State of the art Brystkre/ E1er ASCO 2015 Erik Wist

State of the art Brystkre/ E1er ASCO 2015 Erik Wist

Nyheter som berøres Nyheter som umiddelbart påvirker/endrer klinisk praksis I Norge Nyheter som kan lede til endringer i norsk klinisk praksis Nyheter som bekrefter norsk klinisk praksis Nyheter som gir økt innsikt

Nyheter som umiddelbart endrer norsk klinisk praksis

CALGB 70604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dosing of zoledronic acid in metastatic cancer Presented By Andrew Himelstein at 2015 ASCO Annual Meeting

Trial Schema Presented By Andrew Himelstein at 2015 ASCO Annual Meeting

No significant difference in time to SRE between ZA q 4 weeks vs. ZA q 12 weeks (p = 0.601) Presented By Andrew Himelstein at 2015 ASCO Annual Meeting

No significant differences in pain scores (p = 0.751) Presented By Andrew Himelstein at 2015 ASCO Annual Meeting

Conclusions Presented By Andrew Himelstein at 2015 ASCO Annual Meeting

Nyheter som kan lede til endringer i norsk klinisk praksis

Endokrin behandling av metastatisk brystkreft

CDK4/6-kinaser Vekst av HR positiv brystkreft er avhengig av cyclin dependent kinases CDK4/6, som promoterer G1-S fase cellecyklusprogresjon.

Abstract LBA502 A Double Blind Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and Post-menopausal Women With Hormone Receptor-positive, HER2-negative Advanced Breast Cancer That Progressed on Prior Endocrine Therapy (PALOMA3 Study) Nicholas Turner, 1 Jungsil Ro, 2 Fabrice André, 3 Sherene Loi, 4 Sunil Verma, 5 Hiroji Iwata, 6 Nadia Harbeck, 7 Sibylle Loibl, 8 Cynthia Huang Bartlett, 9 Ke Zhang, 10 Carla Giorgetti, 11 Sophia Randolph, 10 Maria Koehler, 9 Massimo Cristofanilli 12 1 Royal Marsden Hospital, London, UK; 2 National Cancer Center, Goyang-si, Korea; 3 Institut Gustave Roussy, Villejuif, France; 4 Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 5 Sunnybrook Odette Cancer Centre, Toronto, Canada; 6 Aichi Cancer Center Hospital, Nagoya, Japan; 7 Brustzentrum der Universität München, München, Germany; 8 German Breast Group Forschungs GmbH, Neu-Isenburg, Germany; 9 Pfizer Inc, New York City, USA; 10 Pfizer La Jolla, USA; 11 Pfizer Milan, Italy, 12 Thomas Jefferson University, Philadelphia, PA, USA Presented at ASCO 2015; June 1, 2015; Chicago, IL, USA

1. Juni 2015

PALOMA3 Study Design HR+, HER2 ABC Pre-/peri-* or post-menopausal Progressed on prior endocrine therapy: 2:1 Randomization N=521 n=347 Palbociclib (125 mg QD; 3 wks on/1 wk off) + Fulvestrant (500 mg IM q4w) On or within 12 mo adjuvant On therapy for ABC Stratification: 1 prior chemotherapy regimen for advanced cancer *All received goserelin. Visceral metastases Sensitivity to prior hormonal therapy Pre-/peri- vs Postmenopausal n=174 Placebo (3 wks on/ 1wk off) + Fulvestrant (500 mg IM q4w) Post-menopausal patients must have progressed on prior aromatase inhibitor therapy. administered on Days 1 and 15 of Cycle 1. Clinicaltrials.gov NCT01942135

CDK4/6 - hemmere Neutropeni Fulvestrant alene 3.5 % Fulvestrant + palbociclib 78.8 % Febril neutropeni Fulvestrant alene 0.6 % Fulvestrant + palbociclib 0.6 %

