Effect of Extended Adjuvant Endocrine Therapy with Letrozole (L) in Postmenopausal Women with Hormone-receptor

(+) Breast Cancer after Prior Adjuvant Therapy with an Aromatase Inhibitor (AI): NRG Oncology/NSABP B-42
Eleftherios P. Mamounas, MD,1,2 Hanna Bandos, PhD,1,3 Barry C. Lembersky, MD,1,4 Charles E. Geyer, Jr., MD,1,5 Louis Fehrenbacher, MD,1,6
Mark L. Graham, MD,1,7 Soonmyung Paik, MD,1,8 Sandra M. Swain, MD,1,9 D. Lawrence Wickerham, MD,1,10 Norman Wolmark, MD1,10
1NRG Oncology/NSABP (NSABP Legacy trials are now part of the NRG Oncology portfolio), Pittsburgh, PA; 2UF Cancer Center at Orlando Health, Orlando, FL; 3University of Pittsburgh,
Pittsburgh, PA; 4The University of Pittsburgh Cancer Institute, Pittsburgh, PA; 5Massey Cancer Center, Virginia Commonwealth University, Richmond, VA; 6Kaiser Permanente Oncology Clinical
Trials Northern California, Vallejo, CA; 7Southeast Cancer Control Consortium, Goldsboro, NC; 8Yonsei University College of Medicine, Seoul, Korea; 9Lombardi Comprehensive Cancer Center,
Georgetown University Medical Center, Washington, D.C.; 10Allegheny Health Network Cancer Institute, Pittsburgh, PA

Background/Rationale Cohort Characteristics Treatment Compliance

Extended adjuvant endocrine therapy after 5 yrs of No statistically significant differences in the Median duration of treatment was 59.8 months in both
TAM with either AI or TAM improves DFS in early- distribution of pt, tumor, and prior treatment groups
stage breast cancer (BC) characteristics between the two groups: Overall, 62.5% of PLAC pts and 60.3% of LET pts
34-35% <60 years of age completed 5 years of therapy
Optimal duration of adjuvant AI therapy beyond 5 yrs
93% white; 4% black Main reasons for treatment discontinuation:
is unknown
57-58% node-negative Pt withdrawal/refusal: L: 13.8% P: 12.7%
NSABP B-42 aimed to determine whether 5 yrs of 25% had lowest BMD score 2.0 Adverse event: L: 9.6% P: 7.1%
letrozole (LET) vs. placebo (PLAC) improves DFS in 39% received prior tamoxifen Disease progression: L: 4.1% P: 5.2%
pts who have completed 5 yrs of hormonal therapy Other disease/death: L: 2.7% P: 2.7%
61% breast-conserving surgery
with either an AI or TAM AI Declining BD/OSFx: L: 1.4% P: 0.8%
78% HER-2 negative (8% unknown)
B-42 Schema
Results
Postmenopausal Pts with ER+ or PR+ BC
Stage I, II, or IIIa Invasive BC at Diagnosis Disease-Free Survival Overall Survival
Disease-free after 5 Years of Endocrine Rx 100 100
100 92.3%
84.7%
AI x 5 yrs or TAM x 3 yrs AI to 5 yrs # Deaths 91.8%
Disease-Free Survival

80
80 # Events 80 Letrozole
Letrozole 292 Letrozole 164
81.3% Placebo 146
Placebo

Overall Survival
Placebo 339 60

Disease-Free Survival
60 60
Stratification: 40
Pathological nodal status (Negative, Positive) 40 HR=0.85 (0.73-0.999) P = 0.048* 40
HR=1.15 (0.92-1.44) P=0.22
Prior adjuvant TAM (Yes, No) 20

20 20
Lowest BMD T score: (> 2.0, 2.0 SD) *P-value did not reach protocol-defined 0
statistical significance level of 0.0418
0 0
0 2 4 6 7 8 0 2 46 6 7 8
R Years After Random Assignment
0 2
Years
4
AfterRandomization
Years After Random Assignment
8

Letrozole x 5 yrs Placebo x 5 yrs Letrozole 1959 1813 1644 1225 216 Letrozole 1959 1902 1781 1499 287
Placebo 1964 1814 1639 1208 210 Placebo 1964 1902 1791 1528 291

