La malattia HER2-positiva:
strategia terapeutica nella pratica clinica e il futuro
G. RICCIARDI
UOC Oncologia Medica, A.O. Papardo, Messina
Dir. Prof. V. Adamo
giusyricciardi81@hotmail.it Sessione 4:
La malattia metastatica
Outline
HER2+ MBC: where are we now?
Emerging approaches in triple positive MBC
Role of pan-HER inhibitors
Emerging therapeutic strategies in pts with brain metastases
Which new anti-HER2 drugs are coming?
Is there a role for Immunotherapy?
Trastuzumab biosimilars
Final Remarks
Milestone of HER2/anti-HER2
Therapies in BC
Survival with HER2+ Metastatic Disease
Tolaney S, ASCO 2018
What is the optimal regimen in 1 st line
regimen?
Pertuzumab-Trastuzumab-Docetaxel the SOC in 1 st line HER2+ MBC
Swain SM, et al. NEJM 2015
“...in patients with HER2-positive metastatic breast cancer, the addition
of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly increased the median overall
survival to 56.5 months, an improvement of 15.7 months over
survival in the control group...”
56.5 mos
40.8 mos 15.7 mos
Pertuzumab-Trastuzumab-Docetaxel in a real world setting
“...There is some concern and debate about whether results obtained in clinical trials can be applied tout court to clinical practice.
(...) The most relevant differences between our population and patients enrolled in the CLEOPATRA trial was the presence of brain metastases, the prevalence of HR positivity, visceral vs non-visceral pattern of metastasization and the prevalence of (neo)adjuvant pretreatment with HT and trastuzumab. Importantly, as shown by our survival analyses, these differences did
not seem to affect efficacy. (...) Notably, mPFS was unexpectedly much greater in the RL setting than in the CLEOPATRA trial (27.8 vs 18.5 months, respectively)...”
De Placido S, et al. Breast 2018
Pertuzumab: Key Clinical Questions?
What is the efficacy of pertuzumab in trastuzumab – pre- treated “real life” populations?
Can pertuzumab use be delayed until second line setting?
Should pertuzumab be given beyond progression?
NO, but an important question to test in clinical
trial(s)
What is the efficacy of pertuzumab in
trastuzumab-pretreated “real life” populations?
Baseline characteristics of patients enrolled in the CLEOPATRA trial
Baselga J, et al. NEJM 2012
Only a minor fraction of patients enrolled in the CLEOPATRA trial were previously exposed to Trastuzumab
Are the results of the trial reproducible in real practice?
Ricciardi GRR & Adamo V, et al. ASCO 2017
Population 35
Median age (range) 50 (20-71)
ECOG PS, median (range) 0 (0-1)
Menopausal Status, n (%)
Pre-menopausal 16 (45.7)
Post-menopausal 19 (54.3)
Surgery, n (%)
Mastectomy 17 (48.6)
Quadrantectomy 18 (51.4)
Lymphadenectomy n (%) 27 (77.1)
Sentinel Node Biopsy n (%) 7 (20)
Subtypes, n (%)
Luminal B 14 (40)
HER2-enriched 21 (60)
Metastatis sites (%)
Lung 20%
Lymph nodes 14.3%
Liver 11.4%
TRASTUZUMAB
Neoadjuvant, n (%) 12 (34.3)
Adjuvant, n (%) 28 (80)
Median PFS 12 mos
Median FU 55.6 mos Median OS 15.2 mos
Safety and Efficacy of the combination of Pertuzumab plus Trastuzumab plus Docetaxel for HER2-positive MBC in pretreated patients with
Trastuzumab in neo/adjuvant setting: a real-life study
Pertuzumab: Key Clinical Questions?
What is the efficacy of pertuzumab in trastuzumab – pre- treated “real life” populations?
Can pertuzumab use be delayed until second line setting?
Should pertuzumab be given beyond progression?
NO, but an important question to test in clinical
trial(s)
Is there a role for Pertuzumab- Trastuzumab outside of 1 st line?
