Disclosures. ASCO Highlights Breast Cancer. Associa4on of Northern California Oncologists 8/25/14

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1 ASCO Highlights 2014 Associa4on of Northern California Oncologists Breast Cancer Sco+ Christensen, MD Professor, Hematology/Oncology UC Davis Comprehensive Cancer Center Disclosures 1

2 Outline Novel TherapeuFcs/Early Phase Trials Early Stage Breast Cancer Her 2+Breast Cancer MetastaFc Breast Cancer Best Clinical PracFce Novel Therapeu4cs 2

3 Novel Therapeu4cs Angiogenesis Inhibitors Abstract 502 (trebananib) PI3K/AKT/mTOR pathway Abstracts 516, 533 (PI3K Inhibitor BYL719), 553 (AKT Inhibitor MK- 2206) CDK4/6 Inhibitors Abstracts 527, 534, 535 (LY , LEE011, palbociclib) PARP Inhibitors Abstracts 1021, 2569 (PARP Inhibitor veliparib) AR Inhibitors Abstract 545 (enzalutamide + exemestane) HDAC Inhibitors Abstract 556 (vorinostat) Early Stage Breast Cancer LBA1 SOFT/TEXT Combined Analysis LBA505 S0230 POEMS 3

4 TEXT/SOFT Trials Aromatase Inhibitor Question Does adjuvant therapy with the aromatase inhibitor (AI) exemestane improve disease- free survival relafve to tamoxifen in premenopausal women treated with OFS for HR+ breast cancer? Presented by: Olivia Pagani, MD TEXT and SOFT Trial Designs Enrolled: Nov03-Apr11 Premenopausal 12 wks after surgery Planned OFS No planned chemo OR planned chemo Premenopausal 12 wks after surgery No chemo OR Remain premenopausal 8 mos after chemo Presented by: Olivia Pagani, MD R A N D O M I Z E R A N D O M I Z E TEXT (N=2672) Tamoxifen+OFS x 5y Exemestane+OFS x 5y SOFT (N=3066) Tamoxifen x 5y Tamoxifen+OFS x 5y Exemestane+OFS x 5y Joint Analysis (N=4690) Tamoxifen+OFS x 5y Exemestane+OFS x 5y Median follow-up 5.7 years OFS=ovarian function suppression 4

5 TEXT/SOFT Pa4ent Characteris4cs No chemo TEXT (N=1053) No chemo SOFT (N=943) Chemo TEXT (N=1607) Prior chemo SOFT (N=1087) Overall (N=4690) Age <40 yr 16% 9% 30% 49% 27% LN + 21% 8% 66% 57% 42% T-size >2cm 19% 15% 53% 47% 36% HER2 + 5% 3% 17% 19% 12% Surgery to random. (median) 1.5 mo 1.8 mo 1.2 mo 8.0 mo 1.6 mo Presented by: Olivia Pagani, MD Exemestane+OFS Improved DFS Difference 3.8% at 5 years 5.7 years median follow-up Presented by: Olivia Pagani, MD 5

6 Exemestane+OFS Reduced Recurrence 4% absolute improvement in 5-yr freedom from breast cancer for exemestane+ofs No significant difference in overall survival Presented by: Olivia Pagani, MD Selected Adverse Events Exemestane+OFS (N=2318) Tamoxifen+OFS (N=2325) CTCAE v3.0 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Depression 50% 3.8% 50% 4.4% Musculoskeletal 89% 11% 76% 5.2% Osteoporosis (% T< -2.5) 39% (13%) 0.4% 25% (6%) 0.3% Fracture 6.8% 1.3% 5.2% 0.8% Hypertension 23% 6.5% 22% 7.3% Cardiac ischemia/ 0.7% 0.3% 0.3% 0.1% infarction Thrombosis/embolism 1.0% 0.8% 2.2% 1.9% CNS ischemia 0.7% 0.3% 0.3% 0.1% CNS bleeding 0.6% <0.1% 0.9% 0.1% Hot flushes/flashes 92% 10% 93% 12% Sweating 55% -- 59% -- Vaginal dryness 52% -- 47% -- Libido decrease 45% -- 41% -- Dyspareunia 31% 2.3% 26% 1.4% Urinary incontinence 13% 0.3% 18% 0.3% Presented by: Olivia Pagani, MD 6

7 TEXT/SOFT Conclusions Exemestane+OFS, as compared with tamoxifen+ofs, significantly improves DFS, BCFI and DRFI and is a new treatment opfon for premenopausal women with HR + early breast cancer No significant difference in overall survival, conclusions premature at this early point in follow- up of HR+ breast cancer Side effect profile of exemestane+ofs mirrors that seen with AIs in postmenopausal women Some premenopausal women diagnosed with HR+ breast cancer have an excellent prognosis with highly- effecfve endocrine therapy alone Long- term follow- up needed Presented by: Olivia Pagani, MD S0230: POEMS Premature ovarian failure is a common toxicity of chemotherapy administrafon in premenopausal women with breast cancer. SWOG coordinated randomized Phase III study evaluafng the impact of LHRH analog administrafon with chemotherapy for early stage ER/ PR- breast cancer on incidence of premature ovarian failure. Study accrual 2/04 5/11; 257 pafents, 218 evaluable; stages I- III 62% study populafon had complete primary endpoint data 7

8 Preven4on Of Early Menopause Study: POEMS POEMS Trial Design n= 118 Primary endpoint: Ovarian failure at 2 years Secondary endpoint: Pregnancy outcome Ovarian disfuncfon 1,2 yrs Exploratory: DFS/OS Moore H, ASCO 2014 Preven4on Of Early Menopause Study: POEMS CHT CHT+Goserelin p OF 2yrs 22% 8% 0.04 Achieved pregnancy 11% 21% 0.03 DFS OS HR=0.49, 95% CI: , p=0.04 HR=0.43, 95% CI: , p=0.05 Moore H, ASCO

