BREAST CANCER SLIDE DECK 2017 Selected abstracts from:

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1 BREAST CANCER SLIDE DECK 2017 Selected abstracts from: 2017 ASCO ANNUAL MEETING 2 6 June 2017 Chicago, USA Supported by Eli Lilly and Company. Eli Lilly and Company has not influenced the content of this publication

2 Letter from IBCSG DEAR COLLEAGUES It is my pleasure to present this IBCSG slide set which has been designed to highlight and summarise key findings in breast cancer from the major congresses in This slide set specifically focuses on the 2017 American Society of Clinical Oncology Annual Meeting and is available in English, French, Italian, German, Spanish and Japanese. The area of clinical research in oncology is a challenging and ever changing environment. Within this environment, we all value access to scientific data and research that helps to educate and inspire further advancements in our roles as scientists, clinicians and educators. I hope you find this review of the latest developments in breast cancer is of benefit to you in your practice. If you would like to share your thoughts with us we would welcome your comments. Please send any correspondence to ibcsgcc@ibcsg.org. Finally, we are also very grateful to Lilly Oncology for their financial, administrative and logistical support in the realisation of this activity. Yours sincerely, Rolf Stahel President, IBCSG Foundation Council

3 IBCSG Medical Oncology Slide Deck Editors 2017 Giuseppe Curigliano European Institute of Oncology, Milan, Italy Guy Jerusalem C.H.U. Sart Tilman, Liège, Belgium Konstantin Dedes University Hospital Zurich, Cancer Center Zurich, Switzerland

4 Contents Early stage breast cancer Advanced/metastatic breast cancer First line Later lines

5 Early stage breast cancer

6 511: Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC) Tolaney SM et al Study objective To examine the effect of paclitaxel + trastuzumab on recurrence in patients with nodenegative, HER2+ breast cancer Key patient inclusion criteria HER2+ breast cancer (IHC 3+ and/or FISH ratio >2.0) Negative nodes (a single axillary lymph node micrometastasis was allowed) Tumour size <3 cm Left ventricular ejection fraction 50% No prior malignancy in last 5 years (n=410) Paclitaxel 80 mg/m 2 + trastuzumab x12 weeks followed by trastuzumab (weekly or q3w) x39 weeks PD/toxicity/ withdrawal PRIMARY ENDPOINT DFS SECONDARY ENDPOINTS Recurrence-free interval (RFI), breast cancer specific survival (BCSS), OS Tolaney SM, et al. J Clin Oncol 2017;35(Suppl):Abstr 511

7 511: Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC) Tolaney SM et al Key results Analyses incorporated data available through November 2016 and included 2390 patientyears of follow-up DFS event n (%) Mean time to event, months (range) Any recurrence or death 23 (5.7) Local/regional recurrence Ipsilateral axilla (HER2+) Ipsilateral breast (HER2+) 5 (1.2) (12 54) 51 (37 65) New contralateral primary breast cancer HER2+ HER2- Unknown 6 (1.5) (12 59) 87 (84 90) Distant recurrence 4 (1.0) 49 (27 63) Death Non-breast cancer related 8 (2.0) 58 (13 71) Tolaney SM, et al. J Clin Oncol 2017;35(Suppl):Abstr 511

8 511: Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC) Tolaney SM et al Key results (cont.) 7-year data Point estimate (%) 95%CI No. of events* DFS , HR , HR , RFI , BCSS , > OS , Over 6.5 years of follow-up, there were 4 (1.0%) distant recurrences Intrinsic subtyping of 209 samples revealed 68% were HER2 enriched *Events = invasive local/regional recurrence, distant recurrence, death from breast cancer Tolaney SM, et al. J Clin Oncol 2017;35(Suppl):Abstr 511

9 511: Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC) Tolaney SM et al Conclusions When used as an adjuvant therapy for node-negative HER2+ breast cancer, paclitaxel + trastuzumab was associated with few recurrences after a median follow-up of 6.5 years These longer term results indicate that paclitaxel + trastuzumab can be considered a standard treatment for the majority of patients with stage I HER2+ breast cancer Tolaney SM, et al. J Clin Oncol 2017;35(Suppl):Abstr 511

10 LBA500: APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC) Von Minckwitz G et al Study objective To examine the efficacy and safety of pertuzumab when added to chemotherapy and trastuzumab in patients with HER2+ early breast cancer Key patient inclusion criteria HER2+ status (ICH 3 or FISH/CISH+) Node positive (any tumour size except T0) Node negative (tumour >1 cm; tumours >0.5 and 1 cm plus at least 1 of histological/nuclear grade 3, ER- and PgR-negative, or age <35 years) (n=4805) PRIMARY ENDPOINT Invasive disease-free survival (IDFS) *A number of standard anthracycline-taxane-sequences or a non-anthracycline regimen were allowed R 1:1 Pertuzumab + chemotherapy* + trastuzumab (n=2400) Placebo + chemotherapy* + trastuzumab (n=2405) SECONDARY ENDPOINTS Recurrence-free interval (RFI), distant RFI, disease-free interval (DFI), OS, safety, HRQoL 10-year follow-up 10-year follow-up Anti-HER2 therapy for a total of 52 weeks (concurrent with start of taxane) Radiotherapy/ET may be started at the end of adjuvant chemotherapy Von Minckwitz G, et al. J Clin Oncol 2017;35(Suppl):Abstr LBA500

11 LBA500: APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC) Von Minckwitz G et al Key results After a median follow-up of 45.4 months, the addition of pertuzumab reduced the risk of an IDFS event by 19% (p=0.045) vs. placebo First occurrence of IDFS event, n (%) Pertuzumab (n=2400) Placebo (n=2404) Total patients with IDFS event 171 (7.1) 210 (8.7) Category of first IDFS event Distant recurrence Locoregional recurrence Contralateral breast cancer Death without prior event Site of first distant recurrence Lung/liver/pleural effusion CNS Other Bone 112 (4.7) 26 (1.1) 5 (0.2) 28 (1.2) 43 (1.8) 46 (1.9) 9 (0.4) 21 (0.9) 139 (5.8) 34 (1.4) 11 (0.5) 26 (1.1) 61 (2.5) 45 (1.9) 9 (0.4) 30 (1.2) Von Minckwitz G, et al. J Clin Oncol 2017;35(Suppl):Abstr LBA500

