The Expert Thoughts Alessandra Fabi Oncologia Medica 1
My Thoughts Neoadjuvant: from the lessons of the history Adjuvant: Escalation and De-escalation Advanced and HER2+ : field for immunomodulation Brain metastases and outcome: what is changed?
Effect of NCT vs ACT on recurrence and mortality 1998-2003 EBCTCG Lancet Oncology 2018
Dual Inhibition in Neoadjuvant Trials Trial Experimental Anti-HER2 pcr with Trastuzumab pcr with Dual inhibition NeoSphere Pertuzumab 29% 46% NeoALTTO Lapatinib 30% 51% CALGB 40601 Lapatinib 40% 51%* NSABP B41 # Lapatinib 52% 62%* TRYPHAENA $ Pertuzumab NA 55-64% * Not statistically significant, # Received AC-T, $ No single anti-her2 arm
Dual Inhibition in Adjuvant Trials Trial Setting Anti HER2 therapy Primary Endpoint Dual therapy superior to single agents ALTTO adj T T + L T ->L DFS NO APHINITY adj T T + P DFS YES (subtypes*) HR 0.81
De-Escalation Strategies in Oncogene Addicted Cancers Minimize chemotherapy Eliminate chemotherapy
Neoadjuvant Trials of Dual targeted therapy without chemotherapy Study Phase PT HER2- therapy Endocrine therapy Weeks pcr pcr ER+ pcr ER - TBCRC006 II 64 T+L Yes 12 27% 21% 36% TBCRC023 II 33 T+L Yes 12 15% 9% 20% 61 T+L Yes 24 25% 33% 18% PAMELA II 150 T+L Yes 18 31% 18% 43% NeoSphere II 107 T+P No 16 17% 6% 29%
Challenges Predictive Biomarkers for a De-Escalation Approach Mechanisms of Resistance - Dual HER2-targeted therapy with no chemo - Blocking ER in HER2+/ER+ - Novel Anti-HER2 agents - Additional targets/pathways
Determinants of Response/Resistance to anti-her2 therapy 1. ER 2. HER2 level (addiction) 3. PI3K pathway deregulation 4. HER2 mutations 5. Microenvironment/immune infiltrate 6. Adaptive or escape pathways: HER3, metabolic (mevalonate), cell cycle
2017
Are HER2+/ER+ the same tumors? - We may overtreat a subgroup of ER+, HER+ BC in the (neo)-adjuv (enough anti HER2+OT??) - This subgroup may suffer late recurrence (similar to what we see with some HER2-/ER+ cancers) - Can we identify this subgroup drived by ER?
2017
SABC intrinsic subtype differed between HR- and HR+
TBCRC 006 (HELP Study) Stage II/III HER2+ Breast CA N=64 LAPATINIB + TRASTUZUMAB +/- LETROZOLE Wee k 1 W 2 W 3 Biopsy W 4 W 5 W 6 W 7 W 8 W 9 Biopsy W 1 0 W 1 1 W 12 Biopsy Baseline Biopsy PTEN IHC PIK3CA mutations M Rimawi, JCO 2013
Correlation with pcr pcr No pcr Marker n % n % P PTEN (n=59) 0.04 High ( 100) 12 32 25 68 Low (<100) 2 9 20 91 PIK3CA (n=46) 0.14 Wild type 7 28 23 72 Mutation 1 7 13 93 PTEN low or PIK3CA mutation (n=43) 0.006 No 7 39 11 61 Yes 1 4 24 96 There was no correlation between PIK3CA mutation status, PTEN level, and ER.
