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Transcript of Rugo2012
ASCO 2012: Breast Cancer Updates
Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
UCSF Helen Diller Family Comprehensive Cancer Center
Outline• What’s new in the treatment of HER2 positive metastatic breast
cancer?– Emilia - TDM1 compared to lapatinib/capecitabine
• Blackwell et al, #LBA1
– MA.31 - Is lapatinib as good or better than trastuzumab? • Gelmon et al, #LBA671
– NSABP B-41 – lapatinib as neoadjuvant therapy• Robidoux et al, #LBA506
• Do bisphosphonates improve breast cancer outcome?– MA.27 – Impact of osteoporosis and osteoporosis therapy
• Sheperd et al, #501
– AZURE – impact in postmenopausal women• Marshal, Coleman et al, #502
Outline (2)• DCIS
– RTOG 9804 - does everyone with DCIS need radiation?• McCormick et al, #1004
• Evaluating chemotherapy combinations, doses– NSABP B-38 – adding gemcitabine, sequential versus
combination chemotherapy in early stage disease?• Swain et al, #LBA1000
– CALGB 40502 – comparing microtubule toxins in the metastatic setting
• Rugo et al, #CRA1002– What is the role of maintenance chemotherapy for patients with
metastatic disease?• Im et al, #1003
– Can we target the androgen receptor in TNBC?• Gucalp et al, #1006
HER2 Positive MBC
• The problem– Despite high response rates, almost all patients
eventually develop progressive disease
• How can we overcome resistance that we don’t understand?
• Data before pertuzumab and T-DM1:– Start with trastuzumab + chemotherapy/hormone rx– Continue HER2 directed therapy through progression
• Capecitabine/lapatinib > capecitabine (Geyer et al)• Capecitabine/trastuzumab > capecitabine (von Minckwitz et al)• Lapatinib/trastuzumab > lapatinib (Blackwell et al)
T-DM1: Dual Mechanisms of Action
Combined Targeted Therapy
Trastuzumab Biologic Activity
Targeted Intracellular Delivery of DM1a
• T-DM1 binds to the HER2 receptor and is internalized
• DM1 is released inside the cell, resulting in mitotic arrest and apoptosis
• Systemic toxicity is limited due to low HER2 expression in normal tissues
• Blocks downstream HER2 signaling to inhibit proliferation of tumor cells
• Flags HER2-positive tumor cells for destruction via antibody-dependent cell-mediated cytotoxicity
• Inhibits HER2 shedding
aDM1 is 25–500 fold more potent than taxane in cytotoxic assays.
T-DM1 selectively delivers DM1 to HER2-positive tumor cells
Receptor-T-DM1 complex is internalized into HER2-positive cancer cell
Potent antimicrotubule agent is released once inside the HER2-positivetumor cell
T-DM1 binds to the HER2 protein on cancer cells
• Targeted intracellular delivery of a potent antimicrotubule agent, DM1
• Spares normal tissue from toxicity of free DM1• Trastuzumab-like activity by binding to HER2HER2
• Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval
• Primary end points: PFS by investigator assessment, and safety
• Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover
• Key secondary end points: OS, ORR, DOR, CBR, and QOL
• Demographics imbalanced: 29 vs 34 % stage IV at diagnosis, 27 vs 18% exposed to prior trastuzumab, 40 vs 33% exposed to prior taxanes
Phase II Randomized International Open Label Studyb
1:1
HER2-positive, recurrent locally advanced breast cancer or MBC (N=137)First line setting
Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV
+ Docetaxel 75 or 100 mg/m2 q3w
(n=70)
Crossover toT-DM1 (optional)
PDa
T-DM13.6 mg/kg q3w IV
(n=67)PDa
aPatients were treated until PD or unacceptable toxicity.bThis was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred. Hurvitz et al, ESMO 2011
Time (months)Time (months)
PFS by Investigator P
rop
ort
ion
pro
gre
ssi
on
-fre
e P
rop
ort
ion
pro
gre
ssi
on
-fre
e
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 200 2 4 6 8 10 12 14 16 18 20
Number of patients at risk
T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0
Number of patients at risk
T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0
Hazard ratio and log-rank P value were from stratified analysis.
