Pertuzumab e Trastuzumab-DM1. Filippo Montemuro, M.D. Divisione di Oncologia Medica 1 Fondazione del...
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Transcript of Pertuzumab e Trastuzumab-DM1. Filippo Montemuro, M.D. Divisione di Oncologia Medica 1 Fondazione del...
Pertuzumab e Trastuzumab-DM1.
Filippo Montemuro, M.D.
Divisione di Oncologia Medica 1
Fondazione del Piemonte per l’Oncologia/Istituto per la Ricerca e la Cura del Cancro, Candiolo
HER2 targeting has changed the natural history of HER2-positive advanced breast cancer
Dawood et al, J Clin Oncol 28;92, 20091991-2007
Proposed Mechanisms of Action of Trastuzumab
Spector, J Clin Oncol 27;5838, 2009
From linear cascades to integrated networks
Evolutionary processes: Gene Duplication Subfunctionalization (i.e. HER2 no known ligands, HER3 no
tyrosine kinase activity)
Amit I, Wides R, Yarden Y, Molecular Systems Biology 2007
1 ligand 10 ligands
Targeting key pathways in HER signalling…and beyond
LapatinibNeratinibBIBW 2992CanertinibErlotinibGefitinib
Trastuzumab/DM1PertuzumabMM-111
PertuzumabCixitumumab
EverolimusTemsirolimus
ADAM 17 inhibitors
HDAC inhibitors
Endothelial Cell
VEGFR
PDGFR
PDGF
VEGF
BevacizumabSorafenibSunitinibPazopanib
HSP90Inhibitors
HER2:HER3 dimers may provide an escape mechanism from trastuzumab
++++
+++++++
Signaling activity
+ +++
Homodimers Heterodimers
HER1:HER1HER2:HER2
HER3:HER3HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3
HER2:HER4HER3:HER4
Tzahar, et al. Mol Cell Biol 1996Tzahar et al. Mol Cell Biol 1996;
Sergina et al. Nature 2007
Different mechanisms of action of trastuzumab and pertuzumab on heterodimers
Activity of pertuzumab in HER2-negative breast cancer
Gianni et al. J Clin Oncol, 28; 1131, 2010
Toxicity profile of pertuzumab
Gianni et al. J Clin Oncol, 28; 1131, 2010
8 patients experienced drops in LVEF ≥10% to <50%, including 1 CHF
Pertuzumab, demonstrates synergistic activity with trastuzumab
● Preferentially inhibits ligand-independent HER2 signaling
● Prevents shedding of HER2 ECD● Flags cells for destruction by the
immune system
● Inhibits formation of HER2 dimer pairs● Suppresses multiple HER signalling pathways,
leading to a more comprehensive blockade of HER2-driven signalling
● Flags cells for destruction by the immune system
HER2 receptor
TrastuzumabPertuzumab
Subdomain IV of HER2
Dimerization domain of HER2
Junttila et al. Cancer Cell 2009
Activity of trastuzumab and pertuzumab in HER2 positive xenografts
Scheuer et al, Cancer Res 2009
Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy
Pertuzumab + trastuzumab
(n=66)
Cohorts 1 and 21
HER2-positive MBC Progressed on trastuzumab +
chemotherapy (Cohorts 1 and 2, n=66)
HER2-positive MBC Progressed on trastuzumab +
chemotherapy (n=29)
Pertuzumab(n=29)
Pertuzumab + trastuzumab
(n=15)Cohort 32
Primary objectives● Safety and efficacy
Population● ≤3 prior lines cytotoxic therapy (including adjuvant treatment)
1. Baselga et al. JCO 2010; 2. Baselga et al. SABCS 2009
Pertuzumab / trastuzumab combination therapy more active than treatment with either agent alone
Cohorts 1 and 21,2
(P + H) (n=66)
Cohort 33 (P)
(n=27*)
Cohort 33 (P P + H)
(n=11†)
CR, % 7.6 0.0 0.0
PR, % 16.7 3.4 21.4
ORR, % 24.2 3.4 21.4
SD 6 months, % 25.8 6.9 21.4
CBR, % (CR + PR + SD 6 months)
50.0‡ 10.3 37.5
PD, % 50.0 82.8 57.1
1. Gelmon et al. ASCO 2008; 2. Baselga et al. JCO 2010;
3. Baselga et al. SABCS 2009CR, complete response; PR, partial response; SD, stable disease
