GIM4 LEAD: Phase III Trial of Extended Adjuvant

Therapy With Letrozole After Sequential Endocrine

Therapy in Patients With HR+ Early Breast Cancer
CCO Independent Conference Highlights*
of the 2019 ASCO Annual Meeting; May 31 - June 4, 2019; Chicago, Illinois

*CCO is an independent medical education company that provides state-of-the-art medical information to
healthcare professionals through conference coverage and other educational programs.

This activity is supported by educational grants from

Celgene Corporation, Novartis Pharmaceuticals, and Puma Biotechnology.
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 Phase III Trial of Extended Letrozole Adjuvant Therapy in
HR+ Early BC (GIM4 LEAD): Background
 HR+ breast cancer tumors have a high rate of late recurrence, with more
recurrences after 5 yrs than within the first 5 yrs following diagnosis [1]
 Previous studies have demonstrated that extended therapy an aromatase
inhibitor (either letrozole, exemestane, or anastrozole) after 5 yrs of
tamoxifen improves DFS[2-4]
 Aromatase inhibitors are routinely administered in place of tamoxifen or in
sequence with tamoxifen as part of early endocrine therapy [5]
 The LEAD study evaluated the benefit of extended therapy with letrozole in
women who received letrozole as part of their initial 5 yrs of endocrine
therapy for early BC[6]

1. EBCTCB. Lancet. 2005;365:1687. 2. Goss. NEJM. 2003;349:1793. 3. Mamounas. JCO. 2008;26:1965.

4. Jakesz. J Natl Cancer Inst. 2007;99:1845. 5. Schneider. Breast Cancer. 2011;3:113. 6.Del Mastro. ASCO 2019. Abstr 504. Slide credit: clinicaloptions.com
 GIM4 LEAD: Study Design
 Randomized, multicenter phase III trial
Postmenopausal women with ER+
and/or PgR+ stage I-III early BC
(T1-3, N0-N+) who were recurrence-
free after surgery* and adjuvant
tamoxifen† for 2-3 yrs; ECOG PS 0/1;
no T4‡ or inflammatory BC, distant
metastases, or disease recurrence
(N = 2056)
5 Yrs of Extended Letrozole (up to 7-8 yrs of tx)
2.5 mg/day
(n = 1026) Median follow-up:
2-3 Yrs of Letrozole (up to 5 yrs of tx) 10.4 yrs (IQR: 8.8-11.4)
2.5 mg/day
(n = 1030)
*For operable BC. †For patients receiving adjuvant CT,
tamoxifen started within 3 mos of completing CT.
ǂ
Patients with pT4 eligible.

 Primary endpoint: iDFS (ITT population and landmark analysis excluding patients
with DFS event or lost to follow-up before time of tx divergence)
 Secondary endpoints: OS, safety
Del Mastro. ASCO 2019. Abstr 504. Slide credit: clinicaloptions.com
 GIM4 LEAD: Baseline Characteristics
Extended 2-3 Yrs of Extended 2-3 Yrs of
Characteristic Letrozole Letrozole Characteristic Letrozole Letrozole
(n = 1026) (n = 1030) (n = 1026) (n = 1030)
Median age, yrs (range) 61 (41-89) 60 (34-86) HR status, n (%)
 ER+ and PgR+ 866 (84) 855 (83)
Tumor size, n (%)  ER+ or PgR+ 146 (14) 153 (15)
703 (68) 704 (68) 14 (1) 22 (2)
 pT1 252 (25) 261 (25)  Unknown
 pT2 43 (4) 34 (3)
 pT3-4 28 (3) 31 (3) HER2 status, n (%)
 Unknown 60 (6) 63 (6)
 Positive 833 (81) 851 (83)
 Negative
Nodal status, n (%)  Unknown 133 (13) 116 (11)
 pN0 568 (55) 581 (56)
 pN1-3 428 (42) 411 (40)
30 (3) 38 (4) Prior neoadjuvant and/or
 Unknown adjuvant CT, n (%) 450 (44) 455 (44)
 No 565 (55) 557 (54)
Histological grade, n (%) 161 (16) 156 (15)  Yes
 1 11 (1) 18 (2)
589 (57) 564 (55)  Unknown
 2 213 (21) 221 (21)
 3 63 (6) 89 (9) Median tamoxifen
 Unknown duration, yrs (IQR) 2.5 (1.9-3.3) 2.4 (1.9-3.3)