Trastuzumab + docetaxel (n=70)T-DM1 (n=67)
Trastuzumab + docetaxel (n=70)T-DM1 (n=67)
MedianPFS, mos
Hazard ratio 95% CI
Log-rank P value
9.214.2
0.594 0.364– 0.968
0.0353
Hurvitz SA, et al. Abstract 5.001. ESMO 2011.Hurvitz SA, et al. Abstract 5.001. ESMO 2011.
N=137
Crossover allowed to TDM1Significantly less toxicity with TDM1, better patient
reported outcomes
Clinical Rationale for EMILIA• T-DM1
– Two single-arm phase 2 trials in patients who received ≥1 HER2-directed therapies for MBC
– ORR: 25.9% (N=112)1 and 34.5% (N=110)2
• Capecitabine + lapatinib– Randomized phase 3 trial in patients who received prior
trastuzumab
– Median TTP longer with capecitabine + lapatinib (n=163) vs. capecitabine (n=161), no difference in OS
– 8.4 vs. 4.4 months (HR=0.49; P<0.001)4
1Burris HA, et al. J Clin Oncol 2011; 2Krop I, et al. J Clin Oncol 2012; 3Hurvitz S, et al. ESMO 2011; 4Geyer CE, et al. N Engl J Med 2006.
EMILIA Study Design
• Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease
• Primary end points: PFS by independent review, OS, and safety
• Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression
1:1
HER2+ (central) HER2+ (central) LABC or MBC LABC or MBC
(N=980)(N=980)
•Prior taxane and Prior taxane and trastuzumab trastuzumab
•Progression on Progression on metastatic tx or metastatic tx or within 6 mos of within 6 mos of adjuvant txadjuvant tx
PDT-DM1 3.6 mg/kg q3w IV
Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w
+ Lapatinib
1250 mg/day orally qd
PD
Blackwell et al, ASCO 2011
EMILIA - Demographics• 496 vs 495 randomized
• Median age 53, 27% from U.S.
• Prior therapy– All treated with prior taxane– 16% received prior trastuzumab for early stage
disease– 57% received at least one year of prior
trastuzumab, 88% prior treatment for MBC– 79% measurable disease, 53-57% HR+
Progression-Free Survival by Independent Review
496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0
495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0
Cap + Lap
T-DM1
No. at risk by independent review:
Median (mos) No. events
Cap + Lap 6.4 304
T-DM1 9.6 265
Stratified HR=0.650 (95% CI, 0.55, 0.77)
P<0.0001
Unstratified HR=0.66 (P<0.0001).
Subroup analysis:TDM1 superior regardless of line of therapy (1-3) and HR status
Objective Response Rate (ORR) and Duration of Response (DOR) in Patients with Measurable Disease
ORR DOR
Overview of Adverse Events
aCap + Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS; aT-DM1: metabolic encephalopathy.bEvaluable pts: 445 (Cap + Lap); 481 (T-DM1).
aCap + Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS; aT-DM1: metabolic encephalopathy.bEvaluable pts: 445 (Cap + Lap); 481 (T-DM1).
Cap + Lap (n=488)
T-DM1 (n=490)
All-grade AE, n (%) 477 (97.7) 470 (95.9)
Grade ≥3 AE, n (%) 278 (57.0) 200 (40.8)
AEs leading to treatment discontinuation (for any study drug), n (%)
52 (10.7) 29 (5.9)
AEs leading to death on treatment, n (%)a 5 (1.0) 1 (0.2)
LVEF <50% and ≥15-point decrease from baseline, %b
7 (1.6)
8 (1.7)
• Cap and Lap: More grade 3 diarrhea (21 vs 1.6%), hand foot syndrome (16 vs 0%)
• TDM1: More transaminiitis (4 vs 1%), grade 3/4 thrombocytopenia (13 vs 0%)
Summary and Ongoing Trials• T-DM1 superior to cap/lap
– PFS, interim OS, response, safety– Will clearly be a new standard in this setting– Approval expected towards the end of 2012
• Marianne (n=1092, untreated HER2+ MBC)– Three arms
• Trastuzumab + taxane• TDM1 + pertuzumab• TDM1 plus placebo
• Th3RESA (n=795)– Prior trastuzumab/lapatinib/anthra/taxane/cape– 2:1 randomization to TDM1 v TPC
Early Stage Trials• Post-neoadjuvant cooperative group• Neoadjuvant company sponsored• Adjuvant small tumors: ATTEMPT Trial
– Tolaney PI (DFCI)
Stage I BCHER2+N=500
Ra
nd
om
ize
3:1
Trastuzumab emtansine q 3 weeks x 17N=375
Paclitaxel + Trastuzumab weekly x 12 Trastuzumab every 3 weeks x 13
N=125
3
1
Two Questions• Can lapatinib overcome trastuzumab
resistance?– Doesn’t require externalized receptor– Can this agent overcome resistance mediated by
alterations of the PI3K pathway?
