Table 4.

Data on AEs: Two

Study	Sample Size	QOL		LVEF Decline		Cardiac AEs		Febrile Neutropenia		Other Hematologic AEsa
		No.	%	No.	%	No.	%	No.	%	No.	%
	First-Line Setting
Baselga et al10 (CLEOPATRA; 2012)				Declines ≥ 10% from baseline LVEF < 50%:		LVEF grade ≥ 3:
Pertuzumab, trastuzumab, and docetaxel	402				3.8b	5b	1.2	56b	13.8
Trastuzumab, docetaxel, and placebo	406				6.6b	11b	2.8	30b	7.6
Blackwell et al,11 Verma et al12 (EMILIA; 2012)		FACT-B total:		Declines ≥ 10% from baseline resulting in LVEF < 50% in patients assessed after baseline:						Neutropenia:
T-DM1	495	7.1 months (n = 450)		8	1.7					10	2
Lapatinib plus capecitabine	496	4.6 months (n = 445)		7	1.6					21	4.3
		HR, 0.80								Thrombocytopenia:
		95% CI, 0.67 to 0.95								63	12.9
		P = .0121c								1	0.212
Huober et al7 (eLEcTRA; 2012)				Mean change:		No grade 4 cardiac AEs
Trastuzumab plus letrozole	26				7b
Letrozole	31				3b
Letrozole alone (HER2 negative, hormone receptor positive)	35				1b
Kaufman et al8 (TAnDEM; 2009)				≥ 15% from baseline to < 50%:		Grade 3 or 4:
Trastuzumab plus anastrozole	103			1		2
Anastrozole	104			0		2
Schwartzberg et al9 (2010)		FACT-B total:
Lapatinib plus letrozole	111d	104	Mean, 99.3 (SD, 19.16)	3
Placebo plus letrozole	108d	96	Mean, 101.1 (SD, 19.31)	1 (asymptomatic)e
		Subscale week 12 treatment group difference:
		1.5-point difference in favor (BCS)
		1.5-point difference in favor (SWB)g
		P < .05
Andersson et al13 (HERNATA; 2011)				Decline > 14% from baseline:						Leucopenia:
Trastuzumab plus docetaxel	143				7.2				Grade 3, 35.2; grade 4, 2.2		Grade 3, 25.2; grade 4, 15.1
Trastuzumab plus vinorelbine	141				10.9				Grade 3: 10.1; grade 4: 0.7		Grade 3, 12.3; grade 4, 8.7
				P = .40				P < .001		P < .001
Valero et al14 (BCIRG 007; 2011)				LVEF decline > 15%:						Thrombocytopenia:
Docetaxel, carboplatin, and trastuzumab	131				All grades, 6.7			17	1g	2g	15.3
Docetaxel plus trastuzumab	131							16	12.2g	3g	2.3
					5.5			P = NS		P < .001
Inoue et al15 (JO17360; 2010)				Decrease to < 50%:						Leukopenia and neutropenia combined:
Trastuzumab followed by trastuzumab plus docetaxel	55			2	4.1	No CHF		2	4	20	36
Trastuzumab plus docetaxel	53			1	2			4	8	32	60
				Difference between baseline LVEF and lowest LVEF ≥ 10:
				12	24.5
				11	22
Gelmon et al16 (MA.31/GSK EGF108919; 2012)h				Decline < 20% (greatest):
Lapatinib plus taxane followed by lapatinib	318			Week 60, 28 of 42 (of 312)	67			17 (7 postamendment)i
Trastuzumab plus taxane followed by trastuzumab	318			Week 60, 50 of 70 (of 317)	71			7 (6 postamendment)i
	Second-Line Setting
Cameron et al,17 Geyer et al18 (EGF100151; 2010)
Lapatinib plus capecitabine (combination)	198			4 (asymptomatic)j
Capecitabine (monotherapy)	201			4 (asymptomatic)j
Blackwell et al19,20 (EGF104900; 2010, 2012)		Time to deterioration:
Lapatinib alone	145	HR, 0.82 (95% CI, 0.56 to 1.20)		3		3k
Lapatinib plus trastuzumab	146	TOI:		8k,l		10 (1 fatal event)20k
		HR, 0.79 (95% CI, 0.55 to 1.14)
		BCS time to deterioration:
		HR, 1.02 (95% CI, 0.69 to 1.52)

Abbreviations: AE, adverse event; BCS, Breast Cancer Scale; CHF, congestive heart failure; FACT-B, Functional Assessment of Cancer Therapy–General; HR, hazard ratio; LVEF, left ventricular ejection fraction; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; QOL, quality of life; SD, standard deviation; SWB, Spiritual Well-Being Scale; T-DM1, trastuzumab emtansine; TOI, Trial Outcome Index.

^aFor example, thrombocytopenia.

^bMean LVEF change from baseline to minimum during treatment.

^cMedian time to decrease of ≥ 5 points in FACT-B TOI score was delayed in T-DM1 group.

^dTwo patients randomly assigned to letrozole plus placebo arm actually received letrozole plus lapatinib; thus, safety population reports on 106 and 113 patients, respectively.

^eLVEF equals space relative reduction in LVEF to ≥ 20% and below institutional normal limit.

^fMeasuring social/family well-being.

^gAll grades.

^hInterim results.

ⁱProtocol amended to require mandatory primary granulocyte colony-stimulating factor prophylaxis for those receiving lapatinib plus taxane followed by lapatinib (after first 189 patients randomly assigned).

^jNCI CTCAE (version 3.0) grade 3 or 4 left ventricular systolic dysfunction or ≥ 20% absolute decrease in LVEF relative to baseline value and below lower limit of normal of institution.

^kNCI CTCAE (version 3.0) grade ≥ 3 left ventricular systolic dysfunction or decrease in left ventricular ejection fraction 20% relative to baseline value and below lower limit of normal of institution.

^lDecrease of ≥ 20% from baseline and < lower limit of normal of institution.