Urruticoechea A, et al. ASCO 2018
Limitations:
H/X not the SOC in 2nd line
Open label design
No statistically-significant improvement in PFS
Benefit in OS, but less than observed in the CLEOPATRA trial (HR 0.76 vs. 0.68)
Pertuzumab: Key Clinical Questions?
What is the efficacy of pertuzumab in trastuzumab – pre- treated “real life” populations?
Can pertuzumab use be delayed until second line setting?e be delayed until second line setting?
Should pertuzumab be given beyond progression?
NO, but an important question to test in clinical
trial(s)
What is the optimal regimen in 2 nd and
other lines?
Overview of improvements in OS brought by anti-HER2 agents in T-pretreated pts
1Cameron D, et al. Oncologist 2010; 2 Geyer CE, et al. NEJM 2006; 3Blackwell KL, et al. JCO 2012; 5Verma S, et al. NEJM 2012; 6 Krop IE, et al.
Lancet Oncol 2014; 7Wildiers H, et al. SABCS 2015.
0 10 20 30
CAPE
14,88
CAPE + LAP
17,25
Cameron D, 2011 [1, 2]
TPC
25,1
T-DM1
30,9
EMILIA [5]
CAPE + LAP
15,8
T-DM1
22,7
TH3RESA [6, 7]
EGF 104900 [3]
LAP
LAP + T
9,5
14,0
T-DM1 vs. capecitabine plus lapatinib previously treated HER2-positive MBC: the EMILIA trial
Verma S, et al. NEJM 2012; Diéras V, et al. Lancet Oncol 2017
“...T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive
advanced breast cancer previously treated with trastuzumab and a taxane...”
Questions regarding T-DM1
What is the efficacy of T-DM1 in pertuzumab – pre-treated “real life” populations?
Should T-DM1 only be used in the second line
setting?
What is the efficacy of T-DM1 in pertuzumab- pretreated “real life” populations?
Fabi A, et al. Fut Oncol 2017
P + T: mPFS 5.0 months (95% CI: 4.3–5.7);
T only: mPFS 11.0 months (95% CI: 7.8–14.2)
Overall response rate was 33.3% in patients with prior pertuzumab and 57.1% in the remaining subjects.
Disease control rate was 47 and 43%, respectively, and clinical benefit rate was 43.3 and 71.1%, respectively.
Median progression-free survival was 5.0 months in patients with prior pertuzumab and 11.0 months in those without (hazard ratio: 2.02; 95% CI:
1.14–3.58; p = 0.01).
Patients treated with T-DM1 who
previously received pertuzumab have
poorer clinical outcomes compared
with those receiving a trastuzumab-only-
based regimen in the first-line setting.
Questions regarding T-DM1
What is the efficacy of T-DM1 in pertuzumab – pre-treated “real life” populations?
Should T-DM1 only be used in the second line
setting?
Is there a role for T-DM1 in 1 st line HER2-positive MBC?
Perez EA, et al. JCO 2017 & ASCO 2017
T-H= T-DM1 = T-DM1 + P
T-DM1 remains the SoC in 2
ndline
Possible option for first line in pts unsuitable for TPH
What would be the role of T-
DM1 if P (APHINITY trial) will
be moved in the adjuvant
setting in high risk pts?
What is the role of lapatinib in the
pertuzumab/T-DM1 era?
Báez-Vallecillo L, et al. SABCS 2016
Lapatinib remains a therapeutic option for pts with HER2-positive MBC despite being previously treated with multiple anti-HER2 therapies.
≥50% of pts obtained clinical benefit for over 6 mos with no significant toxicity
Lapatinib shows a partial lack of cross-resistance with pertuzumab and T-DM1 thus further emphasizing the benefit of using beyond the 2nd line setting
1. Of the 34 pts identified as the target cohort with prior pertuzumab and/or T-DM1 exposure, 29 were available for outcome analysis
2. In the comparison cohort (n= 536) who had received lapatinib without prior pertuzumab and/or T-DM1 exposure, 445 pts were available for outcome analysis
Current advanced HER2-positive breast cancer treatment guidelines
Pondé N, et al. Cancer Treat Rev 2018
Outline
HER2+ MBC: where are we now?
Emerging approaches in triple positive MBC
Role of pan-HER inhibitors
Emerging therapeutic strategies in pts with brain metastases
Which new anti-HER2 drugs are coming?