Neoadjuvant therapy in HER2+ EBC LESSONS LEARNED FROM NEOADJUVANT TRIALS I. First generation Trastuzumab + chemo > chemo alone
Trastuzumab and chemotherapy Trastuzumab + chemotherapy Chemotherapy alone MD Anderson 1 H+(T FEC) T FEC n=45 n=19 26 60 P=NR NOAH 2 H+(AT T CMF) AT T CMF n=117 n=118 22 43 P<0.0007 0 20 40 60 pcr (%) No evidence of residual invasive cancer, both in breast and axilla No evidence of residual disease in breast tissue pcr, pathological complete response; H, trastuzumab; T, taxane FEC, 5-fluorouracil+epirubicin+cyclophosphamide; AT, doxorubicin+paclitaxel CMF, cyclophosphamide+methotrexate+5-fluorouracil; EC, epirubicin+cyclophosphamide 1. Buzdar AU, et al. 2007,2. Gianni L, et al. 2010
Improved pcr rate translates into improved outcome with Trastuzumab 5-year event-free survival 5-year overall survival *EFS, Event free survival; HR, Hazard ratio; OS, Overall survival. Gianni L, et al. 2014
Dual HER2 blockade LESSONS LEARNED FROM NEOADJUVANT TRIALS II. Second generation Dual HER2 blockade + chemo > single HER2 blockade + chemo
pcr, % 95% CI pcr, % 95% CI Pertuzumab and trastuzumab 50 40 TH (n=107) docetaxel (75 100 mg/m 2 ) trastuzumab (8 6 mg/kg) THP (n=107) docetaxel (75 100 mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab (840 420 mg) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab (840 420 mg) TP (n=96) docetaxel (75 100 mg/m 2 ) pertuzumab (840 420 mg) Study dosing: q3w x 4 Gianni L, et al. Lancet Oncol 2011 S U R G E R Y 30 20 10 0 70 60 50 40 30 20 10 0 2 9 20 T H 37 26 46 TH P 63 17 H P 24 TP ER or PR positive ER and PR negative 29 30 17 TH THP HP TP 6
Beyond dual blockade LESSONS LEARNED FROM NEOADJUVANT TRIALS III. Third generation Identify the subset which can benefit from a chemo-sparing regimen
HER2+ /HR- disease % PCR rates 100 80 60 40 20 29% Dual HER2 blockade alone 62% Dual HER2 blockade + taxane 73-80% Dual HER2 blockade + taxane + other agent (anthrac., carbo) Who are these patients with HER2+ HR- disease who perhaps do not need chemo? Based on NeoSphere, NeoAltto, Tryphaena
HER2+ /HR- disease PIK3CA mutations/ PTEN loss Improved tailoring? TIL s Immune signatures
ADAPT study in HER2+/HR+ International, prospective, randomized phase II trial Wk 12 Pts with ER+ and/or PgR+, HER2+, ct1c - ct4a-c, cn, cm0 BC and adequate organ function, LVEF 50%, normal ECG (N = 375) T-DM1 3.6 mg/kg Q3W (n = 119) T-DM1 3.6 mg/kg Q3W + ET* (n = 127) Trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W + ET* (n = 129) Surgery *Tamoxifen if premenopausal; aromatase inhibitor (of investigator s choice) if postmenopausal. Standard chemotherapy (1-yr trastuzumab) recommended after surgery or 12-wk biopsy (if clinical non-pcr). Primary endpoint: pcr (no invasive carcinoma in breast/nodes) Secondary endpoints: dynamic testing evaluation, EFS, OS, safety 1. Harbeck N, et al. SABCS 2015. Abstract S5-03. 2. Hofmann D, et al. Trials. 2013;14:261.
