Unità Dipartimentale di Oncologia IRCCS Fondazione S. Maugeri Esperienza Real Life Raffaella Palumbo Unità Dipartimentale di Oncologia IRCCS Fondazione S. Maugeri PAVIA

Evidence-based medicine does not make clinical practice … … … people do WHY REAL LIFE ? Aiming to provide a picture of “real life clinical practice” “Moving beyond clinical trials: real life treatment with albumin-bounded paclitaxel (nab-paclitaxel) in MBC A multicenter Italian experience” RETROSPECTIVE ANALYSIS We analyzed the different patterns of treatment and outcome of women receiving single-agent Nab-P for their MBC in 9 Centers of North Italy Patient and tumour characteristics and treatment-related variables were summarized using descriptive statistics, including median and range; the chi-square test was used to compare categorical variables, and p≤0.05 was considered statistically significant A subgroup analysis was performed to identify potential prognostic and/or predictive factors for disease outcome and treatment response Progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meyer method We analyzed the different patterns of treatment and outcome of women receiving single-agent Nab-P for their MBC in 9 Centers of North Italy Patient and tumour characteristics and treatment-related variables were summarized using descriptive statistics, including median and range; the chi-square test was used to compare categorical variables, and p≤0.05 was considered statistically significant A subgroup analysis was performed to identify potential prognostic and/or predictive factors for disease outcome and treatment response Progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meyer method

FOCUS ON … … … WHY REAL LIFE ? A ‘difficult-to-treat’ population “Prospective evaluation of activity, safety and quality of life of nab-paclitaxel as 2nd line chemotheraphy in taxane-pretreated disease” PROSPECTIVE STUDY To evaluate the performance of single-agent Nab-P in women who at the time of disease relapse had yet received the most active agent in the neo-adjuvant setting, ie conventional taxane available data from retrospective or post-hoc analysis no informations regarding QoL

DIFFERENT PATTERNS OF TREATMENT WITH ACTIVITY AND SAFETY OF ALBUMIN–BOUND PACLITAXEL (NAB-PACLITAXEL) IN SECOND AND FURTHER LINES OF CHEMOTHERAPY FOR METASTATIC BREAST CANCER PATIENTS: A TWO-YEAR MULTICENTER ITALIAN EXPERIENCE R. Palumbo1, M.E. Cazzaniga2, E. Simoncini3, C. Tondini4, E. Piazza5, A. Ferzi6, D. Grasso7, M. Danova7, E. Tarenzi8, F. Sottotetti1, F. Villa2, E. Rota Caremoli4, P. Poletti4 A. Gambaro3, F. Tosi3, C. Fasola3, C. Cavalli7, M. Torchio7, V.Gambi8, A.Bernardo1 1Deparmental Unit of Oncology-IRCCS Maugeri Foundation, Pavia; 2Medical Oncology-San Gerardo Hospital, Monza;3Breast Unit, Brescia; 4Medical Oncology-Papa Giovanni XXIII Hospital, Bergamo; 4MedicalOncology-Luigi Sacco Hospital, Milano; 6Medical Oncology-Legnano Hospital; 7Medical Oncology-IRCCS San Matteo Hospital, Pavia; 8Medicine and Oncology Unit-Vigevano Hospital, Pavia; 9Medical Oncology-Falck, Ca’ Granda Hospital, Milano DIFFERENT PATTERNS OF TREATMENT WITH ALBUMIN–BOUNDED PACLITAXEL (NAB-PACLITAXEL) FOR TARGETED CHEMOTHERAPY IN METASTATIC BREAST CANCER PATIENTS: A MULTICENTER ITALIAN EXPERIENCE ON 125 WOMEN TARGETED CHEMOTHERAPY WITH ALBUMIN-BOUND PACLITAXEL (NAB-PACLITAXEL) FOR METASTATIC BREAST CANCER (MBC): A REAL WORLD MULTICENTER ITALIAN EXPERIENCE ON 180 WOMEN