Endpoints Multivariate Analysis for DFS Letrozole Effect on DFS in Subgroups

Primary endpoint: No. of pts % DFS HR HR P P
Characteristic P All Patients Interaction
Disease-Free Survival (DFS): (N=3,923) events (95%CI) 0.85 0.048
Local, regional, distant recurrence, contralateral Placebo 1964 17.3 0.86 Nodes Negative 0.86 0.17
BC, 2nd non-breast primary Ca, and death from any Treatment 0.05 0.16
0.99
Letrozole 1959 14.9 (0.73,1.00) Positive 0.85
cause as first event <60 1350 12.1 1.55 No 0.91 0.34
Age <0.01 Prior TAM 0.27
Secondary endpoints: 60 2573 18.2 (1.29,1.86) Yes 0.75 0.04
Overall Survival Path Nodal Negative 2251 14.3 1.33 0.70 0.03
<0.01 < -2.0 0.16
Status Positive 1672 18.5 (1.13,1.56) T-score 0.92
Breast Cancer-Free Interval (BCFI): > -2.0 0.34
Prior No 2388 17.6 0.78
Recurrence or contralateral BC as first event <0.01
Age
<60 0.86 0.32
Tamoxifen Yes 1535 13.7 (0.66, 0.92) 0.87
Distant Recurrence (DR) Lumpectomy 2386 14.6 1.24
>60 0.84 0.06

Osteoporotic Fractures (OF) Surgery Type <0.01

Mastectomy 1537 18.4 (1.05,1.45) 0.4 0.6 0.8 1 1.2 1.4
Arterial Thrombotic events (AT)

Statistical Considerations Cum. Incidence of BCFI Event Cum. Incidence of Distant Recurrence Adverse Events
Differences in primary and secondary endpoints 12
# Pts # Events 12
# Pts # Events
Letrozole did not statistically
10.0%
between P and L groups were assessed by stratified 10 Letrozole 1959 127 10 Letrozole 1959 73 significantly increase risk of
Cum. Incidence of DR

Placebo 1964 179 Placebo 1964 102 osteoporotic fractures (HR=1.19,

log-rank tests, controlling for stratification variables
Cum. Incidence

8 8
of BCFI Event

5.8% P=0.27)
6 HR=0.7 6 HR=0.72
Hazard ratios and corresponding 95% CIs were (0.56-0.89) 6.7%
The 7-year cumulative incidence
4 4 (0.53-0.97)
calculated based on stratified Cox proportional 3.9% of osteoporotic fractures was
hazards model 2 P=0.003 2
P=0.03 5.4% with letrozole and 4.8%
0 0
To account for alpha-spending during 4 pre-planned 0 2 4 6 7 8 0 2 4 6 7 8
with placebo
interim analyses, adjusted two-sided significance level Years After Random Assignment Years After Random Assignment
Letrozole did not statistically
of 0.0418 was used for primary endpoint analysis significantly increase risk of
Two-sided p-values of <0.05 were considered Outcomes According to Patient Characteristics and Treatment arterial thrombotic (AT) events
(HR=1.21, P=0.29)
significant for secondary endpoint analyses 7-Yr DFS 7-Yr Cum. Incidence 7-Yr Cum. Incidence
Endpoint The 7-year cum. incidence of AT
(%) BCFI Event (%) Distant Recurrence (%)
Definitive analysis: Based on intent-to-treat principle events was 4.0% with letrozole
Characteristic PLAC LET PLAC LET PLAC LET and 3.4% with placebo
Patients with no follow-up and those not at risk for the
primary endpoint were excluded: Path Nodal Negative 83.4 86.5 8.2 5.3 3.6 2.2 There was statistically
Status Positive 78.4 82.4 12.4 8.7 8.7 6.3 significant non-proportionality
Metastases at the time of random assignment
Prior No 79.8 82.0 9.9 6.8 5.9 3.6 in risk of AT events
First event within 30 days from randomization
Tamoxifen Yes 83.7 88.8 10.0 6.5 5.6 4.4 AT events were lower with
Lowest 2.0 77.9 84.3 9.3 5.7 7.3 2.7 letrozole in the first 2.5 yrs
Patient Population (HR=0.55, P=0.054) and
BMD Score > 2.0 82.4 84.9 10.2 7.1 5.3 4.3
statistically significantly higher
From 9/06 to 1/10, 3966 patients were randomized <60 86.0 88.1 9.5 6.7 5.9 4.3
Age (years) after 2.5 yrs (HR=1.85, P=0.007)
43 patients excluded: 36 no follow-up; 7 not at risk for 60 78.8 83.0 10.2 6.7 5.7 3.7
the primary endpoint
Median follow-up for 3923 patients included in efficacy Conclusions
analyses was 6.9 yrs
Our findings suggest that careful assessment of potential risks and benefits is required before recommending
Required 631 DFS events for definitive analysis extended letrozole therapy to patients with early-stage BC, including:
occurred by AUG 2016
Patient and tumor characteristics (age, nodal status), existing co-morbidities, information on bone mineral
density, and tolerance of the AI in the initial 5 yrs
Support: U10CA180868, -180822; UG1CA189867; Novartis
Genomic classifiers that predict risk of late recurrence and/or benefit from extended endocrine therapy may help
to further individualize the recommendation for extended aromatase inhibitor therapy
Abstract # P011