Dr. Tiffany Traina, medical oncologist at Memorial Sloan-Kettering Cancer Center, presents the latest research on metastatic breast cancer reported at the San Antonio Breast Cancer Symposium in December 2015.

1. Latest Research on Metastatic Breast
Cancer from San Antonio Breast
Cancer Symposium 2015 and beyond
Tiffany A.Traina, MD
Section Head,Triple Negative Breast Cancer Clinical Research Program
Associate Member, Breast Medicine Service, Department of Medicine
Memorial Sloan Kettering Cancer Center
Assistant Professor of Medicine, Weill Cornell Medicine

2. Topics of interest from SABCS 2015
• Neoadjuvant carboplatin
• IMMU-132
TNBC
• TH3RESA trialHER2+
• JAVELIN
• KEYNOTE
Immunotherapy
• ABCSG18
• CREATE-X
Other

3. Neoadjuvant platinum for
TNBC?

4. Why platinums inTNBC?
• Platinum activity in BRCA-
associated BC
– BRCA1 is a key mediator of DNA
damage response
– BRCA deficient cells have impaired
ability to repair damage
• 80% of BRCA1-associated BC areTN
• “BRCAness” ofTNBC
– SporadicTNBC have genomic
instability similar to BRCA1-associated
breast cancer
• High pCR rates inTNBC pilot trials
Wilson C A , et al Nat Genet 1999;21:236

5. GeparSixto:
Does carboplatin increase response?
von Minckwitz et al Lancet Oncology 2014 Jun; 15(7)
N = 315

6. Yes, Carboplatin increases pCR
pCR (ypT0N0)
von Minckwitz et al Lancet Oncology 2014 Jun; 15(7)

7. CALGB 40603: Does carboplatin increase pCR?
Sikov et al, J Clin Oncol 2015 Jan 1;33(1):13-21
Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4
Bevacizumab 10 mg/kg q2wks x 9
Bevacizumab 10 mg/kg q2wks x 9
CarboplatinAUC 6 q3wks x 4
CarboplatinAUC 6 q3wks x 4
Paclitaxel 80mg/m2 weekly x 12
Surgery
XRT
No Adjuvant
Systemic
Treatment
Planned
Paclitaxel 80 mg/m2 wkly x 12
Paclitaxel 80 mg/m2 wkly x 12
Paclitaxel 80 mg/m2 wkly x 12
ddAC x 4
ddAC x 4
ddAC x 4
N = 443
2 X 2
Randomization
Primary Endpoint: pCR Breast (ypT0/is N any)
Key
Eligibility
St II-III
ER/PR
<10%
HER2 (-)

8. N=212
Yes, Carboplatin increases pCR
46% (40-53%) 60% (54-66%)
Odds Ratio: 1.76
p = 0.0018
41% (35-48%) 54% (48-61%)
Odds ratio: 1.71
p = 0.0029

9. PaclitaxelddAC
Significant side effects limit tolerability
Slide courtesy of Bill Sikov; SABCS 2013

10. Von Minckwitz et al S2-04 SABCS 2015
Geparsixto: DFS improved with addition of
carboplatin
3 yr DFS:
76.1% vs.
85.8%
HR 0.59
P=0.03

11. Sikov et al S2-05 SABCS 2015
CALGB: Carboplatin did NOT improve breast
cancer related survival

12. CALGB: Carboplatin did NOT improve OS using a
conventional anthracycline, cyclophosphamide and
taxane containing regimen
Sikov et al S2-05 SABCS 2015

13. Why the discrepancy?
Challenge of pCR as a surrogate endpoint
Berry D and HudisC, JAMAOncology, July 2015
• Trials were not powered to show
survival advantage
• Statistically, need a very large
pCR difference to see a survival
advantage
Many unanswered questions re: the
role of platinum inTNBC
• Does the backbone regimen
matter?
• Does type of platinum matter?

14. For individual trials, no association between pCR
and survival benefit
Cortazar et al, Lancet July 2014

15. Is neoadjuvant platinum a new standard?
No, data fell short and uncertainty remains
• Await molecular/biomarker correlatives to narrowly select who
may benefit
– BRCA status
– Other markers of DNA repair problems (HRD)
• Carboplatin added to anthracycline/taxane reasonable when
the goal of pre-op therapy is to reduce tumor volume
• Would not routinely recommend platinum in the adjuvant
setting forTNBC based on these data

