Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Activation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC.

Methods

Patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan–Meier method.

Results

Seventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months.

Conclusions

The combination of alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Moasser MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26(45):6469–6487. https://doi.org/10.1038/sj.onc.1210477

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. 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  PubMed  CAS  Google Scholar 

  3. Tandon AK, Clark GM, Chamness GC, Ullrich A, McGuire WL (1989) HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol 7(8):1120–1128. https://doi.org/10.1200/JCO.1989.7.8.1120

    Article  PubMed  CAS  Google Scholar 

  4. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14(4):320–368. https://doi.org/10.1634/theoncologist.2008-0230

    Article  PubMed  CAS  Google Scholar 

  5. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. https://doi.org/10.1056/nejm200103153441101

    Article  PubMed  CAS  Google Scholar 

  6. Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J (2013) Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14(6):461–471. https://doi.org/10.1016/S1470-2045(13)70130-X

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Swain SM, Baselga J, Kim S-B, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero J-M, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372(8):724–734. https://doi.org/10.1056/NEJMoa1413513

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Mendes D, Alves C, Afonso N, Cardoso F, Passos-Coelho JL, Costa L, Andrade S, Batel-Marques F (2015) The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer – a systematic review. Breast Cancer Res 17(1):140. https://doi.org/10.1186/s13058-015-0648-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh D-Y, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367(19):1783–1791. https://doi.org/10.1056/NEJMoa1209124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 18 (6):732–742. https://doi.org/10.1016/S1470-2045(17)30312-1

  11. Krop IE, Kim SB, Gonzalez-Martin A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, Wildiers H (2014) Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 15(7):689–699. https://doi.org/10.1016/s1470-2045(14)70178-0

    Article  PubMed  CAS  Google Scholar 

  12. Krop IE, Kim S-B, Martin AG, LoRusso PM, Ferrero J-M, Badovinac-Crnjevic T, Hoersch S, Smitt M, Wildiers H Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 18 (6):743–754. https://doi.org/10.1016/S1470-2045(17)30313-3

  13. Pohlmann PR, Mayer IA, Mernaugh R (2009) Resistance to trastuzumab in breast cancer. Clin Cancer Res 15(24):7479–7491. https://doi.org/10.1158/1078-0432.ccr-09-0636

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4):395–402. https://doi.org/10.1016/j.ccr.2007.08.030

    Article  PubMed  CAS  Google Scholar 

  15. Chandarlapaty S, Sakr RA, Giri D, Patil S, Heguy A, Morrow M, Modi S, Norton L, Rosen N, Hudis C, King TA (2012) Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer. Clin Cancer Res 18(24):6784–6791. https://doi.org/10.1158/1078-0432.ccr-12-1785

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Esteva FJ, Guo H, Zhang S, Santa-Maria C, Stone S, Lanchbury JS, Sahin AA, Hortobagyi GN, Yu D (2010) PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 177(4):1647–1656. https://doi.org/10.2353/ajpath.2010.090885

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. D’Amato V, Raimondo L, Formisano L, Giuliano M, De Placido S, Rosa R, Bianco R (2015) Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev 41(10):877–883. https://doi.org/10.1016/j.ctrv.2015.08.001

    Article  PubMed  CAS  Google Scholar 

  18. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127. https://doi.org/10.1016/j.ccr.2004.06.022

    Article  PubMed  CAS  Google Scholar 

  19. Baselga J, Lewis Phillips GD, Verma S, Ro J, Huober J, Guardino AE, Samant MK, Olsen S, de Haas SL, Pegram MD (2016) Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin Cancer Res 22(15):3755–3763. https://doi.org/10.1158/1078-0432.ccr-15-2499

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. André F, Hurvitz S, Fasolo A, Tseng L-M, Jerusalem G, Wilks S, O’Regan R, Isaacs C, Toi M, Burris H, He W, Robinson D, Riester M, Taran T, Chen D, Slamon D (2016) Molecular alterations and everolimus efficacy in human epidermal growth factor receptor 2–overexpressing metastatic breast cancers: combined exploratory biomarker analysis from BOLERO-1 and BOLERO-3. J Clin Oncol 34(18):2115–2124. https://doi.org/10.1200/JCO.2015.63.9161