Is there a role for Immunotherapy?
Trastuzumab biosimilars
Final Remarks
25
Johnston S R Clin Cancer Res 2010;16:1979-1987
pTEN
cbl
Cross-talk between different signal transduction
is the best studies cause of resistance
Kaufman B, et al. JCO 2009, Johnston S, et al. JCO 2009; Burstein HJ, et al. JCO 2014
TAnDEM EGF30008
Anastrazole vs.
Anastrazole + Trastuzumab
Letrozole vs.
Letrozole + Lapatinib
Fulvestrant vs.
Fulvestrant + Lapatinib
Single Agent HER2 Targeted Therapy Adds Modestly To Endocrine Therapy
CALGB 40302
mPFS: 4.8 vs. 2.4 mos mPFS: 8.2 vs. 3.0 mos mPFS: 5.9 vs. 3.3 mos
1 st line Trastuzumab + AI ± Pertuzumab:
the PERTAIN study
Rimawi M, et al. JCO 2018
Rimawi M, JCO 2018
P + T significantly improved PFS compared with trastuzumab alone
in all population
Among patients who did not receive induction chemotherapy: mPFS
was 21.72 mo in the pertuzumab+
trastuzumab arm and 12.45 mo in the trastuzumab arm
PERTAIN efficacy results
ALTERNATIVE: efficacy results
“…Dual HER2 blockade with LAP + TRAS + AI showed superior PFS benefit versus TRAS + AI in pts with HER2-positive/HR-positive MBC.This
combination offers an effective and safe chemotherapy-sparing
alternative treatment regimen for this pts population…”
Johnston SR, et al. JCO 2018
Study Ph. Design Population n. Arm(s) Objectives
DETECT
V/CHEVENDO III Randomized, open-label
1st-3rd line therapy
HER2+/ER+ MBC 270
CHT + T + P vs.
ET + T + P
AEs (primary);
Quality-adjusted survival, ORR, OS, PFS (secondary)
CDK4/6 inhibitors in HER2+ BC
Ongoing clinical trials with anti-HER2 agents + ET+ CDK4/6 inhibitors
Study Ph. Design Population n. Arm(s) Objectives
PATINA II Randomized, open-label
HER2+/ER+ MBC, prior anti-HER2 +
CHT induction therapy
496
Palbociclib + T + P + ET vs.
T + P + ET
PFS (primary);
OS, 3-yr/5-yr OS, ORR, DOR, CBR, PROs
(secondary)
PATRICIA II Randomized, open-label
HER2+ MBC, 2-4 prior anti-HER2
therapy lines
138
ER-: T + Palbociclib ER+: T + Palbociclib ±
Letrozole
PFS (primary);
CBR, ORR, safety (secondary)
MonarcHER II Randomized, open-label
HER2+/ER+ MBC, postmenopausal,
≥2 prior anti-HER2 therapies
225
Abemaciclib + T + Fulvestrant vs.
Abemaciclib + T vs.
T + SoC CHT
PFS (primary);
OS, ORR, DOR, CBR (secondary)
Adapted from Brandão M, et al. Exp Rev Anticancer Ther 2018 Legend: CHT, chemotherapy; T, Trastuzumab; P, Pertuzumab; ET, endocrine therapy.
Outline
HER2+ MBC: where are we now?
Emerging approaches in triple positive MBC
Role of pan-HER inhibitors
Emerging therapeutic strategies in pts with brain metastases
Which new anti-HER2 drugs are coming?
Is there a role for Immunotherapy?
Trastuzumab biosimilars
Final Remarks
pan-HER inhibitors in HER2-positive MBC
STUDY Phase Drug(s) Population ORR PFS OS
LUX-Breast-1 [1] III
Afatinib + VNB vs.
VNB + H
HER2+ MBC, prior trastuzumab
46.1%
vs.
47.0%
5.5 mos vs.
5.6 mos
19.6 mos vs.
28.6 mos
LUX-Breast-3 [2] II
Afatinib vs.
Afatinib + VNB vs.