DATA ANALYSIS 180 women treated at 9 Italian Institutions from February 2011 were included in the analysis, with cut-off data evaluation as of September 2014 Final analysis on the overall population of 215 women included, cut-off data evaluation as of December 2014 submitted TREATMENT SCHEDULES Patients received Nab-P as monotherapy intravenously over 30 minutes at the dose of 260 mg/m2 every 3 weeks or 125 mg/m2 weekly at the discretion of the treating oncologist Steroid premedication was not required before therapy infusion Treatment was given in the outpatient setting up to disease progression or unacceptable toxicity or patient refusal

STUDY POPULATION (1) q3w Nab-P 260 mg/m2 qw Nab-P 125 mg/m2 OVERALL No of patients (%) 95 (52.7) 85 (47.2) 180 (100) Median age, years [range] <65 years ≥65 years 52 [33-68] 67 (70.5) 28 (29.4) 54 [45-82] 41 (48.2) 44 (51.7) 54 [33-82] 108 (60.0) 72 (40.0) ECOG Performance Status 1 2 49 (51.5) 34 (35.7) 12 (12.6) 32 (37.6) 29 (34.1) 24 (28.2) 81 (45.0) 63 (35.0) 36 (20.0) Primary tumour subtype Luminal A Luminal B Triple negative 30 (31.5) 39 (41.0) 26 (27.3) 34 (40.0) 22 (25.8) 64 (35.5) 68 (37.7) 48 (26.6) Prior systemic therapy (early stage) anthracycline-based CT (no taxane) anthracycline + taxane taxane only CMF 43 (45.2) 33 (34.7) 11 (11.5) 8 (8.4) 30 (35.2) 10 (11.7) 4 (4.7) 84 (46.6) 21 (11.6) 12 (6.6) Median DFI, months (range) ≤24 months >24 months 42 (19-96) 37 (38.9) 58 (61.0) 49 (42-134) 33 (38.8) 52 (68.2) 46 (19-134) 70 (38.0) 110 (61.0)

STUDY POPULATION (2) q3w Nab-P 260 mg/m2 qw Nab-P 125 mg/m2 OVERALL No of patients (%) 95 85 180 Prior CT for metastatic disease taxane-based without taxane 68 (71.5) 27 (28.4) 39 (45.8) 46 (54.1) 107 (59.4) 73 (40.5) Median n°of prior CT lines for metastatic disease (range) 1 prior CT line 2 prior CT lines 3 prior CT lines ≥4 CT lines 3 (1-5) 46 (48.4) 25 (26.3) 16 (16.8) 8 (8.40) 4 (2-8) 29 (34.1) 21 (24.7) 19 (22.3) 16 (18.8) 3 (1-8) 75 (44.0) 46 (20.6) 35 (18.6) 24 (13.3) Visceral involvement 45 (52.9) 113 (62.7) Dominant metastatic sites liver lung bone/nodes skin/soft tissues 38 (40.0) 30 (31.5) 11 (11.5) 26 (30.5) 25 (29.4) 15 (17.6) 64 (35.5) 49 (27.2) 41 (22.7) 26 (14.4) Number of metastatic sites 1 2 ≥3 14 (14.7) 18 (18.9) 63 (66.3) 32 (37.6) 46 (25.5) 44 (24.4) 90 (50.0) CT: chemotherapy

TREATMENT ACTIVITY q3w Nab-P n = 95 qw Nab-P n = 85 OVERALL n = 180 Objective RR (%) 50 (52.6) 30 (35.23) 80 (44.4) Complete response Partial response Stable disease ≥16 weeks Progression disease 8 (8.40) 42 (44.2) 29 (30.5) 16 (16.8) 5 (3.00) 25 (29.4) 30 (29.5) 25 (17.6) 13 (7.20) 67 (37.2) 59 (32.7) 41 (22.7) Clinical Benefit rate (CR+PR+SD ≥16 weeks) 79 (83.1) 60 (70.5) 139 (77.2) Median follow-up Median PFS in the whole population Median PFS in 2nd line subgroup Median PFS in ≥3rd line subgroup 18 months (range 6-30) 7.8 months (range 3-23+) 12.9 months (range 6-23+) 4.8 months (range 3-8.8)

