
  30. Karampeazis A, Voutsina A, Souglakos J, et al (2013). Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer, 119, 2754-64. https://doi.org/10.1002/cncr.28132
  31. Kerner GS, Schuuring E, Sietsma J, et al (2013). Common and rare EGFR and KRAS mutations in a Dutch non-small-cell lung cancer population and their clinical outcome. PLoS One, 8, 70346. https://doi.org/10.1371/journal.pone.0070346
  32. Khambata-Ford S, Harbison CT, Hart LL, et al (2010). Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol, 28, 918-27. https://doi.org/10.1200/JCO.2009.25.2890
  33. Kim ES, Herbst RS, Wistuba, II, et al (2011). The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov, 1, 44-53. https://doi.org/10.1158/2159-8274.CD-10-0010
  34. Kim ST, Sung JS, Jo UH, et al (2013). Can mutations of EGFR and KRAS in serum be predictive and prognostic markers in patients with advanced non-small cell lung cancer (NSCLC)? Med Oncol, 30, 328. https://doi.org/10.1007/s12032-012-0328-3
  35. Lara-Guerra H, Waddell TK, Salvarrey MA, et al (2009). Phase II study of preoperative gefitinib in clinical stage I non-small-cell lung cancer. J Clin Oncol, 27, 6229-36. https://doi.org/10.1200/JCO.2009.22.3370
  36. Lind JS, Dingemans AM, Groen HJ, et al (2010). A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer. Clin Cancer Res, 16, 3078-87. https://doi.org/10.1158/1078-0432.CCR-09-3033
  37. Loprevite M, Tiseo M, Chiaramondia M, et al (2007). Buccal mucosa cells as in vivo model to evaluate gefitinib activity in patients with advanced non small cell lung cancer. Clin Cancer Res, 13, 6518-26. https://doi.org/10.1158/1078-0432.CCR-07-0805
  38. Ludovini V, Bianconi F, Pistola L, et al (2011). Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J Thorac Oncol, 6, 707-15. https://doi.org/10.1097/JTO.0b013e31820a3a6b
  39. Ludovini V, Bianconi F, Pistola L, et al (2012). Optimization of patient selection for EGFR-TKIs in advanced non-small cell lung cancer by combined analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations. Cancer Chemother Pharmacol, 69, 1289-99. https://doi.org/10.1007/s00280-012-1829-7
  40. M V-G, T M, Yatabe Y KT, et al (2009). EGFR and HER2 Genomic gain in recurrent non-small cell lung cancer after surgery: impact on outcome to treatment with gefitinib and association with EGFR and KRAS Mutations in a Japanese Cohort. J Thorac Oncol, 4, 318-25. https://doi.org/10.1097/JTO.0b013e31819667a3
  41. Mao C, Qiu LX, Liao RY, et al (2010). KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer, 69, 272-8. https://doi.org/10.1016/j.lungcan.2009.11.020
  42. Marchetti A, Milella M, Felicioni L, et al (2009). Clinical implications of KRAS mutations in lung cancer patients treated with tyrosine kinase inhibitors: an important role for mutations in minor clones. Neoplasia, 11, 1084-92. https://doi.org/10.1593/neo.09814
  43. Massarelli E, Varella-Garcia M, Tang X, et al (2007). KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res, 13, 2890-6. https://doi.org/10.1158/1078-0432.CCR-06-3043
  44. Metro G, Chiari R, Duranti S, et al (2012). Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype. Lung Cancer, 78, 81-6. https://doi.org/10.1016/j.lungcan.2012.06.005
  45. Milella M, Nuzzo C, Bria E, et al (2012). EGFR molecular profiling in advanced NSCLC: a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy. J Thorac Oncol, 7, 672-80. https://doi.org/10.1097/JTO.0b013e31824a8bde
  46. Miller VA, Riely GJ, Zakowski MF, et al (2008). Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol, 26, 1472-8. https://doi.org/10.1200/JCO.2007.13.0062
  47. Murray S, Karavasilis V, Bobos M, et al (2012). Molecular predictors of response to tyrosine kinase inhibitors in patients with Non-Small-Cell Lung Cancer. J Exp Clin Cancer Res, 31, 77. https://doi.org/10.1186/1756-9966-31-77
  48. O'Byrne KJ, Gatzemeier U, Bondarenko I, et al (2011). Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol, 12, 795-805. https://doi.org/10.1016/S1470-2045(11)70189-9
  49. Pan JB, Hou YH, Zhang GJ (2013). Correlation between EGFR mutations and serum tumor markers in lung adenocarcinoma patients. Asian Pac J Cancer Prev, 14, 695-700. https://doi.org/10.7314/APJCP.2013.14.2.695
  50. Pao W, Wang TY, Riely GJ, et al (2005). KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med, 2, 17. https://doi.org/10.1371/journal.pmed.0020017
  51. Pesek M, Benesova L, Belsanova B, et al (2009). Dominance of EGFR and insignificant KRAS mutations in prediction of tyrosine-kinase therapy for NSCLC patients stratified by tumor subtype and smoking status. Anticancer Res, 29, 2767-73.
