Karcinom dojke. PANEL: Semir Bešlija, Zdenka Gojković, Robert Šeparović, Tajana Silovski

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1 Karcinom dojke PANEL: Semir Bešlija, Zdenka Gojković, Robert Šeparović, Tajana Silovski

2 MBC: HER2

3 PHEREXA: Study Design Multicenter, randomized, open-label phase III trial Stratified by prior CNS disease, measurable/nonmeasurable disease, response to first-line trastuzumab Pts with HER2 MBC who have received Tmab and a taxane and progressed during/after Tmabbased therapy (N = 452) Pertuzumab* 42 mg IV Q3W Trastuzumab 6 mg/kg IV Q3W Capecitabine 1 mg/m 2 PO BID for 14d Q3W (n = 228) Trastuzumab 6 mg/kg IV Q3W Capecitabine 125 mg/m 2 PO BID for 14d Q3W (n = 224) *Loading dose: 84 mg IV. Loading dose: 8 mg/kg IV. Treated until PD or unacceptable toxicity Primary endpoint: PFS by independent review Secondary endpoints: OS, PFS by investigator, TTP, TTF, ORR, CBR, DoR, biomarkers, safety Urruticoechea A, et al. ASCO 216. Abstract 54.

4 PHEREXA: Survival PFS (%) PFS (IRF) Median PFS, Mos Cape Tmab Pmab 11.1 Cape Tmab 9. HR:.82 (95% CI: ; P =.7) OS (%) OS Median OS, Mos Cape Tmab Pmab 36.1 Cape Tmab 28.1 HR:.68 (95% CI:.51-.9)* Mos Mos Arm A Arm B Arm A Arm B *Statistical significance cannot be claimed because of hierarchical testing of OS after PFS by IRF assessment. Urruticoechea A, et al. ASCO 216. Abstract 54. Reproduced with permission.

5 PHEREXA: Next Anticancer Therapies Subsequent Treatment in 1% of Pts,* % Pmab Tmab Capecitabine (n = 228) Tmab Capecitabine (n = 218) 1 systemic treatment TKIs (eg, lapatinib) Monoclonal antibodies Tmab Pmab Other Antimetabolites 33 3 Vinca alkaloids Antineoplastic agents T-DM Cytotoxic antibiotics 19 2 Taxanes Alkylating agents Aromatase inhibitors Platinum compounds 12 1 *Additional agents included antiestrogens, angiogenesis inhibitors, topoisomerase inhibitors, gonadotropin and analogues, and sex hormones. Urruticoechea A, et al. ASCO 216. Abstract < 3

6 PHEREXA: Safety Overview AE, % Pmab Tmab Capecitabine (n = 228) Tmab Capecitabine (n = 218) Any AE Grade 3 AE 52 6 Serious AE AE leading to discontinuation of any tx AE leading to capecitabine dose modification AE resulting in death < 1* 1 *Due to general deterioration in physical health (n = 1). Due to cardiac arrest (n = 1), subarachnoid hemorrhage (n = 1). Urruticoechea A, et al. ASCO 216. Abstract 54.

7 PHEREXA: Adverse Events AE,* % Pmab Tmab Capecitabine (n = 228) Tmab Capecitabine (n = 218) All Grades Grade 3 All Grades Grade 3 Diarrhea Nausea Hand foot syndrome Rash 15 5 < 1 Nasopharyngitis 11 6 Neutropenia Insomnia 1 < 1 6 *Occurring in 1% of pts in either arm, with a 5% difference between arms. Urruticoechea A, et al. ASCO 216. Abstract 54.