• Can dual targeting of the HER2 Receptor overcome resistance more effectively?– Maintains benefits of trastuzumab while targeting
the pathway through an alternate mechansim
1 2
Downstream signaling pathways
Cell proliferation Cell survival
21 1 2
TrastuzumabT
LapatinibL L L L L L
Primary Outcome: PFS
RandomizeMA.31/ EGF108919: Metastatic Disease
Sample Size: ~ 600 (536 centrally confirmed HER2+ patients) )
EXPERIMENTAL ARM
24 Weeks: Lapatinib
plus Taxane
Until PD:
Lapatinib
STANDARD ARM
24 Weeks: Trastuzumab
plus Taxane
Until PD:
Trastuzumab
Gelmon et al, LBA671, ASCO 2012
Median PFS TTAX/T= 13.7 monthsMedian PFS LTAX/L = 9.0 monthsHR = 1.48 (95% CI = 1.15 – 1.92), P = 0.003
Progression Free Survival Centrally-confirmed HER2+ Analysis
TTAX/TLTAX/L
TTAX/T LTAX/L
Serious Adverse Events
LTAX/L(Total SAE reports = 136)
TTAX/T(Total SAE reports = 78)
EVENT Total Number*
Number post amendment **
EVENT Total Number*
Number post amendment **
Diarrhea 32 25 Diarrhea 5 3
Febrile Neutropenia
17 7 Febrile Neutropenia
7 6
* Included as one of the adverse event terms within a single SAE report** ** Protocol Amendment after first 189 patients were randomized mandated
primary GCSF prophylaxis for patients on docetaxel and lapatinib
• Discontinuation rates significantly higher for lapatinib arm
Gelmon et al, LBA671, ASCO 2012
Neo-Altto(N=455)
Baselga J et al. Lancet 2012Untch M et al. Lancet Oncology 2012
GeparQuinto(N=615)
Pertuzumab + trastuzumab: improved pCR (NeoSphere, Tryphaena)
NSABP B-41 Schema (n=529)
Operable Breast Cancer HER-2 neu Positive
T > 2 cm
R
AC→ WP + T
AC→ WP + L1250
AC→ WP + T + L 750
SURGERY
Tissue for Biomarkers
Trastuzumab for a total of
1 year
Endpoints: pCR, cardiac events, DFS, OSWP: d 1, 8, 15 q 28 d x 4
WP=Weekly Paclitaxel
Tissue for Biomarkers
Robidoux et al, #LBA506
Results• pCR breast
– 53% (T) vs 53% (L)vs 62% (TL) (P 0.095 for TL vs T)
• pCR breast and nodes– 49% (T) vs 47% (L) vs 60% (TL) (p=0.056 TL vs T)
• pCR based on HER2 (IHC 3+, n=421, 81%)
– 55% (T) vs 53% (L) vs 71% (TL) (p=0.006 TL vs T)
• Completion of protocol defined neoadjuvant Rx– 78% (T) vs 68% (L) vs 63% (TL) (p=0.01)
• Toxicity similar except diarrhea and overall – Grade 3: 2% (T) vs 20% (L) vs 27% (TL) (p<0.001)
ALTTOS
urg
ery
1 year
Lapatinib
LapatinibTrastuzumab
Trastuzumab
Paclitaxel weekly or TCH
+/- Anthracycline
containingCT
Lapatinib Trastuzumab
Closed due to futility
Clinical Context• What does this data mean to our clinical practice?
