1. I-SPY 2: Addition of Pembrolizumab to Neoadjuvant Chemotherapy in HER2-Negative Early Breast Cancer
CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
*Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals
This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

2. I-SPY 2 Pembrolizumab Randomization: Background
Tumors use the inhibitory PD-1 pathway to avoid cellular immune surveillance mechanisms and evade detection
Pembrolizumab: humanized monoclonal anti–PD-1 antibody
Currently approved in melanoma, NSCLC, HNSCC, Hodgkin lymphoma, urothelial carcinoma, and all cancers with microsatellite instability-high or mismatch repair deficiency
Limited activity as monotherapy in heavily pretreated BC[1,2]
Current phase II adaptively-randomized I-SPY 2 trial investigated efficacy of addition of pembrolizumab to neoadjuvant T  AC in pts with high-risk EBC in effort to select regimens for future phase III study[3]
AC, doxorubicin/cyclophosphamide; BC, breast cancer; EBC, early breast cancer; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small-cell lung cancer; T, paclitaxel.
1. Adams S, et al. ASCO Abstract Rugo H, et al. SABCS Abstract S Nanda R, et al. ASCO Abstract 506.
Slide credit: clinicaloptions.com

3. I-SPY 2 Trial: Adaptive Randomization and “Graduation”
Adaptively randomized neoadjuvant trial with multiple concurrent arms (13 agents to date) to minimize number of patients needed to determine efficacy
Agent “graduates” if reaches 85% predicted probability of success in phase III trial
I-SPY 2 Eligibility
I-SPY 2 Adaptive Randomization
Assess
Eligibility
Screening
Consent
Core
Biopsy
Randomization
based on subtype
(HER2- signatures for
pembrolizumab arms)
New patient
accrues;
assess subtype
Outcome
MRI  pCR model
HR+, MP Low Risk
HER2+ (IHC, FISH, TargetPrint) TNBC
HR+, MP High Risk
HR, hormone receptor; MP, MammaPrint; pCR, pathologic CR.
Not
Eligible
Eligible
Update
probabilities
3 HER2– Signatures:
All HER2–
HR+/HER2–
TNBC
I-SPY 2 Low
Risk Registry
Randomized
Consented to Assigned Arm
Slide credit: clinicaloptions.com
Nanda R, et al. ASCO Abstract 506. Reproduced with permission.

4. I-SPY 2 Pembrolizumab Randomization: Study Design
Wk 12
Wk 20-24
Pembrolizumab 200 mg Q3W +
Paclitaxel 80 mg/m2 QW
(n = 69)
Pts with HER2– (either TNBC or HR+ high risk) EBC with tumor ≥ 2.5 cm who is a candidate for pre-op CT; PS 0-2
(N = 249)
4 cycles
Doxorubicin 60 mg/m2 Q3W +
Cyclophosphamide 600 mg/m2
(n = 270)
Surgery
Paclitaxel 80 mg/m2 QW
(n = 180)
CT, chemotherapy; HR, hormone receptor; pCR, pathologic CRPS, performance status; TNBC, triple-negative breast cancer.
Primary endpoint: pCR, no residual cancer in breast or lymph nodes (ypT0/is and ypN0)
Reported by Bayesian model that generates predictive probability of pCR rates
Reponses reported for HER2– “signatures”: all HER2– pts; pts with TNBC; pts with HR+/HER2–
Slide credit: clinicaloptions.com
Nanda R, et al. ASCO Abstract 506.

5. I-SPY 2 Pembrolizumab Randomization: Baseline Characteristics
Pembrolizumab + Paclitaxel (n = 69)
Paclitaxel
(n = 180)
Median age, yrs (range)
50 (27-71)
47 (22-77)
Race, %
White
Black
Asian
Other
81.2
8.7
4.3
5.8
76.7
14.4
7.2
1.7
HR+, %
58.0
52.8
Median tumor size, cm (range)
3.6 ( )
3.95 ( )
Nodal status, %
Positive
Negative
Missing data
37.7
52.2
10.1
43.9
50.5
5.6
HR, hormone receptor.
Slide credit: clinicaloptions.com
Nanda R, et al. ASCO Abstract 506.

6. I-SPY 2 Pembrolizumab Randomization: Prediction of pCR (Primary Endpoint)
I-SPY 2 uses Bayesian model to generate predictive probability of pCR rate by signature, actual pCR rates not reported
Pembrolizumab + paclitaxel predicted to be superior to paclitaxel alone in these populations
HER2– Signature
Estimated pCR Rate (95% CI)
Probability of Superiority of Pembro + Paclitaxel vs Paclitaxel Alone
Predictive Probability of Success With Pembro + Paclitaxel in Phase III Trial
Pembrolizumab + Paclitaxel
Paclitaxel Alone
All HER2–
0.46
( )
0.16
( )
> 99%
99%
TNBC
0.60
( )
0.20
( )
HR+/HER2–
0.34
( )
0.13
( )
88%
HR, hormone receptor; pCR, pathologic CR; Pembro, pembrolizumab; TNBC, triple-negative breast cancer.
Slide credit: clinicaloptions.com
Nanda R, et al. ASCO Abstract 506.