16. IMMU-132

17. Sacituzumab Govitecan (IMMU-132)
A next-generation irinotecan of interest inTNBC
• Trop-2 expressed in >90% ofTNBC
• IMMU-132 is a antibody-drug
conjugate of humanized anti-Trop-
2 coupled with SN-38, the active
metabolite of irinotecan
• Phase I/II ongoing
– N = 60 patients withTNBC
– ≥2 prior chemotherapy regimens;
median of 5 priors
– ORR = 31% (18/58);CBR24 = 45%
– Median PFS 6 months (95% CI: 4.1-
9.4mo)
– Most common side effects: low white
cells, diarrhea, fatigue, anemia
– Serious diarrhea 3% (relatively rare)
Bardia et al, Abstract #1016; ASCO 2015; SABCS 2015

18. FDA Assigns Sacituzumab Govitecan
Breakthrough Designation forTNBC!
February 8, 2016
"We believe breakthrough therapy designation for IMMU-
132 further validates this potential therapeutic for
patients withTNBC, and we are delighted to receive this
important recognition."
Cynthia L. Sullivan
President and CEO of Immunomedics
“The planned phase III trial of sacituzumab govitecan, on which Immunomedics is working
with the FDA, is a multicenter, international, randomized, open-label study that aims to accrue
328 patients with relapsed/refractory metastaticTNBC following ≥2 prior chemotherapies,
including a taxane.The primary outcome measure will be PFS, with secondary endpoints
includingOS,ORR, duration of response, and time to onset of response.”

19. HER2+ Breast Cancer

20. Hudis C. N Engl J Med 2007;357:39-51; Slamon et al NEJM 2001;
Targeting HER2 improves breast cancer
survival!

21. T-DM1
Average number DM1 molecules/monoclonal antibody=3.5
1. Beeram M., et al. J Clin Oncol. 2008;
26 (May 20 suppl; abstr 1028).

22. TDM1 vs.TPC in HER2+ MBC
Wildiers et al; SABCS 2015

23. TDM1 improves OS in HER2+ MBC
Wildiers et al; SABCS 2015

24. Immunotherapy

25. Immunotherapy rationale
• Normal part of
immune
regulation
• Antibodies
that block the
PD-1 pathway
can reactivate
T-cell activity
and
proliferation
• Leading to
enhanced
antitumour
immunity
Wolchok & Chan
Nature 2014
Pembrolizumab
Nivolumab
Atezolizumab

26. Immunotherapy forTNBC
TNBCs have high PD-L1
Early but encouraging results
Pembrolizumab (SABCS 2014)
• PD1 inhibitor. Blocks ability
of tumor to deactivate
immune system
• Small Phase 1 trial
• Responses in ~20% of
women with PD-L1+TNBC
• Well tolerated
Atezolizumab = MPDL3280A
(AACR 2015)
• PD-1 inhibitor
• Small Phase 1 trial
• Responses in ~20% of
patients
• Well tolerated

27. Many potential immunotherapy trials!
Pembrolizumab
1. Pembrolizumab +
capecitabine or paclitaxel
(PI Heather McArthur)
2. Pembrolizumab + eribulin
(industry)
3. Carboplatin +/- pembro
(TBCRC: PI Hope Rugo)
4. Pembro vs.TPC (Industry)
Atezolizumab (MPDL3280A )
• Carboplatin +/-
atezolizumab (TBCRC:
Vanderbilt)
• Nab-paclitaxel +/-
atezolizumab (Industry)

28. JAVELIN: Ph 1b of Avelumab in SolidTumors
Trial Design
• Fully humanized anti-PD1
antibody
• Expansion cohort MBC
– </= 3 lines of cytotoxic tx
– PriorT + A
– Unselected for PD-L1
expression or molecular
subtype
Patient Characteristics
• TNBC 35%
• ER+ 43%
• HER2+ 15%
• Median 3 regimens (0-10)
Dirix et al; SABCS 2015

29. JAVELIN:Toxicity
Dirix et al; SABCS 2015

30. Activity of avelumab in pts with MBC
Dirix et al; SABCS 2015

31. KEYNOTE: Pembrolizumab in PD-L1+ ER+ MBC
Pembrolizumab
• Anti-PD-L1 antibody
• Activity in PD-L1+TNBC
– ORR 19% (5/27; Nanda
SABCS 2014)
– 3/5 responders on drug >11m
• PD-L1 expression inversely
correlated with ER
expression
KEYNOTE-028
• Phase 1b multicohort trial
– ER+ HER2- MBC
– Failure of or inability to receive
standard therapy
– PD-L1+ (≥1% tumor or stroma)
– Measurable disease
• Pembrolizumab 10mg/kg q2
weeks until 8 week scan
– Confirmed POD after 4 weeks
– CR/PR/SD to 24mo or POD or
tox
Rugo et al; SABCS 2015

32. KEYNOTE-028
Pt Characteristics
• 19% (48) of 261 screened
were PD-L1+
• N=25 on study
– 44% had ≥5 prior lines
Rugo et al; SABCS 2015