– TDM-1 is a new and effective treatment for HER2+ metastatic disease progressing on trastuzumab
– Toxicities are unique but generally well tolerated
– Likely to be FDA approved by the end of the year
• Pertuzumab approved in the first-line setting in combination with trastuzumab/docetaxel (PFS 18.5 mo.)
• Lapatinib is associated with more toxicity and less efficacy than trastuzumab in the first-line metastatic setting
• Lapatinib/capecitabine is still an option for later line therapy or in special settings (low EF (?), brain metastases)
Pertuzumab/Trastuzumab/
Taxane
Pertuzumab/Trastuzumab TDM-1 Lapatinib/
Capecitabine?
Multiple drugs in clinical trials: inhibitors of mTOR, HSP90, TKs, vaccines
• Osteoporosis is characterized by decreased bone mineral density.
• The increased bone resorption associated with osteoporosis may provide fertile “soil” for cancer growth.
• Will osteoporosis or therapy for osteoporosis affect outcome in patients with early stage breast cancer?
OsteoporosisOsteoporosis
Observational Studies of Bisphosphonate Use and Breast Cancer Incidence
Author Study Design
Patient Cases (% bisphosphonate)
Control Subjects (%
bisphosphonate)
Breast Cancer
Association
Rennert Case-control
1822 (10.5%) 2207 (14.8%) OR 0.72 (0.57-0.90)
Newcomb Case-control
2336 (4.4%) 2975 (6.2%) OR 0.67 (0.51-0.89)
Chlebowski Cohort 154, 768 women, 2816 (1.8%) bisphosphonate users, 5,092 breast
cancer cases
HR 0.68 (0.52-0.88)
Rennert G, Pinchev M, Rennert HS JCO, 2010 June 12 Epub ahead of print Newcomb PA, Trentham-Dietz A, Hampton JM Bristish J of Cancer 2010;102:799-802 Chlebowski RT, Chen Z, Cauley JA, et al JCO 2010 June 12 Epub ahead of print
Shepherd LE et al, ASCO 2012, #501
• Osteoporosis: 17% (1294)• Osteoporosis therapy: 36% (2711)
– 116 (0.2%) took raloxifene prior to study
– 39 started after randomization
• Of those with osteoporosis– 85% (1101) took osteoporosis therapy
• Of those taking osteoporosis therapy– 25.6% (1610) did not report osteoporosis
Conclusions• Patients with self-reported osteoporosis and
osteoporosis therapy had a lower incidence of breast cancer relapse
• Patients receiving osteoporosis therapy, regardless of report of osteoporosis, had a lower incidence of relapse
• Limitations– Self reporting– Variations in osteoporosis therapy and duration– Event rate (9.2%) and distant relapse rate low
(4.1%)
Stephen Paget1855–1926
'While many researchers have been studying ‘the seed’, the properties of ‘the soil’ may reveal valuable insights into the ‘metastatic peculiarities’ in cancer cases.'
The Distribution of SecondaryGrowths in Cancer of the Breast.
The Lancet. 1889
The seed and soil hypothesis
AZURE: Study Design
Standard therapyStandard therapy
Standard therapy +Zoledronic acid 4 mgStandard therapy +
Zoledronic acid 4 mg
3,360 Breast Cancer
PatientsStage II/III
3,360 Breast Cancer
PatientsStage II/III
Zoledronic acid treatment duration 5 years
Accrual September 2003 - February 2006
RR
6 doses 8 doses 5 dosesQ3-4 weeks Q 3 months Q 6 months 6 doses 8 doses 5 dosesQ3-4 weeks Q 3 months Q 6 months
Months 6 30 60
Coleman et al. N Engl J Med 2011; 365:1396-1405
No difference in disease free or
invasive disease free survival (IDFS)
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.
