new drug development in her2+ breast cancer › pdf › 3. aftimos.pdf · the trastuzumab...

Philippe Aftimos, M.D.Senior Research Physician

Clinical Pharmacology Unit

Institut Jules Bordet

New Drug Development in HER2+ Breast Cancer

Background

• Amplification of HER2 occurs in approximately 20% of breast cancers

• This alteration was associated with shortened survival

• Anti-HER2 therapies changed the prognosis of patients with HER2+ breast cancer

• The CNS remains a sanctuary for the disease

The Trastuzumab (Herceptin®) Story

1979: HER2 oncogene discovery

1984: HER2 protein discovery

1987: HER2 and breast cancer linked

1989: Synthesis of trastuzumab

1998: FDA approval

2006: FDA approval adjuvant setting

19 ans

27 ans

ER+/ HER2+ MBCEndocrine + anti-HER2 therapy

Johnston S et al. JCO 2009 Kaufman B et al. JCO 2009

Chemotherapy + trastuzumab

HER2+ MBCChemotherapy + trastuzumab

What to combine with trastuzumab?

• Paclitaxel

• Docetaxel

• Platinum combo

• Vinorelbine

• Capecitabine

• Gemcitabine

• Monotherapy

Eribulin + Trastuzumab phase II trial first-line:Disease control rate = 96.2%

Wilks S et al. Clinical Breast Cancer 2014

Trastuzumab Beyond Progression:GBG 26/ BIG 03-05 phase 3 trial

Capecitabine 2500 mg/m2

bid d1-14 q21d

(n=78)

MBC HER2-positiveProgression under trastuzumab-based first-line therapy (TFI < 6 wks)

with taxane (n=156)

or monotherapy or non-taxane (n=42)

Capecitabine 2500 mg/m2

bid d1-14 q21d

+

continuation of

Trastuzumab 6 mg/kg q3w

(n=78)

Trastuzumab Beyond Progression:GBG 26/ BIG 03-05 phase 3 trial

PFS:8.2 vs 5.6 months

OS:25.5 vs 20.4 months

Response rate: 48% vs 27%

von Minckwitz G et al. JCO 2009

Pan-HER tyrosine kinase inhibitors

Vandana Abramson, and Carlos L. Arteaga Clin Cancer

Res 2011;17:952-958

©2011 by American Association for Cancer Research

Small molecule TKIs

But also neratinib and afatinib

Lapatinib + Capecitabine

Geyer C et al. NEJM 2006

Class-Specific Toxicities

Geyer C et al. NEJM 2006

Neratinib phase II Trial

Burstein H et al. J Clin Oncol 2010.

Neratinib in the adjuvant setting:1 year of Neratinib vs Placebo after 1 year

of Trastuzumab

Grade 3 diarrhea in 40% of patients.

Chan A et al. ASCO Annual Meeting 2015.

NALA trial in the Metastatic Setting

ClinicalTrials.gov Identifier: NCT01808573

Double HER2 Blockade

Lapatinib + Trastuzumab vs Lapatinib

Blackwell K et al. JCO 2012

Higher pCR rate

Baselga J et al. Lancet 2012.

ALTTO: Double Blockade in the Adjuvant Setting

Piccart-Gebhart M et al. J Clin Oncol 2015.

No improvement indisease-free survival:1 year of trastuzumabremains the standardof care.

Piccart-Gebhart M et al. J Clin Oncol 2015.

Dual HER2 blockade with trastuzumab and pertuzumab in

HER2-amplified breast cancer

Hector Boix-Perales et al. The Oncologist 2014;19:766-773

©2014 by AlphaMed Press

CLEOPATRA: Double HER2 blockade in the 1st line setting

Baselga et al. N Engl J Med 2012;366:109-19

Primary endpoint: Independently assessed PFSSecondary endpoints included Overall survival; PFS by investigator assessment; Safety

Patients withHER2-positive first-line MBC

central confirmation

(N=808)

Placebo + trastuzumab

1:1

Docetaxel≥6 cycles recommended

n=406

n=402

Pertuzumab + trastuzumab

PD

PD

Docetaxel≥6 cycles recommended

CLEOPATRA:Impressive Efficacy and Survival

56.5 mo vs 40.8 mo

Baselga J et al. NEJM 2012.Swain S et al. NEJM 2015.

Baselga J et al. NEJM 2012.Swain S et al. NEJM 2015.