TREATMENT TOXICITY q3w Nab-P n = 95 qw Nab-P n = 85 OVERALL n = 180 WHO grade 3 4 n (%) Anemia 3 (1.60) - Leukopenia 14 (14.7) 7 (7.30) 4 (4.7) 18 (10.0) 7 (3.80) Neutropenia 28 (29.4) 18 (18.9) 12 (14.1) 5 (5.80) 40 (22.2) 23 (12.7) Thrombocytopenia Diarrhea 2 (2.10) Nausea/vomiting 3 (3.15) 2 (2.35) 5 (2.77) Mucositis 1 (1.50) 3 (1.66) Fatigue 4 (4.21) 6 (3.33) Sensory neuropathy 15 (17.6) 8 (12.3) Hypersensitivity reactions Alopecia ** 68 (71.5) 3 (3.52) 71 (39.4) ** grade 1-2 in all patients in the q3w cohort

TREATMENT COMPLIANCE q3w Nab-P n = 95 qw Nab-P n = 85 OVERALL n = 180 Median n° of cycles (range) 6 (3-27) 5 (3-18) Required dose reduction [n (%)] 17 (17.8) 11 (12.9) 28 (15.5) Median treatment duration [months (range)] 8 (6-21) 6 (4-15) 6 (4-21) No significant differences in toxicity profile in the ≥65 years old patients (40%)

RESPONDING PATIENTS ACCORDING TO BASELINE CHARACTERISTICS SUBGROUP ANALYSIS (1) RESPONDING PATIENTS ACCORDING TO BASELINE CHARACTERISTICS Variable N°of patients OR n (%) 95% CI CB 180 80 (44.4) 39.4-56.6 139 (77.2) 79.2-91.3 Age <65 years ≥65 years 108 72 47 (43.5) 33 (45.8) 40.7-61.4 27.0-56.5 88 (81.4) 51 (70.8) 75.8-90.9 76.4-95.9 DFI ≤24 months >24 months 70 110 34 (48.5) 46 (41.8) 35.8-64.1 36.4-57.6 58 (82.8) 81 (73.6) 53.4-80.0 89.6-98.7 Previous adjuvant CT taxane-based without taxanes 84 96 37 (40.4) 43 (44.7) 33.7-58.3 38.2-61.7 69 (82.1) 70 (72.9) 65.8-86.6 85.4-97.6 Metastatic disease sites viscera other 113 67 51 (45.1) 29 (43.2) 34.4-54.2 42.2-74.4 89 (78.7) 50 (74.6) 81.3-94.0 61-2-88.9 OR: Objective Responses; CB: Clinical Benefit

RESPONDING PATIENTS ACCORDING TO BASELINE CHARACTERISTICS SUBGROUP ANALYSIS (2) RESPONDING PATIENTS ACCORDING TO BASELINE CHARACTERISTICS Variable N°of patients OR n (%) 95% CI CB 180 80 (44.4) 39.4-56.6 139 (77.2) 79.2-91.3 Number of involved sites 1-2 ≥3 90 46 (51.6) 34 (37.7) 46.3-76.8 32.5-52.5 64 (71.1) 69 (76.6) 77.6-97.0 75.5-90.5 Previous CT for metastatic disease taxane-based without taxanes 107 73 48 (44.8) 32 (43.8) 35.8-55.8 37.9-70.1 81 (75.7) 58 (79.4) 78.5-82.3 69.0-93.3 Nab-paclitaxel schedule 3-weekly weekly 95 85 49 (51.5) 31 (34.1) 41.2-62.0 26.3-55.4 81 (82.1) 58 (68.2) 72.9-89.0 83.4-98.6 Nab-paclitaxel line of treatment 2nd line 3rd or more lines 75 105 50 (66.6) 30 (28.5) 47.7-72.9 27.6-49.6 68 (90.6) 71 (67.6) 75.5-93.5 75.9-92.1 OR: Objective Responses; CB: Clinical Benefit