AZURE: Invasive DFS and OS by Menopausal Status
0
Time From Randomization (Mos)
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
Pro
port
ion
Aliv
e an
d in
vasi
ve D
isea
se F
ree
IDFS: Pre, Peri, and Unknown Menopause
Adjusted HR: 1.15(95% CI: 0.97-1.36; P = .11)288 vs 256 events
Pts at Risk, nZOL:
No ZOL:1162 1088 996 919 829 393 57 0
1156 1092 995 920 853 388 47 0
0
Time From Randomization (Mos)
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
Pro
port
ion
Aliv
e
OS: Pre, Peri, and Unknown Menopause
Adjusted HR: 0.97(95% CI: 0.78-1.21; P = .81)161 vs 165 events
Pts at Risk, nZOL:
No ZOL:1162 1131 1078 1020 955 466 71 0
1156 1123 1076 1032 963 446 60 0
0
Time From Randomization (Mos)
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
Pro
port
ion
Aliv
e an
d in
vasi
ve D
isea
se F
ree
IDFS: > 5 Yrs Postmenopausal
Adjusted HR: 0.75(95% CI: 0.59-0.96; P = .02)116 vs 147 events
Pts at Risk, nZOL:
No ZOL:519 490 447 418 393 177 25 0
522 482 431 396 368 156 21 0
0
Time From Randomization (Mos)
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
Pro
port
ion
Aliv
e
OS: > 5 Yrs Postmenopausal
Adjusted HR: 0.74(95% CI: 0.55-0.98; P = .04)82 vs 111 events
Pts at Risk, nZOL:
No ZOL:519 502 482 448 422 190 29 0
522 509 475 441 401 177 26 0
N=2318 N=1041
Adjusted for imbalances in ER, lymph node status, and T stage.
HR: 0.70 (95% CI: 0.54-0.92)
HR: 1.32 (95% CI: 1.09-1.59)
Treatment Effects on First IDFS Recurrence Outside Bone by Menopausal Status
Odds Ratio
21 (heterogeneity) = 14.00; P = < .001
1.0 1.2 1.4 1.6 1.8 2.00.2 0.4 0.6 0.8
Pre, Peri and unknown menopause
> 5 yrs postmenopause
Menopausal Group
TOTAL: 6% +/- 8Z = .79, P = .43
No significant differences in bone recurrence by menopausal status or age
Conclusions• In this population of patients, primarily treated with adjuvant
chemotherapy– No effect of zoledronate on breast cancer outcome in the unselected overall
population– Suggestion of improved outcome in pts with >5 years of menopause, due to
recurrence outside bone• Unplanned subset analysis of interest but not sufficient to influence
patient care– Variable results in 7 published trials– Bisphosphonates should be used to prevent or treat bone loss in patients with
breast cancer– Bisphosphonates should not be used only for the purpose of preventing breast
cancer recurrence
• Ongoing studies are evaluating the impact of denosumab on breast cancer outcome in women with early stage disease– D-Care, ABCSG-18– UCSF phase II trial in pts with DTCs
RTOG 9804: Does Good Risk DCIS Always Need Radiation?• Common disease, low long-term risk
• Primary goal of treatment is to prevent invasive IBTR
• Clearly variable risk exist based on biology, age, extent of disease
• We have transitioned from mastectomy to lumpectomy and radiation with essentially equivalent outcomes– Does everyone need radiation?
McCormick et al, #1004
RTOG 9804: Eligibility and Schema
McCormick et al, #1004
No palpable mass, low or intermediate grade, < 2.5 cm, margins > 3 mm
Results at 5 years•Local failure in ipsilateral breast
• 3.2 vs 0.4%• HR 0.14, p=0.0022• 15 vs 2 events
•DFS• Identical• HR 0.84, p=0.48
N=585
Arm 1Observation ± tamoxifen,
20 mg per day for 5 years
Arm 2Radiation therapy to
the whole breast, ± tamoxifen, 20 mg per day for 5 years
Age1. < 502 ≥ 50Final Path Margins1. Negative (re-excision)2. 3-9 mm3. 10 mmMammographic/Pathologic Size of Primary1. ≤ 1 cm2. > 1 cm to ≤ 2.5 cm Nuclei Grade1. Low2. IntermediateTamoxifen Use1. No2. Yes
Summary
• In patients with good risk DCIS, the addition of radiation– Added little to local control– Added nothing to survival
• Use of genomic tests, such as the GH DCIS score, may help refine treatment decisions
• Longer follow-up of this trial will be interesting.
