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A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer

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Summary

Purpose Preclinical data indicate that combination HER2-directed and anti-VEGF therapy may bypass resistance to trastuzumab. A phase I trial was performed to assess safety, activity, and correlates. Experimental design Patients with advanced, refractory malignancy were enrolled (modified 3 + 3 design with expansions for responding tumor types). Patients received lapatinib daily for 21 days, and bevacizumab and trastuzumab every 3 weeks. Correlates included HER2 extracellular domain levels (ECD) and single nucleotide polymorphisms (SNPs). Results Ninety-four patients were treated (median = four prior systemic therapies). The most common related adverse events ≥ grade 2 were diarrhea (n = 33, 35 %) and hypertension (n = 10, 11 %). The recommended phase 2 dose was trastuzumab 6 mg/m2 (loading = 8 mg/m2) and bevacizumab 15 mg/kg every 3 weeks, with lapatinib 1,250 mg daily (full FDA-approved dose of each drug). One patient (1 %) achieved a complete response (CR); eight (9 %), a partial response (PR) (includes breast (n = 7, one of which was HER2 2+ by IHC) and salivary ductal carcinoma (n = 1); and 14 (15 %), stable disease (SD) ≥6 months (total SD ≥ 6 months/PR/CR =23 (25 %). All patients with PR/CR received prior trastuzumab +/− lapatinib. SD ≥ 6 months/PR/CR rate and time to treatment failure (TTF) correlated with elevated baseline HER2 ECD (N = 75 patients tested) but not with HER2 SNPs. Conclusions Combination trastuzumab, lapatinib, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced malignancy.

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References

  1. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712

    Article  CAS  PubMed  Google Scholar 

  2. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376(9742):687–697. doi:10.1016/S0140-6736(10)61121-X

    Article  CAS  PubMed  Google Scholar 

  3. Safran H, Iannitti D, Ramanathan R, Schwartz JD, Steinhoff M, Nauman C, Hesketh P, Rathore R, Wolff R, Tantravahi U, Hughes TM, Maia C, Pasquariello T, Goldstein L, King T, Tsai JY, Kennedy T (2004) Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 22(5):706–712

    Article  CAS  PubMed  Google Scholar 

  4. Glisson B, Colevas AD, Haddad R, Krane J, El-Naggar A, Kies M, Costello R, Summey C, Arquette M, Langer C, Amrein PC, Posner M (2004) HER2 expression in salivary gland carcinomas: dependence on histological subtype. Clin Cancer Res 10(3):944–946

    Article  CAS  PubMed  Google Scholar 

  5. Kim HJ, Yoo TW, Park DI, Park JH, Cho YK, Sohn CI, Jeon WK, Kim BI, Kim MK, Chae SW, Sohn JH (2007) Gene amplification and protein overexpression of HER-2/neu in human extrahepatic cholangiocarcinoma as detected by chromogenic in situ hybridization and immunohistochemistry: its prognostic implication in node-positive patients. Ann Oncol 18(5):892–897. doi:10.1093/annonc/mdm006

    Article  CAS  PubMed  Google Scholar 

  6. Pignochino Y, Sarotto I, Peraldo-Neia C, Penachioni JY, Cavalloni G, Migliardi G, Casorzo L, Chiorino G, Risio M, Bardelli A, Aglietta M, Leone F (2010) Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas. BMC Cancer 10:631. doi:10.1186/1471-2407-10-631

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Clamon G, Herndon J, Kern J, Govindan R, Garst J, Watson D, Green M (2005) Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of cancer and leukemia group B. Cancer 103(8):1670–1675. doi:10.1002/cncr.20950

    Article  CAS  PubMed  Google Scholar 

  8. Yan M, Parker BA, Schwab R, Kurzrock R (2014) HER2 aberrations in cancer: implications for therapy. Cancer Treat Rev 40(6):770–780. doi:10.1016/j.ctrv.2014.02.008

    Article  CAS  PubMed  Google Scholar 

  9. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  CAS  PubMed  Google Scholar 

  10. Kolla SB, Seth A, Singh MK, Gupta NP, Hemal AK, Dogra PN, Kumar R (2008) Prognostic significance of Her2/neu overexpression in patients with muscle invasive urinary bladder cancer treated with radical cystectomy. Int Urol Nephrol 40(2):321–327. doi:10.1007/s11255-007-9283-x

    Article  PubMed  Google Scholar 

  11. Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, Soper JT, Dodge R, Clarke-Pearson DL, Marks P et al (1990) Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 50(13):4087–4091

    CAS  PubMed  Google Scholar 

  12. Hetzel DJ, Wilson TO, Keeney GL, Roche PC, Cha SS, Podratz KC (1992) HER-2/neu expression: a major prognostic factor in endometrial cancer. Gynecol Oncol 47(2):179–185

