The Neoadjuvant Model as a Translational Tool for Drug and Biomarker Development in Breast Cancer

The Neoadjuvant Model as a Translational Tool for Drug and Biomarker Development in Breast Cancer Laura Spring, MD Breast Medical Oncology Massachusetts General Hospital Primary Mentor: Dr. Aditya Bardia

Disclosures Consulting: Novartis Institutional Research funding: Tesaro Non-CME Speaker: DAVA Oncology CME Speaker: Clinical Care Options

Outline Neoadjuvant therapy background - Indications - Goals - Comparisons to adjuvant therapy - Concept of pathologic complete response The neoadjuvant model for drug and biomarker development - Upfront predictions of response - Early measures of response - Optimal outcomes/endpoints

Indications for Neoadjuvant Therapy Absolute Inflammatory breast cancer Other T4 tumors N2 or N3 disease Relative Large tumor/breast ratio in patient desiring breast conserving therapy (BCT) Reduce extent of axillary surgery in node positive patients Can consider whenever you can already determine what the adjuvant systemic therapy plan would be prior to surgery NCCN V. 2.2016; King TA & Morrow M, Nat Rev Clin Oncol 2015; 12:335 343

Typical Treatment Sequences Adjuvant treatment Surgery Chemotherapy +/- Radiation therapy +/- Endocrine therapy Neoadjuvant treatment Chemotherapy Surgery +/- Radiation therapy +/- Endocrine Therapy

Goals of Adjuvant Therapy Goal is to improve survival by treating occult micrometastatic disease Key Considerations: Underlying risk of recurrence Absolute benefits Co-morbid conditions Side effects of treatment Patient preferences Tumor biology A blind procedure?

Goals of Neoadjuvant Therapy Provide systemic therapy to reduce risk of systemic relapse At least equivalent to adjuvant therapy, but started earlier Downstage tumor to help breast surgery Increase rate of breast conserving surgery Convert inoperable/locally advanced to operable Smaller, less deforming lumpectomy Decrease extent of axillary surgery Allow monitoring of tumor response Facilitate clinical investigations and novel drug development: can be much smaller, shorter, and less expensive than adjuvant trials Improve risk assessment: Surrogate for long-term outcomes Tailor therapy to individuals: Response directed therapy (escalation/de-escalation strategies)

Adjuvant vs. Neoadjuvant: Which approach is better? Fisher B, et al. JCO 1997; 15: 2483-93

Wolmark N, et al. J Natl Cancer Inst Monogr 2001; 96 102 NSABP B-18 Results

NSABP B-18 Results Postop chemo Preop chemo Fisher B, et al. JCO 1997; 15: 2483-93

The Role of pcr: Definition Matters reported in the literature: ypt0 ypn0. No invasive or noninvasive residual in breast or nodes. Used by the German study groups (German Breast Group [GBG] and Arbeitsgemeinschaft Gynäkologische Onkologie Breast Group [AGO-B]) as part of the Sinn score. 10 ypt0/is ypn0. No invasive residual in breast or nodes; noninvasive breast residuals allowed. Used by MD Anderson Cancer Center, Austrian Breast and Colorectal Cancer Study Group, and Neo Breast International Group. 6,11,12 ypt0/is ypn0/. No invasive residual in the breast; noninvasive breast residuals and infiltrated lymph nodes allowed. Used by National Surgical Adjuvant Breast and Bowel Project. 5,13 ypt 1mic ypn0/. No gross invasive residuals in the breast; focal invasive and noninvasive residuals in breast and infiltrated lymph nodes allowed. Used by French groups using the Sataloff index. 7 Therefore, to compare the impact of the components of the definition on Acceptable: ypt0/is ypn0 or ypt0 ypn0 B Proportion Surviving E 1.0 0.8 0.6 0.4 0.2 Log-rank P <.001 ypt0 ypn0 (n = 955) yptis ypn0 (n = 309) ypt0/is ypn+ (n = 186) ypt1mic ypn+/- (n = 478) ypt > 1mic ypn+/- (n = 4,449) 0 25 50 75 100 125 Overall Survival (months) von Minckwitz G, et al. JCO 2012; 30:1796 1804

Role of Pathologic Complete Response: Surrogate Endpoint Cortazar P, et al. Lancet 2014; 384:164 172

Role of Pathologic Complete Response Meta-analysis Initial results >18K patients Role of adjuvant therapy: pcr associated with improved longterm outcomes whether or not adjuvant chemotherapy received Updated results of >27K patients with individual patient level data obtained using plot digitizer software to be presented at SABCS (oral abstract 12/5/18 general session) Spring L, et al. AACR 2016, Clin Cancer Res 2016;76(14 Suppl): Abstract #1439

Role of pcr: Young Women Disease-free survival among women 40 and under who received neoadjuvant chemotherapy for breast cancer at MGH 5-year DFS pcr: 91% Residual disease: 60% Spring L, et al. JNCCN 2017; 15:1216 1223

Neoadjuvant Model Who? Early measure of response? Optimal outcome? Compared to adjuvant trials: Smaller 100s not 1000s of patients Faster Endpoint in months not years Better for biomarkers Ease of obtaining tissue and blood Timely response data Baseline Eligible Women Scheduled to Undergo Surgery for Stage II-III Breast ca Baseline Biopsy Baseline Scans R 2 Weeks Novel Therapy No therapy Week 2 Biopsy 12 Weeks Surgery Novel therapy + standard regimen Standard Regimen Blood for Biomarkers such as Circulating Tumor Cells, ctdna Definitive Surgery (Lumpectomy or Mastectomy) Bardia, et al. Targeted Therapies in Breast Cancer. 2012. Modified from Bardia A, et al. Targeted Therapies in Breast Cancer, 2012

