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.

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 2017. Abstract. 1008. 2. Rugo H, et al. SABCS 2016. Abstract S5-07. 3. Nanda R, et al. ASCO 2017. Abstract 506. Slide credit: clinicaloptions.com

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 2017. Abstract 506. Reproduced with permission.

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 2017. Abstract 506.

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 (1.9-13.0) 3.95 (1.2-15.0) 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 2017. Abstract 506.

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 (0.34-0.58) 0.16 (0.06-0.27) > 99% 99% TNBC 0.60 (0.43-0.78) 0.20 (0.06-0.33) HR+/HER2– 0.34 (0.19-0.48) 0.13 (0.03-0.24) 88% HR, hormone receptor; pCR, pathologic CR; Pembro, pembrolizumab; TNBC, triple-negative breast cancer. Slide credit: clinicaloptions.com Nanda R, et al. ASCO 2017. Abstract 506.

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 2017. Abstract 506. Reproduced with permission.

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 2017. Abstract 506.

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 2017. Abstract 506.

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 2017. Abstract 506.

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