  52. Price KA, Azzoli CG, Krug LM, et al (2010). Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer. J Thorac Oncol, 5, 1623-9. https://doi.org/10.1097/JTO.0b013e3181ec1531
  53. Qi WX, Shen Z, Lin F, et al (2012). Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: a systematic review and meta-analysis. Asian Pac J Cancer Prev, 13, 5177-82. https://doi.org/10.7314/APJCP.2012.13.10.5177
  54. Ramalingam SS, Blackhall F, Krzakowski M, et al (2012). Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol, 30, 3337-44. https://doi.org/10.1200/JCO.2011.40.9433
  55. Ready N, Janne PA, Bogart J, et al (2010). Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol, 5, 1382-90. https://doi.org/10.1097/JTO.0b013e3181eba657
  56. Sasaki H, Endo K, Okuda K, et al (2008). Epidermal growth factor receptor gene amplification and gefitinib sensitivity in patients with recurrent lung cancer. J Cancer Res Clin Oncol, 134, 569-77. https://doi.org/10.1007/s00432-007-0320-z
  57. Schittenhelm MM, Kollmannsberger C, Oechsle K, et al (2009). Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer. Mol Cancer Ther, 8, 481-9. https://doi.org/10.1158/1535-7163.MCT-08-1068
  58. Schneider CP, Heigener D, Schott-von-Romer K, et al (2008). Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study. J Thorac Oncol, 3, 1446-53. https://doi.org/10.1097/JTO.0b013e31818ddcaa
  59. Sequist LV, von Pawel J, Garmey EG, et al (2011). Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol, 29, 3307-15. https://doi.org/10.1200/JCO.2010.34.0570
  60. Siegel R, Naishadham D, Jemal A (2013). Cancer statistics, 2013. CA Cancer J Clin, 63, 11-30. https://doi.org/10.3322/caac.21166
  61. Socinski MA, Goldman J, El-Hariry I, et al (2013). A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clin Cancer Res, 19, 3068-77. https://doi.org/10.1158/1078-0432.CCR-12-3381
  62. Spigel DR, Burris HA, 3rd, Greco FA, et al (2011). Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer. J Clin Oncol, 29, 2582-9. https://doi.org/10.1200/JCO.2010.30.7678
  63. Sun J-M, Hwang DW, Califano R, et al (2012). Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer. Drugs, 72, 28-36. https://doi.org/10.2165/1163012-S0-000000000-00000
  64. Tiseo M, Rossi G, Capelletti M, et al (2010). Predictors of gefitinib outcomes in advanced non-small cell lung cancer (NSCLC): study of a comprehensive panel of molecular markers. Lung Cancer, 67, 355-60. https://doi.org/10.1016/j.lungcan.2009.04.021
  65. Tong L, Yang XX, Liu MF, et al (2012). Mutational analysis of key EGFR pathway genes in Chinese breast cancer patients. Asian Pac J Cancer Prev, 13, 5599-603. https://doi.org/10.7314/APJCP.2012.13.11.5599
  66. Tsao AS, Liu S, Lee JJ, et al (2013). Clinical and biomarker outcomes of the phase II vandetanib study from the BATTLE trial. J Thorac Oncol, 8, 658-61. https://doi.org/10.1097/JTO.0b013e31828d08ae
  67. van Zandwijk N, Mathy A, Boerrigter L, et al (2007). EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol, 18, 99-103.
  68. Wang S, An T, Wang J, et al (2010). Potential clinical significance of a plasma-based KRAS mutation analysis in patients with advanced non-small cell lung cancer. Clin Cancer Res, 16, 1324-30. https://doi.org/10.1158/1078-0432.CCR-09-2672
  69. Wu CC, Hsu HY, Liu HP, et al (2008). Reversed mutation rates of KRAS and EGFR genes in adenocarcinoma of the lung in Taiwan and their implications. Cancer, 113, 3199-208. https://doi.org/10.1002/cncr.23925
  70. Yang ZY, Wu XY, Huang YF, et al (2013). Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a systematic review with meta-analysis. Int J Cancer, 133, 1914-25. https://doi.org/10.1002/ijc.28153
  71. Zhao Q, Shentu J, Xu N, et al (2011). Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Lung Cancer, 73, 195-202. https://doi.org/10.1016/j.lungcan.2010.11.007
  72. Zhu CQ, da Cunha Santos G, Ding K, et al (2008). Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol, 26, 4268-75. https://doi.org/10.1200/JCO.2007.14.8924
  73. ZHU Yu-jia, Ying X, Guan-jun R, et al (2010). Efficacy and clinical/molecular predictors of erlotinib monotherapy for Chinese advanced non-small cell lung cancer. Chin Med J 123, 3200-5.
  74. Zucali PA, Ruiz MG, Giovannetti E, et al (2008). Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors. Ann Oncol, 19, 1605-12. https://doi.org/10.1093/annonc/mdn240