CCO Independent Conference Coverage*: The 2015 Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium, December 8-12, 2015 San Antonio, Texas ABCSG-18: Effect of Adjuvant Denosumab on DFS in Postmenopausal Women With Early HR+ Breast Cancer *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 program is supported by educational grants from Genentech and Novartis.

ABCSG18: Background  Adjuvant bisphosphonates have been associated with a significantly reduced rate of breast cancer recurrence in bone and improved survival in postmenopausal women with breast cancer [1]  ABCSG18 trial: phase III trial of denosumab vs placebo in AI-treated postmenopausal women with early HR+ breast cancer –Primary analysis: significant reduction in fracture risk with denosumab vs placebo [2] – HR: 0.50 (95% CI: ; P <.0001) –IDMC recommended unblinding following results of primary analysis, with DFS analysis to be completed before unblinding  Current report from the ABCSG18 study includes the impact of denosumab on DFS in postmenopausal pts with early HR+ breast cancer on AIs [3] 1.EBCTCG, et al. Lancet. 2015;386: Gnant M, et al. Lancet. 2015;386: Gnant M, et al. SABCS Abstract S2-02.

ABCSG-18: Study Design  Prospective, randomized, double-blind, placebo- controlled phase III trial  Primary endpoint: time to first clinical fracture  Secondary endpoints: % change in BMD, vertebral fractures, DFS, OS, BMFS, safety Postmenopausal pts with early HR+ breast cancer receiving adjuvant AI therapy* (N = 3425) Denosumab 60 mg SC Q6M (n = 1711) Placebo SC Q6M (n = 1709) Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. Lancet. 2015;386: *Pts excluded if history of IV bisphosphonate, SERMS, Cushing’s disease, Paget’s disease, hypercalcemia, hypocalcemia, hyperprolactinemia, or other active metabolic bone disease.

ABCSG-18: Baseline Characteristics Characteristic All Pts (N = 3425) Median age, yrs (range)64 (38-91) Tumor size < 2 cm, %72 Node-negative disease, %71 Grading: G3, %19 Ductal invasive histology, %74 Subtype, %  ER+ and PgR+  HER Neoadjuvant chemotherapy, %25 Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS Abstract S2-02.

ABCSG-18: Disease-Free Survival  ITT analysis consistent with sensitivity analysis in which pts switching to another bone-active treatment were censored –Hazard ratio, denosumab vs placebo: (95% CI: ; P =.0424) Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS Abstract S2-02. Reproduced with permission. Impact of Denosumab vs Placebo on DFS (ITT) Disease-Free Survival (%) Mos Since Randomization % 88.9% 83.5% 92.6% 86.8% 80.4%.0510 Placebo Denosumab Number of Events/Patients HR (95% CI) vs Placebo P value 203/ / ( )

ABCSG-18: DFS by Subgroup  Hazard ratio denosumab vs placebo: (95% CI: ; P =.0510) Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS Abstract S2-02. Reproduced with permission. Favors denosumab Favors placebo Entire population Al prior to randomization no yes T-score < -1 T-score ≥ -1 < to 69 ≥ 70 T0/Tis/T1 T2/T3/T4 negative positive G1 G2/GX G3 ductal invasive ductal lobular other ER- or PR- ER+ and PR+ negative positive none adjuvant neo-adjuvant Baseline BMD Age T-stage Nodal status Grade Histology HR status HER2 Prior chemotherapy Hazard Ratio

ABCSG-18: DFS by Tumor Size > 2 cm and Other Subgroups With Significant HR Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS Abstract S2-02. Reproduced with permission. ParameterSignificant HR No AI prior to randomization0.61 T-stage T2/T3/T Ductal invasive histology0.79 ER+/PgR+ status Disease-Free Survival (%) Mos Since Randomization % 87.0% 80.3% 88.9% 80.0% 69.8%.0163 Placebo Denosumab Number of Events/Patients HR (95% CI) vs Placebo P value 83/467 58/ ( )

ABCSG-18: Safety  Incidence of AEs similar between denosumab (80%) vs placebo (79%)  Rate of serious AEs did not differ between arms (30% each arm)  Most common AEs similar to known AI profile –Arthralgia, hot flashes, bone pain, other AI-related symptoms  Osteonecrosis of the jaw not observed in any pts  Death occurred in 3% of pts overall –1 death in denosumab arm considered study drug related  No atypical fractures observed Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS Abstract S2-02. Gnant M, et al. Lancet. 2015;386:

ABCSG-18: Conclusions  Adjuvant denosumab increased DFS in AI-treated postmenopausal women with early HR+ breast cancer [1] –Hazard ratio (ITT): 0.82 (95% CI: ; P =.0515) –Hazard ratio (sensitivity analysis): 0.81 (95% CI: ; P =.0424)  Denosumab is safely administered [2] –No differences in AEs, serious AEs with denosumab vs placebo –No pt experienced necrosis of the jaw, or atypical fracture  Based on increased DFS, [1] safety profile, [2] and reduction in fractures, [2] authors conclude that denosumab should be made available to postmenopausal pts with HR+ breast cancer on AIs Slide credit: clinicaloptions.comclinicaloptions.com 1. Gnant M, et al. SABCS Abstract S Gnant M, et al. Lancet. 2015;386:

Go Online for More CCO Coverage of SABCS 2015! Short slideset summaries of all the key data Additional CME-certified analysis with expert faculty commentary on all the key studies clinicaloptions.com/oncology