Combination of Pertuzumab and Trastuzumab in the Treatment of HER2-Positive Early Breast Cancer: A Review of the Emerging Clinical Data

Figures & data

Table 1 Select Trials in HER2-Positive Early-Stage Breast Cancer

Treatment Category	Patient Population	Number Treated	Primary Endpoint	Treatment Arms	Results and NNT of Select Trials
Neoadjuvant Trastuzumab
NOAH Phase III	HER2+ locally advanced or inflammatory	235	EFS (3-yr and 5-yr)	H+AT x 3➔H+T x 4➔H x 4 + CMF x 3➔ Surgery and RT➔ H alone to week 52	3–yr EFS: 71% (95% CI 61-78) 5-yr EFS: 58% (95% CI 48–66)
				ATx3➔Tx4➔CMFx3➔ Surgery and RT (HER2+)	3–yr EFS: 56% (95% CI 46-65) 5-yr EFS: 43% (95% CI 34–52)
TECHNO Phase II	HER2+ (≥ 2 cm or inflammatory)	217	pCR	EC ➔ H + T	pCR 39%. 3-yr DFS: 88% with pCR; 73% without pCR 3-yr OS: 96% with pCR; 86% without pCR
GeparQuattro Phase III	Uni or bilateral tumor, HER2±, ≥ T1c	1509 (445 HER2+)	pCR	EC ➔ D ± X + H (for HER2+)	pCR 31.7% in HER2+ cohort pCR 15.7% in HER2- cohort
Neoadjuvant Trastuzumab + Pertuzumab
NeoSphere Phase II	HER2+ locally advanced, inflammatory, or early-stage invasive	417	pCR and 5-year PFS	D + P	pCR 24% 5-yr PFS 73%
				D + H	pCR 29% 5-yr PFS 81%
				D + P + H	pCR 45.8% 5-yr PFS 86%
				P + H	pCR 16.8% 5-yr PFS 73%
TRYPHAENA Phase II	HER2+ operable, locally advanced or inflammatory and tumor >2 cm; unilateral invasive	225	Cardiac safety	FEC + H + P ➔ D + H + P	Symptomatic LVSD 0% >/=10% decline in LVEF 5.6%
				FEC ➔ D + H + P	Symptomatic LVSD 2.7% >/=10% decline in LVEF 5.3%
				D + carboplatin + H + P	Symptomatic LVSD 0% ≥10% decline in LVEF 3.9%
BERENICE Phase II	HER2+ locally advanced, inflammatory, or early-stage, unilateral invasive	397	Cardiac safety	ddAC ➔ T + H + P	NYHA III/IV HF events: 1.5% LVEF decline: 6.5% pCR 61.8%
				FEC ➔ D + H + P	NYHA III/IV HF events: 0 LVEF decline: 2.0% pCR 60.7%
TRAIN-2 Phase III	HER2+ Stage II or III	438	pCR	PTC + Ptz	pCR 68%
				FEC-T+Ptz ➔ PTC+Ptz	pCR 67%
KRISTINE Phase III	HER2+ cT2-cT4, cN0-cN3, M0, multi-focal tumors allowed if all HER2+	444	pCR 3-year iDFS	T-DM1 + P	pCR 44.4% 3-year iDFS 93.0%
				TCH + P	pCR 55.7% 3-year iDFS 92.0%
WGS-ADAPT Phase II/III	HER2+, HR-, unilateral disease, cT1-4c, any cN, M0	134	pCR (ypT0/is, ypN0)	HP ➔ surgery ➔EC + pac + H	pCR 34.4%
				P + H x 3 cycles + pac➔surgery➔EC + H *further chemotherapy could be omitted for if pCR after 12-week neoadjuvant therapy.	pCR 90.5%
GeparSepto GBG-69 Phase III	HER2+ or -, TILs, cT2 to cT4a–d or cT1c with high risk features: nodal involvement or HR- or HER2+ or Ki67 >20%	1206	pCR	Nab-pac➔EC P + H for HER2+ tumors	pCR in 38%
				Pac➔EC P + H concurrent for HER2+ tumors	pCR 29%
I-SPY 2 Phase II	HER2+ Stage II or III with clinical tumor size ≥2.5 cm	300	pCR	Pac and H ➔ AC	pCR 22%
				THP ➔ AC	pCR 54%