12 LBA500: APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC) Von Minckwitz G et al Key results (cont.) 3-year outcomes, % Pertuzumab (n=2400) Placebo (n=2404) HR (95%CI); p-value IDFS (primary endpoint) (0.66, 1.00); IDFS including second primary non-breast cancer events* (0.68, 0.99); DFI (0.67, 0.98); RFI (0.63, 0.99); Distant RFI (0.64, 1.04); OS (first interim analysis) (0.66, 1.21); In the node positive subgroup, IDFS was significantly greater with pertuzumab vs. placebo (HR 0.77 [95%CI 0.62, 0.96]; p=0.019) *As per the STEEP definition At 26% of the target events for the final OS analysis Von Minckwitz G, et al. J Clin Oncol 2017;35(Suppl):Abstr LBA500

13 LBA500: APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC) Von Minckwitz G et al Key results (cont.) The safety profile of pertuzumab was consistent with previous trials Grade 3 AEs, n (%) Pertuzumab (n=2364) Placebo (n=2405) Neutropenia 385 (16.3) 377 (15.7) Febrile neutropenia 287 (12.1) 266 (11.1) Anaemia 163 ( 6.9) 113 ( 4.7) Diarrhoea 232 (9.8) 90 ( 3.7) Cardiac safety Heart failure + LVEF decline or cardiac death* 17 (0.7) 8 (0.3) Asymptomatic/mildly symptomatic LVEF decline 64 (2.7) 67 (2.8) *Primary cardiac endpoint; Secondary cardiac endpoint Von Minckwitz G, et al. J Clin Oncol 2017;35(Suppl):Abstr LBA500

14 LBA500: APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC) Von Minckwitz G et al Conclusions When added to trastuzumab + chemotherapy, pertuzumab significantly improved invasive disease-free survival (IDFS) in patients with HER2+ early breast cancer 3-year IDFS was 94.1% with pertuzumab and 93.2% with placebo No new safety signals were identified; cardiac toxicity was similar between treatment groups, although there was a higher incidence of diarrhoea in the pertuzumab arm which mainly occurred during chemotherapy and with trastuzumab Follow-up will continue; the next analysis will be in 2.5 years Von Minckwitz G, et al. J Clin Oncol 2017;35(Suppl):Abstr LBA500

15 501: 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER Conte PF et al Study objective To compare the efficacy of adjuvant trastuzumab when used for 9 weeks or 1 year in patients with HER2+ breast cancer in a non-inferiority trial Key patient inclusion criteria HER2+ breast cancer Node positive or high-risk node negative ECOG PS 0 1 (n=1253) CO-PRIMARY ENDPOINTS DFS, OS AC: doxorubicin + cyclophosphamide q3w EC: epirubicin + cyclophosphamide q3w FEC: fluorouracil, epirubicin + cyclophosphamide q3w R Arm A (1-year): AC or EC x4 then docetaxel 100 mg q3w x4 + trastuzumab 8 mg/kg (initial), 6 mg/kg q3w x14 (n=627) Stratification HR status Nodal status Arm B (9-weeks): Docetaxel 100 mg q3w x3 + trastuzumab 4 mg/kg (initial), 2 mg/kg q1w x9, then FEC x3 (n=626) When indicated, radiation therapy was administered after the completion of chemotherapy. For patients with HR+ tumours, hormonal therapy was initiated after completion of chemotherapy SECONDARY ENDPOINTS 2-year failure rate, cardiac toxicity PD PD Conte PF, et al. J Clin Oncol 2017;35(Suppl):Abstr 501

16 501: 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER Conte PF et al Key results To date, there have been 189 DFS events after a median follow-up of 5.2 years DFS outcomes were comparable between treatment groups: Pre-planned Bayesian analysis revealed that the probability that 9-week treatment is not inferior to 1-year treatment was 0.78 Trastuzumab 1-year (n=627) 9-weeks (n=627) HR (90%CI) DFS 1.15 (0.91, 1.46) No. of events year rate, % OS No. of events 5-year rate (%) (0.73, 1.55) Conte PF, et al. J Clin Oncol 2017;35(Suppl):Abstr 501

17 501: 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER Conte PF et al Key results (cont.) HR (90%CI) p-value DFS subgroups analysis Stage III vs. I+II 2.30 (1.35, 3.94) <0.001 N2+N3 vs. N0+N (1.33, 3.83) <0.001 Conte PF, et al. J Clin Oncol 2017;35(Suppl):Abstr 501

18 501: 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER Conte PF et al Safety At 18 months, LVEF change from baseline significantly greater for 1-year vs. 9-week treatment (p=0.023) Cardiac adverse events were more common in the 1-year group; there was a significant difference in time to first cardiac adverse event of grade 2 Time to first cardiac event grade Number of cardiac events Grade 1-year, n (%) 9-week, n (%) Hazard estimate HR 0.32 (95%CI 0.21, 0.50); p< year 9-week 2 70 (11.2) 22 (3.5) 3 17 (2.7) 7 (1.1) 4 3 (0.5) 3 (0.5) Total 90 (14.4) 32 (5.1) Months from randomisation Conte PF, et al. J Clin Oncol 2017;35(Suppl):Abstr 501

19 501: 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER Conte PF et al Conclusions The trial did not meet its primary endpoint of showing that 9 weeks of trastuzumab treatment was non inferior to 1 year of treatment After a median follow-up of 5.2 years, 5-year DFS was 87.5% for 1 year and 85.4% for 9 weeks of treatment Compared with 1-year adjuvant trastuzumab treatment, the shorter 9-week administration was associated with almost half the rate of severe cardiac toxicity The standard still remains 1 year of trastuzumab Shorter-term treatment with trastuzumab may only be an option for patients who are at high risk of cardiac toxicity and/or at low risk of relapse Conte PF, et al. J Clin Oncol 2017;35(Suppl):Abstr 501

