1.

Summary of T-DM1 clinical trials for HER2-positive advanced or metastatic and early-stage breast cancer

Clinical trial	Phase	Study population	Study design	Results	AEs
T-DM1, trastuzumab emtansine; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PFS, progression-free survival; HR, hazard ratio; OS, overall survival; ORR, objective response rate; pCR, pathological complete response (ypT0/is, i.e., absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement); iDFS, invasive disease-free survival; AEs, adverse events.
Advanced or metastatic breast cancer
EMILIA (2012) (56)	III	Patients (n=991) with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and taxane	G1: lapatinib plus capecitabine G2: T-DM1	Median PFS: G1 vs. G2: 6.4 months vs. 9.6 months (HR=0.65, P<0.001) Median OS: G1 vs. G2: 25.1 months vs. 30.9 months (HR=0.68, P<0.001) ORR: G1 vs. G2: 30.8% vs. 43.6% (P<0.001)	Grade ≥3: G1 vs. G2: 57% vs. 41% G1: diarrhea, nausea, vomiting G2: thrombocytopenia and increased serum aminotransferase levels
TDM4450 g (2013) (57)	II	Patients (n=137) with HER2-positive MBC or recurrent locally advanced breast cancer	G1: trastuzumab plus docetaxel G2: T-DM1	Median PFS: G1 vs. G2: 9.2 months vs. 14.2 months (HR=0.59, P =0.035) ORR: G1 vs. G2: 58.0% vs. 64.2%	Grade ≥3: G1 vs. G2: 90.9% vs. 46.4% Serious AEs: G1 vs. G2: 20.3% vs. 25.8% G1: neutropenia, alopecia, diarrhea G2: thrombocytopenia, increased aminotransferase levels, headache
TH3RESA (2014) (58)	III	Patients (n=602) with HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting	G1: physician’s choice (68.5% chemotherapy plus trastuzumab) G2: T-DM1	Median PFS: G1 vs. G2: 3.3 months vs. 6.2 months (HR=0.528, P<0.0001) OS: G1 vs. G2: 22.7 months vs. 15.8 months (HR=0.68, P=0.0007)	Grade ≥3: G1 vs. G2: 47% vs. 40% Serious AEs: G1 vs. G2: 22% vs. 25% G1: neutropenia, diarrhea G2: thrombocytopenia
MARIANNE (2017) (59)	III	Patients (n=1,095) with HER2-positive, advanced breast cancer and no prior therapy for advanced disease	G1: trastuzumab plus taxane G2: T-DM1 plus placebo G3: T-DM1 plus pertuzumab	Median PFS: G1 vs. G2 vs. G3: 13.7 months vs. 14.1 months vs. 15.2 months (G2 and G3 are not superior to G1) (P>0.05) ORR: G1 vs. G2 vs. G3: 67.9% vs. 59.7% vs. 64.2%	Grade ≥3: G1 vs. G2 vs. G3: 54.1% vs. 45.4% vs. 46.2% G1: alopecia, diarrhea T-DM1: thrombocytopenia, increased aminotransferase, diarrhea
Early-stage breast cancer
KRISTINE (2017) (60)	III	Patients (n=444) with HER2-positive stage II−III operable breast cancer	(Neoadjuvant therapy) G1: docetaxel, carboplatin, trastuzumab plus pertuzumab G2: T-DM1 plus pertuzumab	pCR: G1 vs. G2: 55.7% vs. 44.4% (P=0.016)	Grade ≥3: G1 vs. G2: 64% vs. 13% serious AEs: G1 vs. G2: 29% vs. 5% G1: nausea, headache, increased aminotransferase, G2: nausea, diarrhea, vomiting
KATHERINE (2018) (19)	III	HER2-positive early breast cancer patients (n=1,486) with residual invasive disease at surgery after receiving neoadjuvant therapy containing taxane (with or without anthracycline) and trastuzumab	(Adjuvant therapy) G1: T-DM1 G2: trastuzumab	iDFS: G1 vs. G2: 88.3% vs. 77.0% (HR=0.5, P<0.001)	Grade ≥3: G1 vs. G2: 25.7% vs. 15.4% Serious AEs: G1 vs. G2: 12.7% vs. 8.1% G1: thrombocytopenia, hypertension G2: hypertension
KAITLIN (NCT 01966471)	III	Patients (n=1,846) with operable HER2-positive primary breast cancer	(Adjuvant therapy) G1: trastuzumab plus pertuzumab plus taxane following anthracyclines G2: T-DM1 plus pertuzumab following anthracyclines	Ongoing	Ongoing
ATEMPT (NCT 01853748)	II	Patients (n=512) with stage I HER2-positive breast cancer	(Adjuvant therapy) G1: T-DM1 G2: paclitaxel and trastuzumab	Ongoing	Ongoing