Sponsored by Roche. There is a debate In pretreated Her2+ mBC as to whether the indisputable benefit of T-DM1 (an antibody drug conjugate anti Her2) over lapatinib (a small anti Her2 TKI) seen in the EMILIA trial also translates to CNS disease. The subgroup analysis of the EMILIA clearly shows that patients with CNS disease do not appear to have worse outcomes when treated with the big (T-DM1) as opposed to the small (lapatinib) drug.

1. The controversy over CNS metastases in
Her2+ Breast Cancer: Does size matter?
Mauricio Lema Medina MD - Clínica de Oncología Astorga,
Clinica SOMA, Medellín

2. YOUR LOGO
Disclaimer
 "Esta presentación ha sido creada por el autor de la charla y es de
su propiedad. La información, conceptos y opiniones aquí
expresados son responsabilidad del autor y no comprometen a
Productos Roche S.A., sus colaboradores o compañías vinculadas".

3. @onconerd

4. Page  4
Slamon DJ et al. N Engl J Med 2001;344:783
Overall Survival
Trastuzumab cardiac dysfunction
Seidman A, et al. J Clin Oncol. 2002;20:1215-1221.

5. Page  5
Cameron D, Br Cancer Treat Res, 2008

6. Trastuzumab
Lapatinib

7. Page  7
Baselga J et al. N Engl J Med 2012;366(2):109-19.

8. Genentech Confidential—Internal Use Only
Anatomy of an Antibody-Drug Conjugate (ADC)
Antibody targeted
to tumor
Very potent
chemotherapeutic drug
• Tubulin polymerization inhibitors
• Maytansines (DM1, DM4)
• Auristatins (MMAE, MMAF)
• DNA damaging agents
• Calicheamicins
• Duocarmycins
• Anthracyclines (doxorubicin)
• Humanized monoclonal
Ab (IgG1)
• mAb with Fc
modifications (modulate
ADCC, CDC activity)
• Other mAb fragments
8
Linker stable in
circulation
• Linker biochemistry
• Acid labile (hydrazone)
• Enzyme dipeptides (cleavable)
• Thioether (uncleavable)
• Hindered disulfide (uncleavable)
• Site of conjugation
• Fc, HC, LC

9. Trastuzumab Emtansine (T-DM1):
Mechanism of Action
HER2
Adapted from LoRusso PM, et al. Clin Cancer Res 2011.
Nucleus
Trastuzumab-specific MOA
•Antibody-dependent cellular
cytotoxicity (ADCC)
•Inhibition of HER2 signaling
•Inhibition of HER2 shedding
P
P
P

10. Trastuzumab Emtansine (T-DM1):
Mechanism of Action
Emtansine
release
Inhibition of
microtubule
polymerization
Internalizatio
n
HER2
Adapted from LoRusso PM, et al. Clin Cancer Res 2011.
T-DM1
Lysosome
Nucleus
P
P
P
Trastuzumab-specific MOA
•Antibody-dependent cellular
cytotoxicity (ADCC)
•Inhibition of HER2 signaling
•Inhibition of HER2 shedding

11. MARIANNE
NEGATIVE TRIAL

12. Primary endpoint: PFS by independent review
Verma S, et al. N Engl J Med. 2012 Nov 8;367(19):1783-

13. Secondary endpoint: OS
Verma S, et al. N Engl J Med. 2012 Nov 8;367(19):1783-

14. Trastuzumab
+ Paclitaxel.
2001
Phase III
Trastuzumab
+ Docetaxel
2005
Lapatinib +
Capecitabine
2006
Phase III
Slamon DJ, et al. (2001) N Engl J Med 344:783–792.
Marti M, et al. J Clin Oncol 23:4265–4274.
Geyer, et al. NEJM, 2006
Baselga, et al. NEJM, 2012
Verma, et al. NEJM, 2012
1st-line
Pertuzumab +
Trastuzumab +
Docetaxel
2012
T-DM1
2012
2nd--line
Phase III
CLEOPATRA
Phase III
EMILIA
Current 1st- and 2nd-line therapies in Her2+
MBC

