Point of View on HER2 Positive:
Metastatic
Patrizia Trenta 29/01/18
Key points of SABCS 2017 on HER2+
metastatic disease
• Immunotherapy - PANACEA trial
• New drugs
- New TKI / ADC: Pyrotinib / DS-8201
• New combinations
- CHT + anti HER2 Ab: Metronomic Cyclofosfamide
• Brain metastases
- Italian experience
Immunotherapy: PANACEA study
Immunotherapy: PANACEA study
Her2 + breast cancer has high levels of T cells infiltration
1,2 TILs are predictive of good response (and pCR) to anti HER 2 drugs/CHT in EBC and show a prognostic value in MBC
1,2 Anti Her2 mAbs also show immune mediated mechanism of action (ADCC)
Anti-PD-1 or anti-CD137 mAbs can significantly improve the therapeutic activity of anti-ErbB-2 mAb in preclinical models
31 Loi S et al, Ann Oncol. 2014 Aug;25(8):1544-50 2 Luen SJ, Lancet Oncol. 2017 Jan;18(1):52-62
3 Stagg J, Loi S et al, PNAS. 2011 Apr 26;108(17):7142-7
Immunotherapy: PANACEA study
Primary Objectives
Phase Ib: dose finding for Pembrolizumab in combination with standard dose of Trastuzumab
Phase II: Efficacy (ORR, PFS, DoR, OS, DCR) and safety in PDL1 + group
Secondary Objectives: Efficacy on PDL-1 - subgroup of the drug combination Exploratory: Efficacy Results According to TIL levels at baseline
ER status
HER2 expression
PD-L1 expression
TIL level
Immunotherapy: PANACEA study
Immunotherapy: PANACEA study
Immunotherapy: PANACEA study
Immunotherapy: PANACEA study
PANACEA study met its primary endpoint in
PDL-1 + group (ORR 15%, DCR 25%); durable reponses
No responses in PDL- 1 - group
Metastatic lesions are poorly immunogenic
Stromal TIL > 5% associated to better response (ORR 39%, DCR 47%)
Immunotherapy: PANACEA study
Identification of a new subset of patients within a subset (HER 2+) PDL-1 and sTIL testing to detect who has the best chance to respond to immunotherapy (PDL-1 + and sTIL > 5%)
Data needed in previous lines, in combination and/or in populations more corresponding to clinical practice
Immunotherapy: PANACEA study
Oral irreversible pan-ErbB TKI
ORR 50% and CBR at 24 w 61%, ORR 33,3% in Trastuzumab pretreated patients, 83,3% in Trastuzumab naive 1
New drugs: Pyrotinib
1 Ma et al, JCO Sep 20;35(27):3105-3112
Primary endpoint: ORR (assessed by investigators) Secondary endpoint: PFS, TTP, OS, safety, DoR Stratification based on prior treatments*
n= 65
n= 63
*46% of pts in both groups didn’t receive any anti HER2 mAb before study entry
New drugs: Pyrotinib
0 20 40 60 80 100
Pyr + Cape Lap + Cape
CR PR SD PD ORR
78,5%*
57,1%*
ORR %
* p=0,01
Increased PFS 18 vs 7 months (HR 0.36, p<0,0001), irrespecitve of prior
Trastuzumab
Phase III trial ongoing (NCT02973737)
Grade 3-4 toxicities higher in Pyr/Cap group:
HFS (26,6% vs 20,6%) Diarrhea ( 15,4% vs 4,8%) Neutropenia ( 9,2% vs 3,2%) Vomiting ( 4,6% vs 1,6%)
SAE : 7,7% vs 6,3%
New drugs: Deruxtecan
Novel HER2-targeting ADC with a topoisomerase I inhibitor payload (exatecan derivative), a cleavable peptide-based linker, and a high drug-to-antibody ratio of 7 to 82 Highly membrane permeable
n=24
Doi et al, Lancet 2017
ORR: 43% DcR: 91%
Responses observed at higher doses Antitumor activity in patients
treated with T-DM1 or Trasuzumab and in patients with HER2-low tumors No dose limiting toxic effects or
deaths
New drugs: Deruxtecan
Pivotal phase 2 DESTINY-Breast01 study to examine efficacy and safety of DS- 8201 in patients with HER2-positive unresectable and/or metastatic breast cancer who are resistant or refractory to T-DM1 is ongoing (NCT03248492)
New combinations: older patients
Cyclofosfamide: 50 mg/day
New combinations: older patients
7 months of PFS gain in elderly/frail HER2+ MBC population, with an
acceptable safety profile.
The benefit of avoiding chemotherapy side-effects with the use of dual
anti-HER2 blockade only, does not compensate for a significant loss of activity in the metastatic setting.
A possible option for frail patients
87 of 303 pts with Brain Met (BM group) at baseline
- Efficacy of T-DM1 on BM
- Comparison between BM and nBM group in terms of outcome
Brain Metastases: Italian experience
BM group
n= 87(%) nBM group n= 216 (%) Number of extracranial
sites of disease 2 1 3 4
10 (11,5) 23 (26,4) 25 (28,7) 29 (33)
74 (34,3) 93 (43) 38 (17,6)
11 (5) Number of previous lines
2 1 3
28 (32,9) 24 (28,2) 33 (38,8)
89 (42,4) 49 (23,3) 72 (34,3)
Fabi A. et al, SABCS 2017 P1-17-02
1 Krop IE, Annals of Oncology 26: 113–119, 2015
EMILIA trial: Among patients with CNS metastases, PFS (brain) and Time
to Symptom Progression were similar in T-DM1 and Lapatinib / Capecitabine Arms, while OS was confirmed to be longer for Pts treated with T-DM1 (26 vs 12,9 months, p= 0,008) 1
Brain Metastases: Italian experience
Fabi A. et al, SABCS 2017 P1-17-02
PFS
II line PFS
III line PFS
Fabi A. et al, SABCS 2017 P1-17-02
Final considerations
Really new? Clinically useful? Practice changing?
PANACEA First time for
immunotherapy in HER2+
MBC in a clinical trial
NEW SUBSET in HER2+
disease (PDL 1 and sTIL)
Not now, patient population not completely
corresponding to clinical practice
Yes, if with further data confirm
efficacy
Pyrotinib Yes/No --> New drug with a well known mechanism of action
Not completely, patient population not
completely
corresponding to clinical practice (46% not
pretreated with anti HER2 drugs)
Yes, if phase III results confirm impressive
efficacy
(ORR 78%)
Final considerations
Really new? Clinically useful? Practice changing?
Deruxtecan Yes/No --> New drug with a well known mechanism of action
Patient population quite corresponding to clinical practice (all pretreated with anti HER2 drugs), but
phase I
Yes, if further ongoing trials
confirm efficacy in T-DM1 resistant population
Metronomic Old drug, but new combination in HER 2+
disease
YES, for a particular subgroup of patients
Why not? It may become an option for old or frail patients