Neoadjuvant Model Who? Baseline 2 Weeks 12 Weeks Surgery Eligible Women Scheduled to Undergo Surgery for Stage II-III Breast ca R Novel Therapy No therapy Novel therapy + standard regimen Standard Regimen Definitive Surgery (Lumpectomy or Mastectomy) Baseline Biopsy Baseline Scans Week 2 Biopsy Blood for Biomarkers such as Circulating Tumor Cells, ctdna Bardia, et al. Targeted Therapies in Breast Cancer. 2012. Modified from Bardia A, et al. Targeted Therapies in Breast Cancer, 2012

ER+ BC: Neoadjuvant Endocrine Therapy vs. Neoadjuvant Chemotherapy Meta-analysis studying randomized trials involving NET NET vs. chemotherapy analysis: N = 378; duration 12-24 weeks Response rates (clinical, radiologic, pathologic) and rates of BCT with neoadjuvant chemotherapy vs. endocrine therapy are similar for the appropriate patient population Less toxicity with NET compared to chemotherapy Spring L, et al. JAMA Onc 2016; 2:1477 1486

Predicting Response to Neoadjuvant Therapy TransNEOS: Validation of the Oncotype DX Breast Recurrence Score test on core needle biopsy samples from NEOS as predictor of clinical response to neoadjuvant endocrine therapy for postmenopausal ER+, HER2-negative breast cancer patients. 70% 60% 50% 40% 54% 45% 42% 55% 61% CR + PR SD PD NEOS study: 904 postmenopausal women with T1c-T2, N0 ER+/HER2- breast cancer treated with 24-28 weeks of neoadjuvant letrozole For the patients included in the TransNEOS study (N=294), 53% had RS <18, 29% 18-30, and 18% had RS 31 30% 20% 10% 0% 22% 17% 1% 4% RS < 18 RS 18-30 RS 31 Remaining questions: - Ability to apply to N+? - Would turnaround time on testing be an issue? - Could novel agents improve endocrine sensitivity of patients with high scores? Iwata et al. SABCS 2017 (PD5-03)

Neoadjuvant Model Early measure of response? Baseline 2 Weeks 12 Weeks Surgery Eligible Women Scheduled to Undergo Surgery for Stage II-III Breast ca R Novel Therapy No therapy Novel therapy + standard regimen Standard Regimen Definitive Surgery (Lumpectomy or Mastectomy) Baseline Biopsy Baseline Scans Week 2 Biopsy Blood for Biomarkers such as Circulating Tumor Cells, ctdna Bardia, et al. Targeted Therapies in Breast Cancer. 2012. Modified from Bardia A, et al. Targeted Therapies in Breast Cancer, 2012

On-treatment Ki67 Predicts Endocrine Sensitivity and Relapse Risk IMPACT Trial ER+ Stage 2/3 N = 158 Anastrozole x 12 weeks Combination x 12 weeks Tamoxifen x 12 weeks S U R G E R Y RFS according to Ki67 Expression at 2 Weeks IMPACT: In a multivariable analysis, higher Ki67 expression after 2 weeks of endocrine therapy was associated with lower RFS (p =.004) while higher Ki67 expression at baseline was not. Dowsett M, et al. JNCI 2007; 99:167 170

Elevated CTC Score during Neoadjuvant Treatment Predicts Residual Disease 54 neoadjuvant breast cancer patients at MGH were assessed for CTCs during therapy using a 17-gene digital RNA signature of CTCs developed in the Haber Lab The baseline CTC score was positive in 43% of patients Patients with high CTC scores at cycle 3 or later were significantly more likely to have residual disease Kwan T, Bardia A, Spring LM, et al. Cancer Discov 2018; 8(10); 1-14

Neoadjuvant Model Optimal outcome? Baseline 2 Weeks 12 Weeks Surgery Eligible Women Scheduled to Undergo Surgery for Stage II-III Breast ca R Novel Therapy No therapy Novel therapy + standard regimen Standard Regimen Definitive Surgery (Lumpectomy or Mastectomy) Baseline Biopsy Baseline Scans Week 2 Biopsy Blood for Biomarkers such as Circulating Tumor Cells, ctdna Bardia, et al. Targeted Therapies in Breast Cancer. 2012. Modified from Bardia A, et al. Targeted Therapies in Breast Cancer, 2012

Alternative Surrogate Outcome Measures to pcr: RCB

Symmans WF, et al. JCO 2017; 10: 1049-1060 Residual Cancer Burden

Leveraging Residual Disease: The CREATE-X Trial Masuda N, et al. NEJM 2017; 376:2147 2159 5-yr DFS: 74.1% vs. 67.6%, HR 0.7 (p=0.01) **TNBC: 69.8% vs. 56.1%, HR 0.58; HR+ HR = 0.84 5-yr OS: 89.2% vs. 83.6%, HR 0.59 (p=0.01) **TNBC: 78.8% vs. 70.3%, HR 0.52

Conclusions Adjuvant = neoadjuvant in terms of long-term outcomes, but many additional benefits with neoadjuvant approach Achievement of pcr is highly prognostic on a patient level, especially for TNBC and HER2+ breast cancer Upfront use of genomic assays such as Oncotype may help identify appropriate candidates for neoadjuvant chemotherapy among patients with ER+ breast cancer pcr rates are too low in ER+ breast cancer to serve as a primary outcome for clinical trials, and other options such as the RCB score are more suitable The neoadjuvant model provides an efficient trial design for assessment of novel therapies and the identification of predictive and prognostic biomarkers, including circulating biomarkers

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