Breast Cancer: ASCO Poster Review

Breast Cancer: ASCO Poster Review Carmen Criscitiello, MD, PhD Istituto Europeo di Oncologia Milano

HER2+ SUBTYPE

Research questions in early HER2+ BC De-escalation of toxicity without compromising efficacy Need for novel biomarkers to better select subset of patients who might be spared chemotherapy

HER2-E Subtype and ERBB2 mrna as predictors of pcr to lapatinib-trastuzumab Prat A, et al. Abstract 509

HER2-E Subtype and ERBB2 mrna as predictors of pcr to lapatinib-trastuzumab 265 sample were profiled: 65.7% HER2-E Within HER2-E subtype: 84.0% ERBB2 high 46.0% ERBB2 low Prat A, et al. Abstract 509

HER2-E/ERBB2-high combined biomarker and pcr rate The combination of the HER2-E subtype with high ERBB2 mrna levels together is a promising biomarker for sensitivity to HER2-targeted therapy Prat A, et al. Abstract 509

RESPECT trial: trastuzumab +/- chemo in elderly patients with HER2 early BC Sawaki, et al. Abstract 509

RESPECT trial: Demographics (n=266) Median age 73,5 years 6. M0 Sawaki, et al. Abstract 509

RESPECT trial: DFS (not achieved) 6. M0 Sawaki, et al. Abstract 509

Research question in metastatic HER2+ BC HER2-target therapies have remarkably improved survival for metastatic HER2+ BC, but there remains a need for improved outcome by using novel therapies

DS-8201a is a HER2-targeted antibody drug conjugate (ADC) with novel topoisomerase I inhibitor payload and linker technology Iwata, et al.

Trastuzumab deruxtecan (DS-8201) in pts with HER2-expressing advanced solid tumors: first-inhuman phase I study Iwata, et al.

Consistent tumor shrinkage N = 104 N = 33 Confirmed ORR in the overall population: 49.8% Iwata, et al.

Efficacy outcome Iwata, et al.

PHEREXA: A clinical trial of pertuzumab in second-line metastatic BC Arm A: Pertuzumab + trastuzumab + capecitabine HER2-positive MBC (N = 450) R Arm B: Trastuzumab + capecitabine Urruticoechea A, et al. Abstract 1013

PHEREXA: Final Analysis PFS OS Urruticoechea A, et al. Abstract 1013

TNBC SUBTYPE

Research questions in early TNBC Defining the role of platinum in TNBC pts who receive NACT Defining the role of immunotherapy in TNBC pts who receive NACT

Platinum-based Neoadjuvant Chemotherapy in TNBC: A Systematic Review and Meta-analysis of Randomized Controlled Trials Nine RCTs, 2109 pts included pcr pcr rate 37.0% (ctrl) vs 52.1% (exp) (OR 1.96, 95% CI 1.46 2.62, P<0.001) Poggio F, et al. Annals of Onc 2018

Platinum-based Neoadjuvant Chemotherapy in TNBC: A Systematic Review and Meta-analysis of Randomized Controlled Trials EFS HR 0.72, 95% CI 0.49 1.06, P=0.094 OS HR 0.86, 95% CI 0.46 1.63, P=0.651 Poggio F, et al. Annals of Onc 2018

Randomized Phase II Neoadjuvant Study (GeparNuevo) to Investigate the Addition of Durvalumab to a Taxane-Anthracycline Containing Chemotherapy in Triple Negative Breast Cancer (TNBC)

GeparNUEVO Study Design

Primary Endpoint - pathological complete response <br />pcr ypt0, ypn0

Subgroup Analysis pcr rates

Research question in metastatic TNBC New therapeutic approaches to improve outcome

A phase II, single arm study assessing the efficacy of pembrolizumab plus RT in mtnbc RT is used for local control in MBC RT may induce distant tumor response (abscopal effect) Hypothesis is that immunotherapy may increase abscopal effect of RT McArthur, et al. Abstract 1017

Study design Single-arm phase II study Chemo-resistant, PD-L1 unselected, mtnbc, 1 site to irradiate and 1 site outside the RT field to follow for response Primary endopoint: ORR at 13 weeks Intervention: RT 3000 cgy delivered in 5 daily fractions; pembro 200 mg IV within 3 days of the first RT fraction, then every 3 weeks until PD McArthur, et al. Abstract 1017

Results Key patient characteristics (N=17) Median 3 (range 0-8) prior therapies for mtnbc 13/17 (76%) had visceral metastases Responses 8 pts (47%) not evaluable at week 13 (5 died, 3 rapid PD) 9 pts evaluable at week 13 (3 PR, 1 SD, 5 PD) ORR in the ITT population was 3/17 (18%) Toxicity Radiation dermatitis (29%), fatigue (18%), nausea (12%) McArthur, et al. Abstract 1017

LUMINAL SUBTYPES

Research question in early luminal BC Defining optimal duration of adjuvant endocrine therapy

Genomic stratification with BC Index (BCI) of ER+ EBC pts with limited long-term risk of BC death To use the BCI genomic tool to identify a minimal risk cohort of ER+ EBC pts who might not need extended adjuvant ET Studied population: n=600, postmenopausal, ER+/HER2-, stage I-II, no chemo. Randomized to 2-5 years of tamoxifen vs not. Followed for 17 years. Kaklamani, et al. Abstract 516

