debu tripathy, md professor of medicine university of southern california norris comprehensive...
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Debu Tripathy, MDProfessor of MedicineUniversity of Southern CaliforniaNorris Comprehensive Cancer Center
Highlights from the San Antonio Breast Cancer Symposium:
Triple-Negative Breast Cancer
Key SABCS Abstracts on Triple Negative Breast Cancer
S5-01. CALGB 40603 -Addition of carboplatin to neoadjuvant weekly paclitaxel – impact on pCR
S1-06. GeparSixto: Impact of Carboplatin and Tumor infiltrating lymphocytes (TILs)
S1-01. TILs in TNBC: ECOG 2197 and 1199
S5-02. Veliparib/carboplatin plus standard neoadjuvant therapy in TNBC: Results from the I-SPY 2 TRIAL
P2-09-02. BMN 673 in BRCA-mutation-related breast cancer
S6-01. JAK2 in Residual TNBC
S4-03. Sequencing of TNBC metastases – novel genes of specific ontogeny and association with outcome
CALGB 40603: Neoadjuvant Paclitaxel ± Carboplatin ± Bevacizumab in TNBC
Sikov WM, et al. SABCS 2013, Abstract S5-01
Stage II-III TNBC
(N = 443)
Paclitax. 80 mg/m2 qw x 12
Paclitax. 80 mg/m2 qw x 12 Carbo AUC 6 q3w x 4
Paclitax. 80 mg/m2 qw x 12 Bevaciz. 10 mg/kg q2w x 9
Paclitax. 80 mg/m2 qw x 12
Carbo AUC 6 q3w x 4 Bevaciz. 10 mg/kg q2w x 9
dd ACX 4
Surgery +Radiation as
needed
Randomize
CALGB 40603: Neoadjuvant Paclitaxel ± Carboplatin ± Bevacizumab in TNBC
Sikov WM, et al. SABCS 2013, Abstract S5-01
CALGB 40603: Pathologic CR (ypT0/is N0)
pCR %No Carbo (N = 212)
Carbo (N = 221)
All(N = 433)
No Bev (N = 218) 39 49 44 OR = 1.36p = 0.057Bev (N = 215) 43 60 52
All (N = 433) 41 54
OR = 1.71; p = 0.0029Carbo/Bev interaction
p = .43
Sikov WM, et al. SABCS 2013, Abstract S5-01
*1 death due to uncontrolled hypertension.
CALGB 40603 – Serious Adverse Events
Chemo Chemo + Bev
Chemo + Carbo
Chemo + Carbo + Bev
N Evaluable
Total 15 39 29 46
FN during AC 5 15 10 17
Nausea/vomiting/dehydration 1 5 5 6
Bleeding 0 2 0 5
DVT or PE 1 6 1 4
Infection (normal ANC) 4 10 2 9
GI perforation 0 1 0 1
CALGB 40603: Take Home Points
• Carboplatin increases pCR rate
• Bevacizumab show trend toward better pCR rate
• No interaction between bevacizumab and carboplatin for efficacy
• Bev leads to more Grade III HTN, febrile neutropenia, bleeding, thrombus, surgical complications
• Carbo leads to more Gr III/IV neutropenia, thrombocytopenia and attenuates amount of paclitaxel delivered
• Long-term impact on DFS, OS not known
GeparSixto: Addition of Neo Adj Carboplatin
Von Minckwitz G, et al ASCO 2013, Abstract # 1004
GeparSixto: Carboplatin Impact on pCR
Von Minckwitz G, et al ASCO 2013, Abstract # 1004
Carboplatin Impact on pCR: HER+ vs. TNBC
Von Minckwitz G, et al ASCO 2013, Abstract # 1004
Incremental Improvements in TNBC pCR
Von Minckwitz G, et al ASCO 2013, Abstract # 1004
+ Bevacizumab
+ Platinum
pCR Rates: Based on Tumor-Infiltrating Lymphocytes (TILs)
All Patients Pdox PDoxCarbo0
10
20
30
40
50
60
70
80
4037
44
34 34 34
60
45
69
All CasesNo TILsTILs
pC
R R
ate
(%
)
Denkert C, et al. SABCS 2013, Abstract S1-06
P<0.005 P=0.09 P<0.005
GeparSixto: Impact of TILs for Carboplatin Neoadjuvant Tx for TN and HER2+ Early
Breast Cancer
Denkert C, et al. SABCS 2013, Abstract S1-06
Stromal TILs (per 10%) OR (95% CI) P Value Test for Interaction
All patients
PM 1.11 (1.00-1.22) .04 0.006
PM + carboplatin 1.35 (1.21-1.49) < .0005
Triple negative
PM 1.09 (0.96-1.25) NS 0.27
PM + carboplatin 1.22 (1.06-1.39) .004
HER2+
PM 1.13 (0.98-1.30) NS 0.007
PM + carboplatin 1.53 (1.29-1.82) < .0005
ECOG 2197 and 1199: Stromal TILs in Adjuvant Therapy for TNBC
Adams S, et al. SABCS 2013, Abstract S1-07
DF
S P
rob
abili
ty
DD
FS
Pro
bab
ility
OS
Pro
bab
ility
P=0.02
Years Years
P=0.05 P=0.03
sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80
sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80
sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80
Years
ECOG 2197 and 1199: sTILs in Adjuvant Therapy for TNBC
• Stromal TILs associated with better prognosis (DFS, DRFI, OS) after standard adjuvant therapy in TNBC (multivariate model)
– DFS HR: 0.84 (95% CI: 0.74-0.95; P = .005)
– DRFI HR: 0.81 (95% CI: 0.68-0.97; P = .02)
– OS HR: 0.79 (95% CI: 0.67-0.92; P = .003)
• For every 10% incremental gain of stromal TILs:
– 14% reduction of risk for recurrence/death (P = .02)