8 PHEREXA: Cardiac Safety Cardiac Event, n (%) Pmab Tmab Capecitabine (n = 228) All symptomatic LVSD considered possibly related to study treatment 5/5 pts received anthracyclines; 4/5 pts had cardiac medical history; 3/5 pts received chest radiotherapy 3/5 pts had BL LVEF < 5% Tmab Capecitabine (n = 218) LVSD 17 (7) 7 (3) Symptomatic LVSD* NYHA Class II NYHA Class III NYHA Class IV 5 (2) 3 (1) 1 (< 1) 1 (< 1) Asymptomatic LVSD 15 (7) 7 (3) *Symptomatic congestive heart failure and LVEF drop. Asymptomatic LVEF drop 1% below BL and value < 5%, or asymptomatic LVEF drop requiring tx or leading to discontinuation. At clinical cutoff, 4 cases had resolved, 1 resolving but lost to follow-up Urruticoechea A, et al. ASCO 216. Abstract 54.

9 PHEREXA: Conclusions Addition of pertuzumab to trastuzumab capecitabine in HER2 MBC pts progressing during/after trastuzumab: Does not significantly improve PFS, as assessed by IRF Increases median OS by 8 mos; statistical significance could not be claimed due to hierarchical test of OS after primary endpoint (PFS by IRF) No new safety signals observed Urruticoechea A, et al. ASCO 216. Abstract 54.

10 MBC: Hormone Receptor

11 PALOMA-2: Study Design Multicenter, international, double-blind, randomized phase III trial Stratified by disease site (visceral vs nonvisceral), disease-free interval (de novo metastatic; 12 mos vs > 12 mos), prior neoadjuvant or adjuvant hormonal therapy (yes vs no) Postmenopausal women with ER/HER2- advanced breast cancer, no prior treatment for advanced disease, no Al resistance (N = 666) Palbociclib 125 mg QD (3/1 schedule) Letrozole 2.5 mg QD (n = 444) Placebo (3/1 schedule) Letrozole 2.5 mg QD (n = 222) Primary endpoint: PFS by investigator Secondary endpoints: response, OS, safety, biomarkers, pt-reported outcomes Finn R, et al. ASCO 216. Abstract 57.

12 PALOMA-2: PFS Outcome Palbociclib Letrozole (n = 444) Investigator-assessed Number of events, n (%) Median PFS, mos (95% CI) Blinded independent central review Number of events, n (%) Median PFS, mos (95% CI) 194 (44) 24.8 (22.1-NR) 152 (34) 3.5 (27.4-NR) Placebo Letrozole (n = 222) 137 (62) 14.7 ( ) 96 (43) 19.3 ( ) HR (95% CI; P Value).58 ( ; <.1).65 ( ;.5) Blinded independent central review confirmed investigator-assessed PFS advantage Benefit with palbociclib letrozole evident across all subgroups Finn R, et al. ASCO 216. Abstract 57.

13 PALOMA-2: Secondary Endpoints Outcome [1] Palbociclib Letrozole ITT population ORR,* % (95% CI) CBR, % (95% CI) Pts with measurable disease ORR,* % (95% CI) CBR, % (95% CI) n = ( ) 85 ( ) n = ( ) 84 (8.-88.) *Confirmed CR PR. Confirmed CR PR SD 24 wks. Placebo Letrozole n = ( ) 7 ( ) n = ( ) 71 ( ) OR (95% CI) 1.4 ( ) 2.39 ( ) 1.55 ( ) 2.23 ( ) P Value.31 < Clinical benefit consistent with phase II open-label PALOMA-1 study [2] 1. Finn R, et al. ASCO 216. Abstract Finn RS, et al. Lancet Oncol. 214;16:25-35.

14 PALOMA-2: Safety AEs (All Causality), % Palbociclib Letrozole (n = 444) Placebo Letrozole (n = 222) Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any AE Hematologic AE in 15% of pts in either arm Neutropenia* < 1 Leukopenia* Anemia* 24 5 < Thrombocytopenia* 16 1 < 1 1 Nonhematologic AE in 25% of pts in either arm Fatigue < 1 Nausea 35 < Arthralgia Alopecia Diarrhea Cough Headache 21 < Hot flash *Includes clustered MedDRA preferred terms. Finn R, et al. ASCO 216. Abstract 57.

