The controversy over CNS metastases in Her2+ Breast Cancer: Does size matter?

Mauricio Lema Medina MD - Clínica de Oncología Astorga, Clinica SOMA, Medellín

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Page 4Slamon 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.

Page 5Cameron D, Br Cancer Treat Res, 2008

Trastuzumab

Lapatinib

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

Genentech Confidential—Internal Use Only

Anatomy of an Antibody-Drug Conjugate (ADC)

Antibody targeted to tumor

Very potentchemotherapeutic 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

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

PP

P

Trastuzumab Emtansine (T-DM1): Mechanism of Action

Emtansine release

Inhibition of microtubule

polymerization

Internalization

HER2

Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

T-DM1

Lysosome

Nucleus

PP

P

Trastuzumab-specific MOA• Antibody-dependent cellular cytotoxicity (ADCC)

• Inhibition of HER2 signaling• Inhibition of HER2 shedding

MARIANNE

NEGATIVE TRIAL

Primary endpoint: PFS by independent review

Verma S, et al. N Engl J Med. 2012 Nov 8;367(19):1783-91

Secondary endpoint: OS

Verma S, et al. N Engl J Med. 2012 Nov 8;367(19):1783-91

Trastuzumab + Paclitaxel.

2001

Phase III

Trastuzumab + Docetaxel

2005

Lapatinib + Capecitabine

2006Phase 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, 2012Verma, et al. NEJM, 2012

1st-line

Pertuzumab +Trastuzumab +

Docetaxel2012

T-DM12012

2nd--line

Phase IIICLEOPATRA

Phase IIIEMILIA

Current 1st- and 2nd-line therapies in Her2+ MBC

Trastuzumab + Paclitaxel.

2001

Phase III

Trastuzumab + Docetaxel

2005

Lapatinib + Capecitabine

2006Phase 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, 2012Verma, et al. NEJM, 2012

1st-line

Current 1st- and 2nd-line therapies in Her2+ MBC

Pertuzumab +Trastuzumab +

Docetaxel2012

T-DM12012

2nd--line

Phase IIICLEOPATRA

Phase IIIEMILIA

Krop IE, Lancet Oncol, 2014

Overall response rate

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 agentChemotherapy* + trastuzumabLapatinib + trastuzumabHormonal therapy + trastuzumabChemotherapy + lapatinib

83.268.510.31.62.7

Single-agent chemotherapy* 16.8

*Most commonly used chemotherapy agents: vinorelbine, gemcitabine, eribulin, paclitaxel, docetaxel.

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).

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

The problem of CNS metastases in Her2+ MBC

Question

Is there a rôle for lapatinib as opposed to a monoclonal antibody in

CNS metastases in Her2+ MBC?

*Includes six patients who were receiving no systemic therapy at the time of CNS metastasisMBC, 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

• 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.

• 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.

• 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

Tras

tuzu

mab

in C

SF

(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

• 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 riskNo T

T

Survival after CNS (months)

Surv

ival

rate

0 4 20 24 28 328 12 16 36 40 44

258 228 188 93151 70126 51 36 33 16119 48 27 515 410 3 2

No trastuzumabTrastuzumab

No trastuzumab

(N = 119)

Trastuzumab(N = 258)

Median survival (months) 3.7 17.5HR (95% Cl) 0.25 (0.20-0.33)

Log-rank P value <0.001

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.

• 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

• 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 20No. at riskLap + Cap

Tras + Cap271 194 129 2779 748

Time from randomisation (months)

Aliv

e w

ithou

t pr

ogre

ssio

n (%

)

100

80

60

40

20

0

0 5 25 30 35 4010 15 20No. at risk

Lap + CapTras + Cap

271 147 49 720 420269 154 56 1526 726

Time from randomisation (months)

Aliv

e w

ithou

t pr

ogre

ssio

n (%

)

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

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Question

Is there a rôle for lapatinib as opposed to a monoclonal antibody in CNS metastases in

Her2+ MBC?

Not in first line.

Secondary endpoint: OS

Verma S, et al. N Engl J Med. 2012 Nov 8;367(19):1783-91

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

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

• 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%)

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

10

8

A

B

Does treatment A cause more arrows than treatment B?

Krop I, et al. EMILIA investigators, SABCS 2013

Krop I, et al. EMILIA investigators, SABCS 2013

Krop I, et al. EMILIA investigators, SABCS 2013

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 KadcylaECOG PS al momento de terminar el estudio fue similar entre los grupos

Question

Is there a rôle for lapatinib as opposed to a monoclonal antibody in CNS metastases in

Her2+ MBC?

Not in second-line, either.

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).

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