– 18% reduction of risk for distant recurrence (P = .04)
– 19% reduction of risk for death (P = .01)
Adams S, et al. SABCS 2013, Abstract S1-07
Paclitaxel + Trastuzumab* +
New Agent A
Paclitaxel + New Agent C
Eligible for NAC
Paclitaxel+ Trastuzumab
Paclitaxel + Trastuzumab* +
New Agent B
Paclitaxel
Paclitaxel + New Agent E
AC
ACHER 2 (+)
HER 2(–)
Randomize
Randomize
Surgery
Surgery
Learn and adapt from each patient
as we go along
Paclitaxel + New Agent F
Paclitaxel + Trastuzumab* +
New Agent C
Paclitaxel + New Agent DPaclitaxel +
New Agent GH
Paclitaxel + Trastuzumab* +
New Agent F
MRI
ResidualDisease(Pathology)
Key
I-SPY 2 TRIAL SchemaLearn, Drop, Graduate, and Replace Agents Over Time
Rugo H, et al. SABCS 2013, Abstract S5-02
Agent Overview
Drug Class Company Start Date
ABT-888 (Veliparib)
PARP Inhibitor Abbott March 2010
Neratinib (HKI-272)
Tyrosine Kinase Inhibitor
Puma/Pfizer March 2010
AMG 386 Vascular Disruptor Amgen October 2011
AMG 479 + Metformin
IGFR Inhibitor + Metformin
Amgen April 2012
MK2206 AKT Inhibitor Merck July 2012
Pertuzumab HER Dimerization Inhibitor
Genentech/Roche June 2013
T-DM1 + Pertuzumab
ADC: Trastuzumab + Mertansine
Genentech/Roche June 2013
Rugo H, et al. SABCS 2013, Abstract S5-02
I-SPY 2 Trial Adaptive Design
• Adaptive randomization– Uses a pre-specified and automated algorithm– Randomization probabilities update as study
proceeds» By signature, and based on MRI and pCR results
• Algorithm triggers the decision to “graduate” when 60-120 patients are enrolled
• 85% predicted likelihood of success in a randomized phase 3 neoadjuvant trial– N=300 patients– pCR is the endpoint
Rugo H, et al. SABCS 2013, Abstract S5-02
Veliparib/Carboplatin GRADUATES in the Triple Negative Signature
SIGNATURE
Estimated pCR Rate(95% probability interval) Probability
Veliparib +Carbo is
Superior to Control
Predictive Probability of
Success in Phase 3
Veliparib/Carbo
ConcurrentControl
All HER2- 33% (22-43%)
22% (10-35%)
92% 55%
HR+/HER2- 14% (4-27%)
19% (6-35%)
28% 9%
HR-/HER2- 52% (35-69%)
26% (11-40%) 99% 90%
Rugo H, et al. SABCS 2013, Abstract S5-02
SafetyConcurrent
ControlVeliparib/
Carboplatin
N 44 63
Hematologic, > grade 3 (%) 4.5 26.4
Febrile neutropenia 4.5 13.9
Neutropenia 11.4 37.5
Thrombocytopenia 0.0 15.3
Anemia 0.0 30.6
Gastrointestinal , all < grade 3 (%)
54.5 54.2
Stomatitis 6.8 12.5
Nausea 50 51.4
Vomiting 11.4 19.4
Diarrhea 9.1 25
Rugo H, et al. SABCS 2013, Abstract S5-02Paclitaxel dose reductions in 27%
Response to PARP Inhibitor BMN 673 Phase I Study
Mina LA, et al. SABCS 2013, Abstract P2-09-02
9/18 patients with TNBC
BMN 673 Update
• BMN 673 showed single-agent antitumor activity and favorable progression-free survival in BRCA-related advanced breast cancer
o 72% clinical benefit rate in in BRCA-related breast cancer
o 6% CR, 39% PR, 28% SD ≥ 24 wks
• Generally well tolerated, with common drug-related toxicities seen in < 30% of patients and include myelosuppression, fatigue, nausea, and alopecia
• Phase III trial of BMN 673 in combination with chemotherapy in patients with MBC and deleterious germline mutations of BRCA1 or 2 is ongoing and randomized trial compared to physicians choice is planned
Mina LA, et al. SABCS 2013, Abstract P2-09-02
Genomic Analysis of Residual TNBC After Neoadjuvant Therapy
Deep Sequencing(Foundation Medicine) for 182 oncogenes in 72 evaluable cases with enough “coverage”
JAK2 was novel and not seen in primary cases so far
Balko JM, et al. SABCS 2013, Abstract S6-1
JAK2 in TNBC• JAK2 is a receptor coupled TK that activates STAT
proliferation and differentiation pathway is involved in stem cell maintenance
• JAK2 mutations and amplification seen in TNBC, with amplification expansion seen upon treatment
• JAK2 amplification associated with worse survival in TNBC
• JAK2 inhibitor trials underway in breast cancer
Balko JM, et al. SABCS 2013, Abstract S6-1
Exome Sequencing of TNBC Metastases: Pathogenesis and Treatment Targets
Germline, Primary, Metastasis Comparisons
Blackwell K, et al. SABCS 2013, Abstract S4-03
Primary andMetastatic Mutations
N=331
Metastatic-specificN=31
ABCA12, ADAM18 ARGHAP21, BRWD3, CCDC84, DCHS2,DLEC1, DOCK5, DYNCH1,FANCM, GRIN2C, TP53,
MTOR, TRPM2,others
4/6 genes with PFS differenceinvolved in macromoleculemetabolism