Novel Antibodies

Margetuximab: MGAH22 (macrogenics)

• Chimeric anti-HER2 monoclonal antibody

• Specificity and affinity similar to trastuzumab

• Fc domain engineered for increased binding to both alleles of human CD16A

• Margetuximab may have utility in patients with low HER2 expressing tumors or carrying the CD16A low-binding allele.

Nordstrom J et al. Breast Cancer Research 2011

Margetuximab HER-2 Binding


Margetuximab ADCC


Margetuximab phase I trial(solid tumors expressing HER2)

• Patients with refractory carcinomas that overexpress HER2 for whom no standard therapy was available were enrolled

• Regimen A: 3W/4 Regimen B: Q3W

• Fifty-two patients received M (34 patients received 0.1 to 6.0 mg/kg in Regimen A and 18 patients received 10 to 18 mg/kg in Regimen B)

• The MTD was not reached

Burris H et al. ASCO 2015

Margetuximab phase I trial(solid tumors expressing HER2)

• Toxicity:– Mostly Grade 1 and 2 – Infusion-related reactions – Constitutional symptoms such as pyrexia, nausea,

anemia, diarrhea, and fatigue

• Activity:– PR were observed in 8 patients and SD in 21 patients– Tumor reductions were observed in 11 of 19 patients

with BC, including 4 patients with confirmed PR, 3 of whom had received prior trastuzumab and lapatinib

– Median PFS for patients with BC was 169 days

Burris H et al. ASCO 2015

Margetuximab: current development

• SOPHIA trial (NCT02492711)

– Phase III– HER2 positive MBC– 2 prior lines of anti-HER2 therapy– Chemo

• Margetuximab in HER-2 2+, FISH negative MBC (NCT01828021)

– Phase II– Recruitment to end soon (tentative on clinicaltrials.gov)

• Macrogenics and Merck collaboration– Announced in October 2015– Pembrolizumab + margetuximab in HER2+ gastric cancer

Antibody-Drug Conjugates

T-DM1:Trastuzumab-based antibody-drug conjugate

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

TDM4450g: T-DM1 compared with trastuzumab + docetaxel in the first-line treatment of HER2+ MBC

Hurvitz S et al. JCO 2013.

• Randomized, Phase II, international, open-label study

• Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval

• Primary endpoints: PFS by investigator assessment, and safety

• Data analyses were based on clinical data cut-off Nov 15, 2010 prior to T-DM1 crossover

• Key secondary endpoints: OS, ORR, DOR, CBR, and quality of life

1:1

HER2-positive,

recurrent LABC

or MBC

(N=137)

Trastuzumab

+ Docetaxel

Crossover toT-DM1

(optional)PD

T-DM1 PD

LABC = locally advanced breast cancer;

PD = progressive disease; PFS = progression-free survival;OS = overall survival;

ORR = objective response rate; DOR = duration of response; CBR = clinical benefit rate

TDM4450g: T-DM1 improved PFS compared with trastuzumab + docetaxel

Hurvitz S et al. JCO 2013.

Pro

po

rtio

n p

rog

res

sio

n-f

ree

Time (months)

0 2 4 6 8 10 12 14 2016 18

0.0

0.2

0.4

0.6

0.8

1.0

Trastuzumab + docetaxel (n=70)

T-DM1 (n=67)

HR = hazard ratio; CI = confidence intervals

14.2

9.2

Median PFS

(months)

0.594

(0.364, 0.968)

HR

(95% CI) p value

0.0353

TDM4450g: T-DM1 Safety Profile

Hurwitz S et al. JCO 2013

EMILIA Phase III study: T-DM1 vs lapatinib + capecitabine in patients previously treated with

trastuzumab and taxane

Verma S et al. NEJM 2012

• Stratification factors: World region, number of prior chemo regimens for MBC or

unresectable LABC, presence of visceral disease

• Primary end points: PFS by independent review, OS, and safety

• Key secondary end points: PFS by investigator, ORR, DOR, time to symptom progression

1:1

HER2+ (central) LABC or MBC

(N=980)

• Prior taxane and trastuzumab

• Progression on metastatic

treatment or within 6 months of

adjuvant therapy

PDT-DM1

Lapatinib

+ Capecitabine PD

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0

495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Cap + Lap

T-DM1

No. at risk by independent review:

Median

(months)

No. of

events

Cap + Lap 6.4 304

T-DM1 9.6 265

Stratified HR=0.650 (95% CI, 0.55, 0.77)

P<0.0001

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Pro

po

rtio

n p

rog

ress

ion

-fre

e

Time (months)

Unstratified HR=0.66 (P<0.0001).