Del Mastro. ASCO 2019. Abstr 504. Slide credit: clinicaloptions.com

 GIM4 LEAD: Treatment Compliance
Extended Letrozole 2-3 Yrs of Letrozole
Characteristic
(n = 1026) (n = 1030)
Treatment completed, n (%) 582 (57) 779 (76)

Median duration of letrozole, yrs (IQR) 5.0 (2.4-5.0) 2.4 (1.9-2.8)

444 (43) 251 (24)
Early discontinuation, n (%) 133 (13) 87 (8)
 Toxicity 96 (9) 37 (4)
 Patient refusal 65 (6) 35 (3)
 Primary disease event 35 (3) 27 (3)
 Not begun 115 (11) 65 (6)
 Other

Del Mastro. ASCO 2019. Abstr 504. Slide credit: clinicaloptions.com

 GIM4 LEAD: DFS
DFS ITT Population* (N = 2056) DFS Landmark Analysis† (N = 1891)
100 100

80 Extended arm 80 Extended arm

60 60
DFS (%)

DFS (%)
10-y estimated 10-y estimated
Control arm Control arm
DFS, % (95% CI) DFS, % (95% CI)
40 40
Control (n = 1030) 74 (70-77) Control (n = 948) 72 (68-76)
Extended (n = 1026) 77 (73-81) Extended (n = 943) 77 (72-80)
20 20
HR: 0.84 (95% CI: 0.69-1.03); P = 0.09 HR: 0.81 (95% CI: 0.65-1.00); P = 0.051
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10
Yrs Yrs
No. at risk No. at risk
Control 1030 999 967 919 873 805 731 611 485 332 236 135 35 5 Control 948 893 844 773 682 552 413 284 175 83 18
Extended 1026 990 963 917 875 814 739 636 512 397 254 120 38 3 Extended 943 903 850 788 692 574 451 326 187 80 22

*Median follow-up: 10.4 yrs.

†
Time zero set as time when treatment diverged for the two arms (2-3 yrs after randomization).

Del Mastro. ASCO 2019. Abstr 504. Reproduced with permission. Slide credit: clinicaloptions.com
 GIM4 LEAD: DFS First Events
ITT Population (N = 2056) Extended Letrozole 2-3 Yrs of Letrozole
(n = 1026) (n = 1030)

DFS first event, n (%) 69 (6.7) 77 (7.5)

 Distant recurrence 21 (2.0) 28 (2.7)
 Local recurrence 57 (5.5) 65 (6.3)
 Second primary cancer, any 31 (3.0) 36 (3.5)
 Second primary cancer, breast 26 (2.5) 29 (2.8)
 Second primary cancer, nonbreast 42 (4.1) 49 (4.8)
 Death without recurrence

Del Mastro. ASCO 2019. Abstr 504. Slide credit: clinicaloptions.com

 GIM4 LEAD: Invasive DFS by Subgroup
P P
Characteristic HR* (95% CI) Characteristic HR* (95% CI)
Value Value
Age, yrs  < 55 1.22 (0.73-2.05) .384 HR status†  ER+ and PgR+ 0.80 (0.64-1.02) .662
 55-64 0.80 (0.56-1.12)  ER+ or PgR+ 0.93 (0.54-1.58)
 65-75 0.65 (0.44-0.96)
0.80 (0.36-1.74) HER2 status‡  Negative 0.91 (0.72-1.15) .002
 ≥ 76 0.19 (0.071-0.512)
 Positive
Tumor pT1 0.85 (0.64-1.11) .725 Length of
size

