Highlights from the San Antonio Breast Cancer Symposium: Triple-Negative Breast Cancer

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 EvaluableTotal 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

pCR

Rat

e (%

)

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

DFS

Pro

babi

lity

DD

FS P

roba

bilit

y

OS

Prob

abili

ty

P=0.02

Years Years

P=0.05 P=0.03sTIL=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 OverviewDrug 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 30.6Gastrointestinal , 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 cancero 72% clinical benefit rate in in BRCA-related breast cancero 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