15 PALOMA-2: AE Summary Outcome, % Palbociclib Letrozole (n = 444) Most AEs resulting in d/c reported as single events, most commonly neutropenia with palbociclib (1.6%) or fatigue with placebo (.9%) 1 on-study, treatment-related death because of pulmonary embolism/respiratory failure in placebo arm Placebo Letrozole (n = 222) Serious AE Serious AE occurring in 1% of pts Febrile neutropenia Pulmonary embolism AE-related d/c AE-related death Finn R, et al. ASCO 216. Abstract 57.

16 PALOMA-2: Conclusions First-line palbociclib letrozole significantly improved median PFS vs placebo letrozole in women with ER/HER2- advanced breast cancer Median PFS improved by > 1 mos compared with placebo 24.8 vs 14.5 mos, HR:.58 (95% CI: ; P <.1) Palbociclib clinical benefit observed in all prespecified subgroups Palbociclib well tolerated with neutropenia, leukopenia the most frequently reported AEs PALOMA-2[1] data confirm PALOMA-1 [2] results and constitute the longest median PFS improvement to date in the frontline setting in advanced ER breast cancer 1. Finn R, et al. ASCO 216. Abstract Finn RS, et al. Lancet Oncol. 215;16:25-35.

17 MBC: TNBC

18 Atezolizumab Nab-Paclitaxel in Metastatic TNBC: Phase Ib Study Design GP28328: a multicenter, multicohort phase Ib study; arm F includes pts with TNBC (metastatic or unresectable, locally advanced) [1,2] Pts with TNBC 2 previous systemic cytotoxics, ECOG PS /1, no CNS cancer or untreated/active CNS metastases, available tumor sample Atezolizumab Nab-paclitaxel Safety Cohort (n = 8) Primary endpoint: safety and tolerability B Atezolizumab Nab-paclitaxel - Cycle 1, Day 1 Cycle 2, Day 1 Cycle 3, Day 1 Serial Biopsy Cohort B B B (n = 24) Cycle 1, Day 1 Cycle 2, Day 1 Cycle 3, Day 1 (Wks) Atezolizumab (8 mg) nab-paclitaxel (125 mg/m 2 ), as long as clinical benefit received; nab-paclitaxel for at least 4 cycles, unless disease progression or unacceptable toxicity; if discontinued, atezolizumab as monotherapy Secondary endpoints: response per RECIST v1.1 (ORR, DoR, PFS) and immunemodified response criteria; pharmacokinetics; biomarker analyses 1. Adams S, et al. ASCO 216. Abstract ClinicalTrials.gov. NCT

19 Atezolizumab Nab-Paclitaxel in mtnbc: Safety and Tolerability (Primary Endpoint) Median safety follow-up: 6.1 mos (range: ) Median duration of exposure: 5.4 mos (range: -17) for atezolizumab; 4.2 mos (range: -12) for nab-paclitaxel No reported deaths were related to study treatment Treatment-Related AE (Grade 3/4 AEs Occurring in 1% of Pts), % Pts (N = 32) All Grades Grade 3 All 1 69 Neutropenia/decreased neutrophil count Thrombocytopenia and decreased platelet count 16 9 Diarrhea 41 6 Anemia 22 6 Decreased white blood cell count 9 6 Adams S, et al. ASCO 216. Abstract 19.

20 Atezolizumab Nab-Paclitaxel in mtnbc: Safety and Tolerability (Primary Endpoint) Atezolizumab-Related AE (Any Grade AE in 1% of Pts), % Pts (N = 32) All Grades Grade 3 Fatigue Neutropenia/decreased neutrophil count 28 9 Pyrexia Diarrhea 19 3 Peripheral neuropathy/peripheral sensory neuropathy Nausea Alopecia Headache Pruritus Additional atezolizumab-related grade 3/4 AEs: syncope, type 1 diabetes mellitus, anemia, thrombocytopenia/platelet count decreased (n = 3), febrile neutropenia, AST increased, white blood cells decreased, and pneumonia mycoplasmal (n = 1 except where indicated) Adams S, et al. ASCO 216. Abstract 19.

