1. ALTERNATIVE: Dual HER2 Blockade + Aromatase Inhibitor in Postmenopausal Women With HER2+, HR+ MBC
CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
*Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals
HR, hormone receptor; mBC, metastatic breast cancer.
This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

2. ALTERNATIVE: Background
HER2+ MBC generally treated with CT and HER2 blockade, irrespective of HR status[1]
Decreased risk of progression with addition of single HER2 blockade to endocrine therapy without CT in HER2+, HR+ MBC[2,3]
Dual HER2 blockade associated with greater clinical benefit in neoadjuvant[4] and MBC[5] settings vs single HER2 blockade
ALTERNATIVE compared CT-sparing regimen of dual HER2 blockade with LAP + TRAS vs single HER2 blockade with LAP or TRAS in combination with AI treatment in pts with progressive HER2+, HR+ MBC following TRAS + CT[6]
AI, aromatase inhibitor; CT, chemotherapy; ET, endocrine therapy; HR, hormone receptor; LAP, lapatinib; mBC, metastatic breast cancer; TRAS, trastuzumab.
1. Montemurro F, et al. Ann Oncol. 2013;24: Kaufman B, et al. J Clin Oncol. 2009;27:
3. Johnston S, et al. J Clin Oncol. 2009;27: Baselga J, et al. Lancet. 2012;379: Swain SM, et al. N Engl J Med. 2015;372: Gradishar WJ, et al. ASCO Abstract 1004.
Slide credit: clinicaloptions.com

3. ALTERNATIVE: Study Design
International, randomized phase III trial (data cutoff: March 11, 2016)
Stratified by prior TRAS in (neo)adjuvant or metastatic setting, choice of AI (steroidal vs nonsteroidal)
Postmenopausal women with HER2+, ER+, and/or PgR+ MBC whose disease progressed during/after TRAS + CT in (neo)adjuvant or metastatic setting; prior ET in (neo)adjuvant and/or first-line metastatic settings allowed;
ECOG PS 0/1, not appropriate for CT
(N = 355)
LAP 1000 mg/day + TRAS* + AI†
(n = 120)
Until PD,
unacceptable AE, death, withdrawal, or investigator discretion
TRAS* + AI†
(n = 117)
LAP 1500 mg/day + AI†
(n = 118)
*TRAS loading dose 8 mg/kg IV, then 6 mg/kg IV Q3W.
†Investigator’s choice: LET 2.5 mg/day, ANA 1 mg/day, or EXE 25 mg/day.
AE, adverse event; AI, aromatase inhibitor; ANA, anastrozole; CBR, clinical benefit rate; CNS, central nervous system; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; EXE, exemestane; LAP, lapatinib; LET, letrozole; MBC, metastatic breast cancer; PD, progressive disease; PS, performance status; QoL, quality of life; TRAS, trastuzumab.
Primary endpoint: PFS with LAP + TRAS + AI vs TRAS + AI (investigator assessed by radiographic imaging)
Changed from original primary endpoint of OS per non–data-driven protocol amendment in agreement with regulatory authorities (March 18, 2016)
Secondary endpoints: other PFS comparisons, ORR, CBR, OS, safety, QoL
Slide credit: clinicaloptions.com
Gradishar WJ, et al. ASCO Abstract 1004.

4. ALTERNATIVE: Baseline Characteristics
Histology confirmed by central testing
HR+: 241/285 pts (84.5%)
HER2+: 190/270 pts (70.4%)
HER2+ and HR+: 154/190 (81% of HER2+)
Pt or Disease Characteristic, %
LAP + TRAS + AI
(n = 120)
TRAS + AI
(n = 117)
LAP + AI
(n = 118)
Median age, yrs (range)
57 (32-80)
54 (30-84)
57 (33-82)
Metastases
Visceral
Nonvisceral
Both 24 35 41 22 42 15
Disease per organ
Bone
Breast
Liver
Lung
Lymph nodes
Other 51 12 28 48 39 11 32 44 47 27 43 26
Measurable disease at screening 74 71 68
Tx History, %
LAP + TRAS + AI
(n = 120)
TRAS + AI
(n = 117)
LAP + AI
(n = 118)
Earlier anticancer tx CT
Hormonal
100 96 97 98
Trastuzumab use
(Neo)adjuvant
Metastatic setting* 74 26 65 35 71 29
≥ 3 prior CT regimens 4 2 6
AI, aromatase inhibitor; CT, chemotherapy; HR, hormone receptor; LAP, lapatinib; TRAS, trastuzumab; tx, treatment.
*With or without (neo)adjuvant.
Slide credit: clinicaloptions.com
Gradishar WJ, et al. ASCO Abstract 1004.