    Article  PubMed  Google Scholar 

  21. Loibl S, von Minckwitz G, Schneeweiss A, Paepke S, Lehmann A, Rezai M, Zahm DM, Sinn P, Khandan F, Eidtmann H, Dohnal K, Heinrichs C, Huober J, Pfitzner B, Fasching PA, Andre F, Lindner JL, Sotiriou C, Dykgers A, Guo S, Gade S, Nekljudova V, Loi S, Untch M, Denkert C (2014) PIK3CA mutations are associated with lower rates of pathologic complete response to anti–human epidermal growth factor receptor 2 (HER2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol 32(29):3212–3220. https://doi.org/10.1200/JCO.2014.55.7876

    Article  PubMed  CAS  Google Scholar 

  22. Nahta R, O’Regan RM (2010) Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway. Clin Breast Cancer 10 Suppl 3:S72-78. https://doi.org/10.3816/CBC.2010.s.015

    Article  CAS  Google Scholar 

  23. Wilks ST (2015) Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway. Breast 24(5):548–555. https://doi.org/10.1016/j.breast.2015.06.002

    Article  PubMed  Google Scholar 

  24. O’Brien NA, McDonald K, Tong L, von Euw E, Kalous O, Conklin D, Hurvitz SA, di Tomaso E, Schnell C, Linnartz R, Finn RS, Hirawat S, Slamon DJ (2014) Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT. Clin Cancer Res 20(13):3507–3520. https://doi.org/10.1158/1078-0432.ccr-13-2769

    Article  PubMed  Google Scholar 

  25. Yao E, Zhou W, Lee-Hoeflich ST, Truong T, Haverty PM, Eastham-Anderson J, Lewin-Koh N, Gunter B, Belvin M, Murray LJ, Friedman LS, Sliwkowski MX, Hoeflich KP (2009) Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin Cancer Res 15(12):4147–4156. https://doi.org/10.1158/1078-0432.ccr-08-2814

    Article  PubMed  CAS  Google Scholar 

  26. Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng L-M, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay M-A, Rao S, Pacaud LB, Taran T, Slamon D Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol 16 (7):816–829. https://doi.org/10.1016/S1470-2045(15)00051-0

  27. Andre F, O’Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L (2014) Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15(6):580–591. https://doi.org/10.1016/s1470-2045(14)70138-x

    Article  PubMed  CAS  Google Scholar 

  28. Furet P, Guagnano V, Fairhurst RA, Imbach-Weese P, Bruce I, Knapp M, Fritsch C, Blasco F, Blanz J, Aichholz R, Hamon J, Fabbro D, Caravatti G (2013) Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorganic Med Chem Lett 23(13):3741–3748. https://doi.org/10.1016/j.bmcl.2013.05.007

    Article  CAS  Google Scholar 

  29. Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, Liu M, Kauffmann A, Guthy D, Erdmann D, De Pover A, Furet P, Gao H, Ferretti S, Wang Y, Trappe J, Brachmann SM, Maira S-M, Wilson C, Boehm M, Garcia-Echeverria C, Chene P, Wiesmann M, Cozens R, Lehar J, Schlegel R, Caravatti G, Hofmann F, Sellers WR (2014) Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther 13(5):1117–1129. https://doi.org/10.1158/1535-7163.mct-13-0865

    Article  PubMed  CAS  Google Scholar 

  30. Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL (2017) A phase Ib study of alpelisib (BYL719), a PI3Kalpha-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer. Clin Cancer Res 23(1):26–34. https://doi.org/10.1158/1078-0432.ccr-16-0134

    Article  PubMed  CAS  Google Scholar 

  31. Juric D, Burris H, Schuler M, Schellens J, Berlin J, Seggewiß-Bernhardt R, Gil-Martin M, Gupta A, Rodon J, Tabernero J, Janku F, Rugo HS, Bootle D, Quadt C, Coughlin C, Demanse D, Blumenstein L, Baselga J (2014) Phase I study of the PI3Kα inhibitor BYL719, as a single agent in patients with advanced solid tumors (AST). Ann Oncol 25 (suppl_4):iv150–iv150. https://doi.org/10.1093/annonc/mdu331.11