15. Trastuzumab
+ Paclitaxel.
2001
Phase III
Trastuzumab
+ Docetaxel
2005
Lapatinib +
Capecitabine
2006
Phase III
Slamon DJ, et al. (2001) N Engl J Med 344:783–792.
Marti M, et al. J Clin Oncol 23:4265–4274.
Geyer, et al. NEJM, 2006
Baselga, et al. NEJM, 2012
Verma, et al. NEJM, 2012
1st-line
Current 1st- and 2nd-line therapies in Her2+
MBC
Pertuzumab +
Trastuzumab +
Docetaxel
2012
T-DM1
2012
2nd--line
Phase III
CLEOPATRA
Phase III
EMILIA

16. Krop IE, Lancet Oncol, 2014
Overall response rate

17. TH3RESA: Treatment Choice in
TPC Arm
• 80.4% of pts assigned to TPC arm received trastuzumab-
containing combination regimen
Slide credit: clinicaloptions.comWildiers H, et al. SABCS 2015. Abstract S5-05.
Treatment Regimen in TPC Arm, %
TPC
(n = 184)
Combination regimen including anti-HER2 agent
Chemotherapy* + trastuzumab
Lapatinib + trastuzumab
Hormonal therapy + trastuzumab
Chemotherapy + lapatinib
83.2
68.5
10.3
1.6
2.7
Single-agent chemotherapy* 16.8
*Most commonly used chemotherapy agents: vinorelbine, gemcitabine, eribulin, paclitaxel, docetaxel.

18. TH3RESA: Final OS Analysis
• Median OS significantly improved with use of T-DM1 vs physician-
selected therapy in pretreated pts with HER2+ MBC: HR 0.68 (95%
CI: 0.54-0.85; P = .0007)
• Disposition: discontinuation occurred in 67.1% T-DM1 arm vs 79.3
TPC arm
• 44.9% of TPC arm pts received T-DM1 crossover therapy
Slide credit: clinicaloptions.comWildiers H, et al. SABCS 2015. Abstract S5-05.
Median OS, Mos
TPC
(n = 198)
T-DM1
(n = 404)
Stratified HR (95%
CI)
P Value
All pts 15.8 22.7 0.68 (0.54-0.85)* .0007
Sensitivity analysis (pts censored at
crossover to T-DM1)
15.6 22.7 0.58 (0.43-0.77) .0002
*Prespecified crossing boundary = HR < 0.748 (P < .012).

19. Interim conclusions
CLEOPATRA, EMILIA and TH3RESA establish their investigational arms as
the new standards of care in Her2+ MBC in first-, second-, and further- line,
respectively.
Lapatinib consistently UNDERPERFORMS when compared to
trastuzumab-based combinations in Her2+ MBC (and in adjuvant and
neoadjuvant trials as well)
Trastuzumab + Pertuzumab + Taxane triplet is SOC in 1st-line.
Trastuzumab emtansine (T-DM1) is SOC in 2nd- and further- line

20. The problem of CNS metastases in Her2+
MBC

21. Question
Is there a rôle for lapatinib as
opposed to a monoclonal antibody in
CNS metastases in Her2+ MBC?

22. *Includes six patients who were receiving no
systemic therapy at the time of CNS metastasis
MBC, metastatic breast cancer; OS, overall survival. Brufsky AM, et al. Clin Cancer Res 2011; 17:4834–4843.
CNS metastases in HER2-positive breast cancer:
Incidence and survival
registHER is the largest prospective observational study of patients with
HER2-positive MBC (N = 1012)
13.0 months
20.3 months
9.6 months
Incidence of CNS metastases (%)
Median OS after diagnosis
of CNS metastases
At MBC diagnosis
Overall
During sixth line
and beyond
During fifth line
During fourth line
During third line
During second line
During first line