Behandlingslinje 1 Behandlingslinje 2+3 Medikament Spesifikasjon Kommentar Aromatasehemmer (AI) Fulvestrant 500 mg/ dose 1 Eksemestan + everolimus Tamoxifen + everolimus Aromatasehemmer* Fulvestrant (eller tamoxifen) Ikke aktuell ved kort sykdomsfritt intervall etter adjuvant AI. Ikke førstevalg ved kort sykdomsfritt intervall etter adjuvant tamoxifen. 3 Dersom tidligere progresjon på letrozol/anastrozol Dersom tidligere progresjon på AI og eksemestan ikke er aktuelt behandlingsvalg Dersom tidligere ikke benyttet eller kun en type AI er benyttet tidligere og everolimus ikke er ønsket behandling Dersom tidligere ikke benyttet 1 Effekten av fulvestrant oppfattes sammenlignbar med AI. Tamoxifen er et sekundært alternativ, men oppfattes å ha noe mindre effekt sammenlignet med AI Behandlingsvalg i 2. og 3. linje kan være avhengig av individuell vurdering av hva som vil være til nytte for den enkelte pasient (inkludert sykdomsstadium, forventet effekt og bivirkningsnivå) *Steroidal AI kan benyttes etter progresjon på nonsteroidal AI (eller motsatt) Behandlingslinje 4 og videre Et av de behandlingsvalg som ikke er benyttet tidligere Megestrol Acetat Østrogenbehandling Hvis aktuelt, bør slik behandling styres av onkolog med spesialkompetanse i endokrin terapi.

Study Design MONALEESA-3 (CRibociclibF2301) A Phase III, randomized, study of fulvestrant with or without ribociclib for the treatment of postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment for advanced disease Patient Population: Postmenopausal women HR+/HER2- advanced BC Treatment naive metastatic disease or after 1 prior hormonal treatment No prior chemotherapy for advanced disease (adj or neo-adj treatment allowed) Screening Randomization 2:1 fulvestrant + ribociclib (n~440) One interim futility analysis; one interim efficacy analysis Stratification : -visceral disease -prior hormonal therapy Crossover not permitted fulvestrant + placebo (n~220) Endpoints Primary PFS (Local Read) Secondary OS PFS (BIRC) ORR DOR TTR ECOG QoL Safety PK profile

Endokrin adjuvant behandling

St. Gallen 2015 More generally, the Panel considered that factors arguing for inclusion of OFS were age 35 or less; persisting premenopausal oestrogen level after adjuvant chemotherapy; or the involvement of 4 or more axillary nodes. and a large majority would use this with exemestane rather than tamoxifen

Bekymringer OFS i studien er ikke bare bruk av GnRH-agonist, men også oophorectomi (17 %) og RT av ovarier enten upfront eller senere (ikke kjent) Bekymring med goserelin og høy BMI Mye bivirkninger Høyt frafall i studien (22 % sluttet innen 4 år)

60 mg 2 ganger per år

L Gianni, T Pienkowski, Y-H Im, L-M Tseng, M-C Liu, A Lluch, <br />E Starosławska, J de la Haba-Rodriguez, S-A Im, JL Pedrini, B Poirier, <br />P Morandi, V Semiglazov, V Srimuninnimit, GV Bianchi, <br />V McNally, H Douthwaite, G Ross, P Valagussa Presented By Luca Gianni at 2015 ASCO Annual Meeting

NeoSphere: study design and pcr results p = 0.0198 Pa@ents with operable or locally advanced/ inflammatory HER2- posi@ve BC Chemo- naive & primary tumors >2 cm (N=417) TD (n=107) trastuzumab (8 6 mg/kg) docetaxel (75 100 mg/m 2 ) PTD (n=107) pertuzumab (840 420 mg) trastuzumab (8 6 mg/kg) docetaxel (75 100 mg/m 2 ) PT (n=107) pertuzumab (840 420 mg) trastuzumab (8 6 mg/kg) PD (n=96) pertuzumab (840 420 mg) docetaxel (75 100 mg/m 2 ) Study dosing: q3w x 4 S U R G E R Y pcr, % ± 95% CI bpcr, % ± 95% CI 60 50 40 30 20 10 0 80 70 60 50 40 30 20 10 0 p = 0.0141 p = 0.003 bpcr tpcr 45,8 39,3 29,0 21,5 24,0 16,8 11,2 17,7 TD PTD PT PD HR- posi^ve HR- nega^ve 63,2 36,8 5,9 20,0 26,0 27,3 30,0 17,4 TD PTD PT PD HR, hormone receptor; HR- posi@ve = estrogen and/or progesterone receptor- posi@ve; HR- nega@ve = estrogen and progesterone receptor- nega@ve Gianni L, et al. Lancet Oncol 2012; 13:25 32 31

