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Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial

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Abstract

Background

C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib.

Methods

Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437.

Results

Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p = 0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p = 0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p = 0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p = 0.021) and OS (HR 0.31; p = 0.006) in all and EGFR mutated patients.

Conclusions

A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.

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References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer J Int Cancer. 2015;136(5):E359–86. doi:10.1002/ijc.29210.

    Article  CAS  Google Scholar 

  2. Arrieta O, Campos-Parra AD, Zuloaga C, Aviles A, Sanchez-Reyes R, Manriquez ME, et al. Clinical and pathological characteristics, outcome and mutational profiles regarding non-small-cell lung cancer related to wood-smoke exposure. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2012;7(8):1228–34. doi:10.1097/JTO.0b013e3182582a93.

    CAS  Google Scholar 

  3. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. The IASLC lung cancer staging project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2007;2(8):706–14. doi:10.1097/JTO.0b013e31812f3c1a.

    Google Scholar 

  4. Arrieta O, Guzman-de Alba E, Alba-Lopez LF, Acosta-Espinoza A, Alatorre-Alexander J, Alexander-Meza JF, et al. National consensus of diagnosis and treatment of non-small cell lung cancer. Rev Investig Clin Organo Hosp Enferm Nutr. 2013;65 Suppl 1:S5–84.

    Google Scholar 

  5. Campos-Parra AD, Cruz-Rico G, Arrieta O. Personalized treatment in non-small cell lung cancer. Rev Investig Clin Organo Hosp Enferm Nutr. 2012;64(4):377–86.

    Google Scholar 

  6. Okamoto I, Mitsudomi T, Nakagawa K, Fukuoka M. The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations. Ther Adv Med Oncol. 2010;2(5):301–7. doi:10.1177/1758834010370698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ray M, Salgia R, Vokes EE. The role of EGFR inhibition in the treatment of non-small cell lung cancer. Oncologist. 2009;14(11):1116–30. doi:10.1634/theoncologist.2009-0054.

    Article  CAS  PubMed  Google Scholar 

  8. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80. doi:10.1056/NEJMra0802714.

    Article  CAS  PubMed  Google Scholar 

  9. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(21):2866–74. doi:10.1200/JCO.2010.33.4235.

    Article  CAS  Google Scholar 

  10. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. doi:10.1056/NEJMoa0810699.

    Article  CAS  PubMed  Google Scholar 

  11. Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830–8. doi:10.1016/S1470-2045(15)00026-1.

    Article  CAS  PubMed  Google Scholar 

  12. Arrieta O, Anaya P, Morales-Oyarvide V, Ramirez-Tirado LA, Polanco AC. Cost-effectiveness analysis of EGFR mutation testing in patients with non-small cell lung cancer (NSCLC) with gefitinib or carboplatin-paclitaxel. Eur J Health Econ HEPAC Health Econ Prev Care. 2015. doi:10.1007/s10198-015-0726-5.

    Google Scholar 

  13. Arrieta O, Cardona AF, Corrales L, Campos-Parra AD, Sanchez-Reyes R, Amieva-Rivera E, et al. The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer. Lung Cancer. 2015;87(2):169–75. doi:10.1016/j.lungcan.2014.12.009.

    Article  PubMed  Google Scholar 

  14. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786–92. doi:10.1056/NEJMoa044238.

    Article  CAS  PubMed  Google Scholar 

  15. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73. doi:10.1371/journal.pmed.0020073.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26. doi:10.1126/scitranslmed.3002003.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Canadas I, Rojo F, Taus A, Arpi O, Arumi-Uria M, Pijuan L, et al. Targeting epithelial-to-mesenchymal transition with Met inhibitors reverts chemoresistance in small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(4):938–50. doi:10.1158/1078-0432.CCR-13-1330.

    Article  CAS  Google Scholar 

  18. Nakamura T, Matsumoto K, Kiritoshi A, Tano Y, Nakamura T. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions. Cancer Res. 1997;57(15):3305–13.

    CAS  PubMed  Google Scholar 

  19. Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17(1):77–88. doi:10.1016/j.ccr.2009.11.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T, et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 2008;68(22):9479–87. doi:10.1158/0008-5472.CAN-08-1643.

    Article  CAS  PubMed  Google Scholar 

  21. Keating GM. Afatinib: a review of its use in the treatment of advanced non-small cell lung cancer. Drugs. 2014;74(2):207–21. doi:10.1007/s40265-013-0170-8.

    Article  CAS  PubMed  Google Scholar 

  22. Spicer JF, Rudman SM. EGFR inhibitors in non-small cell lung cancer (NSCLC): the emerging role of the dual irreversible EGFR/HER2 inhibitor BIBW 2992. Target Oncol. 2010;5(4):245–55. doi:10.1007/s11523-010-0140-y.

    Article  PubMed  Google Scholar 

  23. De Greve J, Teugels E, Geers C, Decoster L, Galdermans D, De Mey J, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. 2012;76(1):123–7. doi:10.1016/j.lungcan.2012.01.008.