23. • Surgery (neurosurgery)
– Used to treat single, usually large symptomatic lesions in patients without active
extracranial disease1,2
• SRS
– Delivers a single, precisely aimed dose of radiation with minimal effect on the
surrounding brain tissue3
– Delivered alone or with WBRT2
– Used to treat ≤4 small (≤2 cm) lesions unsuitable for surgical resection1,2
• WBRT
– Delivers a reduced dose of radiation to the entire brain2,3
– Frequently used in MBC therapy in patients with multiple, CNS lesions1,2
– Delivered solely or following surgery2
Local therapies: Overview
1. Bartolotti M, et al. Future Oncol 2013; 9:1653–1664;
2. Kaal EC & Vecht CJ. CNS Drugs 2007; 21:559–579;
3. Soon YY, et al. Cochrane Database Syst Rev 2014; ePub ahead of print.SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy.

24. • BBB – barriers of drug delivery to the CNS include:1
– Molecules with molecular weight >500 Da may be too large to cross
– Molecules may not have the appropriate lipophilicity
– Uncharged molecules have higher permeability compared with charged
molecules
– Active efflux transport proteins, including P-glycoprotein, facilitate removal of
drugs
– Molecules may be exposed to degrading enzymes
• BBB may be structurally and functionally compromised by:
– Brain radiotherapy2,3
– Tumour cells entering and growing within the CNS3
– Hypoxic damage to endothelial cells within the BBB4
1. Gabathuler R. Neurobiol Dis 2010: 37:48–57;
2. Fokas E, et al. Biochim Biophys Acta 2013; 1835:61–75;
3. Mehta AI, et al. Cancer Treat Rev 2013; 39:261–269;
4. Hawkins BT & Davis TP. Pharmacol Rev 2005; 57:173–185.
Systemic therapies: The blood–brain barrier
BBB, blood–brain barrier.

25. • Trastuzumab is a large, monoclonal
antibody (~185 kDa)1
• Studies indicate that trastuzumab can
penetrate the BBB to reach the CSF
and brain tissue2,3
• Radiolabelled trastuzumab was
detected in known brain
tumour lesions (n = 3)3
• Penetration may be enhanced by BBB
impairment caused by meningeal
carcinomatosis
or radiotherapy2
BBB, blood–brain barrier; CSF,
cerebrospinal fluid; MBC,
metastatic breast cancer.
1. Chien AJ & Rugo HS. Breast Cancer Res Treat 2013; 137:1–12;
2. Stemmler H-J, et al. Anticancer Drugs 2007; 18:23–28;
3. Dijkers EC, et al. Clin Pharmacol Ther 2010; 87:586–592.
Trastuzumab
TrastuzumabinCSF(ng/mL)
420:1 76:1 49:1
Median levels of reactive trastuzumab in CSF of MBC patients1
Serum:CSF
trastuzumab ratio
Although a large molecule, trastuzumab may cross BBB in patients with CNS metastases

26. • Prospective observational trial – explored
natural history of disease, treatment
patterns and associations between
specific therapies and outcomes for
patients with HER2-positive MBC (N =
1023) who developed CNS metastases
• CNS metastases were present in 377
patients (37.3%)
• Trastuzumab after diagnosis of CNS
metastases significantly improved OS by
over 13 months to a median of
17.5 months
• Trastuzumab was independently
associated with reduced hazard of death
after CNS metastases
(n = 258; HR 0.33; 95% CI
0.25–0.46; p < 0.001)
Post CNS metastases diagnosis, trastuzumab significantly improved OS and was independently associated
with reduced risk of death
Post-CNS survival of patients
Real-world data: registHER
CI, confidence interval; HR, hazard ratio; MBC, metastatic breast cancer;
OS, overall survival. Brufsky AM, et al. Clin Cancer Res 2011; 17:4834–4843.
1.0
0.8
0.6
0.4
0.2
0.0
No. at risk
No T
T
Survival after CNS (months)
Survivalrate
0 4 20 24 28 328 12 16 36 40 44
258 228 188 93151 70126 51 36 33 16
119 48 27 515 410 3 2
No trastuzumab
Trastuzumab
No
trastuzumab
(N = 119)
Trastuzumab
(N = 258)
Median survival (months) 3.7 17.5
HR (95% Cl) 0.25 (0.20-0.33)
Log-rank P value <0.001

