NeoadjuvantTreatment In BC When, How, Who?

NeoadjuvantTreatment In BC When, How, Who? Clifford Hudis, M.D. Chief, Breast Cancer Medicine Service, MSKCC Professor of Medicine, Weill Cornell Medical College President, ASCO 15

Potential Benefits Of Pre-Operative Treatment 1. Early treatment improves DFS/OS? 2. Tailor therapy based on in-breast response? 3. Local control by converting inoperable to operable? 4. Minimize local surgery by converting MRM to Breast Conservation? 5. Clinical research (To obtain paired specimens or sequential imaging or others)?

Overall, DFS/OS: Pre = Post Operative AC NSABP B-18 N= S 747 S 759 Fisher et al, JCO 1997 15:2483

Response as Surrogate For DFS in B-18 % 100 80 60 40 20 0 Year pcr (88 pts.) pinv (159 pts.) cpr (295 pts.) cnr (140 pts.) P=0.00005 0 1 2 3 4 5 6 7 8 100 80 60 40 20 0 %

However, response is not known when choosing pre-op therapy, so the group soutcome is not changed! Surgery: 40 LN + Systemic CRx 85%DFS 60 LN - 100 pts Systemic CRx Surgery: 80 <CR 85%DFS 20 CR

Potential Of Pre-Operative Chemotherapy 1. Early treatment improves DFS/OS? 2. Tailor therapy based on in-breast response? 3. Local control by converting inoperable to operable? 4. Minimize local surgery by converting MRM to Breast Conservation? 5. Clinical research (To obtain paired specimens or sequential imaging or others)?

The only way earlier therapy would improve DFS/OS would be if we could tailor treatment based on response.

..can we?

Aberdeen Pre-Op Trial Smith, I. C. et al. J Clin Oncol; 20:1456-1466 2002

Summary CR CVAP x 4 NO RESPONSE Docetaxel x 4 RESPONSE CVAP x 4 Docetaxel x 4 11% 33% 56% Smith, I. C. et al. J Clin Oncol; 20:1456-1466 2002

Gepartrio: Schema NX NX Vinorelbine Capecitabine Core biopsy: uni/bilateral ct2-4 cn0-3 size 2 cm* NC Ultrasound R TAC TAC x 6 TAC Docetaxel Adriamycin Cyclophosph. +G-CSF CR/ PR R TAC x 8 *Excluding low risk (T2 + ER/PR pos. + cno + G1/2 + > 35y.) von Minckwitz, et al. San Antonio, 2005 # 38

GEPAR-TRIO Clinical Response Assessed after 2 cycles and Eventual Rates of pcr Response @ Cycle 2 Eventual pcr CR 40% PR 20% NC 5% PD 0% Von Minckwitz, NCI, 2007

GEPAR-TRIO Outcomes among patients with no tumor change after 2 cycles Treatment NX x 4 TAC x 4 No. randomized 303 324 No. reported 233 242 RR clinical 67% 72% RR ultrasound 64% 60% BCS 60% 58% pcr 5.9% 5.3% No differences were statistically significant Von Minckwitz, SABCS 2005

Response Guided Therapy Might Improve DFS* * In subgroups (esp ER+), if confirmed prospectively. von Minckwitz et al, JCO 2013 doi: 10.1200/JCO.2012.45.0940 October 10, 2013 vol. 31 no. 29 3623-3630

Overall, DFS/OS: Pre = Post Operative AC NSABP B-18 N= Lumpectomy S 747 Increased 12% S 759 Fisher et al, JCO 1997 15:2483

NSABP B27 Surgery 767 T1-3, N0-1 ACX4 768 Docetaxel Surgery 776 Surgery Docetaxel Bear et al. J Clin Oncol 24:2019-2027. 2006

Outcomes (pcr, BCT) pcr w/ w/out DCIS 26% Surgery Groups 1,3 Group 2 13% 14% Planned Lumpectomy 48%,49% 51% 9 18 10 Actual Lumpectomy 61.6% 63.7% No statistical difference in OS, DFS, RFS Bear et al. J Clin Oncol 24:2019-2027. 2006

Beware: Off-Study Pre-op Therapy Can Raise Unanswerable Questions: 3.5 cm tumor, 7 (+) LN s MRM/LE AxLND - AC->T q2 - XRT AC->T q2 MRM/LE AxLND 1cm, 2 (+) LN s - More Chemo? - XRT s/p MRM?