Four risk groups identified Trial results Minimal risk group (28% of cohort) had 99% BCSS years 5-20 Kaklamani, et al. Abstract 516

Four risk groups identified Trial results Minimal risk group (28% of cohort) had 99% BCSS years 5-20 Only BCI score and tumor size were independent predictors of 20-year BCSS in a multivariate model Kaklamani, et al. Abstract 516

Persistance of CTCs in high risk EBC pts 5 years after adjuvant chemo and late recurrence: The adjuvant SUCCESS trial 3754 high-risk BC pts CTC quantification was performed 5 years after chemotherapy, then correlated with long-term outcome Primary objective: to assess significance of CTCs at 5 years in predicting long-term outcome Janni W, et al. Abstract 515

Results from the SUCCESS trial 206 (5.5%) pts had known CTC status and long term follow-up data 16 (7.8%) pts were CTC positive ( 1 CTC; range 1-53 CTC) Median follow-up after CTC assessment 1 year 13 recurrences observed (11/153 HR+, 2/53 HR-) Janni W, et al. Abstract 515

Results from the SUCCESS trial 206 (5.5%) pts had known CTC status and long term follow-up data 16 (7.8%) pts were CTC positive ( 1 CTC; range 1-53 CTC) Median follow-up after CTC assessment 1 year 13 recurrences observed (11/153 HR+, 2/53 HR-) In HR+ pts, CTC status was a significant prognostic factor for RFS (univariable HR 5.14, 95% CI 1.47 18.03, p = 0.011 and in multivariable cox regressions adjusted for clinico-path features HR 5.95, 95%CI 1.14 31.16, p = 0.035) Janni W, et al. Abstract 515

Research question in metastatic luminal BC Identification of clinical or molecular features, which may predict patients more likely to benefit from CDK 4/6i treatment

Benefit of CDK 4/6 inhibition in less common BC subsets: A FDA pooled analysis Limited data on the benefit and value of adding CDK4/6i to ET in less common subtypes: Progesterone receptor negative (PR-) de novo metastatic lobular cancer bone-only disease DFI > 12 months Pooled raw patient-level data from 5 RCTs of CDK4/6i in 1L/2L (PALOMA-2, PALOMA-3, MONALEESA-2, MONARCH-2, MONARCH-3) Gao JJ, et al. Abstract 1024

All clinical subsets benefit from CDK4/6i PR- (N=490) PFS 16.5 vs 7.4 months 9.1 months HR 0.50, 95% CI 0.40-0.64 Lobular (N=264) PFS 16.1 vs 9.2 months 6.9 months HR 0.58, 95% CI 0.42-0.80 Bone-only (N=875) PFS 27.9 vs 15.5 months 12.4 months HR 0.55, 95% CI 0.45-0.67 Gao JJ, et al. Abstract 1024

All clinical subsets benefit from CDK4/6i De novo metastatic (N=617) PFS 27.8 vs 16.8 months 11.0 months HR 0.59, 95% CI 0.46-0.76 DFI>12 months (N=929) PFS 25.7 vs 14.2 months 11.5 months HR 0.55, 95% CI 0.46-0.67 Gao JJ, et al. Abstract 1024

Treatment effect of palbociclib plus ET by prognostic and intrinsic subtype: A joint analysis of PALOMA2 and PALOMA3 To evaluate: The effect of treatment-free interval (TFI) in PALOMA-2 or diseasefree interval (DFI) in PALOMA-3 on PFS outcomes Effect of Luminal subtype on the benefit of treatment with Palbociclib Finn, et al. Abstract 1023

Neither TFI nor DFI impacted benefit of palbociclib PALOMA-2 STEPP analysis of TFI (N=334) PALOMA-3 STEPP analysis of DFI (N=355) Finn, et al. Abstract 1023

Both Luminal A and B subtypes benefitted from palbociclib PALOMA-2 (N=364) PALOMA-3 (N=142) Finn, et al. Abstract 1023

First-line ribociclib + letrozole in HR+/HER2- ABC: MONALEESA-2 mrna biomarker analyses mrna expression data from baseline samples was obtained from 391/668 randomized pts mrna expression was assessed using the NanoString 230-gene panel To assess correlations between gene expression levels and PFS, pts were classified into low or high mrna expression subgroups using the median expression (50%) as the cut-off Hortobagyi, et al. Abstract 1022

The addition of ribociclib provided a PFS benefit across all gene expression signatures Estrogen receptor gene CDK pathway trascription factor Genes implicated in CDK4/6i resistance CCNA2, CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, RB1, E2F1, E2F3, TFDP1, TP53 AKT1, AKT2, PIK3CA, PTEN BRAF, HRAS, KRAS, MAPK3K8, NRAS, RAF1, NF1 AREG, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, FYN, IGF1, KDR, KIT, PDGFA, PDGFRA, PDGFRB, TYRO3 Hortobagyi, et al. Abstract 1022

High ESR1 expression trended towards greater ribociclib benefit PFS by ESR1 gene expression level Trend for longer PFS with high ESR1 expression in both treatment groups Letrozole+ribo: PFS 29.6 vs 22.1 months Letrozole alone: PFS 16.9 vs 13.2 months Trend towards greater benefit from CDK4/6i in pts with high ESR1 expression (HR 0.39 vs 0.74) Hortobagyi, et al. Abstract 1022

Grazie