TPC
HER2+ BC with progressive BMs prior Trastzumab and/or Lapatinib
0%*
vs.
8%*
vs.
14%*
2.74 mos vs.
2.83 mos vs.
4.23 mos
13.27 mos vs.
8.58 mps vs.
11.98 mos
Martin M, 2013 [3] II
Neratinib vs.
Lap-Cape
HER2+ MBC, prior trastuzumab
29%
vs.
41%
4.5 mos vs.
6.8 mos
19.7 mos vs.
23.6 mos
Saura C, 2014 [4] I/II Neratinib + Cape
HER2+ MBC, prior trastuzumab and lapatinib
64% (no prior lapatinib) 57% (prior
lapatinib)
9.27 mos (no prior lapatinib) 8.26 mos (prior
lapatinib)
N.R.
TBCRC 022 [5] II Neratinib HER2+, BMs 8%* 1.9 mos N.R.
NEfERT-T [6] II
Neratinib-Tax vs.
H-Tax
HER2+, 1st line
74.8%
vs.
77.6%
12.9 mos
vs. 12.9 mos N.R
1Harbeck N, et al. Lancet Oncol 2016; 2Cortes J, et al. Lancet Oncol 2015; 3Martin M, et al. Eur J Cancer 2013; 4 Saura C, et al. JCO 2014; 5Freedman RA, et al.
JCO 2016; 6 Awada A, et al. JAMA Oncol 2016
* Intracranial ORR
Outline
HER2+ MBC: where are we now?
Emerging approaches in triple positive MBC
Role of pan-HER inhibitors
Emerging therapeutic strategies in pts with brain metastases
Which new anti-HER2 drugs are coming?
Is there a role for Immunotherapy?
Trastuzumab biosimilars
Final Remarks
CNS tropism
Limited systemic options
In the RegisHER study 37% of pts with HER2+ BC had brain mts detected over the study
7% of diagnosis
30% over course of their disease
Worse outcome with presence of brain mts
median survival 26.3 months with vs 44.6 months without
Sperduto PW, et al. J Neurooncol. 2013; Brufsky AM, et al. Clin Cancer Res 2011
Brain Metastases from Breast Cancer
HER2-positive Breast Cancer With Brain Metastases in the era of HER2-targeted therapy
Morikawa A, et al. Clin Breast Cancer 2018
“...Significantly better survival from BM was noted for patients with higher performance status,
fewer BM lesions, continued use of HER2- targeted therapy after BM
diagnosis, and better controlled extracranial
metastatic disease.
…Systemic Treatment anti-HER2 play an important role especially in
HER2+ patients: Median OS from BMs onset can
now exceed 2 years .”
Adapted from Duchnowska R, et al. Cancer Treat Rev 2018
Completed prospective clinical trials of TKIs in HER2+
BC with established brain metastases
Study Phase n previous CHT/anti-HER2
Previous
WBRT Arm(s) CNS
ORR
TTP/PFS (mos)
OS (mos) EGF105084 [1] II 237
50 yes/yes 100% Lapatinib
Lapatinib + Capecitabine
6%
20%
2.4 3.6
6.4 N.R.
LANDSCAPE [2] II 45 yes/no 0% Lapatinib + Capecitabine 66% 5.5 91% at
6 mos
EMILIA [3] III 95* yes/yes 60%
51%
T-DM1
Lapatinib + Capecitabine N.R. 5.6 5.7
26.8 12.9 Shawky et al. [4] II 21 yes/yes 76% Lapatinib + Capecitabine 33% 5.5 11.0
TBCRC [5] II 37 yes/yes 65% Neratinib + Capecitabine 49% 5.5 13.5
LUX-Breast 3 [6] II 121 yes/yes
65%
74%
60%
Afatinib
Afatinib + Vinorelbine TPC
0%
8%
14%
2.6 2.7 4.1
13 8 12
*Subset analysis
[1] Lin NU, et al. Clin Cancer Res 2009; [2] Bachelot T, et al. Lancet Oncol 2013; [3 ]Krop IE, et al. Ann Oncol 2015; [4] Shawsky H, et al. J Egypt Natl Cancer Inst 2014; [5] Freedman RA, et al. JCO 2016; [6] Cortes J, et al. Lancet Oncol 2015.