    Article  CAS  PubMed  Google Scholar 

  13. Tan D, Deeb G, Wang J, Slocum HK, Winston J, Wiseman S, Beck A, Sait S, Anderson T, Nwogu C, Ramnath N, Loewen G (2003) HER-2/neu protein expression and gene alteration in stage I-IIIA non-small-cell lung cancer: a study of 140 cases using a combination of high throughput tissue microarray, immunohistochemistry, and fluorescent in situ hybridization. Diagn Mol Pathol 12(4):201–211

    Article  CAS  PubMed  Google Scholar 

  14. Gravalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19(9):1523–1529. doi:10.1093/annonc/mdn169

    Article  CAS  PubMed  Google Scholar 

  15. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L (1996) Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14(3):737–744

    CAS  PubMed  Google Scholar 

  16. Tripathy D, Slamon DJ, Cobleigh M, Arnold A, Saleh M, Mortimer JE, Murphy M, Stewart SJ (2004) Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 22(6):1063–1070. doi:10.1200/JCO.2004.06.557

    Article  CAS  PubMed  Google Scholar 

  17. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L (2004) A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64(18):6652–6659. doi:10.1158/0008-5472.CAN-04-1168

    Article  CAS  PubMed  Google Scholar 

  18. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743. doi:10.1056/NEJMoa064320

    Article  CAS  PubMed  Google Scholar 

  19. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O’Shaughnessy J (2012) Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 30(21):2585–2592. doi:10.1200/JCO.2011.35.6725

    Article  CAS  PubMed  Google Scholar 

  20. Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ, Hung MC (2008) Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell 13(5):385–393. doi:10.1016/j.ccr.2008.03.015

    Article  PubMed Central  PubMed  Google Scholar 

  21. Janku F, Huang HJ, Angelo LS, Kurzrock R (2013) A kinase-independent biological activity for insulin growth factor-1 receptor (IGF-1R): implications for inhibition of the IGF-1R signal. Oncotarget 4(3):463–473

    PubMed Central  PubMed  Google Scholar 

  22. Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284(5422):1994–1998

    Article  CAS  PubMed  Google Scholar 

  23. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3(5):391–400. doi:10.1038/nrd1381

    Article  CAS  PubMed  Google Scholar 

  24. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349(5):427–434. doi:10.1056/NEJMoa021491

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22(11):2184–2191. doi:10.1200/JCO.2004.11.022

    Article  CAS  PubMed  Google Scholar 

  26. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740. doi:10.1200/JCO.2008.19.8721

    Article  CAS  PubMed  Google Scholar 

  27. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI (2007) Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a gynecologic oncology group study. J Clin Oncol 33:5165–5171. doi:10.1200/JCO.2007.11.5345

    Article  Google Scholar 

  28. Wright JD, Viviano D, Powell MA, Gibb RK, Mutch DG, Grigsby PW, Rader JS (2006) Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer. Gynecol Oncol 103(2):489–493. doi:10.1016/j.ygyno.2006.03.023

    Article  CAS  PubMed  Google Scholar 

  29. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23(4):792–799. doi:10.1200/JCO.2005.05.098

    Article  CAS  PubMed  Google Scholar 

  30. Yen L, You XL, Al Moustafa AE, Batist G, Hynes NE, Mader S, Meloche S, Alaoui-Jamali MA (2000) Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 19(31):3460–3469. doi:10.1038/sj.onc.1203685

    Article  CAS  PubMed  Google Scholar 

  31. Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein M, Stieber P, Vernes JM, Gutierrez J, Hong K, Beryt M, Hepp H, Slamon DJ, Pegram MD (2004) Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 10(5):1706–1716

    Article  CAS  PubMed  Google Scholar 

  32. du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel RS (2006) Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. Clin Cancer Res 12(3 Pt 1):904–916. doi:10.1158/1078-0432.CCR-05-1109

    Article  PubMed  Google Scholar 

  33. Hurvitz S, Pegram M, Lin L, Chan D, Allen H, Dichmann R, et al. (2009) Final results of a phase II trial evaluating Trastuzumab and Bevacuzumab as first line treatment of HER2-amplified advanced breast cancer. Thirty-Second Annual Cancer Therapy & Research Center-American Association for Cancer Research San Antonio Breast Cancer Symposium 2009 San Antonio, TX: American Association for Cancer Research; 2009

  34. Rugo HS, Chien AJ, Franco SX, Stopeck AT, Glencer A, Lahiri S, Arbushites MC, Scott J, Park JW, Hudis C, Nulsen B, Dickler MN (2012) A phase II study of lapatinib and bevacizumab as treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 134(1):13–20. doi:10.1007/s10549-011-1918-z

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O’Shaughnessy J (2010) Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28(7):1124–1130. doi:10.1200/JCO.2008.21.4437

    Article  CAS  PubMed  Google Scholar 

  36. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gomez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horvath Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379(9816):633–640. doi:10.1016/S0140-6736(11)61847-3