AC q 2 wk P q 2 wk
N+N+AC q 2 wk PG q2 wk
TAC q 3 wkAll arms pegfilgrastim or filgrastim
ER positive: hormonal therapy for 5 yrs after chemo
80% ER+65% 1-3+ nodes
NSABP B-38 Schema (n=4894, med FU 5.3 yrs)
Stratification: # nodes, HR status + or neg, Surgery and RT
Swain et al, LBA#1000P = paclitaxel 175 mg/m2G = gemcitabine 1000 mg/m2
# at risk1610 1532 1424 1331 1217 7191618 1554 1452 1348 1240 7541613 1533 1453 1350 1244 730
NSABP B-38 Disease-Free Survival
* Stratified log-rank test adjusting for randomization factors
Survival, Toxicity and Conclusions• Overall survival no different between arms• More deaths on treatment in the TAC arm than AC/P
or AC/PG (13/5/7, p=0.2)• Addition of gemcitabine did not improve outcome• DD AC/P similar to TAC
– More FN, anemia, diarrhea, less neuropathy with TAC
• This trial started in 2004 and completed accrual in 2007– About 10 years from initial planning to negative results– We can no longer do large trials testing therapy based
solely on extent of disease
- -
Control
Exp 11
Exp 2
N = 900 (planned)
Strata:Adj taxanesER/PR status
-
nab-paclitaxel 150 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks2
ixabepilone 16 mg/m2 weekly +bevacizumab 10 mg/kg q 2 wks3
Restage q 2 cycles until
disease progression
CALGB 40502 - NCCTG N063H - CTSU 40502An Open Label Phase III Trial of Firstline Therapy for Locally Recurrent or Metastatic Breast Cancer
• All chemotherapy was given on a 3 week on, one week off schedule• Patients could discontinue chemotherapy and continue
bevacizumab alone after 6 cycles if stable or responding disease
paclitaxel 90 mg/m2 weekly + bevacizumab 10 mg/kg q 2 wks1
1. Miller et al, N Engl J Med, 2007 2. Gradishar et al, J Clin Oncol, 2009 3. Dickson et al, Proc ASCO 2006.
Months From Study Entry
Pro
port
ion
Pro
gres
sion
-Fre
e
0 10 20 30
0.0
0.2
0.4
0.6
0.8
1
PacNabIxa
Comparison HR P-value 95% CI
nab vs. pac 1.19 0.12 0.96-1.49
ixa vs. pac 1.53 < 0.0001 1.24-1.90
CALGB 40502Progression-Free Survival By Treatment Arm
paclitaxelnab-paclitaxelixabepilone
Agent N Median PFS
paclitaxel 283 10.6
nab-Paclitaxel 271 9.2
ixabepilone 245 7.6
Months From Study Entry
Pro
port
ion
Aliv
e
0 10 20 30
0.0
0.2
0.4
0.6
0.8
1
PacNabIxa
CALGB 40502Overall Survival
Comparison
HR P-value 95% CI
nab vs. pac 1.02 0.92 0.75-1.38
ixa vs. pac 1.28 0.10 0.95-1.72
Agent N Median OS
paclitaxel 283 26
nab-paclitaxel 271 27
ixabepilone 245 21
Dose Reductions by Cycle 3
Cycle 2 Cycle 3
Dose reduction
Fre
quency (
%)
010
20
30
40
50
nab Pac Ixa nab Pac Ixa
Cycle 3
45%
15% 15%
ixanab pac
All Cause Cumulative Discontinuation by Cycle
Arm Grade 3+
nab (N = 258)
25%p=0.012
pac (N = 262)
16%
ixa (N = 237)
25%p=0.022
Sensory Neuropathy nab
(N = 258)pac
(N = 262)ixa
(N = 237)
Leukopenia 17% p = 0.0004
7% 3% p = 0.042
Neutropenia 47%p = 0.0001
18% 7%p = 0.0002
Hypertension 7% 8% 11%
Fatigue 16% p = 0.010
9% 15% p = 0.036
Pain 10%p = 0.010
4% 4%
Motor neuropathy
10%p = 0.0003
2% 6% p = 0.021
Other AEs – Grade 3+
Summary and interpretation• Neither weekly nab-paclitaxel or ixabepilone are
superior to weekly paclitaxel
• Weekly paclitaxel appears to offer better progression-free survival than ixabepilone
• Hematologic toxicity was greater with nab-paclitaxel; sensory neuropathy was greater in both experimental arms compared to paclitaxel
• Paclitaxel is a reasonable choice in a similar setting
• 100 mg/m2 is the most appropriate dose for weekly nab-paclitaxel
Study Design: Role of Maintenance Therapy
324 MBC patients with
no prior chemotherapy