27. Lapatinib
• Lapatinib is a small (581 Da) lipophilic inhibitor of HER2 and EGFR1
• CNS penetration
– In preclinical studies, normal brain concentrations of lapatinib are low and limited by active
efflux transport at the BBB2–3
– In brain metastases from patients with HER2-positive breast cancer (CASE4107 trial; N = 10),
both lapatinib and capecitabine were detected at clinically relevant concentrations4
• Studies have evaluated lapatinib in patients with breast cancer and CNS metastases1,5
– Lapatinib monotherapy
– Lapatinib and capecitabine
– Lapatinib and trastuzumab (also comparing lapatinib with trastuzumab)
• The majority of studies evaluating lapatinib required patients to have an ECOG PS 0–2 and prior
treatment with trastuzumab5
1. Chien AJ & Rugo HS. Breast Cancer Res Treat 2013; 137:1–12;
2. Polli JW, et al. Drug Metab Dispos 2008; 36:695–701;
3. Polli JW, et al. Drug Metab Dispos 2009; 37:439–442;
4. Morikawa A, et al. ASCO 2013 (Abstract 514);
5. Larsen PB, et al. Can Treatment Rev 2013; 39:720–727.
BBB, blood–brain barrier; ECOG, Eastern Cooperative Oncology Group;
PS, performance status.

28. • Exploratory analysis showed fewer cases of CNS involvement at first progression in the
combination therapy group (p = 0.045)2
– Four patients in the combination therapy group
– Thirteen patients in the monotherapy group
• Safety profiles were similar between treatment groups1,2
* Patients had progressed after treatment with regimens that included an
anthracycline, a taxane and trastuzumab.
1. Geyer CE, et al. N Engl J Med
2006; 355:2733–2743;
2. Cameron D, et al. Breast
Cancer Res Treat 2008;
112:533–543.
EGF100151: Pivotal Phase III trial comparing capecitabine with capecitabine +
lapatinib
Exploratory analysis suggested beneficial effect of lapatinib + capecitabine vs.
capecitabine alone on the risk of CNS metastases at first progression

29. • Primary endpoint was incidence of CNS as site of first relapse*
− No difference between lapatinib + capecitabine (3%) versus trastuzumab + capecitabine (5% )
− OR 0.65 (95% CI 0.26, 1.63; p = 0.360)
• PFS and OS were longer for those who received trastuzumab + capecitabine (ITT population)
– In the trastuzumab-naïve group, trastuzumab + capecitabine had superior efficacy
• Safety profile similar between treatment arms and consistent with established profile
• Study was inconclusive for primary endpoint due to low incidence of brain metastases in both arms
* Patients were excluded if they had CNS metastases at baseline.
CI, confidence interval; IDMC, Independent Data Monitoring Committee;
ITT, intent-to-treat; OR, odds ratio; OS, overall survival; PFS, progression-free survival.
Pivot X, et al. ESMO 2012
(Abstract LBA11; oral
presentation).
CEREBEL: Randomised, controlled trial comparing either lapatinib +
capecitabine or trastuzumab + capecitabine
Investigator-assessed PFS (ITT population) OS (ITT population)
100
80
60
40
20
0
0 5 25 30 35 4010 15 20
No. at risk
Lap + Cap
Tras + Cap
271 194 129 2779 748
Time from randomisation (months)
Alivewithout
progression(%)
100
80
60
40
20
0
0 5 25 30 35 4010 15 20
No. at risk
Lap + Cap
Tras + Cap
271 147 49 720 420
269 154 56 1526 726
Time from randomisation (months)
Alivewithout
progression(%)
269 207 140 2997 661 1
Lap + Cap
(N = 271)
Tras + Cap
(N = 269)
Median PFS, months 6.6 8.0
Hazard ratio (95% Cl) 1.30 (1.04 – 1.64)
Stratified log-rank p value 0.021
Lap + Cap Tras + Cap
Lap + Cap
(N = 271)
Tras + Cap
(N = 269)
Median OS, months 22.7 27.3
Hazard ratio (95% Cl) 1.34 (0.95-1.90)
Stratified log-rank
p value
0.095
Lap + Cap Tras + Cap
• Study failed to demonstrate its primary endpoint of decreased incidence of CNS as site of first relapse
with lapatinib + capecitabine treatment
• Similar CNS metastasis incidence, but longer survival times, with trastuzumab- versus lapatinib-based
regimens
• IDMC recommended termination of trial at a pre-specified interim analysis

