1. No category

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
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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
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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 Cristofanilli12
1Royal
Marsden Hospital, London, UK; 2National Cancer Center, Goyang-si, Korea; 3Institut Gustave Roussy, Villejuif,
France; 4Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 5Sunnybrook Odette Cancer Centre,
Toronto, Canada; 6Aichi Cancer Center Hospital, Nagoya, Japan; 7Brustzentrum der Universität München, München,
Germany; 8German Breast Group Forschungs GmbH, Neu-Isenburg, Germany; 9Pfizer Inc, New York City, USA; 10 Pfizer
La Jolla, USA; 11Pfizer Milan, Italy, 12Thomas Jefferson University, Philadelphia, PA, USA
Presented at ASCO 2015; June 1, 2015; Chicago, IL, USA
1. Juni 2015 PALOMA3 Study Design
n=347
•  HR+, HER2– ABC
•  Pre-/peri-* or post-menopausal
2:1 Randomization
•  Progressed on prior endocrine
therapy:
N=521
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
•  ≤1 prior chemotherapy regimen
for advanced cancer
*All received goserelin.
• 
Stratification:
●  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
Medikament
Spesifikasjon
Aromatasehemmer (AI)
Ikke aktuell ved kort
sykdomsfritt intervall etter
adjuvant AI.
Ikke førstevalg ved kort
sykdomsfritt intervall etter
adjuvant tamoxifen.3
Fulvestrant 500 mg/ dose1
Eksemestan + everolimus
Tamoxifen +
everolimus
Aromatasehemmer*
Behandlingslinje 2+3
Fulvestrant
(eller tamoxifen)
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
Kommentar
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)
Et av de behandlingsvalg som
ikke er benyttet tidligere
Megestrol Acetat
Behandlingslinje 4 og
videre
Østrogenbehandling
Hvis aktuelt, bør slik
behandling styres av
onkolog med
spesialkompetanse i
endokrin terapi.
MONALEESA-3 (CRibociclibF2301)
Study Design
Randomization 2:1
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
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
fulvestrant + ribociclib
(n~440)
Crossover not permitted
fulvestrant + placebo
(n~220)
One interim futility analysis; one interim efficacy analysis
Stratification :
-visceral disease
-prior hormonal therapy
Endpoints
•  Primary
•  PFS (Local
Read)
•  Secondary
•  OS
•  PFS (BIRC)
•  ORR
•  DOR
•  TTR
•  ECOG
•  QoL
•  Safety
•  PK profile
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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 S PTD (n=107) pertuzumab (840→420 mg) trastuzumab (8→6 mg/kg) docetaxel (75→100 mg/m2) PT (n=107) pertuzumab (840→420 mg) trastuzumab (8→6 mg/kg) PD (n=96) pertuzumab (840→420 mg) docetaxel (75→100 mg/m2) Study dosing: q3w x 4 U pCR, % ± 95% CI Pa@ents with operable or locally advanced/ inflammatory HER2-­‐posi@ve BC Chemo-­‐naive & primary tumors >2 cm (N=417) 60 R tpCR 30 20 10 45,8 29,0 39,3 24,0 21,5 80 70 60 50 40 30 20 10 0 16,8 PTD 11,2 PT 17,7 PD HR-­‐posi^ve HR-­‐nega^ve 63,2 5,9 36,8 26,0 20,0 TD HR, hormone receptor; HR-­‐posi@ve = estrogen and/or progesterone receptor-­‐posi@ve; HR-­‐nega@ve = estrogen and progesterone receptor-­‐nega@ve bpCR 40 TD E Y p = 0.003 50 G R p = 0.0141 0 bpCR, % ± 95% CI TD (n=107) trastuzumab (8→6 mg/kg) docetaxel (75→100 mg/m2) PTD 27,3 17,4 30,0 PT PD Gianni L, et al. Lancet Oncol 2012; 13:25–32 31 PFS, % PFS: all arms of therapy, ITT population
n at risk
TD
PTD
PT
PD
100 90 80 70 60 50 40 30 20 10 0 TD PTD 5-year PFS, %
(95% CI)
0 12 TD
PTD
PT
PD
n=107 n=107 n=107 n=96
81 (71– 86 (77– 73 (64– 73 (63–
87)
91)
81)
81)
24 36 48 PT PD 60 Months 107
107
107
96
101
99
93
85
89
94
86
76
83
88
80
72
78
86
77
69
58
63
55
57
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, % DFS: all arms of therapy, ITT population