What About Drug Development?

Potential BenenfitsOf Pre-Operative Treatment 1. Early treatment improves DFS/OS? 2. Tailor therapy based on in-breast response? 3. Local control by converting inoperable to operable? 4. Minimize local surgery by converting MRM to Breast Conservation? 5. Clinical research (To obtain paired specimens or sequential imaging or others)?

Is Pre-Operative Systemic Therapy A Solution To The Challenges Of Drug Development? Smaller: Every patient has an event Faster: Trial is done when the last patient is assessed (surgery or imaging)

What Is A Better Neo-Adjuvant Regimen? Improved OS? Improved DFS? Improved Response? Clinically meaningful: Increased conversion from inoperable? Increased conversion to breast conservation? Drug Development? pcris a surrogate? Does incrementally increasingpcrcorrespond to distant recurrence/os?

What If We Prospectively Define The Subsets? (Eliminating Luminal A and perhaps B.)

NeOAdjuvantHerceptin (NOAH) trial: Study design H + AT q3w x 3 cycles HER2-positive LABC (IHC 3+ or FISH+) n=117 n=118 AT q3w x 3 cycles HER2-negative LABC (IHC 0/1+) n=99 AT q3w x 3 cycles H + T q3w x 4 cycles T q3w x 4 cycles T q3w x 4 cycles H q3w x 4 cycles + CMF q4w x 3 cycles CMF q4w x 3 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy a Surgery followed by radiotherapy a Surgery followed by radiotherapy a H continued q3w to week 52 19 (16%) patients crossed to H after November 2005 Gianni, abstr # 503 AT, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); T, paclitaxel (175 mg/m 2 ); a Hormone receptor-positive patients will receive adjuvant tamoxifen Gianni et al, Proc ASCO 2013, abs 503

pcrbasedon treatment improvedefs in HER2+ groups Trastuzumab vs. no Trastuzumab Stratum Sample size EFS HR (95% CI) p pcr 45 vs. 23 0.29 (0.11 0.78) 0.0135 non pcr 72 vs. 95 0.92 (0.61 1.39) NS pcr vs. non pcr Stratum Sample size EFS HR (95% CI) p Trastuzumab 45 vs. 72 0.17 (0.08 0.38) <.0001 no Trastuzumab 23 vs. 95 0.57 (0.29 1.13) NS p-value for interaction treatment*pcr effect = 0.037 Gianni et al, Proc ASCO 2013, abs 503

NeoSPHERE: How Large a change in pcrwill indicate improvement in DFS/OS? Trast Docetaxel Pertuz - Docetaxel Trast - Pertuz Trast - Pertuz Docetaxel ITT (Overall) 29% 24% 46% 17% ER- 37% 30% 63% 27% ER+ 20% 17% 26% 6% Gianni et al, Lancet Oncol 2012; 13: 25 32 PublishedOnline December 7, 2011 DOI:10.1016/S1470-2045(11)70336-9

Does This Always Predict? Neo-ALTTO Study Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF 50% N=455 Stratification: T 5 cm vs. T > 5 cm ER or PgR + vs. ER & PgR N 0-1 vs. N 2 Conservative surgery or not R A N D O M I Z E lapatinib paclitaxel trastuzumab paclitaxel lapatinib trastuzumab paclitaxel 6 wks + 12 wks S U R G E R Y F E C X 3 lapatinib trastuzumab lapatinib trastuzumab 34 weeks 52 weeks of anti-her2 therapy

Neo-ALTTO: Less Clear That Incremental pcr Improvement Varies by Hormone Receptor Status Baselga et al Lancet 2012; 379: 633 40 Published Online January 17, 2012 DOI:10.1016/S0140-6736(11)61847-3

Neo-ALLTO Did NOT Predict Inferiority: ALLTO 3-weekly Trastuzumab for 52 weeks Lapatinib for 52 weeks Weekly Trastuzumab (12 weeks) Washout (6 weeks) Lapatinib + 3-weekly Trastuzumab for 52 weeks Lapatinib (34 weeks) http://www.cancer.gov/clinicaltrials/noteworthy-trials/altto

[TITLE] Presented By Lisa A. Carey, MD at 2013 ASCO Annual Meeting Carey et al. abstr # 500

[TITLE] Presented By Lisa A. Carey, MD at 2013 ASCO Annual Meeting

Small preoperative studies have biostatisticalrisks

What about TNBC?