30. YOUR LOGO
Question
Is there a rôle for lapatinib as
opposed to a monoclonal antibody in
CNS metastases in Her2+ MBC?
Not in first line.

31. Secondary endpoint: OS
Verma S, et al. N Engl J Med. 2012 Nov 8;367(19):1783-

33. Metástasis en el SNC: EMILIA
• Al momento de entrar (todos) y en el seguimiento
(indicado pero no mandatorio por protocolo) de las
pacientes del estudio EMILIA, los pacientes (“screening”)
fueron sometidos a una RM o TC.
• Las pacientes con metástasis asintomáticas en el SNC
que fueron tratadas con radioterapia fueron elegibles
para entrar al estudio (14 días después de la ultima
sesión de radioterapia).
• EXCLUSIÓN:
– Los pacientes con metástasis al SNC que no fueron tratadas
o sintomáticas o que requirieron tratamiento para el control
de síntomas ≤2 meses a la aleatorización.
– Pacientes con metástasis al SNC únicamente

34. Las características generales de los
grupos son similares entre los pacientes
con metástasis al SNC y el análisis del
grupo completo
Excepción: Los pacientes con metástasis
al SNC tuvieron una mayor tendencia a
tener ECOG PS1 (vs 0), ≥3 sitio de
metástasis y compromiso visceral

35. • Mayor duración del tratamiento e intensidad de la dosis para el
grupo de pacientes con T-DM1
• El % de pacientes con metástasis al SNC, al momento de la
evaluación, que requirieron una reducción de la dosis de
Lapatinib vs Kadcyla fue similar (24,5% vs 23,3%)

36. Resultados: Eficacia
El porcentaje de pacientes que tuvieron progresión al SNC fue bajo y similar entre
los dos brazos del estudio (XL vs Kadcyla), sin importar si tenían metástasis al SNC
al momento de entrar al estudio

37. 10
8
A
B
Does treatment A cause more arrows than
treatment B?

38. Krop I, et al. EMILIA investigators, SABCS 2013

39. Krop I, et al. EMILIA investigators, SABCS 2013

40. Krop I, et al. EMILIA investigators, SABCS 2013

41. Terapias subsiguientes (siguientes líneas)
OJO: Al momento del corte del análisis (julio 31, 2012) ningún paciente con
metástasis al SNC del brazo XL hizo “cross over” a Kadcyla
ECOG PS al momento de terminar el estudio fue similar entre los grupos

42. Question
Is there a rôle for lapatinib as
opposed to a monoclonal antibody in
CNS metastases in Her2+ MBC?
Not in second-line, either.

43. Conclusion
There is NO signal that the superiority of trastuzumab
emtansine over lapatinib-based therapies is confined
to non-CNS metastatic Her2+ MBC patients.
Trastuzumab emtansine should be considered the
treatment of choice in Her2+ MBC after progression
on a trastuzumab-based therapy, regardless of the
metastatic site(s).

44. @onconerd