*n=27, as at data cut-off 2/29 patients had not reached overall best response endpoint (8 cycles of assessment during this phase); †n=11, as at data cut-off 4/15 patients had not reached overall best response endpoint(8 cycles of assessment during this phase); ‡at data cut-off, 21 (31.8%) patients had not experienced PD
Toxicity, non cardiac
Baselga et al, J Clin Oncol, 28;1138, 2010
Cardiac toxicity
Baselga et al, J Clin Oncol, 28;1138, 2010
Further development of this combination
Accrual completedAccrual completed
HER2-positive MBC No prior chemotherapy for MBC
(except 1 prior hormonal regimen)(n=800*)
Trastuzumab + docetaxel +
placebo
Trastuzumab + docetaxel + pertuzumab
1:1
Cleopatra
HER2-positive MBC 2nd line, progressed on prior trastuzumab
(n=450)
Trastuzumab + capecitabine +
placebo
Trastuzumab + capecitabine +
pertuzumab
1:1
125 centers, 20 countries125 centers, 20 countries
Pherexa
The NEOSPHERE trial
Trastuzumab + Docetaxel
Trastuzumab + Docetaxel + Pertuzumab
Trastuzumab + Pertuzumab
Docetaxel + Pertuzumab
Surgery
FEC X 3 trastuzumab q3w until week 52
FEC X 3 trastuzumab q3w until week 52
Trastuzumab + Docetaxel
FEC X 3 trastuzumab q3w until week 52
HER2+LABC
400 patients
FEC X 3 trastuzumab q3w until week 52
End Points:-pCR-Biomarker analysis
Gianni et al. SABCS 2011
Gianni et al. SABCS 2011
Gianni et al. SABCS 2011
Gianni et al. SABCS 2011
Gianni et al. SABCS 2011
Gianni et al. SABCS 2011
PI3K inhibition
Multiple targeting with trastuzumab, pertuzumab and GDC-0941
Trastuzumab-DM1
T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells
Receptor-T-DM1 complex is internalized into HER2-positive cancer cell
Potent antimicrotubule agent is released once inside the HER2-positivetumor cell
T-DM1 binds to the HER2 protein on cancer cells
• Trastuzumab-like activity by binding to HER2• Targeted intracellular delivery of a potent antimicrotubule
agent, DM1
Phase I study in patients with HER2-positive advanced breast cancer
Phase I study in patients with HER2-positive advanced breast cancer
Clinical Study DescriptionsStudy TDM4258g (n=112) Study TDM4374g (n=110)
Study design Multi-institutional, single-arm Phase II US studies
Patient population (all with locally confirmed HER2-positive MBC)
Received prior chemotherapy for MBC
Progressed after exposure to at least one HER2-directed therapy (trastuzumab)
Previously treated with an anthracycline, a taxane, capecitabine, lapatinib and trastuzumab
Received at least two HER2-directed regimens for MBC, and progressed on the last regimen received
Prior systemic therapy
Received a median of 3 prior chemotherapy agents for MBC (range 1–12)
All received prior trastuzumab; 67/112 (60%) patients had also received prior lapatinib
Received a median of 7 prior chemotherapy agents for MBC (range 1–15)
All received prior lapatinib and trastuzumab
Study treatmentT-DM1 (3.6 mg/kg) was given by IV infusion over 30–90 minutes every 3 weeks (q3w) until disease progression
Primary objectivesObjective response rate (ORR) per RECIST by independent review facility (IRF)
Antitumor Activity, All Treated Patients
TDM4374g* (n=110)
TDM4258g† (n=112)
ORR,% (95% CI)‡ 32.7 (24.1–42.1) 25.9 (18.4–34.4)
Clinical benefit rate, % (95% CI)§ 38.8 (38.8–57.9) 39.3 (30.3–48.3)
ORR=objective response rate.* Approximately 9 months minimum follow-up from last patient in (LPI)† Approximately 12 months minimum follow-up from LPI‡ Complete or partial response determined by 2 tumor assessments ≥ 28 days apart§ Includes patients who achieved an ORR, partial response, or stable disease of ≥ 6 months
• Both Phase II studies demonstrated clinically meaningful ORR for single-agent T-DM1.