    Article  PubMed  Google Scholar 

  24. Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141–51. doi:10.1016/S1470-2045(14)71173-8.

    Article  CAS  PubMed  Google Scholar 

  25. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13(5):528–38. doi:10.1016/S1470-2045(12)70087-6.

    Article  CAS  PubMed  Google Scholar 

  26. Masago K, Togashi Y, Fujita S, Sakamori Y, Okuda C, Kim YH, et al. Clinical significance of serum hepatocyte growth factor and epidermal growth factor gene somatic mutations in patients with non-squamous non-small cell lung cancer receiving gefitinib or erlotinib. Med Oncol. 2012;29(3):1614–21. doi:10.1007/s12032-011-0009-7.

    Article  CAS  PubMed  Google Scholar 

  27. Han JY, Kim JY, Lee SH, Yoo NJ, Choi BG. Association between plasma hepatocyte growth factor and gefitinib resistance in patients with advanced non-small cell lung cancer. Lung Cancer. 2011;74(2):293–9. doi:10.1016/j.lungcan.2011.02.021.

    Article  PubMed  Google Scholar 

  28. Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(27):3327–34. doi:10.1200/JCO.2012.44.2806.

    Article  CAS  Google Scholar 

  29. Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–22. doi:10.1016/S1470-2045(13)70604-1.

    Article  CAS  PubMed  Google Scholar 

  30. Blumenschein Jr GR, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(26):3287–96. doi:10.1200/JCO.2011.40.3774.

    Article  CAS  Google Scholar 

  31. Takigawa N, Segawa Y, Maeda Y, Takata I, Fujimoto N. Serum hepatocyte growth factor/scatter factor levels in small cell lung cancer patients. Lung Cancer. 1997;17(2-3):211–8.

    Article  CAS  PubMed  Google Scholar 

  32. Toiyama Y, Miki C, Inoue Y, Okugawa Y, Tanaka K, Kusunoki M. Serum hepatocyte growth factor as a prognostic marker for stage II or III colorectal cancer patients. Int J Cancer J Int cancer. 2009;125(7):1657–62. doi:10.1002/ijc.24554.

    Article  CAS  Google Scholar 

  33. Tanaka K, Miki C, Wakuda R, Kobayashi M, Tonouchi H, Kusunoki M. Circulating level of hepatocyte growth factor as a useful tumor marker in patients with early-stage gastric carcinoma. Scand J Gastroenterol. 2004;39(8):754–60. doi:10.1080/00365520410005973.

    Article  CAS  PubMed  Google Scholar 

  34. Gupta A, Karakiewicz PI, Roehrborn CG, Lotan Y, Zlotta AR, Shariat SF. Predictive value of plasma hepatocyte growth factor/scatter factor levels in patients with clinically localized prostate cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(22):7385–90. doi:10.1158/1078-0432.CCR-07-5110.

    Article  CAS  Google Scholar 

  35. Seidel C, Borset M, Turesson I, Abildgaard N, Sundan A, Waage A. Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma. Nord Myeloma Study Group Blood. 1998;91(3):806–12.

    CAS  Google Scholar 

  36. Garcia-Navarrete R, Garcia E, Arrieta O, Sotelo J. Hepatocyte growth factor in cerebrospinal fluid is associated with mortality and recurrence of glioblastoma, and could be of prognostic value. J Neuro-Oncol. 2010;97(3):347–51. doi:10.1007/s11060-009-0037-8.

    Article  CAS  Google Scholar 

  37. Arrieta O, Garcia E, Guevara P, Garcia-Navarrete R, Ondarza R, Rembao D, et al. Hepatocyte growth factor is associated with poor prognosis of malignant gliomas and is a predictor for recurrence of meningioma. Cancer. 2002;94(12):3210–8. doi:10.1002/cncr.10594.

    Article  CAS  PubMed  Google Scholar 

  38. Martinez-Rumayor A, Arrieta O, Guevara P, Escobar E, Rembao D, Salina C, et al. Coexpression of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor cMET predict recurrence of meningiomas. Cancer Lett. 2004;213(1):117–24. doi:10.1016/j.canlet.2004.04.026.

    Article  CAS  PubMed  Google Scholar 

  39. Passiglia F, Van Der Steen N, Raez L, Pauwels P, Gil-Bazo I, Santos E, et al. The role of cMet in non-small cell lung cancer resistant to EGFR-inhibitors: did we really find the target? Curr Drug Targets. 2014;15(14):1284–92.

    Article  CAS  PubMed  Google Scholar 

  40. Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt Jr JH, Blumenschein Jr GR, et al. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(32):4105–14. doi:10.1200/JCO.2012.47.4189.

    Article  CAS  Google Scholar 

  41. Spigel DR, Edelman MJ, O’Byrne K, Paz-Ares L, Shames DS, Yu W, et al. Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb and IV NSCLC: results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial. J Clin Oncol. 2014;32:5s (suppl; abstr 8000).