21 Atezolizumab Nab-Paclitaxel in mtnbc: Efficacy (Secondary Endpoints) Best Overall Response (RECIST v1.1) First Line (n = 13) Second Line (n = 9) Third Line (n = 1) Among 12 responders, 6 (5%) remain on atezolizumab; 1 for > 17 mos Median DoR not reached; PFS and OS data not yet mature All (N = 32) Confirmed ORR, % (95% CI) 46 (19-75) 22 (3-6) 4 (12-74) 38 (21-56) CR, % 8 3 PR, % SD, % PD, % Missing or not estimable, % 11 3 Median DoR, mos (range) NE (2.9 to 11.5) NE (9.1 to 13.1) NE (1.9 to 5.6) Responses observed in pts regardless of PD-L1 expression level; trend toward increase in baseline TILs for responding pts Adams S, et al. ASCO 216. Abstract 19.

22 Atezolizumab Nab-Paclitaxel in Metastatic TNBC: Conclusions Atezolizumab nab-paclitaxel well tolerated and active in metastatic TNBC [1] Safety profile similar to that of single agents Durable responses achieved across all lines of therapy Clinical response seen regardless of PD-L1 expression Ongoing phase III randomized trial evaluating this combination in previously untreated metastatic TNBC [2] 1. Adams S, et al. ASCO 216. Abstract ClinicalTrials.gov. NCT

23 MBC: Surgical Resection

24 MF7-1: Study Design Multicenter phase III trial Treatment-naive pts with de novo stage IV breast cancer amenable for complete resection (N = 274) Local Resection of Breast ± Axilla (n = 138) Systemic Therapy (n = 136) Systemic Therapy Local Therapy for Local Progression Primary endpoint: OS Secondary endpoints: morbidity and mortality, locoregional progression/relapse, QoL Soran A, et al. ASCO 216. Abstract 15.

25 MF7-1: Additional Methods BCS or mastectomy at preference of treating physician and pt Must achieve free surgical margins Whole-breast radiation therapy for all BCS; for mastectomy, based on institutional practice Axillary clearance in pts with proven metastases SoC systemic therapy administered immediately after randomization (systemic therapy arm) or after primary resection (surgery arm) Metastatic site biopsy, treatment at discretion of treating physician Soran A, et al. ASCO 216. Abstract 15.

26 MF7-1: OS Survival Local Surgery (n = 138) Systemic Therapy (n = 136) HR (95% CI) Surgery improved median survival by 9 mos P Value 3-yr survival, % yr survival, % Median OS, mos ( ).5 Soran A, et al. ASCO 216. Abstract 15.

27 MF7-1: OS by Pt Subgroups 5-Yr Survival, % Median OS, Mos Subgroup Surgery ST P Value Surgery ST P Value ER/PR (n = 218) HER2/neu- (n = 189) < 55 yrs of age (n = 159) Bone only metastasis (n = 126) Solitary bone metastasis (n = 53) Multiple pulmonary/liver metastases (n = 28) No locoregional progression/relapse (n = 257) *3-yr survival Locoregional progression/relapse: surgery, 1% (n = 2); systemic therapy, 11% (n = 15); P =.1 Soran A, et al. ASCO 216. Abstract * 67*

28 MF7-1: Conclusions 3-yr survival similar with or without primary breast tumor resection With longer follow-up, significant improvement in 5-yr and median OS in surgery arm vs systemic therapy alone Significant OS benefit with initial surgery in pts with ER/PgR, HER2/neu-, solitary bone metastasis, and those younger than 55 yrs of age Pts with multiple liver/pulmonary metastases experienced worse OS with initial surgery Incidence of locoregional progression 11-fold higher in initial systemic therapy group Soran A, et al. ASCO 216. Abstract 15.

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