n at risk
TD
PTD
PT
PD
100 90 80 70 60 50 40 30 20 10 0 TD PTD 5-year DFS, %
(95% CI)
0 12 TD
PTD
PT
PD
n=107 n=107 n=107 n=96
81 (72– 84 (72– 80 (70– 75 (64–
88)
91)
86)
83)
24 36 48 PT PD 60 Months 103
101
96
92
92
96
91
81
85
92
87
76
79
88
81
72
77
85
75
66
12
17
10
29
rves are truncated at 60 months (the end of scheduled follow-up). However, summary statistics shown here take into account all follow-up
ts 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, % PFS for tpCR and No tpCR by hormone receptor status, ITT popula^on – HR nega^ve tumors n at risk tpCR HR-­‐
nega^ve No tpCR HR-­‐
nega^ve 100 90 80 70 60 50 40 30 20 10 0 tpCR HR-­‐nega^ve 5-­‐year PFS, % (95% CI) HR (95% CI) 0 12 HR-­‐nega@ve No tpCR tpCR n=134 n=72 72 (64– 84 (72–
79) 91) 0.65 (0.32–1.30) 24 36 No tpCR HR-­‐nega^ve 48 60 Months 72 69 64 60 58 43 147 125 108 102 97 82 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, % PFS for tpCR and No tpCR by hormone receptor status, ITT popula^on – HR posi^ve tumors n at risk tpCR HR-­‐
posi^ve No tpCR HR-­‐
posi^ve 100 90 80 70 60 50 40 30 20 10 0 5-­‐year PFS, % (95% CI) HR (95% CI) 0 12 HR-­‐posi@ve No tpCR tpCR n=163 n=22 80 (73– 90 (67–
86) 98) 0.66 (0.15–2.79) 24 36 tpCR HR-­‐posi^ve No tpCR HR-­‐posi^ve 48 60 Months 22 22 19 19 18 12 175 161 153 142 137 96 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.
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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
Trastuzumab + docetaxel
•  HER2-positive (central) LABCa
or MBC
(8 mg/kg LD then 6 mg/kg + 100 or 75 mg/m2 q3w) OR
Trastuzumab + paclitaxel
(4 mg/kg LD then 2 mg/kg + 80 mg/m2 qw)
•  No prior chemotherapy for
LABC/MBC
•  >6 months from prior
neo-/adjuvant vinca alkaloid
or taxane chemotherapy
T-DM1 + placebob
(3.6 mg/kg + 840 mg LD then 420 mg q3w)
T-DM1 + pertuzumab
N = 1095
(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. aLocally progressive or recurrent and not amenable to resection with curative intent; bPertuzumab placebo.
Progression-Free Survival by IRF
Progression-Free Survival (%)
100
80
60
HT
T-DM1
T-DM1+P
Median PFS
(mo.)
13.7
14.1
15.2
Events (no.)
231
236
217
Stratified HR
(97.5% CI) vs
HT
—
0.91 (0.73–
1.13)
P=0.31
0.87 (0.69–
1.08)
P=0.14
—
0.91 (0.73–
1.13)
Stratified HR
(97.5% CI) vs
T-DM1
40
20
HT
T-DM1
T-DM1+P
0
0
6
12
18
24
30
Time (mo.)
36
42
48
365
367
363
265
257
261
163
176
177
107
133
135
75
104
109
21
28
25
5
3
5
1
No. at Risk
HT
T-DM1
T-DM1+P
Non-inferiority: Established if the upper limit of the 97.5% CI for the HR is below 1.1765 (non-inferiority margin).
50
67
75
54
Overall Survival (First Interim Analysis)
100
Survival (%)
80
60
40
20
HT
T-DM1
T-DM1+P
0
0
6
12
18
NR, not reached.
HT NR T-DM1 NR T-DM1+P NR 123
116
0.86
(0.64–
48
1.16) 115
0.82
(0.61–
54
1.11) — 42
Time (mo.)
No. at Risk
HT
T-DM1
T-DM1+P
24
Median OS
(mo.) Events (no.)
Stratified HR
(97.5% CI) vs
36
HT 30
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
Objective Response and Duration of Response by IRF
Objective Response Rate
Duration of Response
100
100
80
67.9%
59.7%
Patients, %
70
64.2%
60
50
40
Patients without progression, %
90
80
Median,
mo.
(95% CI) 60
20
20
12.5
(10.5–
16.6) 20.7
(14.8–
25.0) TDM1+P 21.2
(15.8–
29.3) HT
T-DM1
T-DM1+P
0
195/287
181/303
0
192/299
6
12
18
HT
T-DM1
Error bars depict 95% confidence intervals.
T-DM1+P
HT
T-DM1
T-DM1+P
24
30
36
42
5
14
11
1
Time (mo.)
No. at Risk
0
T-DM1 40
30
10
HT 195
181
192
150
150
162
81
110
118
55
85
92
37
65
75
24
35
44
1
48
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Maintenance of Health-Related Quality of Life
Presented By Paul Ellis at 2015 ASCO Annual Meeting
[TITLE]
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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.