PFS: all arms of therapy, ITT population PFS, % 100 90 80 70 60 50 40 30 20 10 0 TD PTD PT PD PT n=107 n=107 n=107 n=96 PD 5-year PFS, % (95% CI) 81 (71 87) 86 (77 91) 73 (64 81) 73 (63 81) 0 12 24 36 48 60 Months n at risk TD 107 101 89 83 78 58 PTD 107 99 94 88 86 63 PT 107 93 86 80 77 55 PD 96 85 76 72 69 57 TD PTD Kaplan Meier curves are truncated at 60 months (the end of scheduled follow-up). However, summary statistics shown here take into account all follow-up Three late events occurred with PTD: two cases of progressive disease (PD) at 63 and 71 months, and one death due to an unrelated cerebrovascular accident withou

DFS: all arms of therapy, ITT population DFS, % 100 90 80 70 60 50 40 30 PT 20 TD PTD PT PD n=107 n=107 n=107 n=96 PD 10 5-year DFS, % 81 (72 84 (72 80 (70 75 (64 0 (95% CI) 88) 91) 86) 83) 0 12 24 36 48 60 Months n at risk TD 103 92 85 79 77 12 PTD 101 96 92 88 85 17 PT 96 91 87 81 75 10 PD 92 81 76 72 66 29 TD PTD ves are truncated at 60 months (the end of scheduled follow-up). However, summary statistics shown here take into account all follow-up s occurred with PTD: one case of PD at 67 months, and one death due to an unrelated cerebrovascular accident without PD at 72 months

PFS for tpcr and No tpcr by hormone receptor status, ITT popula^on HR nega^ve tumors PFS, % n at risk tpcr HR- nega^ve No tpcr HR- nega^ve 100 90 80 70 60 50 40 30 20 10 0 HR- nega@ve No tpcr tpcr n=134 n=72 5- year PFS, % (95% CI) 72 (64 79) 84 (72 91) HR (95% CI) 0.65 (0.32 1.30) 0 12 24 36 48 60 Months 72 69 64 60 58 43 147 125 108 102 97 82 tpcr HR- nega^ve No tpcr HR- nega^ve Kaplan Meier curves are truncated at 60 months (the end of scheduled follow- up). However, summary sta@s@cs shown here take into account all follow- up One late event occurred in the tpcr HR- nega@ve group, a death due to an unrelated cerebrovascular accident without PD at 76 months 34

PFS for tpcr and No tpcr by hormone receptor status, ITT popula^on HR posi^ve tumors PFS, % n at risk tpcr HR- posi^ve No tpcr HR- posi^ve 100 90 80 70 60 50 40 30 20 10 0 HR- posi@ve No tpcr tpcr n=163 n=22 5- year PFS, % (95% CI) 80 (73 86) 90 (67 98) HR (95% CI) 0.66 (0.15 2.79) 0 12 24 36 48 60 Months 22 22 19 19 18 12 175 161 153 142 137 96 tpcr HR- posi^ve No tpcr HR- posi^ve Kaplan Meier curves are truncated at 60 months (the end of scheduled follow- up). However, summary sta@s@cs shown here take into account all follow- up. One late event occurred in the tpcr HR- nega@ve group, a death due to an unrelated cerebrovascular accident without PD at 76 months; two late events in the No tpcr HR- posi@ve group due to PD at 63 and 71 months 35

Conclusion Presented By Luca Gianni at 2015 ASCO Annual Meeting 36

CONCLUSIONS Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy.