PD
CR/PR/SDCR/PR/SD
Off the study
Observation till PD
till PD
6 cycles of PG
Stratification
1. Visceral diseases2. Prior adjuvant taxane3. Response(CR/PR vs. SD)4. HR(+) vs. HR(-)
RRPG regimenPaclitaxel 175 mg/m2 Day 1Gemcitabine 1,250 mg/m2 Day 1 & 8 every 3 weeks
Prospective, phase III, multi-center, randomized studyEnroll period: 2007.05 – 2010.09
Primary Endpoint; PFS from Randomization
Secondary Endpoints; OS, Toxicities, QoL, and Response Duration
Im et al, #1003
N=231
N=116
N=115
75% HR positive, ~20% received hormone therapy in the metastatic setting
• Subgroup analysis– Primary benefit in HR negative
(n=59), and in premenopausal women
• Toxicity– More toxicity in the maintenance
arm > cycle 6– QOL similar between the two arms
• Interpretation complicated by lack of use of hormone therapy in the control arm– This should not change our
general management of patients in this setting
– For hormone receptor negative disease, better to continue at least a low dose of chemotherapy
Other Interesting Data• Targeting the androgen receptor in ER/PR negative
disease (Gucalp et al, #1006, TBCRC)– 12% of screened patients were AR+– Treated with bicalutamide 150 mg/day
• 26 patients– Median age 66– 15% visceral metastases– Median 1 prior chemotherapy regimen for MBC
• 24% clinical benefit rate (5/24)– Disease in LN, breast and bone, one GI
• A larger trial is planned
Summary• New HER2 directed therapy provides increased efficacy
without significant toxicity– Adjuvant and neoadjuvant trials are ongoing or planned
• Zoledronate may improve outcome in subsets of women with early stage breast cancer and high bone turnover– This is not practice changing– The current recommendation is to use potent bisphosphonates to
treat osteoporosis, or osteopenia in high risk women
• Radiation appears to add little benefit to patients with low risk DCIS treated with BCT
Summary (2)• Early stage disease
– Gemcitabine does not add to DD AC/P but increases toxicity– Approach to clinical trials needs to change
• Its all about biology and understanding the drivers of disease
• Metastatic disease– Paclitaxel is the preferred microtubule targeting agent in 1st
line MBC– Maintenance chemotherapy may provide benefit, but this is
likely to be in HR negative or resistant disease– More studies targeting the androgen receptor are warranted
Phase 1b Study: all BCPLX3397 oral daily dosing
Eribulin: 1.4 mg/m2 iv, day 1 and 8Each cycle of treatment lasts 21 days
PLX3397 oral daily dosingEribulin: 1.4 mg/m2 iv, day 1 and 8
Each cycle of treatment lasts 21 days
First Cohort = 600 mg/day3-6 patients
First Cohort = 600 mg/day3-6 patients
Second Cohort = 800 mg/day3-6 patients
Second Cohort = 800 mg/day3-6 patients
Third Cohort = 1000 mg/day3-6 patients
Third Cohort = 1000 mg/day3-6 patients
Phase II Study: Metastatic TNBC
Lead in period of 5-7d with PLX3397 at MTD oral daily dosing (day -7/5 to day 0)
Phase II Study: Metastatic TNBC
Lead in period of 5-7d with PLX3397 at MTD oral daily dosing (day -7/5 to day 0)
Starting Day 1Add Eribulin 1.4 mg/m2 iv day 1 and 8Each cycle of treatment lasts 21 days
Starting Day 1Add Eribulin 1.4 mg/m2 iv day 1 and 8Each cycle of treatment lasts 21 days
Biopsy for immune profiling
Biopsy for immune profiling
PI: Hope S. Rugo, UCSF, Lisa Coussens, OHSU, Shelley Hwang, Duke. Clinical trial sites: UCSF, Vanderbilt (Mayer), Duke (Blackwell)
KOMEN Promise Grant:Can inhibition of
macrophages reverse chemotherapy resistance?
Phase II Primary Endpoint:PFS at 12 weeks