    Article  Google Scholar 

  32. Santa-Maria CA, Nye L, Mutonga MB, Jain S, Gradishar WJ (2016) Management of metastatic HER2-positive breast cancer: where are we and where do we go from here? Oncology (Williston Park, NY) 30 (2):148–155

  33. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S (2009) Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a german breast group 26/breast international group 03–05 study. J Clin Oncol 27(12):1999–2006. https://doi.org/10.1200/JCO.2008.19.6618

    Article  CAS  Google Scholar 

  34. Muzaffar M, Jia J, Liles D, Naveed M, Kumari A (2016) Acute pancreatitis associated with ado-trastuzumab emtansine. Am J Ther 23(2):e572-574

    Article  Google Scholar 

  35. Tolaney S, Burris H, Gartner E, Mayer IA, Saura C, Maurer M, Ciruelos E, Garcia AA, Campana F, Wu B, Xu Y, Jiang J, Winer E, Krop I (2015) Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Res Treat 149(1):151–161. https://doi.org/10.1007/s10549-014-3248-4

    Article  PubMed  CAS  Google Scholar 

  36. Saura C, Bendell J, Jerusalem G, Su S, Ru Q, De Buck S, Mills D, Ruquet S, Bosch A, Urruticoechea A, Beck JT, Di Tomaso E, Sternberg DW, Massacesi C, Hirawat S, Dirix L, Baselga J (2014) Phase Ib study of Buparlisib plus trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on trastuzumab-based therapy. Clin Cancer Res 20(7):1935–1945. https://doi.org/10.1158/1078-0432.ccr-13-1070

    Article  PubMed  CAS  Google Scholar 

  37. Sarker D, Ang JE, Baird R, Kristeleit R, Shah K, Moreno V, Clarke PA, Raynaud FI, Levy G, Ware JA, Mazina K, Lin R, Wu J, Fredrickson J, Spoerke JM, Lackner MR, Yan Y, Friedman LS, Kaye SB, Derynck MK, Workman P, de Bono JS (2015) First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res 21(1):77–86. https://doi.org/10.1158/1078-0432.ccr-14-0947

    Article  PubMed  CAS  Google Scholar 

  38. Shapiro GI, Rodon J, Bedell C, Kwak EL, Baselga J, Brana I, Pandya SS, Scheffold C, Laird AD, Nguyen LT, Xu Y, Egile C, Edelman G (2014) Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res 20(1):233–245. https://doi.org/10.1158/1078-0432.ccr-13-1777

    Article  PubMed  CAS  Google Scholar 

  39. Patnaik A, Appleman LJ, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Weiss GJ, Sachdev JC, Chadha M, Fulk M, Ejadi S, Mountz JM, Lotze MT, Toledo FGS, Chu E, Jeffers M, Peña C, Xia C, Reif S, Genvresse I, Ramanathan RK (2016) First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann Oncol 27(10):1928–1940. https://doi.org/10.1093/annonc/mdw282

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Sanabria Bohorquez SM, Savage HM, Sampath D, Salphati L, Lin RS, Jin H, Parmar H, Hsu JY, Von Hoff DD, Baselga J (2017) Phase I dose-escalation study of Taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors. Cancer Discov. https://doi.org/10.1158/2159-8290.cd-16-1080

    Article  PubMed Central  PubMed  Google Scholar 

  41. Krop I, Winer EP (2014) Trastuzumab emtansine: a novel antibody–drug conjugate for HER2-positive breast cancer. Clin Cancer Res 20(1):15–20. https://doi.org/10.1158/1078-0432.ccr-13-0541

    Article  PubMed  CAS  Google Scholar 

  42. Rodón J, Curigliano G, Delord JP, Harb W, Azaro A, Donnet V, Han Y, Blumenstein L, Wilke C, Beck JT (2016) A phase Ib dose-finding study of alpelisib (ALP; BYL719) and paclitaxel (PTX) in advanced solid tumors (aST). Ann Oncol 27(suppl_6):375P-375P. https://doi.org/10.1093/annonc/mdw368.18