Nyheter som bekrefter norsk klinisk praksis

Phase III, randomized study of trastuzumab emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study Presented By Paul Ellis at 2015 ASCO Annual Meeting

MARIANNE Study Design HER2-positive (central) LABC a or MBC No prior chemotherapy for LABC/MBC >6 months from prior neo-/adjuvant vinca alkaloid or taxane chemotherapy N = 1095 Trastuzumab + docetaxel (8 mg/kg LD then 6 mg/kg + 100 or 75 mg/m 2 q3w) OR Trastuzumab + paclitaxel (4 mg/kg LD then 2 mg/kg + 80 mg/m 2 qw) T-DM1 + placebo b (3.6 mg/kg + 840 mg LD then 420 mg q3w) T-DM1 + pertuzumab (3.6 mg/kg + 840 mg LD then 420 mg q3w) Stratification factors: World region, Prior neo-/adjuvant therapy (if Yes: prior trastuzumab/lapatinib), Visceral disease Primary end point: PFS by independent review facility (IRF), non-inferiority and superiority assessed Key secondary end points: OS, PFS by investigator, ORR, Safety, Patient-reported outcomes LD, Loading dose. a Locally progressive or recurrent and not amenable to resection with curative intent; b Pertuzumab placebo.

Progression-Free Survival by IRF HT T-DM1 T-DM1+P 100 Median PFS (mo.) 13.7 14.1 15.2 Events (no.) 231 236 217 Progression-Free Survival (%) 80 60 40 20 HT T-DM1 T-DM1+P Stratified HR (97.5% CI) vs HT Stratified HR (97.5% CI) vs T-DM1 0.91 (0.73 1.13) P=0.31 0.87 (0.69 1.08) P=0.14 0.91 (0.73 1.13) No. at Risk 0 0 6 12 18 24 30 36 42 48 54 Time (mo.) HT T-DM1 T-DM1+P 365 367 363 265 257 261 163 176 177 107 133 135 75 104 109 50 67 75 21 28 25 5 3 5 1 Non-inferiority: Established if the upper limit of the 97.5% CI for the HR is below 1.1765 (non-inferiority margin).

Overall Survival (First Interim Analysis) 100 80 Survival (%) No. at Risk 60 40 20 0 HT T-DM1 T-DM1+P Median OS (mo.) 0 6 12 18 24 30 36 42 48 54 Time (mo.) HT T-DM1 T-DM1+P NR NR NR Events (no.) 123 116 115 Stratified HR (97.5% CI) vs HT 0.86 (0.64 1.16) 0.82 (0.61 1.11) HT T-DM1 T-DM1+P 365 367 363 335 345 341 303 321 309 273 291 282 250 263 257 218 224 231 98 104 106 25 37 28 1 3 1 NR, not reached.

Objective Response and Duration of Response by IRF 100 Objective Response Rate 100 Duration of Response Patients, % 90 80 70 60 50 40 30 67.9% 59.7% 64.2% Patients without progression, % 80 60 40 20 HT T-DM1 T-DM1+P Median, mo. (95% CI) HT 12.5 (10.5 16.6) T-DM1 20.7 (14.8 25.0) T- DM1+P 21.2 (15.8 29.3) 20 0 10 0 195/287 181/303 192/299 HT T-DM1 T-DM1+P No. at Risk HT T-DM1 T-DM1+P 0 6 12 18 24 30 36 42 48 54 195 181 192 150 150 162 81 110 118 55 85 92 Time (mo.) 37 65 75 24 35 44 5 14 11 1 1 Error bars depict 95% confidence intervals.

Maintenance of Health-Related Quality of Life Presented By Paul Ellis at 2015 ASCO Annual Meeting

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Nyheter som gir økt innsikt

Kjemohjerne

Chemotherapy-related cognitive impairment (CRCI), and neurotransmitter signaling, longevity, and inflammation pathways in 366 breast cancer (BC) patients and 366 agematched cancer-free controls: A prospective, nationwide, longitudinal URCC NCORP study.

This is the largest longitudinal study showing significant CRCI amongbc patients receiving CT compared to cancerfree controls. CRCI in BC patients is influenced by neurotransmitter signaling and longevity genes and leads to increased inflammation.