20 502: Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-her2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer Moreno-Aspitia A et al Study objective To compare 1 year of anti-her2 therapy with lapatinib, trastuzumab, trastuzumab lapatinib or lapatinib + trastuzumab in the adjuvant treatment of HER2- positive early breast cancer * 3-weekly trastuzumab PD Key patient inclusion criteria HER2+ early breast cancer (n=8381) R * Weekly trastuzumab * Lapatinib Lapatinib PD PD * Lapatinib + 3-weekly trastuzumab PD PRIMARY ENDPOINT DFS *Patients could receive paclitaxel q1w or docetaxel q3w; docetaxel + carboplatin q3w; or neither of these Lapatinib arm was closed early as it crossed the protocolspecified futility boundary at the first interim analysis 52 weeks SECONDARY ENDPOINTS OS, TTR, time to distant recurrence (TTDR), brain metastases, cardiac and overall safety Moreno-Aspitia A, et al. J Clin Oncol 2017;35(Suppl):Abstr 502

21 502: Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-her2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer Moreno-Aspitia A et al Key results After a median follow-up of 6.9 years (as of December 2016), there were 705 DFS events in the lapatinib + trastuzumab vs. trastuzumab (fewer than the planned 850 events) Since the primary analysis (December 2013), there have been a further 20.3 events per 1000 patient-years for lapatinib + trastuzumab (vs for trastuzumab) 6-year results Lapatinib + Trastuzumab Trastuzumab trastuzumab (n=2093) lapatinib (n=2091) (n=2097) DFS rate, % Events, n HR (95%CI) vs. trastuzumab p-value 0.86 (0.74, 1.00) (0.81, 1.08) OS, % Deaths HR (95%CI) vs. trastuzumab p-value 0.86 (0.70, 1.06) (0.71, 1.08) Moreno-Aspitia A, et al. J Clin Oncol 2017;35(Suppl):Abstr 502

22 502: Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-her2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer Moreno-Aspitia A et al Key results (cont.) AEs, n (%) L+T (n=2061) T L (n=2076) L (n=2057) T (n=2076) Any AE 1979 (96) 1956 (94) 1964 (96) 1834 (88) AEs related to treatment 1922 (93) 1801 (87) 1857 (90) 1329 (64) Any serious AE 459 (22) 391 (19) 461 (22) 326 (16) Serious AEs related to treatment 276 (13) 191 (9) 275 (13) 116 (6) Cardiac AEs, n (%) Patients with events, n (%) 181 (9) 144 (7) 120 (6) 220 (11) Events, n Serious 33 (15) 28 (17) 19 (13) 29 (11) Investigational product-related 186 (84) 128 (77) 81 (57) 232 (87) Leading to withdrawal 83 (38) 38 (23) 14 (10) 90 (34) Fatal (grade 5) 2 (<1) 3 (2) 2 (1) 2 (<1) Moreno-Aspitia A, et al. J Clin Oncol 2017;35(Suppl):Abstr 502

23 502: Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-her2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer Moreno-Aspitia A et al Conclusions The hazard ratios for DFS in this updated analysis (after 5 years of follow-up) are similar to those observed in the primary analysis The event rate remains lower than anticipated Cardiac toxicity remains low Moreno-Aspitia A, et al. J Clin Oncol 2017;35(Suppl):Abstr 502

24 503: SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph nodepositive, early breast cancer (BC) Colleoni M et al Study objective To compare the efficacy of letrozole, when used continuously or intermittently, among patients with HR+ breast cancer who had completed ET Key patient inclusion criteria Postmenopausal women with HR+, lymph node-positive breast cancer Completed 4 6 years of adjuvant ET (n=4884) R 5 years of continuous letrozole 2.5 mg/day (n=2441) Stratification Prior ET (selective oestrogen receptor modulators, aromatase inhibitors, both) 5 years of intermittent letrozole* (n=2443) PD PD HRQoL examined in a substudy from baseline to 2 years PRIMARY ENDPOINT DFS *Letrozole taken for the first 9 months of years 1 4, then 12 months in year 5 SECONDARY ENDPOINTS Breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), OS Colleoni M, et al. J Clin Oncol 2017;35(Suppl):Abstr 503

25 503: SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph nodepositive, early breast cancer (BC) Colleoni M et al Key results After a median follow-up of 60 months and among 4851 evaluable patients, there was no significant difference between the continuous and intermittent groups 5-year results Continuous (n=2426) Intermittent (n=2426) DFS, % Events, n HR (95%CI); p-value 1.08 (0.93, 1.26); year DFS, % SERM(s) only 90.0 (n=435) 87.3 (n=438) Both SERM(s) and AI(s) 87.5 (n=977) 85.3 (n=979) AI(s) only 85.9 (n=1014) 85.6 (n=1008) Colleoni M, et al. J Clin Oncol 2017;35(Suppl):Abstr 503

26 503: SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph nodepositive, early breast cancer (BC) Colleoni M et al Key results (cont.) 5-year results Continuous (n=2426) Intermittent (n=2426) BCFI, % Events, n HR (95%CI); p-value 0.98 (0.81, 1.18); 0.84 DRFI, % Events, n HR (95%CI); p-value 0.88 (0.71, 1.09); 0.25 OS, % Deaths, n HR (95%CI); p-value 0.85 (0.68, 1.06); 0.16 Colleoni M, et al. J Clin Oncol 2017;35(Suppl):Abstr 503

27 503: SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph nodepositive, early breast cancer (BC) Colleoni M et al Key results (cont.) Sites of first DFS event, % Continuous (n=2426) Intermittent (n=2426) DFS events Breast cancer events as first site Local Contralateral breast ± above Regional ± above Soft tissue/distant LN ± above Distant bone ± above Distant visceral ± above Second (non-breast) malignancy Death without prior cancer event Death, incomplete information Colleoni M, et al. J Clin Oncol 2017;35(Suppl):Abstr 503