NAB-PACLITAXEL IN TAXANE-PRETREATED MBC

NAB-PACLITAXEL IN TAXANE-PRETREATED MBC

IN TAXANE-PRETREATED MBC NAB-PACLITAXEL IN TAXANE-PRETREATED MBC median number of given cycles: 6 (range 4-27) 92% of patients received nab-P at the protocol-specified dose and 40% of them had ≥9 cycles; median relative DI: 98% G-CSF support given in 5 women during 8 cycles of treatment; administration delayed by one week in 9/52 patients onset of sensory neuropathy after a median of 6 cycles (range 3-14) median time to improvement to a lower grade: 19 days (16-26)

IN TAXANE-PRETREATED MBC NAB-PACLITAXEL IN TAXANE-PRETREATED MBC No need for premedication and short-term infusion allowed good patient compliance in the whole population. Information on treatment tolerability was available for all the treated patients (Table 5). ‘Very good’ tolerability was reported in 28%-33% of the patients receiving nab-paclitaxel compared to 19% for last therapy, while the percentage of patients reporting ‘insufficient’ tolerability did not exceed 6%. Overall, 60% of all the patients reported an improvement in tolerability of nab-paclitaxel compared with their last therapy, mostly from ‘satisfactory’ to ‘good’ or from ‘good’ to ‘very good’.

No need for premedication and short-term infusion allowed good patient compliance in the whole population 60% of all the patients reported an improvement in tolerability of nab-P compared with their last therapy, mostly from ‘satisfactory’ to ‘good’ or from ‘good’ to ‘very good’

STUDY KEY POINTS Our “real world” experience, consistent with efficacy published results, confirm that Nab-paclitaxel is a valid chemotherapy option as second and further chemotherapy line in MBC, also for patients pretreated with taxane in the adjuvant and/or metastatic setting Both the 3-weekly and weekly schedules produced encouraging ORR, PFS and CB values, with globally manageable toxicities and good patient compliance in the outpatient setting, in women given long-term treatment too For clinicians, in the daily decision making, the chance of a flexible schedule of administration allows a better targeted therapeutic approach to each woman at the different points of her history, basing on both the disease-related factors and patient attitudes

NAB-PACLITAXEL REAL LIFE EXPERIENCES Ottawa Hospital cancer center Ontario 42 pts da giugmo 2006 a dicembre 2010 Weekly NAB 13.6 months and 10.8 months for q3w (p=0.03) 17.3. months for women achieving CB and 7.7 for non CB (p=0.001) British Columbia 132 pa (122 per analisi) dal 2007 al 2011 British Columbia CANADA No substantial difference in median TTF for the group with ptior taxane-exposure compared with the non-exposure group (96 days versus 73.5 days, p=0.58) Espeienz aIndian su 43 pz q3w Aigner J, Marmé F, Smetanay K, Schuetz F, Jaeger D, Schneeweiss A  Nab-Paclitaxel monotherapy as a treatment of patients with metastatic breast cancer in routine clinical practice. Anticaner Res 33(8): 3407-13, 2013 RK Singh, S Pankaj, S Kumar, V Rajkota A Retrospective Study of Efficacy and Safety of Albumin-Bound Paclitaxel in Metastatic Breast Cancer Worl J Oncol 5: 204-209, 2014

WHICH SCHEDULE FOR WHICH PATIENTS ? q3w Nab-Paclitaxel age <65 years DFI ≤24 months triple negative subtype predominant visceral disease qw Nab-Paclitaxel age ≥65 years <2 metastatic sites no visceral involvement ongoing trials investigating potentially predictive biomarkers of treatment response and disease outcome

THANK YOU Medical Oncology-San Gerardo Hospital, Monza Breast Unit, Brescia Medical Oncology-Luigi Sacco Hospital, Milano Medical Oncology-Papa Giovanni XXIII Hospital, Bergamo Medical Oncology-Legnano Hospital Medical Oncology-IRCCS San Matteo Hospital, Pavia Medicine and Oncology Unit-Vigevano Hospital, Pavia Medical Oncology-Falck, Ca’ Granda Hospital, Milano Deparmental Unit of Oncology-IRCCS Maugeri Foundation, Pavia