0.77 (0.52-1.15)  ≤ 2.5 yrs 0.87 (0.64-1.19) .745
 pT2 prior  > 2.5 yrs 0.80 (0.59-1.08)
 pT3-4 0.61 (0.23-1.59) tamoxifen
 Unknown 0.55 (0.06-5.25)
Previous CT  No 0.76 (0.53-1.09) .811
Nodal  pN0 0.62 (0.44-0.87) 0.034 0.91 (0.69-1.20)
status 1.08 (0.81-1.46)  Yes
 pN+  Unknown 1.00 (0.03-39.5)
 Unknown 0.07 (0.00-1.62)
All patients -- 0.81 (0.65-1.01)
Histologic  1 0.79 (0.42-1.51) .952
grade  2 0.84 (0.63-1.10) *HR of 0 – 1: extended therapy better; HR > 1: control therapy better.
 3 0.83 (0.51-1.34) †
Missing HR information in 24 pts. ‡Missing HER2 information in 221 pts.
 Unknown 0.70 (0.24-2.02)

Del Mastro. ASCO 2019. Abstr 504. Slide credit: clinicaloptions.com

 GIM4 LEAD: OS
DFS ITT Population (N = 2056) DFS Landmark Analysis* (N = 1891)
100 Extended arm 100 Extended arm

80 80 Control arm
Control arm
60 60
DFS (%)

DFS (%)
10-y estimated 10-y estimated
40 DFS, % (95% CI) DFS, % (95% CI)
40
Control (n = 1030) 90 (88-92) Control (n = 948) 92 (90-93)
20 Extended (n=1026) 91 (89-93) 20 Extended (n = 943) 92 (90-94)
HR: 0.82 (95% CI: 0.62-1.07); P = 0.149 HR: 0.86 (95% CI: 0.63-1.18); P = 0.357
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10
Yrs Yrs
No. at risk No. at risk
Control 1030 1020 1004 988 966 927 886 853 788 665 523 335 107 7 Control 948 941 920 883 849 806 732 588 411 211 54
Extended 1026 1018 1004 986 966 942 913 861 807 693 545 339 111 6 Extended 943 931 917 891 860 807 725 601 426 230 66

*Time zero set as time when treatment diverged for the two arms (2-3 yrs after randomization).
Del Mastro. ASCO 2019. Abstr 504. Reproduced with permission. Slide credit: clinicaloptions.com
 GIM4 LEAD: Adverse Events of Interest
Extended Letrozole 2-3 Yrs of Letrozole
(n = 977) (n = 983)
Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4
Arthralgia 311 (32) 29 (3) 263 (27) 22 (2)
Myalgia 95 (10) 9 (1) 65 (7) 7 (1)
Hot flashes 127 (13) 119 (12)
Alopecia 35 (4) 31 (3)
Osteoporosis* 81 (8) 47 (5)
Bone fractures 9 (1) 5 (<1)
Hypercholesterolemia 22 (2) 32 (3)
Hypertension 19 (2) 7 (1)
Cardiovascular event 6 (1) 1 (<1)
*79 patients in extended letrozole group and 103 patients in control letrozole group had baseline osteoporosis.

Del Mastro. ASCO 2019. Abstr 504. Slide credit: clinicaloptions.com

 GIM4 LEAD: Conclusions
 Following 2-3 yrs of tamoxifen treatment, extended adjuvant treatment
with letrozole for 5 yrs vs 2-3 yrs led to a 19% reduction of invasive DFS
events in patients with HR+ early breast cancer (HR: 0.81; 95% CI: 0.65-
1.00; P = .051)
‒ Extended letrozole in this setting did not result in significant improvement
of OS (HR: 0.86; 0.63-1.18; P = .357)
 Investigators suggest that 2-3 yrs of tamoxifen followed by 5-6 yrs of
aromatase inhibitor therapy is a potential treatment strategy for
patients with a history of breast cancer who are at risk of disease
recurrence

Del Mastro. ASCO 2019. Abstr 504. Slide credit: clinicaloptions.com

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