28 503: SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph nodepositive, early breast cancer (BC) Colleoni M et al Key results (cont.) Worst grade reported Continuous (n=2411) Intermittent (n=2417) CTCAE v3 Grade 1 5 Grade 3 5 Grade 1 5 Grade 3 5 Fractures Osteoporosis Myalgia Arthralgia Bone pain Cardiac ischaemia CNS cerebrovascular ischaemia CNS haemorrhage Hypertension Hot flushes/flashes Insomnia Fatigue Depression Any grade 3 5 targeted event Colleoni M, et al. J Clin Oncol 2017;35(Suppl):Abstr 503

29 503: SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph nodepositive, early breast cancer (BC) Colleoni M et al Conclusions Compared with continuous treatment with letrozole, extended intermittent letrozole did not improve DFS in postmenopausal women with HR+ breast cancer Based on prior ET status, there was a trend to a differential effect The rate of AEs was similar between treatment groups Some HRQoL outcomes were better with intermittent treatment The similar outcomes associated with intermittent and continuous letrozole could be clinically relevant for those patients who may benefit from temporary treatment breaks Colleoni M, et al. J Clin Oncol 2017;35(Suppl):Abstr 503

30 504: Prospective WSG phase III PlanB trial: Final analysis of adjuvant 4xEC 4x doc vs. 6x docetaxel/cyclophosphamide in patients with high clinical risk and intermediate-to-high genomic risk HER2-negative, early breast cancer Harbeck N et al Study objective To examine the non-inferiority of anthracycline-free docetaxel/cyclophosphamide vs. anthracycline-taxane based chemotherapy in patients with high-risk, HER2-, early breast cancer Key patient inclusion criteria High-risk pn0 (T2-4, G2-3, <35 years, or high upa/pai-1) or pn+ HER2- early breast cancer Aged 75 years (n=2449) R Arm A: anthracycline-free Docetaxel + cyclophosphamide x6 Arm B: standard anthracyclinetaxane based Epirubicin + cyclophosphamide x4, then docetaxel x4 PD PD PRIMARY ENDPOINT DFS SECONDARY ENDPOINTS Safety, OS Harbeck N, et al. J Clin Oncol 2017;35(Suppl):Abstr 504

31 504: Prospective WSG phase III PlanB trial: Final analysis of adjuvant 4xEC 4x doc vs. 6x docetaxel/cyclophosphamide in patients with high clinical risk and intermediate-to-high genomic risk HER2-negative, early breast cancer Harbeck N et al Key results The 5-year DFS rate was 90% in both treatment arms (HR [95%CI 0.77, 1.29]) In the HR+ subgroup, DFS rates were greater among patients with a recurrence score 25% (Arm A 94%; Arm B 95%) vs. a recurrence score >25 (Arm A 86%; Arm B 85%) The 5-year OS were also equal at 95% in both groups (HR 0.94 [95%CI 0.66, 1.35]) Compared with Arm A, there were significantly more dose reductions and cycle delays in Arm B (6.6% vs. 19.7% and 4.0% vs. 6.7%, respectively; all p 0.004) Harbeck N, et al. J Clin Oncol 2017;35(Suppl):Abstr 504

32 504: Prospective WSG phase III PlanB trial: Final analysis of adjuvant 4xEC 4x doc vs. 6x docetaxel/cyclophosphamide in patients with high clinical risk and intermediate-to-high genomic risk HER2-negative, early breast cancer Harbeck N et al Key results (cont.) Of the grade 3 4 AEs of interest, leukopenia, neutropenia, nausea, vomiting, polyneuropathy, palmar syndrome, mucositis, arthralgia, pain and fatigue occurred significantly more frequently in Arm B vs. Arm A Grade 3 4 AEs occurring in >5%, n (%) Arm A Arm B Leukopenia 598 (50.8) 671 (57.5) Neutropenia 598 (50.8) 676 (57.9) Febrile neutropenia 63 (5.3) 45 (3.9) Infection 82 (7.0) 62 (5.3) Pain 37 (3.1) 61 (5.2) Fatigue 35 (3.0) 68 (5.8) Harbeck N, et al. J Clin Oncol 2017;35(Suppl):Abstr 504

33 504: Prospective WSG phase III PlanB trial: Final analysis of adjuvant 4xEC 4x doc vs. 6x docetaxel/cyclophosphamide in patients with high clinical risk and intermediate-to-high genomic risk HER2-negative, early breast cancer Harbeck N et al Conclusions Anthracycline-free docetaxel + cyclophosphamide was non-inferior to anthracyclinetaxane-based chemotherapy with HER2- early breast cancer There were no differences in efficacy in the high-risk subgroups of patients (triplenegative status, nodal status or high recurrence score) Further prospective studies are urgently needed before final conclusions on the impact of anthracyclines in HER2-negative breast cancer can be drawn Harbeck N, et al. J Clin Oncol 2017;35(Suppl):Abstr 504

34 506: Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2 Nanda R et al Study objective To determine which tumour types respond to which experimental neoadjuvant therapy in patients with invasive breast cancer Key patient inclusion criteria Invasive breast cancer Tumour 2.5 cm by exam or 2 cm by imaging Candidate for preoperative chemotherapy R Pembrolizumab 200 mg q3w x4 + paclitaxel 80 mg/m 2 q1w x12 (n=69) PD Study MRI and biopsy PS <2 (n=1020) Paclitaxel 80 mg/m 2 q1w (n=180) PD PRIMARY ENDPOINT pcr Nanda R, et al. J Clin Oncol 2017;35(Suppl):Abstr 506

35 506: Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2 Nanda R et al Key results Pembrolizumab graduated in all HER2- signatures that were examined In TNBC, the pcr rate with pembrolizumab was 3 times that of control In HR+/HER2- the pcr rate was 2.5 times that of control Signature Estimated pcr rate (95% probability interval) Pembrolizumab Control Probability pembrolizumab is superior, % Predictive probability of success in phase 3, % All HER (0.34, 0.58) 0.16 (0.06, 0.27) >99 99 TNBC 0.60 (0.43, 0.78) 0.20 (0.06, 0.33) >99 >99 HR+/HER (0.19, 0.48) 0.13 (0.03, 0.24) >99 88 Nanda R, et al. J Clin Oncol 2017;35(Suppl):Abstr 506