  42. Perol M. Negative results of METLung study: an opportunity to better understand the role of MET pathway in advanced NSCLC. Transl Lung Cancer Res. 2014;3(6):392–4. doi:10.3978/j.issn.2218-6751.2014.09.06.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Mok TT E, Greater SL, Chang G, Yang J, Gyuris J, Han M, et al., editors. 205P - Efficacy analysis of gefitinib +/- ficlatuzumab in serum proteomic based subgroups of patients with previously untreated lung adenocarcinoma. Madrid: ESMO 2014; 2014.

    Google Scholar 

  44. Mok TET, Park K, Jac J, Han M, PayumoFC, Credi M, et al. Randomized phase II study of ficlatuzumab (formerly AV-299), an anti-hepatocyte growth factor (HGF) monoclonal antibody (MAb) in combination with gefitinib (G) in Asian patients (pts) with NSCLC. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(suppl; abstr TPS213).

  45. Okamoto W, Okamoto I, Tanaka K, Hatashita E, Yamada Y, Kuwata K, et al. TAK-701, a humanized monoclonal antibody to hepatocyte growth factor, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation. Mol Cancer Ther. 2010;9(10):2785–92. doi:10.1158/1535-7163.MCT-10-0481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang W, Li Q, Yamada T, Matsumoto K, Matsumoto I, Oda M, et al. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15(21):6630–8. doi:10.1158/1078-0432.CCR-09-1001.

    Article  CAS  Google Scholar 

  47. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99. doi:10.1056/NEJMoa1411817.

    Article  PubMed  Google Scholar 

  48. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372(18):1700–9. doi:10.1056/NEJMoa1413654.

    Article  PubMed  Google Scholar 

  49. Kris MG, Camidge DR, Giaccone G, Hida T, Li BT, O’Connell J, et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2015;26(7):1421–7. doi:10.1093/annonc/mdv186.

    CAS  Google Scholar 

  50. Platform ETO. Afatinib in NSCLC With HER2 Mutation (NICHE). ClinicalTrials.gov. 2015-. https://clinicaltrials.gov/ct2/show/NCT02369484. Accessed 1 Dec 2015.

  51. Arrieta O, Cardona AF, Federico Bramuglia G, Gallo A, Campos-Parra AD, Serrano S, et al. Genotyping non-small cell lung cancer (NSCLC) in Latin America. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2011;6(11):1955–9. doi:10.1097/JTO.0b013e31822f655f.

    Google Scholar 

  52. Arrieta O, Cardona AF, Martin C, Mas-Lopez L, Corrales-Rodriguez L, Bramuglia G, et al. Updated Frequency of EGFR and KRAS Mutations in nonsmall-cell lung cancer in Latin America: The Latin-American consortium for the investigation of lung cancer (CLICaP). J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2015;10(5):838–43. doi:10.1097/JTO.0000000000000481.

    CAS  Google Scholar 

  53. Arrieta O, Ramirez-Tirado LA, Baez-Saldana R, Pena-Curiel O, Soca-Chafre G, Macedo-Perez EO. Different mutation profiles and clinical characteristics among Hispanic patients with non-small cell lung cancer could explain the “Hispanic paradox”. Lung Cancer. 2015;90(2):161–6. doi:10.1016/j.lungcan.2015.08.010.

    Article  PubMed  Google Scholar 

  54. Arrieta O, Rios Trejo MA, Michel RM. Wood-smoke exposure as a response and survival predictor in erlotinib-treated nonsmall cell lung cancer patients. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2009;4(8):1043. doi:10.1097/JTO.0b013e3181ae2497.

    Google Scholar 

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Acknowledgements

Boehringer Ingelheim México S.A. (Mexico City) provided afatinib as a donation, with no interference in the trial design or the results.

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Authors and Affiliations

  1. Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico

    Oscar Arrieta, Enrique Caballe-Perez, Jorge-Negueb Martínez-Hernández, Ivan Martinez-Alvarez & Eleazar Omar Macedo-Pérez

  2. Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico

    Oscar Arrieta, Graciela Cruz-Rico, Laura-Alejandra Ramírez-Tirado & Giovanny Soca-Chafre

  3. Cancer Care in the Elderly Clinic, Department of Geriatrics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga No. 15, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico

    Enrique Soto-Perez-de-Celis

  4. Laboratory of Translational Cancer Research and Cellular Therapy, Oncology Hospital, Medical Center Siglo XXI, Mexican Institute of Social Security (IMSS), CP 06720, Mexico City, Mexico

    Horacio Astudillo-de la Vega

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  1. Oscar Arrieta
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OA, GCR, ESPC, LART, ECP, JNMH, GSC, IMA, OEMP, and HAV declare no conflict of interest.

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Arrieta, O., Cruz-Rico, G., Soto-Perez-de-Celis, E. et al. Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial. Targ Oncol 11, 619–629 (2016). https://doi.org/10.1007/s11523-016-0425-x

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