“...The triplet combination of tucatinib, capecitabine, and trastuzumab demonstrated preliminary activity in pretreated HER2-positive pts with MBC, including patients previously
treated with pertuzumab, T-DM1 and lapatinib.
The mPFS in pts with brain metastases of 6.7 months was encouraging when compared with other systemic therapies used
in a similar patient population....”
Murthy R, et al. Lancet Oncol 2018; Borges VF, et al. JAMA Oncol 2018
“...The combination of tucatinib and T-DM1 demonstrated preliminary activity in pretreated pts with ERBB2/HER2-
positive MBC as reflected by a mPFS of 8.2months (95%CI, 4.8-10.3 months). The mPFS among pts with brain metastases was 6.7 months (95% CI, 4.1-10.2 months), which is encouraging compared with other systemic therapies used to treat a similar pts population...”
Phase II study of Tucatinib vs. Placebo in Combination
with Capecitabine & Trastuzumab in HER2+ MBC
Outline
HER2+ MBC: where are we now?
Emerging approaches in triple positive MBC
Role of pan-HER inhibitors
Emerging therapeutic strategies in pts with brain metastases
Which new anti-HER2 drugs are coming?
Is there a role for Immunotherapy?
Trastuzumab biosimilars
Final Remarks
New combination strategies in HER2-positive MBC
Pondé N, et al. Cancer Treat Rev 2018
Antibody-drug conjugates
Tolaney S. ASCO 2018
SYD985: preliminary data from HER2-positive MBC expansion cohort of the phase 1 study
Saura C, et al. ASCO 2018
FDA granted Fast Track Designation
Novel Anti-HER2 Antibodies: Margetuximab
Novel Anti-HER2 Antibodies: Other
Outline
HER2+ MBC: where are we now?
Emerging approaches in triple positive MBC
Role of pan-HER inhibitors
Emerging therapeutic strategies in pts with brain metastases
Which new anti-HER2 drugs are coming?
Is there a role for Immunotherapy?
Trastuzumab biosimilars
Final Remarks
The prevalence of somatic mutations across human cancer types
Alexandrov LB, et al. Nature 2013
Lower median rate of somatic mutations detected compared to most immune
sensitive cancers
HER2+ Breast Cancer are higly infiltrated with T cells
Quantity is prognostic and TIL biomarker is robust surrogate
Trastuzumab has know immune MOA
Trastuzumab elicits antitumor immunity producing antibody-dependent cellular cytotoxicity (ADCC)
Rationale for immunotherapy in HER2- positive breast cancer
Solinas C, et al. ESMO Open. 2017; Denkert C, et al. Lancet Oncol 2017; Stagg J, et al. Proc Natl Acad Sci U S A. 2011
Pembrolizumab + Trastuzumab in HER2- positive MBC: the phase I/II PANACEA study
Loi S, et al. SABCS 2017
Higher stromal TILs (sTILs) associated with better response and disease control
Loi S, et al. SABCS 2017
sTILs ≥5% as potential predictive marker
Outline
HER2+ MBC: where are we now?
Emerging approaches in triple positive MBC
Role of pan-HER inhibitors
Emerging therapeutic strategies in pts with brain metastases
Which new anti-HER2 drugs are coming?
Is there a role for Immunotherapy?
Trastuzumab biosimilars
Final Remarks
HERITAGE: EFFICACY RESULTS
Rugo HS, et al. ASCO 2018
Outline
HER2+ MBC: where are we now?
Emerging approaches in triple positive MBC
Role of pan-HER inhibitors
Emerging therapeutic strategies in pts with brain metastases
Which new anti-HER2 drugs are coming?
Is there a role for Immunotherapy?
Trastuzumab biosimilars
Final Remarks
Final Remarks
Pertuzumab and T-DM1 led to improved outcomes with favorable toxicity in 1
stand 2
ndline HER2+ MBC, respectively, and are the preferred regimens in these settings;
However, some important clinical questions (Pertuzumab in T-pretreated pts? Pertuzumab outside 1st line?
T-DM1 in pertzumab-pretreated pts?) are still open.