33. ABCSG-18: A role for
“adjuvant” denosumab

34. ABCSG18: Background
• Adjuvant bisphosphonates have been associated with a significantly
reduced rate of breast cancer recurrence in bone and improved survival in
postmenopausal women with breast cancer[1]
• ABCSG18 trial: phase III trial of denosumab vs placebo in AI-treated
postmenopausal women with early HR+ breast cancer
– Primary analysis: significant reduction in fracture risk with denosumab vs
placebo[2]
• HR: 0.50 (95% CI: 0.39-0.65; P < .0001)
– IDMC recommended unblinding following results of primary analysis, with DFS
analysis to be completed before unblinding
• SABCS report from the ABCSG18 study includes the impact of
denosumab on DFS in postmenopausal pts with early HR+ breast cancer
on AIs[3]
1. EBCTCG, et al. Lancet. 2015;386:1353-1361.
2. Gnant M, et al. Lancet. 2015;386:433-443.
3. Gnant M, et al. SABCS 2015. Abstract S2-02.

35. ABCSG-18: Study Design
• Prospective, randomized, double-blind, placebo-controlled phase III trial
• Primary endpoint: time to first clinical fracture
• Secondary endpoints: % change in BMD, vertebral fractures, DFS, OS,
BoneM+FS, safety
Postmenopausal pts
with early HR+ breast
cancer receiving
adjuvant AI therapy*
(N = 3425)
Denosumab 60 mg SC Q6M
(n = 1711)
Placebo SC Q6M
(n = 1709)
Gnant M, et al. Lancet. 2015;386:433-443.
*Pts excluded if history of IV bisphosphonate, SERMS,Cushing’s disease, Paget’s disease, hypercalcemia,
hypocalcemia, hyperprolactinemia, or other active metabolic bone disease.

36. ABCSG-18: Disease-Free Survival
• ITT analysis consistent with sensitivity analysis in which pts switching to another bone-active treatment
were censored
– Hazard ratio, denosumab vs placebo: 0.807 (95% CI: 0.66-0.99; P = .0424)
Gnant M, et al. SABCS 2015. Abstract S2-02.
Impact of Denosumab vs Placebo on DFS (ITT)
100
90
80
70
60
0
Disease-FreeSurvival(%)
Mos Since Randomization
900 6 12 18 24 30 36 42 48 54 60 66 72 78 84
93.8%
88.9%
83.5%
92.6%
86.8%
80.4%
.0510Placebo
Denosumab
Number of
Events/Patients
HR (95% CI)
vs Placebo P value
203/1709
167/1711
0.816 (0.66-1.00)

37. Denosumab improves DFS when consider cross-over
Gnant et al; SABCS 2015

38. Indirect Comparison with EBCTCG, Lancet 2015

39. Denosumab data is consistent with EBCTG

40. 3% absolute reduction in breast cancer mortality in
post-menopausal women (18%)

41. CREATE-X: Ph III trial of
adjuvant capecitabine

42. Does capecitabine improve DFS after pre-op
chemo?
Lee S-J,Toi et al; SABCS 2015
Capecitabine 2,500 mg/m2/day po Day 1-14 in a 21-day cycle x6 cycles
** Safety interim analysis after N=50, IDMC recommended 8 cycles of tx

43. CREATE-XTrial Design
Statistics
• Primary endpoint 5y DFS
– Estimate 62% vs 70%
– HR 0.74, 2 sided alpha 5%
– 352 events expected from
900 pts
– Planned 1 interim analysis for
DFS at 2 years
Eligibility
• Age 20-74
• Stage I-IIIB
• HER2 negative
• Non-pCR and/or LN+ after
pre-operative
chemotherapy
• No prior oral 5-FU
Lee S-J,Toi et al; SABCS 2015

44. CREATE-X Results
Patient characteristics
• Med age 48y
• ~60% Premenopausal
• ~40% Stage III
• ~60% LN+
• ~63% ER+
• NeoadjTx Received
– A+T/AT 94%
– TC 1%
– 5-FU containing 60%
• Endocrine tx (67%) and
radiation (72%)
Capecitabine Compliance
• Reduced: 24-37%
• Discontinued: ~18-25%
≥Gr 3Tox Control Capecitabine
Neutropenia 1.6% 6.6%
Diarrhea 0.4% 3%
HFS 10.9%
Lee S-J,Toi et al; SABCS 2015

45. Capecitabine improves DFS/OS following pre-
operative chemotherapy
Lee S-J,Toi et al; SABCS 2015
5% improvement in overall survival!
Across all subsets
42% improvement ifTNBC

46. Exciting innovation and
technology…

47. Cutting edge technology to personalize cancer
treatment!

48. Clinical trial enrolling now at MSK…
Device Drugs
Lead PI:Traina. NCT# 02521363

49. ThankYou!