7. I-SPY 2 Pembrolizumab Randomization: pCR Probability Distributions by Signature
Curves represent probability distribution of pCR rate, where the midpoint of the curve is the estimated pCR
Separation of curves shows strength of probability, width of curve shows certainty
HER2-
HR-/HER2-
HR+/HER2-
Control: 13%
Control: 16%
Pembrolizumab: 46%
Control: 20%
Pembrolizumab: 34%
Pembrolizumab: 60%
pCR, pathologic CR; PI, probability interval; HR, hormone receptor.
0.2
0.4
0.6
0.8
1.0
0.2
0.4
0.6
0.8
1.0
0.2
0.4
0.6
0.8
1.0
pCR rate
pCR rate
pCR rate
95% PI: 6% - 27%
95% PI: 6% - 33%
95% PI: 3% - 24%
95% PI: 34% - 58%
95% PI: 43% - 78%
95% PI: 19% - 48%
Slide credit: clinicaloptions.com
Nanda R, et al. ASCO Abstract 506. Reproduced with permission.

8. Pembrolizumab + Paclitaxel
I-SPY 2 Pembrolizumab Randomization: Select Treatment-Related Adverse Events
Adverse Event, %*
Pembrolizumab + Paclitaxel
(n = 69)
Paclitaxel
(n = 180)
All Grades
Grades 3-5
Febrile neutropenia
7.2
6.7
Neutropenia
5.8
1.4
1.7
Anemia
27.5
4.3
18.9
3.9
Fatigue
79.7
81.1
0.6
Nausea
73.9
71.7
Vomiting
34.8
18.3
Diarrhea
49.3
37.8
2.2
Peripheral motor neuropathy
13.0
4.4
Peripheral sensory neuropathy
50.7
59.4
1.1
*Duration of surveillance: Start of treatment to 30 days after surgery or 60 days beyond treatment for those not undergoing surgery.
Slide credit: clinicaloptions.com
Nanda R, et al. ASCO Abstract 506.

9. Pembrolizumab + Paclitaxel
I-SPY 2 Pembrolizumab Randomization: Adverse Events of Special Interest
Adrenal insufficiency reported in 6 pts in pembrolizumab arm
≥ 3 cases secondary adrenal insufficiency, related to hypophysitis
1 case presented during pembrolizumab treatment; others presented > 10 wks beyond last dose of pembrolizumab
Presentation variable (nausea, vomiting, fatigue, weakness)
All pts on cortisol replacement therapy
Protocol amended to include serial morning cortisol level screening, in addition to serial thyroid function tests
Adverse Event, %
Pembrolizumab + Paclitaxel
(n = 69)
Paclitaxel
(n = 180)
All Grades
Grades 3-5
Hypothyroidism
8.7
1.4
0.6
Hyperthyroidism
4.3
Adrenal insufficiency*
7.2
Hepatitis
2.9
Pneumonitis
1.1
Colitis
Pruritus
24.6
11.1
*Primary or secondary.
Slide credit: clinicaloptions.com
Nanda R, et al. ASCO Abstract 506.

10. I-SPY 2 Pembrolizumab Randomization: Conclusions
Pembrolizumab “graduated” from I-SPY 2: pembrolizumab predicted to augment activity of paclitaxel in neoadjuvant T  AC for HER2– pts with EBC
Tripled estimated pCR rate in TNBC signature (60% vs 20%)
Near tripled estimated pCR rate in HR+/HER2– signature (34% vs 13%); first agent to graduate I-SPY 2 in HR+/HER2– tumors
More adrenal insufficiency with pembrolizumab + paclitaxel than in previous studies of pembrolizumab in advanced cancer
First report regarding the incidence and time course of immune-mediated toxicities in EBC
Additional experimental arm for I-SPY 2 with pembrolizumab continuing through anthracycline portion of neoadjuvant chemotherapy ongoing
AC, doxorubicin/cyclophosphamide; BC, breast cancer; EBC, early breast cancer; HR, hormone receptor; T, paclitaxel; TNBC, triple-negative breast cancer.
Slide credit: clinicaloptions.com
Nanda R, et al. ASCO Abstract 506.

11. Go Online for More CCO Coverage of ASCO 2017!
Short slideset summaries and additional CME-certified analyses with expert faculty commentary on key studies in:
Breast cancer
Gastrointestinal cancer
Genitourinary cancer
Gynecologic cancers
Hematologic malignancies
Lung cancer
Skin cancer
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