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. 2018 Nov 9:10:1758835918807339.
doi: 10.1177/1758835918807339. eCollection 2018.

Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09)

Sara Hurvitz  1 , Rashi Singh  2 , Brad Adams  3 , Julie A Taguchi  4 , David Chan  5 , Robert A Dichmann  6 , Aurelio Castrellon  7 , Eddie Hu  3 , Jonathan Berkowitz  6 , Aruna Mani  7 , Brian DiCarlo  8 , Rena Callahan  3 , Ira Smalberg  9 , Xiaoyan Wang  3 , Ivana Meglar  3 , Diego Martinez  3 , Evthokia Hobbs  3 , Dennis J Slamon  3
Affiliations

Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09)

Sara Hurvitz et al. Ther Adv Med Oncol. .

Abstract

Background: Improving outcomes for patients with human epidermal growth factor 2-positive (HER2+) central nervous system (CNS) metastases remains an unmet clinical need. This trial evaluated a novel combination of everolimus, lapatinib and capecitabine for this disease.

Methods: Patients with trastuzumab-pretreated, HER2+ breast cancer brain metastasis without prior therapy with a mammalian target of rapamycin (mTOR) inhibitor were eligible. Patients received lapatinib and everolimus daily (continuously) and capecitabine twice daily (d1-14) in 21-d cycles. The primary endpoint was the 12-week CNS objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), best CNS ORR and extra-CNS ORR.

Results: A total of 19 participants were enrolled and treated with ⩾1 dose of the study drug. The median age was 58.5 years, the median number of therapies for metastatic breast cancer was 2.5 (0-11). Pretrial, 74% of participants had received prior lapatinib, capecitabine or both. A total of 63% had received previous CNS radiation or surgical resection and CNS radiation. The maximum tolerated doses were lapatinib at 1000 mg, everolimus at 10 mg, and capecitabine at 1000 mg/m2. Phase II proceeded with capecitabine at 750 mg/m2 due to better tolerability. The most common grade 3/4 adverse events were mucositis (16%), diarrhea, fatigue, and hypokalemia (11% each). Of 11 participants evaluable for 12-week CNS ORR, 3 (27%) had partial response and 7 (64%) had stable disease. The best CNS ORR in eligible participants was 28% (5/18). The median PFS and OS were 6.2 and 24.2 months, respectively.

Conclusions: This novel triplet combination of lapatinib, everolimus, and capecitabine is well tolerated and yielded a 27% response rate in the CNS at 12 weeks in heavily pretreated participants. Larger studies are warranted to further evaluate this regimen.

Trial registration: ClinicalTrials.gov: NCT01783756. Registered 05 February 2013, https://clinicaltrials.gov/ct2/show/NCT01783756.

Keywords: HER2+ breast cancer; PI3K/Akt/mTOR inhibitor; capecitabine; chemotherapy; everolimus; lapatinib; metastatic brain tumors; tyrosine kinase inhibitor.

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Conflict of interest statement

Conflict of interest statement: SH: Research Funding: Amgen, Ambryx, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Genentech/Roche, GSK, Immunomedics, Lilly, Macrogenics, Medivation, Merrimack, Novartis, Cascadian, OBI Pharma, Pfizer, Pieris, PUMA, Seattle Genetics, Dignitana (In addition to research funding) “Chief Medical Officer (unpaid position) for TRIO-U; AM: Employment: Genentech, stock ownership: Roche, research funding: Oncothyreon, EMD-Serono; JM: research funding: BMS; BD research funding: Astra Zeneca, Novartis, Syndax, Halozyme, Roche/Genentech, Takeda, Armo, BMS (online); RC: stock ownership-Merck, consulting: Novartis, Pfizer; AC: Consulting: Myriad, Biotheranostics; Research Funding: Cascadian Therapeutics, Pfizer, Novartis, PUMA Biotechnology; IS: Employment: Tower Imaging Medical Group, Consulting: Nektar; XW, BA, EH, RD, JT, IM, RS: None; DC: Stock: Abbvie, Gilead Sciences, Exelexis, Seattle Genetics, Loso, Tesaro, Exact Sciences, Consulting: Counsyl; DJS: Board Member: BioMarin, Stock Ownership: Pfizer, BioMarin, Amgen, Cascadian Therapeutics, Seattle Genetics, Consultant/Ad Board/Honoraria: Pfizer, Lilly, Novartis, Contracted Research: Pfizer, Syndax, Novartis, Lilly; DM: None; BMS: JB Research Funding.

Figures

Figure 1.
Figure 1.
Consort diagram.
Figure 2.
Figure 2.
Magnetic resonance imaging showing partial response in three patients at the 12-week timepoint. Left panel: baseline; right panel: 12 weeks after therapy. All patients initiated therapy with capecitabine 750 mg/m2, everolimus 10 mg and lapatinib 1000 mg.
See this image and copyright information in PMC

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