GeparSixto [TITLE] 1 -pcr 2 -compliance, tox, Efficacy based on subtypes clinical CR, and BCS TNBC-Bevacizumab (B) added HER2+-Trastuzumab + Lappatanib (HL) added Presented By Gunter Von Minckwitz, MD at 2013 ASCO Annual Meeting

[TITLE] Presented By Gunter Von Minckwitz, MD at 2013 ASCO Annual Meeting

CALGB 40603: Schema Eligibility: Stage II-III (except T4d) ER/PR-poor, HER2- Paclitaxel 80mg/m 2 weekly x 12 ddac x 4 Registration Randomization Required Research Biopsies Optional Research Blood Tests and Tissue Banking Paclitaxel 80mg/m 2 weekly x 12 ddac x 4 Bevacizumab 10 mg/kg q2wks x 9 doses Paclitaxel 80mg/m 2 weekly x 12 ddac x 4 Carboplatin AUC 6 q3weeks x 4 Paclitaxel 80mg/m 2 weekly x 12 ddac x 4 Carboplatin AUC 6 q3weeks x 4 Bevacizumab 10 mg/kg q2wks x 9 doses Surgery XRT No Adjuvant Chemo planned N= 362 - Primary endpoint: path CR in breast

Same Question: What increment in pcr predicts improved DFS/OS? CTNeoBC Selected Trials - 12 neoadjuvant randomized controlled trials - pcr clearly defined with all necessary data collected - Long-term follow-up EFS and OS data collected TRIALS Patients (n) GBG/AGO: 7 6377 NSABP: 2 3171 EORTC/BIG: 1 1856 ITA: 2 1589 Total # patients 12993 Cortazar et al, SABCS 2013

Trial level correlation between pcr & EFS A perfect scenario example (simulated-data) R 2 ~ 1 Cortazar et al, SABCS 2013

The magnitude of improvement in pcr rate did not predict EFS and OS R 2 =0.01 R 2 =0.18 Cortazar et al, SABCS 2013

Subgroup analysis EFS OS R 2 =0.07 R 2 =0.21 Excluding patients with HR+ Grade 1 or 2 Triple negative subgroup R 2 =0.01 R 2 =0.003 NOAH R 2 =0.33 R 2 =0.03 NOAH Her2+ subgroup Cortazar et al, SABCS 2013

The meta-analysis could not establish the magnitude of pcr improvement that predicts long-term increased EFS and OS. Cortazar et al, SABCS 2013

Where do we stand? We need a validated endpoint for regular approval pcr is not yet an established surrogate endpoint and we do not have sufficient experience to validate it Uncertainty regarding the ultimate outcome: Long-term efficacy (EFS and OS) Long-term safety We will need long term follow-up and confirmation of ultimate outcome The Neoadjuvant Regulatory Path could be opened through Accelerated Approval Courtesy P. Cortazar

First NeoadjuvantApproval: Pertuzumab ODAC voted yes FDA Decision and label Length of rx? 3-6 cycles Population: Risk? T2 or N+ or LABC or IBC Only Pre-op! Chemotherapy partners/options? Docetaxel http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125409s051lbl.pdf

What Happens Clinically Now? 44 y/o, 3cm, ER-negHER2+ BC Conventional approach: - Definitive surgery - Node assessment - AC->T/H (or your preference) - +/-RT

Improved approach: - New agent added to pre-op T/H? - Then what? - Other CRx? - Duration anti-her2? - More systemic therapy? - (Not to mention local Rx) - Long term safety? Still need a large confirmatory adjuvant trial, so what, exactly, are we gaining with approval?

I Support Pre-Op Studies! Good screen for activity (but not against?) May ultimately indicate improved DFS/OS Can provide informative imaging and tissue correlates But: there is a risk of compromising proven effective therapies and of dramatically increasing long term cost at the population level Limited toxicity assessment Limited ability to study optimal duration

Thank You