9 POEMS Conclusions LHRH analog (goserelin) administrafon with chemotherapy for ER- early stage breast cancer was associated with less premature ovarian failure and more subsequent pregnancies. Premenopausal ER- breast cancer pafents should consider this new treatment strategy to prevent premature ovarian failure There is no direct evidence evaluafng this approach in ER+ breast cancer pafents TheoreFcal concerns exist concerning OFS reducing chemotherapy efficacy in ER+ breast cancer In an exploratory analysis, monthly goserelin administrafon was associated with improved DFS and OS in premenopausal ER- breast cancer Her2+ Breast Cancer LBA4 ALTTO Abs 528 TBCRC 022 NeraFnib 9

10 ALTTO Trial Phase III randomized, mulfcenter internafonal trial enrolling over 8000 women Study hypothesized dual Her2 blockade would result in improvements in breast cancer recurrence and death compared to anf- Her2 monotherapy NeoALTTO trial documented higher pathologic CR rate at Fme of definitve surgery with usage of dual Her2 blockade AnFcipated that ALTTO would confirm neoadjuvant results in the adjuvant senng ALTTO Trial: Adjuvant Double Her2 Blockade Sequen1al or concomitant chemotherapy Piccart M, ASCO

11 ALTTO Trial Piccart M, ASCO 2014 Piccart M, ASCO

12 ALTTO Trial: DFS Piccart M, ASCO 2014 ALTTO Trial: OS Piccart M, ASCO

13 ALTTO Trial: Selected AEs Per Arm MAIN DIFFERENCES IN AEs BY TREATMENT ARM No cardiac toxicity concerns Piccart M, ASCO 2014 ALTTO Trial Conclusions Primary endpoint: not met 20-40% of pts in the lapafnib arms did not reach 85% of the planned lapafnib dose Neoadjuvant results of the NeoALTTO trial did not translate into improved survival in the adjuvant setfng Excellent performance of the control arm in a populafon "closer to real world pafents Results will fuel confnuing debate 13

14 TBCRC022 MulFcenter Phase II open label study evaluafng use of nerafnib in metastafc Her2+ breast cancer with CNS metastases Preclinical evidence suggests nerafnib may cross blood/brain barrier Eligible pafents had measurable disease progression aqer local CNS therapy and received nerafnib 240 mg po daily over a 28 day cycle Primary endpoint was CNS ORR; MRI brain imaging obtained every 2C 40 women enrolled, most had received 2 prior therapies; 85% had received lapafnib, 38% received prior WBRT, 23% received SRS, and 29% received both CNS ORR: 8% (3 pts) PR, 10% (4 pts) SD 6 months, 30% (12 pts) SD <6 months; median number of cycles was 2 (1 15+) Most common gr 3 AE was diarrhea (29%) TRBC022 Conclusions NeraFnib is associated with a low CNS ORR in Her2+ metastafc breast cancer CNS metastases Durable stable disease control was observed in a number of pafents Diarrhea ameliorated somewhat with prophylacfc anf- diarrheal therapy (loperamide) InvesFgators concluded further invesfgafon was warranted and are exploring combinafon therapy 14

15 Metasta4c Breast Cancer LBA9500 OPTIMIZE 2 OPTIMIZE 2 Phase III randomized trial enrolling 403 women with metastafc breast cancer involving bone Previous studies have demonstrated reducfons in SREs with monthly administrafon of zoledronic acid Concerns exist over observed toxicifes (ONJ, Renal Insufficiency, Atypical Fractures) associated with prolonged monthly administrafon of zoledronic acid Study evaluated safety and efficacy of a less frequent dosing schedule of zoledronic acid compared to current standard Hortobagyi, LBA9500, ASCO

16 OPTIMIZE 2 Non- inferiority study All pafents received monthly IV bisphosphonate (zoledronate or pamidronate) for 1 year prior to randomizafon to either confnued monthly treatment with zoledronic acid or every 3 months at the current FDA- approved dose (4 mg) Median follow- up: 11.9 months At 2 years, incidence of SREs was similar (22% vs. 23%, p=0.724) in the two arms indicafng non- inferiority No stafsfcally significant differences in toxicifes were observed Hortobagyi, LBA9500, ASCO 2014 OPTIMIZE 2 Conclusions Women with metastafc breast cancer and bony metastases can safely and effecfvely switch to a less frequent dosing schedule of bisphosphonate therapy aqer 1 year of monthly treatment. Less frequent dosing schedule is safe and effecfve Less frequent dosing schedule was associated with numerically fewer toxicifes, but the difference was not stafsfcally significant Results should be interpreted caufously given the modest sample size and somewhat limited follow- up Fme 16

17 Best Clinical Prac4ce Clinical Prac4ce Changes AIs now have level 1 evidence supporfng usage in the premenopausal senng in associafon with OFS and demonstrate similar improvements in DFS observed in the postmenopausal senng compared to tamoxifen Less premature ovarian failure and improved ferflity preservafon is observed with OFS during chemotherapy administrafon in ER- breast cancer and is associated with improvements in DFS and OS Dual anf- Her2 blockade with trastuzumab/lapafnib did not improve DFS or OS and was associated with increased toxicity in the adjuvant senng Less frequent bisphosphonate administrafon aqer 1 year of monthly therapy is safe and non- inferior to confnued monthly treatment in metastafc breast cancer with bony metastases 17

18 Thank You 18