36 506: Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2 Nanda R et al Key results (cont.) AEs of special interest hypothyroidism (8.7% vs. 0.6%), hyperthyroidism (4.3% vs. 0%) and adrenal insufficiency (8.7% vs. 0%) were more frequent with pembrolizumab than control, respectively TRAEs, n (%) Pembrolizumab (n=69) Control (n=180) All grades Grade 3 5 All grades Grade 3 5 Febrile neutropenia 5 (7.2) 5 (7.2) 12 (6.7) 12 (6.7) Neutropenia without fever 4 (5.8) 1 (1.4) 3 (1.7) 0 (0) Anaemia 19 (27.5) 3 (4.3) 34 (18.9) 7 (3.9) Fatigue 55 (79.7) 4 (5.8) 146 (81.1) 1 (0.6) Nausea 51 (73.9) 3 (4.3) 129 (71.7) 0 (0) Vomiting 24 (34.8) 1 (1.4) 33 (18.3) 0 (0) Diarrhoea 34 (49.3) 5 (7.2) 68 (37.8) 4 (2.2) Peripheral motor neuropathy 9 (13.0) 1 (1.4) 8 (4.4) 0 (0) Peripheral sensory neuropathy 35 (50.7) 1 (1.4) 107 (59.4) 2 (1.1) Nanda R, et al. J Clin Oncol 2017;35(Suppl):Abstr 506

37 506: Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2 Nanda R et al Conclusions When added to standard therapy, pembrolizumab improved pcr rates in all patients with HER2- breast cancer that met the I-SPY 2 eligibility criteria; response was greater in those patients with TNBC Rates of adrenal insufficiency were higher than previously reported in patients with advanced cancer; replacement therapy is effective Nanda R, et al. J Clin Oncol 2017;35(Suppl):Abstr 506

38 520: Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC) Geyer CE et al Study objective To examine response with veliparib + carboplatin or carboplatin alone when added to neoadjuvant paclitaxel followed by doxorubicin + cyclophosphamide in patients with early stage TNBC Segment weeks Segment weeks Key patient inclusion criteria Histologically confirmed, invasive TNBC (ct2 T4 N0 2 or ct1 N1 2) Documented gbrca testing R 2:1:1 Veliparib 50 mg bid + carboplatin AUC 6 mg/ml/min q3w + paclitaxel 80 mg/m 2 q1w (n=316) Placebo bid + carboplatin AUC 6 mg/ml/min q3w + paclitaxel 80 mg/m 2 q1w (n=160) Doxorubicin + CP* Surgery (n=634) Placebo bid + placebo + paclitaxel 80 mg/m 2 q1w (n=158) PRIMARY ENDPOINT pcr in breast and lymph nodes *Doxorubicin + cyclophosphamide 60 mg/m 2 or 600 mg/m 2 q2w or q3w SECONDARY ENDPOINTS Event-free survival (EFS), OS, rate of conversion to eligibility for breast conservation surgery, safety Geyer CE, et al. J Clin Oncol 2017;35(Suppl):Abstr 520

39 520: Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC) Geyer CE et al Key results Of 634 randomised patients, the mean age was 51 years and ~15% had the deleterious gbrca mutation Patients, % Veliparib + carboplatin + paclitaxel (n=316) Carboplatin + paclitaxel (n=160) Paclitaxel (n=158) pcr 53.2* CRR 83.4* Intent to perform a breast conserving surgery Minimal residual disease 68.3* *p<0.001 vs. paclitaxel Geyer CE, et al. J Clin Oncol 2017;35(Suppl):Abstr 520

40 520: Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC) Geyer CE et al Key results (cont.) Grade 3 4 TRAEs, neutropenia, thrombocytopenia and anaemia, were increased with the addition of carboplatin Veliparib did not appear to increase toxicity TEAEs, n (%) Veliparib + carboplatin + paclitaxel (n=313) Carboplatin + paclitaxel (n=158) Paclitaxel (n=157) Grade (85.9) 134 (84.8) 71 (45.2) SAE 95 (30.4) 42 (26.6) 22 (14.0) Leading to veliparib discontinuation 18 (5.8) 9 (5.7) 4 (2.5) Leading to carboplatin discontinuation 17 (5.4) 10 (6.3) 1 (0.6) Leading to paclitaxel discontinuation 36 (11.5) 11 (7.0) 4 (2.5) Fatal AE 1 (0.3) 0 0 Deaths (includes non-treatment-emergent) 9 (2.9) 4 (2.5) 4 (2.5) Geyer CE, et al. J Clin Oncol 2017;35(Suppl):Abstr 520

41 520: Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC) Geyer CE et al Conclusions Compared with paclitaxel, veliparib added to carboplatin + paclitaxel both followed by doxorubicin + cyclophosphamide significantly improved pcr Conversely, veliparib + carboplatin + paclitaxel did not show any improvement in pcr vs. carboplatin + paclitaxel both followed by doxorubicin + cyclophosphamide; the improved pcr was due to carboplatin, an effect that was independent of gbrca mutation status The addition of carboplatin was associated with: Slight prolongation of time to, and increase in dose reductions of, paclitaxel Increased haematological and gastrointestinal toxicities Geyer CE, et al. J Clin Oncol 2017;35(Suppl):Abstr 520

