1. 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.

2. 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: 0.39-0.65; 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;386:1353-1361. 2.Gnant M, et al. Lancet. 2015;386:433-443. 3.Gnant M, et al. SABCS 2015. Abstract S2-02.

3. 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;386:433-443. *Pts excluded if history of IV bisphosphonate, SERMS, Cushing’s disease, Paget’s disease, hypercalcemia, hypocalcemia, hyperprolactinemia, or other active metabolic bone disease.

4. 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+  HER2+ 83 6 Neoadjuvant chemotherapy, %25 Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS 2015. Abstract S2-02.

5. 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: 0.807 (95% CI: 0.66-0.99; P =.0424) Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS 2015. Abstract S2-02. Reproduced with permission. Impact of Denosumab vs Placebo on DFS (ITT) 100 90 80 70 60 0 Disease-Free Survival (%) Mos Since Randomization 900612182430364248546066727884 93.8% 88.9% 83.5% 92.6% 86.8% 80.4%.0510 Placebo Denosumab Number of Events/Patients HR (95% CI) vs Placebo P value 203/1709 167/1711 0.816 (0.66-1.00)

6. ABCSG-18: DFS by Subgroup  Hazard ratio denosumab vs placebo: 0.816 (95% CI: 0.66-1.00; P =.0510) Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS 2015. Abstract S2-02. Reproduced with permission. Favors denosumab Favors placebo 0.20.5123 Entire population Al prior to randomization no yes T-score < -1 T-score ≥ -1 < 60 60 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 0.82 0.61 0.87 0.77 0.85 0.73 0.83 0.96 0.92 0.66 0.84 0.82 0.63 0.87 0.84 0.79 0.94 1.00 1.08 0.75 0.82 0.76 0.82 0.82 0.77 Hazard Ratio

7. ABCSG-18: DFS by Tumor Size > 2 cm and Other Subgroups With Significant HR Slide credit: clinicaloptions.comclinicaloptions.com Gnant M, et al. SABCS 2015. Abstract S2-02. Reproduced with permission. ParameterSignificant HR No AI prior to randomization0.61 T-stage T2/T3/T4 0.66 Ductal invasive histology0.79 ER+/PgR+ status0.75 100 90 80 70 60 0 Disease-Free Survival (%) Mos Since Randomization 900612182430364248546066727884 92.6% 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 58/479 0.663 (0.47-0.93)

8. 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 2015. Abstract S2-02. Gnant M, et al. Lancet. 2015;386:433-443.

9. 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: 0.66-1.00; P =.0515) –Hazard ratio (sensitivity analysis): 0.81 (95% CI: 0.66-0.99; 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 2015. Abstract S2-02. 2. Gnant M, et al. Lancet. 2015;386:433-443.

10. 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