5. ALTERNATIVE: PFS and OS
Primary endpoint: 38% reduction in risk of progression with LAP + TRAS + AI vs TRAS + AI in ITT population
Trend across all subgroups favors therapy with LAP + TRAS + AI for PFS analysis
Endpoint
LAP + TRAS + AI (n = 120)
TRAS + AI (n = 117)
LAP + AI (n = 118)
PFS
PFS events, n (%)
62 (52)
75 (64)
74 (63)
mPFS, mos (95% CI)
11.0 ( )
5.7 ( )
8.3 ( )
HR (95% CI) vs TRAS + AI
0.62 ( ) P = .0064 -
0.71 ( ) P = .0361 OS
OS events, n (%)
21 (18)
30 (26)
31 (26)
mOS, mos (95% CI)
46.0 (46.0-NR)
40.0 (23.0-NR)
45.1 (22.3-NR)
0.60 ( ) P = .070
0.82 ( ) P = .440
AI, aromatase inhibitor; ITT, intent to treat; LAP, lapatinib; mOS, median OS; mPFS, median PFS; NR, not reached; TRAS, trastuzumab.
Slide credit: clinicaloptions.com
Gradishar WJ, et al. ASCO Abstract 1004.

6. ALTERNATIVE: Response
Endpoint, %
LAP + TRAS + AI
(n = 120)
TRAS + AI
(n = 117)
LAP + AI
(n = 118)
Best response CR PR SD PD 5 27 43 15
< 1 13 45 31 7 12 53 24
CBR 41 33
ORR: CR + PR,* % (95% CI)
31.7 ( )
13.7 ( )
18.6 ( )
*Pts with unknown/missing responses categorized as nonresponders.
AI, aromatase inhibitor; CBR, clinical benefit rate; LAP, lapatinib; mOS, median OS; NR, not reached; PD, progressive disease; SD, stable disease; TRAS, trastuzumab.
Odds ratio for ORR vs TRAS + AI
LAP + TRAS + AI: 2.83 (95% CI: ; P = .0017)
LAP + AI: (95% CI: ; P = .2829)
Slide credit: clinicaloptions.com
Gradishar WJ, et al. ASCO Abstract 1004.

7. ALTERNATIVE: Pt Disposition and Safety
Disposition, n
LAP + TRAS + AI (n = 118)
TRAS + AI (n = 116)
LAP + AI (n = 119)
Protocol therapy ongoing 29 21 19
Treatment discontinued 89 95
100
Reason for discontinuation PD 75 84 83 AE 5 7 11
Other 9 4 6
AE, %
LAP + TRAS + AI (n = 118)
TRAS + AI (n = 116)
LAP + AI (n = 119)
Drug-related AEs 83 42 74
Any-cause SAE 14 10 17
Drug-related SAE 5 2 4
On-treatment deaths* 3
AE, adverse event; AI, aromatase inhibitor; LAP, lapatinib; PD, progressive disease; SAE, serious adverse event; TRAS, trastuzumab.
*All deaths due to PD except 2 in LAP + AI group (cardiogenic shock and organ failure) and 1 in TRAS + AI group (cardiopulmonary arrest).
Slide credit: clinicaloptions.com
Gradishar WJ, et al. ASCO Abstract 1004.

8. ALTERNATIVE: Adverse Events
AEs in ≥ 15% of Pts
In Any Arm,* %
LAP + TRAS + AI
(n = 118)
TRAS + AI
(n = 116)
LAP + AI
(n = 119)
All
Grade 3/4
Grade 3-4
Any
Any event 92 34 74 22 32
Diarrhea 69 13 9 51 6
Rash 36 2 28 3
Paronychia 30 15
Nausea
Decreased appetite 18
Stomatitis 17
< 1
Cough 8
ALT increase 7 4
AST increase 5
Headache 10 16
AE, adverse event; AI, aromatase inhibitor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LAP, lapatinib; TRAS, trastuzumab.
Slide credit: clinicaloptions.com
Gradishar WJ, et al. ASCO Abstract 1004.

9. ALTERNATIVE: Conclusions
PFS significantly prolonged with addition of dual HER2 blockade (LAP + TRAS) + AI vs TRAS + AI in pts with HER2+/hormone receptor+ MBC previously treated with ET and TRAS (mPFS: 11.0 vs 5.7 mos; HR: 0.62; P = .0064)
PFS benefit observed in all subgroups
ORR, CBR, OS also improved with LAP + TRAS + AI
Trend for PFS benefit with dual HER2 blockade + AI vs LAP + AI also observed (mPFS: vs 8.3 mos)
mPFS prolonged with LAP + AI vs TRAS + AI (HR: 0.71; P = .0361)
LAP + TRAS + AI associated with more frequent AEs
Similar serious AE rates in all arms, with lower rate of AE-related d/c in LAP + TRAS + AI arm
Investigators concluded that dual HER2 blockade with LAP + TRAS + AI provides effective, well-tolerated non-CT option for pts in which CT is not appropriate
AE, adverse event; AI, aromatase inhibitor; CBR, clinical benefit rate; CT, chemotherapy; d/c, discontinuation; ET, endocrine therapy; LAP, lapatinib; mBC, metastatic breast cancer; mPFS, median PFS; TRAS, trastuzumab.
Slide credit: clinicaloptions.com
Gradishar WJ, et al. ASCO Abstract 1004.

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