42 Advanced/metastatic breast cancer

43 Advanced/metastatic breast cancer First line

44 1001: Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18) Finn RS et al Study objective To examine survival outcomes and safety of palbociclib + letrozole vs. letrozole alone in patients with advanced ER+/HER2- breast cancer Key patient inclusion criteria Part 1: postmenopausal women with advanced ER+/HER2- breast cancer (n=66) Part 2: postmenopausal women with ER+/HER2- screened for CCND1 amplification and/or loss of p16 (n=99) (n=165) PRIMARY ENDPOINT PFS R 1:1 Palbociclib 125 mg/day (3 weeks on/1 week off) + letrozole 2.5 mg/day (n=84) Stratification Letrozole 2.5 mg/day (n=84) SECONDARY ENDPOINTS OS, ORR, clinical benefit, DoR, safety PD/ death/ toxicity Disease site (visceral vs. bone only vs. other) Disease-free interval (>12 vs. 12 months from end of adjuvant therapy to recurrence or de novo advanced disease) PD/ death/ toxicity Finn RS, et al. J Clin Oncol 2017;35(Suppl):Abstr 1001

45 1001: Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18) Finn RS et al Key results Overall survival probability, % No. at risk Palbociclib + letrozole Letrozole OS (ITT) Time, months Palbociclib + letrozole Letrozole Palbociclib + letrozole (n=84) 8 3 Letrozole (n=81) Patients with events, n (%) 60 (71) 56 (69) mos, months (95%CI) 37.5 (31.4, 47.8) 34.5 (27.4, 42.6) HR (95%CI) (0.623, 1.294) p-value Finn RS, et al. J Clin Oncol 2017;35(Suppl):Abstr 1001

46 1001: Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18) Finn RS et al Conclusions In the PALOMA-1 study, in patients with ER+/HER2- advanced breast cancer, palbociclib combined with letrozole was associated with a non-significant trend towards an improvement in OS It is expected that a larger sample of patients with front-line ER+ breast cancer would be required to detect a difference in OS Because of the small sample size, this trial was not powered to perform formal hypothesis testing of OS Survival data from the phase 3, PALOMA-2 study is expected soon Finn RS, et al. J Clin Oncol 2017;35(Suppl):Abstr 1001

47 1008: Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mtnbc): KEYNOTE-086 cohort A Adams S et al Study objective To examine the safety and anti-tumour activity of pembrolizumab as monotherapy for PD-L1-positive metastatic TNBC Key patient inclusion criteria Centrally confirmed metastatic TNBC 1 prior systemic therapy for metastatic disease with documented PD Tumour PD-L1 combined positive score (CPS) 1% ECOG PS 0 1 (n=170) Pembrolizumab 200 mg IV q3w For 2 years or until PD/toxicity/ withdrawal CO-PRIMARY ENDPOINTS ORR Safety SECONDARY ENDPOINTS DoR, DCR, PFS, OS Adams S, et al. J Clin Oncol 2017;35(Suppl):Abstr 1008

48 1008: Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mtnbc): KEYNOTE-086 cohort A Adams S et al Key results Total population (n=170) PD-L1 positive (n=105) PD-L1 negative (n=64) ORR, n (%) [95% CI] 8 (4.7) [2.3, 9.2] 5 (4.8) [1.8, 10.9] 3 (4.7) [1.1, 13.4] DCR, n (%) [95% CI] 13 (7.6) [4.4, 12.7] 10 (9.5) [5.1, 16.8] 3 (4.7) [1.1, 13.4] Best overall response, n (%) CR 1 (0.6) 1 (1.0) 0 PR 7 (4.1) 4 (3.8) 3 (4.7) SD 35 (20.6) 22 (21.0) 12 (18.8) PD 103 (60.6) 66 (62.9) 37 (57.8) NE 5 (2.9) 2 (1.9) 3 (4.7) Not able to assess 19 (11.2) 10 (9.5) 9 (14.1) Median time to response, months (range) 3 ( ) Median DoR, months (range) 6.3 ( ) Median PFS, months (95%CI) 2.0 (1.9, 2.0) 2.0 (1.9, 2.1) 1.9 (1.6, 2.0) Median OS, months (95%CI) 8.9 (7.2, NR) 8.3 (6.9, 10.5) 10.0 (6.2, NR) Adams S, et al. J Clin Oncol 2017;35(Suppl):Abstr 1008

49 1008: Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mtnbc): KEYNOTE-086 cohort A Adams S et al Key results (cont.) AE, n (%) Any grade Grade 3 4 Treatment-related occurring in 5% Fatigue 35 (20.6) 1 (0.6) Nausea 18 (10.6) 1 (0.6) Decreased appetite 13 (7.6) 0 Hypothyroidism 13 (7.6) 0 Diarrhoea 12 (7.1) 3 (1.8) Asthenia 11 (6.5) 0 Arthralgia 10 (5.9) 0 Pruritus 10 (5.9) 0 Immune mediated occurring in 3 patients Hypothyroidism 19 (11.2) 0 Hyperthyroidism 8 (4.7) 0 Pneumonitis 6 (3.5) 1 (0.6) Adams S, et al. J Clin Oncol 2017;35(Suppl):Abstr 1008

50 1008: Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mtnbc): KEYNOTE-086 cohort A Adams S et al Conclusions Pembrolizumab monotherapy demonstrated anti-tumour activity over a median follow-up period of 10.9 months as a first-line therapy for heavily pre-treated patients with PD-L1- positive metastatic TNBC ORR was 4.7% (95%CI 2.3, 9.2) and DCR 7.6% (4.4, 12.7) Activity was independent of PD-L1 expression, while ORR was lower in patients with poor prognostic factors (liver metastases; 3 metastatic organ sites; visceral disease; serum lactate dehydrogenase) Pembrolizumab monotherapy was generally well tolerated Adams S, et al. J Clin Oncol 2017;35(Suppl):Abstr 1008

51 Advanced/metastatic breast cancer Later lines

52 1000: MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy Sledge GW et al Study objective To determine the efficacy and safety of abemaciclib + fulvestrant vs. placebo + fulvestrant in women with HR+/HER2- advanced breast cancer Key patient inclusion criteria Pre/peri/postmenopausal women with HR+/HER2- advanced breast cancer ET resistant, progressed on neoadjuvant, during or within 1 year of adjuvant ET, or on first-line ET No chemotherapy for metastatic breast cancer ECOG PS 1 (n=669) R 2:1 Abemaciclib 200 mg* bid q12h + fulvestrant 500 mg (n=446) Stratification Metastatic site Resistance to prior ET (primary vs secondary). Placebo + fulvestrant 500 mg (n=223) PD PD PRIMARY ENDPOINT Investigator-assessed PFS SECONDARY ENDPOINTS ORR, response, CBR, safety *Dose reduced by protocol amendment in all new and ongoing patients from 200 to 150 mg bid after 178 patients enrolled Sledge GW, et al. J Clin Oncol 2017;35(Suppl):Abstr 1000