    Article  Google Scholar 

  43. Vuylsteke P, Huizing M, Petrakova K, Roylance R, Laing R, Chan S, Abell F, Gendreau S, Rooney I, Apt D, Zhou J, Singel S, Fehrenbacher L (2016) Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study. Ann Oncol 27(11):2059–2066. https://doi.org/10.1093/annonc/mdw320

    Article  PubMed  CAS  Google Scholar 

  44. Loibl S, de la Pena L, Nekljudova V, Zardavas D, Michiels S, Denkert C, Rezai M, Bermejo B, Untch M, Lee SC, Turri S, Urban P, Kummel S, Steger G, Gombos A, Lux M, Piccart MJ, Von Minckwitz G, Baselga J, Loi S (2017) Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2 + primary breast cancer: a randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Eur J Cancer 85:133–145. https://doi.org/10.1016/j.ejca.2017.08.020

    Article  PubMed  CAS  Google Scholar 

  45. Martin M, Chan A, Dirix L, O’Shaughnessy J, Hegg R, Manikhas A, Shtivelband M, Krivorotko P, Batista Lopez N, Campone M, Ruiz Borrego M, Khan QJ, Beck JT, Ramos Vazquez M, Urban P, Goteti S, Di Tomaso E, Massacesi C, Delaloge S (2017) A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4). Ann Oncol 28(2):313–320. https://doi.org/10.1093/annonc/mdw562

    Article  PubMed  CAS  Google Scholar 

  46. Ma CX, Luo J, Naughton M, Ademuyiwa F, Suresh R, Griffith M, Griffith OL, Skidmore ZL, Spies NC, Ramu A, Trani L, Pluard T, Nagaraj G, Thomas S, Guo Z, Hoog J, Han J, Mardis E, Lockhart C, Ellis MJ (2016) A phase I Trial of BKM120 (Buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res 22(7):1583–1591. https://doi.org/10.1158/1078-0432.ccr-15-1745

    Article  PubMed  CAS  Google Scholar 

  47. Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M (2017) Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(7):904–916. https://doi.org/10.1016/s1470-2045(17)30376-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, Yardley DA, Melichar B, Forero-Torres A, Lee SC, de Boer R, Petrakova K, Vallentin S, Perez EA, Piccart M, Ellis M, Winer E, Gendreau S, Derynck M, Lackner M, Levy G, Qiu J, He J, Schmid P (2016) Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 17(6):811–821. https://doi.org/10.1016/S1470-2045(16)00106-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Barok M, Tanner M, Köninki K, Isola J (2011) Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Res 13(2):R46-R46. https://doi.org/10.1186/bcr2868

    Article  CAS  Google Scholar 

  50. Kim S-B, Dent R, Im S-A, Espié M, Blau S, Tan AR, Isakoff SJ, Oliveira M, Saura C, Wongchenko MJ, Kapp AV, Chan WY, Singel SM, Maslyar DJ, Baselga J (2017) Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Oncology 18:1360–1372

    Article  Google Scholar 

Download references

Financial support

Novartis.

Author information

Author notes

  1. Sarika Jain and Ami N. Shah have contributed equally to this work.

Authors and Affiliations

  1. Lynn Sage Breast Cancer Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 676 N St. Clair St. Suite 850, Chicago, IL, 60611, USA

    Sarika Jain, Ami N. Shah, Cesar A. Santa-Maria, Kalliopi Siziopikou, Alfred Rademaker, Irene Helenowski, Massimo Cristofanilli & William J. Gradishar

Authors
  1. Sarika Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ami N. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cesar A. Santa-Maria
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kalliopi Siziopikou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alfred Rademaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Irene Helenowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Massimo Cristofanilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William J. Gradishar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William J. Gradishar.

Ethics declarations

Conflict of interest

Dr. Cristofanilli is a consultant for Novartis, received funding and remuneration from Pfizer. Dr. Santa-Maria received research funding from Medimmune and Pfizer. The remaining authors declare they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jain, S., Shah, A.N., Santa-Maria, C.A. et al. Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy. Breast Cancer Res Treat 171, 371–381 (2018). https://doi.org/10.1007/s10549-018-4792-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-018-4792-0

Keywords

Search

Navigation