ADAPT Trial Outcome, n/n (%) T-DM1 T-DM1 + ET pcr (ypt0 or ypt0/is, ypn0) All pts* Premenopausal women Postmenopausal women 48/117 (41.0) 22/58 (37.9) 26/59 (44.1) *P <.001 for comparison between each T-DM1 arm vs trastuzumab + ET. Low cellularity (< 500 tumor cells) or Ki67 decline 30%in 3-wk biopsy. Harbeck N, et al. SABCS 2015. Abstract S5-03. 51/123 (41.5) 24/63 (38.1) 27/60 (45.0) Trastuzumab + ET 18/119 (15.1) 8/59 (13.6) 10/60 (16.7) Near pcr (ypt1a) 14/117 (12.0) 14/123 (11.4) 5/119 (4.2) Early response Nonresponders Responders 9/36 (25.0) 24/61 (39.3) 6/25 (24.0) 36/76 (47.4) 5/40 (12.5) 11/62 (17.7)
Adjuvant therapy in HER2 positive EBC Optimal Adjuvant Therapy in 2018 for the average patient with HER2-positive breast cancer
Long-term DFS benefit with adjuvant Trastuzumab for 1 year Study HERA 1 4 CT+/-RT H vs. CT+/-RT BCIRG 006 5 AC TH H vs. AC T TCH vs. AC T Combined analysis 6-8 (NCCTG N9831/ NSABP B-31) AC TH H vs. AC T HR, hazard ratio Follow-up (years) 1 3387 0.54 2 3401 0.64 4 3401 0.76 8 3401 0.76 5 N 3222 1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007; 3. Gianni L, et al. 2011, 4. Goldhirsch A, et al 2013 5. Slamon D, et al. 2011; 6. Romond EH, et al. 2005; 7. Perez EA, et al. 2011; 8. Perez EA, et al. 2014 HR 0.64 0.75 2 3351 0.48 4 4045 0.52 8 4046 0.60 0 Favours 1 Favours 2 Trastuzumab HR (95% CI) observation
Escalation: where do we start from? 1. Longer trastuzumab duration (Hera 2y arm ) 2. Adding bevacizumab to trastuzumab (Beth ) 3. Dual HER2 blockade - Lapatinib + trastuzumab (ALTTO) - Pertuzumab + trastuzumab (APHINITY ) 4. T-DM1 after neoadjuvant CT + trastuzumab in case of residual disease (Katherine?) 5. Extended neratinib ( )
Extended Neratinib HER2+ Stage II-IIIC node positive BC following CT + 12 months of trastuzumab (adj) (N=2821) R Neratinib 240 mg orally daily for 1 year Placebo Orally daily for 1 year DFS DFS CT, chemotherapy; adj, adjuvant; DFS, disease-free survival; BC, breast cancer. Press release - Puma Biotechnology July 22nd, 2014 Extended DFS by 33% compared with placebo (HR = 0.67; P =.0046) Martin et al Lancet 2017
ITT ER+ Impact of Hormonal Therapy? HER2+/HT+ different tumors? ER-
Katherine Neoadjuvant CT + trastuzumab Residual invasive cancer R T-DM1 Trastuzumab Primary endpoint : IDFS 900/1400 patients recruited as of today
KAITLIN HER2+ Node+ or Node-, ERand T>2cm R AC x 4 or FEC x3 AC x 4 or FEC x3 TAXANE TRASTUZUMAB PERTUZUMAB T-DM1 PERTUZUMAB IDFS HO 89,5% 93,1% 1300/2500 women recruited Worrysome : taxane + trastuzumab = T-DM1 = T-DM1 + pertuzumab in the first line metastatic MARIANNE trial! 35
SABCS 5 studies
SABC STANDARD TREATMENT: TRASUZUMAB FOR 1 YR Sold SABCS 2017 SABCS 2017 SABCS
De-Escalation treatment in HER2+: from where? 1. Tumor size 2. Age 3. Response to preoperative therapy
Point 1 APT Trial HER2+ Node Negative < 3 cm N=406 Enroll P P P P P P P P P P P P T T T T T T T T T T T T PACLITAXEL 80 mg/m 2 + TRASTUZUMAB 2 mg/kg x 12 T T T T T T T T T T T T T 3-year DFS 95% Conf. Interval 98.7% 97.6% to 99.8% Poisson p-value: <0.0001 FOLLOWED BY 13 EVERY 3 WEEK DOSES OF TRASTUZUMAB (6 mg/kg) Tolaney et al, NEJM 2015
SABCS SABCS 2017 SABCS 2017
ATEMPT trial (randomized phase II) T-DM1 Stage I R(3:1) Trastuzumab + Paclitaxel Objectives: Primary DFS Secondary Outcome Measures :DFS in Patient Groups Defined by Tumor Size < 1cm or >/= 1 cm and HR Percentage of participants with Grade 3-4 Cardiac Dysfunction Recruitment ongoing from 2013
Point 2 age > 60 yrs stage I III HER2+ Age and adj therapy ATOP trial (phase II) T-DM1 for 1 yr age 69 81 RESPECT trial (randomized phase II) Trastuzumab alone stage I IIIA HER2+ Recruitment ongoing Trastuzumab plus chemotherapy.