53 1000: MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy Sledge GW et al Key results Compared with placebo + fulvestrant, abemaciclib + fulvestrant was associated with significantly longer PFS (p< ) The HR for the PFS benefit (by BICR) was (95%CI 0.363, 0.584); p< PFS, % PFS in the ITT Median PFS Abemaciclib + fulvestrant: 16.4 months Placebo + fulvestrant: 9.3 months HR (95%CI 0.449, 0.681) p< No. at risk Abemaciclib Placebo Time, months Sledge GW, et al. J Clin Oncol 2017;35(Suppl):Abstr 1000

54 1000: MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy Sledge GW et al Key results (cont.) ORR, response and CBR were greater in patients who received abemaciclib + fulvestrant ITT population ORR, % CR, % CBR, % Abemaciclib + fulvestrant ITT (n=446) 35.2* * Measurable (n=318) 48.1* * Placebo + fulvestrant ITT (n=223) Measurable (n=164) *p<0.001 Sledge GW, et al. J Clin Oncol 2017;35(Suppl):Abstr 1000

55 1000: MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy Sledge GW et al Key results (cont.) TRAE occurring in 20%, n (%) Abemaciclib + fulvestrant (n=441) Placebo + fulvestrant (n=223) All Grade 3 Grade 4 All Grade 3 Grade 4 Any 435 (98.6) 241 (54.6) 26 (5.9) 199 (89.2) 46 (20.6) 5 (2.2) Diarrhoea 381 (86.4) 59 (13.4) 0 55 (24.7) 1 (0.4) 0 Neutropenia 203 (46.0) 104 (23.6) 13 (2.9) 9 (4.0) 3 (1.3) 1 (0.4) Nausea 199 (45.1) 12 (2.7) 51 (22.9) 2 (0.9) Fatigue 176 (39.9) 12 (2.7) 60 (26.9) 1 (0.4) Abdominal pain 156 (35.4) 11 (2.5) 35 (15.7) 2 (0.9) Anaemia 128 (29.0) 31 (7.0) 1 (0.2) 8 (3.6) 2 (0.9) 0 Leukopenia 125 (28.3) 38 (8.6) 1 (0.2) 4 (1.8) 0 0 Decreased appetite 117 (26.5) 5 (1.1) 0 27 (12.1) 1 (0.4) 0 Vomiting 114 (25.9) 4 (0.9) 0 23 (10.3) 4 (1.8) 0 Headache 89 (20.2) 3 (0.7) 34 (15.2) 1 (0.4) Sledge GW, et al. J Clin Oncol 2017;35(Suppl):Abstr 1000

56 1000: MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy Sledge GW et al Conclusions Among patients with HR+/HER2- advanced breast cancer who progressed on prior ET, abemaciclib 150 mg (reduced from 200 mg) + fulvestrant was effective and significantly improved survival Dosed on a continuous cycle, abemaciclib was generally well-tolerated Approximately one-quarter of patients had grade 3 and 4 neutropenia Diarrhoea (grade 3 which occurred early in 13.4% of patients receiving abemaciclib + fulvestrant vs. 0.4% receiving fulvestrant) was managed with dose adjustment and antidiarrhoea treatment On the basis of these results, the monarche trial will begin recruitment in Q to examine the combination of abemaciclib with ET as adjuvant therapy in patients with HR+/HER2- high-risk breast cancer Sledge GW, et al. J Clin Oncol 2017;35(Suppl):Abstr 1000

57 1002: A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mbc) (TREnd trial) Malorni L et al Study objective To compare the efficacy of palbociclib alone with palbociclib + ET in patients with HR+/HER2- metastatic breast cancer Key patient inclusion criteria Postmenopausal women with HR+/HER2- metastatic breast cancer Pre-treated with 1 or 2 prior ET 1 prior line of chemotherapy permitted (n=115) PRIMARY ENDPOINT CBR: CR, PR and SD for 24 weeks R Palbociclib 125 mg/day (3 weeks on/1 week off) (n=58) Stratification Disease site (visceral vs. other) Palbociclib 125 mg/day (3 weeks on/1 week off) + pre-progression ET* (n=57) SECONDARY ENDPOINTS Safety, PFS PD Number of prior lines of ET for mbc (1 vs. 2) Duration of prior line of ET (>6 vs. 6 months) PD *Aromatase inhibitor or fulvestrant Malorni L, et al. J Clin Oncol 2017;35(Suppl):Abstr 1002

58 1002: A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mbc) (TREnd trial) Malorni L et al Key results Palbociclib + ET (n=57) Palbociclib (n=58) CBR, n (%) [95%CI] 31 (54) [41.5, 63.7] 35 (60) [47.8, 72.9] CR, n (%) 0 (0) 0 (0) PR, n (%) 6 (10) 4 (7) SD, n (%) 25 (44) 31 (53) Duration of clinical benefit, months (95%CI) 11.5 (8.5, 17.8) 6 (3.9, 10.8) Survival probability p-value (exploratory) 0.12 HR 0.69 (95%CI 0.4, 1.1) PFS Palbociclib + ET (n=57) Palbociclib (n=58) Patients with events, n (%) 40 (70) 50 (86) mdocb, months (95%CI) 10.8 (5.6, 12.7) 6.5 (5.4, 8.5) Palbociclib + ET Palbociclib Time, months Malorni L, et al. J Clin Oncol 2017;35(Suppl):Abstr 1002

