Laura Biganzoli
Oncologia Medica Ospedale di Prato Istituto Toscano Tumori
Le prospettive di ricerca
Established treatment option for advanced HR+HER2- breast cancer
Finn et al. N Engl J Med 2016 Hortobagyi et al. N Engl J Med 2016 Di Leo et al. ESMO 2017
Cristofanilli et al. Lancet Oncol 2016
Sledge et al. J Clin Oncol 2017
PALBOCICLIB RIBOCICLIB ABEMACICLIB
Increased toxicity Increased costs
Main Challenge
• Identification of the patients to be treated
biomarkers of response/resistance
Part 1 PAL + LET (N=34)
LET (N=32)
Number of Events (%) 15 (44) 25 (78) Median PFS, months
(95% CI)
26.1 (11.2, NR)
5.7 (2.6, 10.5) Hazard Ratio
(95% CI)
0.299 (0.156, 0.572)
p-value <0.0001
Part 2 PAL + LET
(N=50)
LET (N=49)
Number of Events (%) 26 (52) 34 (69) Median PFS, months
(95% CI)
18.1 (13.1, 27.5)
11.1 (7.1, 16.4) Hazard Ratio
(95% CI)
0.508 (0.303, 0.853)
p-value 0.0046
UNSELECTED (ER+/HER2 neg) CCD1 amplif. and/or p16 loss
Part 1 (N=66)
• Phase II, 1° line
• ER+, HER2– BC status Palbociclib 125 mg QD +
Letrozole 2.5 mg QD Letrozole 2.5 mg QD Part 2
(N=99)
• Same as part 1 but with CCND1 amplification and/or loss of p16
R
PALOMA 1- role of CCD1 and p16
0 4 8 12 16 20 24 28 32 36 40
Time (Month) 0
10 20 30 40 50 60 70 80 90 100
Progression Free Survival Probability (%)
0 4 8 12 16 20 24 28 32 36 40
Time (Month) 0
10 20 30 40 50 60 70 80 90 100
Progression Free Survival Probability (%)
Finn R. et al Lancet Oncology 2015; 16: 25–35
PIK3CA WT PIK3CA Mut
PIK3CA status (exon 9 and 20 hotspots) was determined by BEAMING assay on circulating DNA in 395 pts in PALOMA 3
PIK3CA status does not impact the magnitude of benefit from palbociclib
PIK3CA mutation status- PALOMA-3
Cristofanilli M, et al. Lancet Oncol. 2016;17(4):425–439.
Biomarkers of resistance
● Genetic loss of RB1 may be a marker of primary resistance to CDK4/6 inhibitors; uncommon in HR+ subtypes
● Functional loss of the Rb pathway can be measured by gene- expression studies
● Gene-expression signatures focusing on inactivation of the Rb pathway have been developed and characterized in breast cancer patients datasets
● The correlation between these signatures with response to CDK 4/6 inhibitors has not been explored
Thangavel C et al. Endocr Relat Cancer 2011
Rb loss signature in Luminal BC
E2F1 and E2F2 high vs low breast cancers in the TCGA*
RBsig
87 genes
Expression data
Genes correlated with E2F1 and E2F2
expression
Functional analysis
Association with molecular subtypes
*TCGA: The Cancer Genome Atlas, CCLE: Cancer Cell Line Encyclopedia
We have derived a new signature of Rb loss-of-function (RBsig)
with the specific aim of testing whether this might
help in discriminating between palbociclib resistant vs sensitive breast cancer cell lines
The RB Sig as a potential tool to predict primary resistance to CDK 4-6 inhibitors
Malorni et al. Oncotarget 2016
RBsig expression in BC subtypes
RBsig levels are higher basal BC and, among Luminal BC, are higher in LumB
Malorni et al. Oncotarget 2016
All tumors
p-value < 7e-32 p-value < 7e-11 p-value < 0.002
Luminal A/B Basal
Rb1 status Rb1 status Rb1 status
RBsig correlates with RB1 status in BC subtypes
RBsig levels are higher in BC samples with loss of Rb, across multiple BC subtypes
Malorni et al. Oncotarget 2016
BC gene expression meta- dataset (N=3458)
Recurrence free survival (RFS) of pts with ER+
tumors, untreated or endocrine treated only
Prognostic value in BC patients
ER+, untreated p= 2.22e-09
HR=2.37 (1.8-3.2, p=1.87e-08)
Luminal A, untreated p= 1.14e-11
HR=3.34 (2.3-4.8, p=6.97e-10)
Luminal B, untreated p= 0.0001
HR=2.52 (1.55-4.08, p=0.0003)
200
RBsig
Does RBsig hold prognostic information in ER+ BC?
Malorni et al. Oncotarget 2016
Sensitive/Resistant info*
BC cell lines expression data from RNA-seq experiment (GSE48213)
discriminate CDK4/6i sensitive vs resistant
BC cell lines
*Finn RS et al. BCR 2009; 11:R77
RBsig
RBsig identifies CDK4/6i resistant vs sensitive cell lines with and Area Under the
Curve (AUC) of 0,7778
Does RBsig predict response to CDK4/6 inhibitors?