Question: EC/taxane + trastuzumab and pertuzumab vs with a taxane + trastuzumab and pertuzumab? Point 3 We consider using escalation of biologic therapy as a mechanism to de-escalate chemotherapy. If adding pertuzumab to trastuzumab-based chemotherapy is found to improve long-term outcomes in the APHINITY trial, perhaps patients may achieve similar outcomes with less chemotherapy and highly effective biologic therapy
MY TOUGHTS Escalation attempts : preliminary conclusions Failed X X X Trastuzumab x 2y Trastuzumab + bevacizumab Trastuzumab + lapatinib Trastuzumab followed by neratinib Succeeded? Trastuzumab + pertuzumab?? T-DM1 after neoadj CT + trast? X
MY THOUGHTS De-Escalation attempts : preliminary conclusions Failed Succeeded X(so far ) Shorten trastuzumab duration Eliminate the anthracycline component? Use T-DM1 + pertuzumab instead of taxane + trastuzumab + pertuzumab? Use of only trastuzumab without CT in stage I older pts X (in selected pts!)??
METASTATIC DISEASE
HER2+ Disease TILs come to stage HER2 + no longer the only prognostic factor of disease and predictive of response TILs associated with improved prognosis among patients with HER2-positive breast cancer The TIL count predicts a pathologic complete response to neoadjuvant chemotherapy, trastuzumab, and lapatinib Increased TIL count predicted better distant DFS in HER2+ early BC pts (FinHER, NeoALTTO) higher TIL values are significantly associated with improved overall survival, suggesting that the effect of antitumour immunity extends to the advanced setting (Cleopatra data) Ali HR, Ann Oncol 2014; Bianchini G, Lancet Oncol 2014; Denkert C, J Clin Oncol 2010; Dieci MV et al, Ann Oncol 2015; Denkert C, J Clin Omncol 2015; Loi S, Ann Oncol 2014,
Stromal TILs and Survival in HER2+ Further clinical studies in this cancer subtype should consider TILs as a stratification factor Luen, Lancet Oncol 2016
Postulated mechanism of engagement of the innate and adaptive immune system through HER2-targeted monoclonal antibodies CTL ADCC IFNγ Tumor NK Coated monoclonal antibodies have demonstrated debris Tumor cell to generate an in vivo vaccine-like effect IFNγ Phagocytosis IL-2 death (immunogenic or not immunogenic) NK/DC crosstalk Debris or dying cells DC Cross presentation Trastuzumab, rituximab and others CTL CD4 Th1 Legend Tumor cell NK cell Cytotoxic T-cell Activated Cytotoxic T-cell CD4 (Th1) Dendritic cells MHC I MHC II TCR HER2 FcγR Trastuzumab/pertuzumab Bianchini G & Gianni L. Lancet Oncol 2014
HER2 targeted monoclonals combinations
Preclinical studies are supportive of benefit for combining anti- HER2 antibodies and immune checkpoints inhibitors Anti-HER2 mab and Anti-PD1 TDM1 and Anti-PD1/Abti-CTLA4 Stagg J et al PNAS 2011 Muller P et al Sci Transl Med 2015
Panacea Study SABCS 2017 CS 2017 Loi 2017
017 Loi 2017
Immunotherapy excitement in breast cancer Trial ongoing with immunechekpoint inhibitors 41 67 trials 38 TNBC (only) 12 ER+/HER2- (only) 6 HER2+ (only) 10 trials 77 66 trials of combinations Only breast cancer Multiple solid Phase I or II Phase III Marketed ClinicalTrialsGov (updated 15-09-2017)
who survives longer with brain metastases? Martin, Jama 2017
HER2+ population
Survival Mounsey, Clin Breast Cancer 2017
The HERBA trial a retrospective study on pts with HER2+ BC and brain metastases 154 HER2+ve BC pts diagnosed with BMs from January 2005 to December 2014 Median OS from the diagnosis of BMs was 24.5 months, with no significant difference between pts diagnosed in period 2005-2009 (25.2 months) and those diagnosed in period 2010-2014 (21.5 months; p=0.42). No significant difference in terms of mos between pts with and those without previously diagnosed systemic metastases (23 vs 27 months; p=0.469) and this data suggest that the occurrence of BMs is a predominant prognostic factor for HER2+ve BC pts Gori et al. 2017
Grazie