    Article  CAS  PubMed  Google Scholar 

  37. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern cooperative oncology group. Am J Clin Oncol 5(6):649–655

    Article  CAS  PubMed  Google Scholar 

  38. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13(3):176–181. doi:10.1016/S1053-4296(03)00031-6

    Article  PubMed  Google Scholar 

  39. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  CAS  PubMed  Google Scholar 

  40. Falchook G S, Wheler JJ, Naing A, Hong DS, Moulder SL, Piha-Paul SA, Ng CS, Jackson E, Kurzrock R (2010) A phase I study of bevacizumab in combination with sunitinib, sorafenib, and erlotinib plus cetuximab, and trastuzumab plus lapatinib. Paper presented at the American Society of Clinical Oncology Annual Meeting, Chicago, IL

  41. Falchook GS, Janku F, Tsao AS, Bastida CC, Stewart DJ, Kurzrock R (2013) Non-small-cell lung cancer with HER2 exon 20 mutation: regression with dual HER2 inhibition and anti-VEGF combination treatment. J Thorac Oncol 8(2):e19–20. doi:10.1097/JTO.0b013e31827ce38e

    Article  PubMed Central  PubMed  Google Scholar 

  42. Burris HA 3rd (2004) Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9(Suppl 3):10–15

    Article  CAS  PubMed  Google Scholar 

  43. Falchook GS, Moulder SL, Wheler JJ, Jiang Y, Bastida CC, Kurzrock R (2013) Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer. Ann Oncol 24(12):3004–3011. doi:10.1093/annonc/mdt395

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O’Shaughnessy J (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29(10):1252–1260. doi:10.1200/JCO.2010.28.0982

    Article  CAS  PubMed  Google Scholar 

  45. Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, Steger GG, Suter TM, Toi M, Parmar M, Laeufle R, Im YH, Romieu G, Harvey V, Lipatov O, Pienkowski T, Cottu P, Chan A, Im SA, Hall PS, Bubuteishvili-Pacaud L, Henschel V, Deurloo RJ, Pallaud C, Bell R (2013) Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 14(10):933–942. doi:10.1016/S1470-2045(13)70335-8

    Article  CAS  PubMed  Google Scholar 

  46. Falchook GS, Lippman SM, Bastida CC, Kurzrock R (2014) Human epidermal receptor 2-amplified salivary duct carcinoma: regression with dual human epidermal receptor 2 inhibition and anti-vascular endothelial growth factor combination treatment. Head Neck 36(3):E25–27. doi:10.1002/hed.23429

    Article  PubMed  Google Scholar 

  47. Kodack DP, Chung E, Yamashita H, Incio J, Duyverman AM, Song Y, Farrar CT, Huang Y, Ager E, Kamoun W, Goel S, Snuderl M, Lussiez A, Hiddingh L, Mahmood S, Tannous BA, Eichler AF, Fukumura D, Engelman JA, Jain RK (2012) Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc Natl Acad Sci U S A 109(45):E3119–3127. doi:10.1073/pnas.1216078109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Frank B, Hemminki K, Wirtenberger M, Bermejo JL, Bugert P, Klaes R, Schmutzler RK, Wappenschmidt B, Bartram CR, Burwinkel B (2005) The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk. Carcinogenesis 26(3):643–647. doi:10.1093/carcin/bgh342

    Article  CAS  PubMed  Google Scholar 

  49. Kallel I, Kharrat N, Al-fadhly S, Rebai M, Khabir A, Boudawara TS, Rebai A (2010) HER2 polymorphisms and breast cancer in Tunisian women. Genet Test Mol Biomark 14(1):29–35. doi:10.1089/gtmb.2009.0069

    Article  CAS  Google Scholar 

  50. Kostler WJ, Schwab B, Singer CF, Neumann R, Rucklinger E, Brodowicz T, Tomek S, Niedermayr M, Hejna M, Steger GG, Krainer M, Wiltschke C, Zielinski CC (2004) Monitoring of serum Her-2/neu predicts response and progression-free survival to trastuzumab-based treatment in patients with metastatic breast cancer. Clin Cancer Res 10(5):1618–1624

    Article  PubMed  Google Scholar 

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Acknowledgments

We would like to thank the patients and their families for their participation in this clinical trial. We would also like to thank Adrienne Howard for regulatory protocol assistance. This work was supported by the Paul Calabresi Career Development Award for Clinical Oncology K12 CA088084.

Conflict of interest

Dr. Falchook receives research funding and travel reimbursement from GlaxoSmithKline. The other authors declare that they have no conflict of interest.

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Paul Calabresi Career Development Award for Clinical Oncology K12 CA088084

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Correspondence to Gerald S. Falchook.

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Falchook, G.S., Moulder, S., Naing, A. et al. A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer. Invest New Drugs 33, 177–186 (2015). https://doi.org/10.1007/s10637-014-0173-7

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