Adjuvant Trastuzumab
HERA Phase III	HER2+ pN≥0, pT≥1c	5102	10-yr DFS	SPM + 1 yr H	10 yr DFS 69%	10-yr DFS SPM+H vs SPM NNT 17
				SPM + 2 yr H	10 yr DFS 69%
				SPM + obs	10 yr DFS 63%
NSABP B-31/NCCTG N9831 Joint analysis	HER2+ c and pT1-3, cN0-1, pN1, pN2a, or pN3a	4046	OS	AC➔T	10-yr OS 75.2% 10-year DFS 62.2%	10-yr DFS ACTH vs ACT NNT 9 10-yr OS ACTH vs ACT NNT 11
				AC➔T+H (AC➔T➔H excluded from joint analysis)	10-yr OS 84% 10-year DFS 73.7%
BCIRG006 Phase III	HER2+ T1-3, cN0-1, M0. No residual disease or DCIS. pN1 or pN0 and one or more: size > 2 cm, HR–, grade 2-3, or < 35 yrs	3222	10-yr DFS 10-yr OS	AC➔D	10-yr DFS: 67.9% 10-yr OS: 78.7%	10-yr DFS ACDH vs ACD NNT 20 10-yr OS ACDH vs ACD NNT 22 10-yr DFS TCH vs ACD NNT 15 10-yr OS TCH vs ACD NNT 14
				AC➔DH	10-yr DFS:74.6% 10-yr OS: 85.9%
				TCH	10-yr DFS: 73% 10-yr OS: 83.3%
APT Phase II	HER2+, ≤ 3 cm, T0	410	DFS	Pac + H ➔ H	7-year DFS 93% 7-year OS 95% 7-year RFI 97.5%
Adjuvant Therapy for Residual Disease
KATHERINE Phase III	HER2+ residual disease after neoadjuvant chemo + H cT1-4/N0-3/M0 at presentation	1486	iDFS	K	3-yr iDFS 88.3%	3-yr iDFS K vs H NNT 9
				H	3-yr iDFS 77.0%
Adjuvant Pertuzumab and Trastuzumab
APHINITY Phase III	HER2+, pN≥1 (initially open to pN0), excluded cT4 and inflammatory cancers	4805	iDFS	P + H + taxane-based chemotherapy	3-yr iDFS 94.1% 6-yr iDFS 90.6%	6-yr DFS PHtax vs Htax NNT 36 6-yr OS PHtax vs Htax NNT 100
				Placebo + H + taxane-based chemotherapy	3-yr iDFS 93.2% 6-yr iDFS 87.8%
KAITLIN Phase III	HER2+ pN≥1, pT≥1, any HR status; or pN0 tumor size >2.0 cm and HR negative	1846	iDFS in LN+ and ITT	FEC/AC/EC ➔THP or DHP	3-yr iDFS 94.1% (LN+)3-yr iDFS 94.2% (ITT)
				FEC/AC/EC➔KP	3-yr iDFS 92.7% (LN+) 3-yr iDFS 93.1% (ITT)

Abbreviations: AC, doxorubicin, cyclophosphamide; AT, doxorubicin, paclitaxel; CMF, cyclophosphamide, methotrexate, and fluorouracil; dd, dose-dense; D, docetaxel; DFS, disease-free survival; EFS, event-free survival; FEC-T, 5-fluorouracil, epirubicin, cyclophosphamide, trastuzumab; HF, heart failure; H, trastuzumab; HP, trastuzumab, pertuzumab; HR, hormone receptor; ITT, intention to treat; iDFS, invasive disease-free survival; K, T-DM1; LN, lymph node; LVSD, left ventricular systolic dysfunction; NNT, number needed to treat; obs, observation; OS, overall survival; pcR, pathologic complete response; PFS, progression-free survival; Pac, paclitaxel; PTC, paclitaxel, trastuzumab, carboplatin; Ptz and P, pertuzumab; RFI, recurrence-free interval; RT, radiation therapy; SPM, standard perioperative management; T, paclitaxel; tax, taxane-based chemotherapy; TCH, docetaxel, carboplatin, trastuzumab; T-DM1, trastuzumab emtansine; THP, paclitaxel, trastuzumab, pertuzumab; TILs, tumor-infiltrating lymphocytes; X, capecitabine.