59 1002: A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mbc) (TREnd trial) Malorni L et al Key results (cont.) AEs, n (%) Palbociclib + ET (n=57) Palbociclib (n=58) Grade 3 Grade 4 Grade 3 Grade 4 Neutropenia 35 (61) 6 (11) 28 (48) 11 (19) Leukopenia 20 (35) 2 (4) 17 (29) 1 (2) Anaemia 2 (4) Thrombocytopenia 1 (2) 0 1 (2) 0 Mucositis 3 (5) Infection 2 (4) 0 2 (3) 0 Arthralgia/myalgia 1 (2) Fatigue (2) 0 Treatment disc. due to AEs, n (%) 4 (9) 3 (6) Malorni L, et al. J Clin Oncol 2017;35(Suppl):Abstr 1002

60 1002: A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mbc) (TREnd trial) Malorni L et al Conclusions When used alone, palbociclib had clinical activity in patients with HR+/HER2- metastatic breast cancer who had previously received ET Palbociclib + ET compared with palbociclib alone was associated with increased PFS and duration of clinical benefit, suggesting that palbociclib could reverse resistance to the prior line of ET Malorni L, et al. J Clin Oncol 2017;35(Suppl):Abstr 1002

61 1004: Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE Gradishar WJ et al Study objective To examine the safety and efficacy of dual vs. single HER2 blockade (lapatinib + trastuzumab vs. either agent alone) + aromatase inhibitors in patients with HR+/HER2+ metastatic breast cancer progressing after chemotherapy Key patient inclusion criteria Postmenopausal women with confirmed ER+ and/or PgR+ HER2+ metastatic breast cancer Progressed on (neo)adjuvant/first-line trastuzumab + chemotherapy ECOG PS 0 1 (n=355) PRIMARY ENDPOINT PFS R 1:1:1 Stratification Trastuzumab* + lapatinib 1000 mg/day + aromatase inhibitors (n=120) Trastuzumab* + aromatase inhibitors (n=117) Lapatinib 1500 mg/day + aromatase inhibitors (n=118) Prior trastuzumab Investigator s choice of aromatase inhibitor SECONDARY ENDPOINTS ORR, CBR, OS, safety PD/toxicity/ death/ withdrawal PD/toxicity/ death/ withdrawal PD/toxicity/ death/ withdrawal *8 mg/kg, then 6 mg/kg IV q3w As per physician s choice Gradishar WJ, et al. J Clin Oncol 2017;35(Suppl):Abstr 1004

62 1004: Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE Gradishar WJ et al Key results Proportion alive and progression free PFS in the ITT Trastuzumab + lapatinib + AI (n=120) Trastuzumab + AI (n=117) Events, n (%) 62 (52) 75 (64) Median PFS, months (95%CI) 11 (8.3, 13.8) 5.7 (5.5, 8.4) HR (95%CI); p-value 0.62 (0.45, 0.88); No. at risk Trastuzumab + lapatinib + AI Trastuzumab + AI Time since randomisation, months Gradishar WJ, et al. J Clin Oncol 2017;35(Suppl):Abstr 1004

63 1004: Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE Gradishar WJ et al Key results (cont.) There was no significant difference in OS between treatment groups Best response, % Trastuzumab + lapatinib + AI (n=120) Trastuzumab + AI (n=117) Lapatinib + AI (n=118) CR 5 <1 7 PR SD PD CBR, % ORR: CR+PR, % (95%CI) 31.7 (23.5, 40.8) 13.7 (8.0, 21.3) 18.6 (12.1, 26.9) OR 2.83 (95%CI 1.43, 5.89); p= OR (95%CI 0.69, 3.3); p= Gradishar WJ, et al. J Clin Oncol 2017;35(Suppl):Abstr 1004

64 1004: Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE Gradishar WJ et al Key results (cont.) AEs occurring in >10%, % Trastuzumab + lapatinib + AI (n=118) Trastuzumab + AI (n=116) Lapatinib + AI (n=119) Any G3/4 Any G3/4 Any G3/4 Any Diarrhoea Rash Paronychia Nausea Decreased appetite Stomatitis <1 Arthralgia 13 < Dermatitis acneiform <1 Fatigue 12 < Vomiting 10 0 <1 < Cough ALT increase AST increase Headache < Gradishar WJ, et al. J Clin Oncol 2017;35(Suppl):Abstr 1004

65 1004: Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE Gradishar WJ et al Conclusions Among previously treated patients with HR+/HER2+ metastatic breast cancer, trastuzumab + lapatinib + AI was associated with longer PFS than trastuzumab + AI; however, adverse events were more frequent with trastuzumab + lapatinib than either treatment alone This combination could be an effective chemotherapy sparing option for the subgroup of HR+/HER2+ patients who are not candidates for chemotherapy Gradishar WJ, et al. J Clin Oncol 2017;35(Suppl):Abstr 1004

66 1005: TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM) Freedman RA et al Study objective To examine the efficacy and safety of neratinib + capecitabine in patients with HER2+ breast cancer brain metastases Key patient inclusion criteria HER2+ metastatic breast cancer CNS progression Measurable disease: 1 CNS lesion 10 mm No prior lapatinib or capecitabine ECOG PS 0 2 (n=37) Neratinib 240 mg/day PO + capecitabine 750 mg/m 2 bid for 14 days then 7 days off* PD PRIMARY ENDPOINT CNS ORR SECONDARY ENDPOINTS CNS response, PFS, OS, safety *Loperamide prophylaxis (16 mg/day) was recommended during cycle 1 Freedman RA, et al. J Clin Oncol 2017;35(Suppl):Abstr 1004

67 1005: TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM) Freedman RA et al Key results As of 1 April 2017 n=31* CNS ORR (by CNS volumetric response), % (95%CI) 49 (32, 66) CNS ORR (by RANO-BM criteria), % (95%CI) 24 (12, 41) Median time to CNS progression, months month PFS, % 38 Median OS, months (events) 13.5 (19) 12-month estimated survival, % (95%CI) 57 (39, 72) RANO-BM: response assessment in neuro-oncology-brain metastases *6 patients did not reach re-staging evaluation and were categorised as zero Freedman RA, et al. J Clin Oncol 2017;35(Suppl):Abstr 1004