Malorni et al. Oncotarget 2016
Possible role of CDK 4/6 inhibitors in HER2- positive BC
Rationale
• 50% of HER2+ BC co-express ER
• CDK4/6 pathway is downstream to both ER and HER2 pathways
• Combination of CDK4/6 inhibitors and endocrine
therapies or anti-HER2 agents proved to be synergistic in vitro
(Finn RS, et al. Breast Cancer Res 2009)• CDK4/6 inhibitors have also shown activity in models
of acquired resistance to endocrine or HER2-targeted
therapies
(Witkiewicz AK. et al. Genes & Cancer, 2014)The NA-PHER2 Study
HPPF x 6 four-weekly cycles
Herceptin+pertuzumab+palbociclib+FLV Surgery
Pts with early/locally advanced HER2+ AND ER+ BC
H= trastuzumab 8mg/kg 6 mg/kg x 6 P= pertuzumab 840 mg 420 mg x 6
Palbociclib 125 mg/day x 21 days q 28 x 5 FLV=fulvestrant 500 mg q 4 wks x 5
ITT population n=30
Gianni et al. SABCS 2016
pCR 30% in breast; 27% in breast & axilla
• De-escalation ie. take maximum benefit from targeted therapy avoiding chemotherapy is an
extremely appealing concept in patients with triple positive breast cancer
• Chemotherapy+anti HER2 therapy = standard
BIOMARKERS
Meta-dataset of 10 neoadj. trials of CHT +/- anti HER2 therapy with GEP data RBsig was computed and the correlation with pCR was explored
(ER+ /HER2+ pts N= 211)
ttest: 0.09435 pCR
Non pCR
RBsig in ER+/HER2+ BC
ER+/ HER2+
CT+H (N=117) In ER+/HER2+ pts
treated with CHT+
anti-HER2:
RBsig LOW tumors had lower pCR rates compared to
RBsig HIGH
Risi E. et al SABCS 2016
Signature of RB deficiency have been shown to potentially predict response to neoadjuvant chemotherapy
Herschkowitz et al. Breast Cancer Res 2008; Ertel et al. Cell Cycle 2010
Hypothesis
RBsig may help selecting pts with ER+/HER2+ BC who could be spared CHT and treated with ET+ anti-HER2+
CDK4/6 inh
• Pts with RBsig LOW
ET+ anti-HER2+ CDK4/6 inh. will be more active than CHT+ anti-HER2
• Pts with RBsig HIGH
CHT+ anti-HER2 will be more active than ET+ anti-
HER2+ CDK4/6 inh.
TOUCH: trial design
Stratification criteria:
•G8 score (>14 vs ≤14)
•N1 or T>5cm diameter vs. N0 and T 1-5 cm
Primary objective: To explore the interaction between the RBsig status (HIGH or LOW) and pCR
Primary endpoint: pCR (ypT0/ypTis ypN0)
Conclusions
• CDK4/6 inhibitors represent a new treatment option in ER+/HER2neg MBC
• Biomarkers for selecting patients more likely to benefit from CDK4/6 inhibition would be of great clinical utility to maximize benefit and containing costs
• Biomarkers would be of great utility also to develop new
treatment strategies using multiple target blockades
Backup
Statistical assumptions
RBsig
Prevalence A: Palbociclib + letrozole + trastuzumab
B: Paclitaxel +
trastuzumab Odds Ratio (A:B) pCR rate
RBsig low 50% 30% 15% 2.429
RBsig high 50% 10% 50% 0.111
unselected 20% 32.5%
Hypothesized pCR rates in subgroups for sample size determination
An assessable sample size of 120 patients with successful RBsig results was determined to provide 86% power for the test of treatment-by-RBsig
interaction (two-sided α=0.05).
The enrolled sample size is inflated by 20% to 144 patients to account for non-assessable RBsig status (which is determined after randomization).
AR ND MO ZI AT OI N Operable BC
ER+/HER2+
Age ≥65 yo Core biopsy
mandatory
Palbociclib 125 mg/day x21 days q28x 4 Letrozole 2.5 mg/day orally x 16 weeks
Trastuzumab 8 mg/kg 6 mg/kg q 3 wks x 5 Pertuzumab 840 mg 420 mg q 3 wks x 5
Surgery
1:1
TOUCH: trial design
Stratification criteria:
•G8 score (>14 vs ≤14)
•N1 or T>5cm diameter vs. N0 and T 1-5 cm
Primary objective: To explore the interaction between the RBsig status (HIGH or LOW) and pCR
Primary endpoint: pCR (ypT0/ypTis ypN0)
Paclitaxel 80mg/m2 days 1,8,18 q 28 x4
Trastuzumab 8 mg/kg 6 mg/kg q 3 wks x 5 Pertuzumab 840 mg 420 mg q 3 wks x 5
Acknowledgements
(MFAG 14371)
Translational Research Unit, Hospital of Prato
“Sandro Pitigliani” Medical Oncology Unit, Hospital of Prato Functional Genomics & Bioinformatics Units, Proxenia S.r.l