Prior Chemotherapy and Anti-HER2 Therapy:TDM4258g
Summary of activity as a single agent: TDM4258g
Activity according to HER2 status
Adverse events
Patients treated with TDM1 retain sensitivity to further antiHER2-based therapy
Randomized, phase II, international, open-label study HER2-positive, measurable disease required Stratification factors
World region, prior adjuvant trastuzumab therapy, disease-free interval Primary endpoints: PFS by INV, safety Key Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control
Study Design
1:1 HER2-positive, recurrent locally advanced BC or MBC (n=137)
T-DM13.6 mg/kg Q3W until PD
Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W
+ Docetaxel 75 or 100 mg/m2 Q3W
CrossoverT-DM1PD
Perez EA, et al. Abstr LBA3. ESMO 2010Perez EA, et al. Abstr LBA3. ESMO 2010
Objective Response by Investigator (ITT)Randomized Patients
T-DM1(n=67)
Trastuzumab + Docetaxel
(n=70)
Patients with an Objective Response,* n (%) 32 (47.8) 29 (41.4)
95% CI (35.4, 60.3) (30.2, 53.8)
Patients with Clinical Benefit,† n (%) 37 (55.2) 40 (57.1)
95% CI (43.1, 67.2) (44.8, 68.9)
Objective Responses, n (%)
Complete Response 3 (4.5) 1 (1.4)
Partial Response 29 (43.3) 28 (40.0)
Stable Disease‡ 22 (32.8) 29 (41.4)
Progressive Disease 8 (11.9) 4 (5.7)
Unable to Evaluate 4 (6.0) 4 (5.7)* Objective response = complete or partial response based on RECIST 1.0 determined on two consecutive tumor assessments at least 4 weeks apart† Clinical benefit = objective response or maintained stable disease for at least 6 months from start of study treatment‡ Stable disease includes 11 patients with unconfirmed partial response (5 in T-DM1 arm and 6 in the trastuzumab + docetaxel arm) Perez EA, et al. Abstr LBA3. ESMO 2010Perez EA, et al. Abstr LBA3. ESMO 2010
AE Summary Safety Evaluable Patients
T-DM1(n=67)
Trastuzumab+Docetaxel(n=68)
Any AE, n (%) 63 (94.0) 68 (100.0)
Grade ≥3 AE 25 (37.3) 51 (75.0)
Serious AE* 13 (19.4) 15 (22.1)
Three most common AEs (any grade) in T-DM1 arm Nausea Fatigue Pyrexia
32 (47.8)31 (46.3)24 (35.8)
27 (39.7)29 (46.2)14 (20.6)
Three most common AEs (any grade) in trastuzumab + docetaxel arm Alopecia Neutropenia Diarrhea
1 (1.5)5 (7.5)
7 (10.4)
45 (66.2)39 (57.4)31 (45.6)
* AEs that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability/incapacity, or are congenital anomalies/birth defects
* AEs that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability/incapacity, or are congenital anomalies/birth defects
Perez EA, et al. Abstr LBA3. ESMO 2010Perez EA, et al. Abstr LBA3. ESMO 2010
Phase Ib/II trial of T-DM1 + pertuzumab in patients with locally-advanced and MBC who were previously treated with trastuzumab
Phase Ib: 3+3 dose escalation• Cohort I: T-DM1 3.0 mg/kg; pertuzumab
(840 mg loading dose, 420 mg maintenance dose)• Cohort II: T-DM1 3.6 mg/kg; pertuzumab
(840 mg loading dose, 420 mg maintenance dose)Phase II
• Expansion at dose level established in Phase Ib
Dose escalation phase(completed)
Expansion phase(completed)
Phase Ib/II: HER2-positive MBC in all therapeutic lines
(n=67)
T-DM1 + pertuzumab
(n=9)
T-DM1 + pertuzumab
(n=58, including 22 first line)
Primary endpoints:• Safety• ORR by RECIST 1.0
Secondary endpoints:• PFS• DoR
Heavily pretreated population:• Median of 6 prior therapeutic agents in the metastatic setting
Miller et al. ASCO 2010
T-DM1 + pertuzumab shows promising efficacy in patients pretreated with trastuzumab + lapatinib
Cohort I, n (%) (n=3)
Cohort II, n (%) (n=25)
Total, n (%) (n=28)
PR 2 (66.7) 8 (32.0) 10 (35.7)
SD 1 (33.3) 12 (48.0) 13 (46.4)
PD 0 4 (16.0) 4 (14.3)
Missing 0 1 (4.0) 1 (3.6)
ORR was 35.7% (10/28 patients), per investigator assessment All responses were confirmed PRs 1/13 patients with SD had an unconfirmed response
Miller et al. ASCO 2010Miller et al. ASCO 2010
T-DM1 + pertuzumab has an encouraging safety and tolerability profile
Key AE, % Grade 3, % Grade 4, % Total (all grades), %*
Any Events 36.4 4.5 100
Fatigue 13.6 0 52.3
Nausea 4.5 0 5 .0
Thrombocytopenia 6.8 4.5 27.3
Diarrhea 2.3 0 25.0
Vomiting 4.5 0 22.7
AST increase 6.8 0 20.5
Dyspnea† 2.3 0 20.5
AST, aspartate aminotransferase Miller et al. ASCO 2010Miller et al. ASCO 2010
*One Grade 5 AE was reported (pneumonia) in a patient who died before her first tumor assessment. This AE was considered to be unrelated to study treatment †Primarily attributed to pneumonia or the disease under study (lung metastases & pleural effusions)
*One Grade 5 AE was reported (pneumonia) in a patient who died before her first tumor assessment. This AE was considered to be unrelated to study treatment †Primarily attributed to pneumonia or the disease under study (lung metastases & pleural effusions)
First-line T-DM1 + pertuzumab vs trastuzumab + docetaxel
Clinicaltrials.gov
Primary endpoints● PFS (independent assessment)● SafetySecondary endpoints● ORR (independent assessment)● OS● 1-year survival● PFS● ORR (investigator assessment)● CBR● TTF● DoR● Safety and tolerability
HER2-positive MBCNo prior chemotherapy
(n=1092)
Trastuzumab + taxane
T-DM1 + placebo
T-DM1 +pertuzumab
Global study starts summer 2010332 centers in 40 countries