Independently assessed PFS benefit for T-DM1


496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4

495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + Lap

T-DM1

No. at risk: Time (months)

78.4%64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n s

urv

ivin

g

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

Median (months) No. of events

Cap + Lap 25.1 182

T-DM1 30.9 149

Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006

Efficacy stopping boundary P=0.0037 or HR=0.727

Significant Overall survival benefit for T-DM1


EMILIA Safety Profile


2

T-DM1c

(optional

crossover)

TH3RESA (T-DM1 versus TPC) phase III trial in heavily pretreated patients

• Stratification factors: World region, number of prior regimens for advanced BC,d

presence of visceral disease

• Co-primary endpoints: PFS by investigator and OS

• Key secondary endpoints: ORR by investigator and safety

PD

PDT-DM1

3.6 mg/kg q3w IV(n=400)

Treatment of

physician’s choice

(TPC)b

(n=200)

HER2-positive (central) advanced BCa

(N=600)

≥2 prior HER2-directed therapies for advanced BC

Prior treatment with trastuzumab, lapatinib, and a

taxane

1

Wildiers H. ECC 2013

PFS benefit by Investigator Assessment

Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.

Unstratified HR=0.521 (P<0.0001).

198 120 62 28 13 6 1 0

404 334 241 114 66 27 12 0

TPC

T-DM1

No. at risk:Time (months)

1412108642

0.0

0.2

0.4

0.6

0.8

1.0

0

Pro

po

rtio

n p

rog

ress

ion

-fre

e

TPC

(n=198)

T-DM1

(n=404)

Median (months) 3.3 6.2

No. of events 129 219

Stratified HR=0.528 (95% CI, 0.422, 0.661)

P<0.0001


First Interim OS Analysis: trend towards OS benefit

198

404

169

381

125

316

80

207

51

127

30

65

9

30

0

0

TPC

T-DM1

No. at risk:

3

7

Time (months)

44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.

Unstratified HR=0.57 (P=0.004).

1612108642

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n s

urv

ivin

g

0 14

Observed 21% of targeted events

TPC

(n=198)

T-DM1

(n=404)

Median (months) 14.9 NE

No. of events 44 61

Stratified HR=0.552 (95% CI, 0.369, 0.826); P=0.0034

Efficacy stopping boundary HR<0.363 or P<0.0000013


SYD985: a novel ADC with a cleavable linker-duocarmycin payload

Miranda M.C. van der Lee et al. Mol Cancer Ther

2015;14:692-703


In vitro profile of SYD985 vs T-DM1 in cell lines with different HER2 expression

Miranda M.C. van der Lee et al. Mol Cancer Ther

2015;14:692-703


mTOR inhibitors and trastuzumab

Inhibition of the HER2–

PI3K–FOXO-survivin axis by

trastuzumab and PI3K

inhibitors.

Brent N. Rexer, and Carlos L. Arteaga Cancer Res 2013;73:3817-3820


Trastuzumab and mTOR inhibitors

Study design. q28 days, every 28 days.

Fabrice Andre et al. JCO 2010;28:5110-5115

©2010 by American Society of Clinical Oncology

Phase I proof of concept trial:Objective responses after resistance to taxanes and trastuzumab

BOLERO-1 phase III trial in the 1st line setting: Reversal of trastuzumab resistance?

Hurwitz S et al. Lancet Oncol 2015.

BOLERO-3 phase III trial

Andre F et al. Lancet Oncol 2014

BOLERO-3: Longer PFS with the addition of everolimus


BOLERO-3 Safety Profile


Immunotherapy and anti-HER2 combos

Preclinical: anti-HER2 + anti-PD1

Stagg J et al. PNAS 2011.

PANACEA trial

HER-TDB: bispecific antibody that targets HER2 and activates T cell

Junttila T et al. Cancer research 2014

Brain Metastases

Favor Lapatinib + Capecitabinefor Brain Metastases?

Landscape: yes

• Phase II, 45 patients

• Patients with newly diagnosedbrain metastases

• 29 patients (66%) with PR

• 37 patients (84%) had tumorshrinkage

• Median time to radiotherapy : 8.3months

• 22 patients (49%) with grade 3 or 4AEs

Cerebel: no

• Phase III, 540 patients

• Cap + Lap vs Cap + Tras

• Primary endpoint: CNS as first siteof relapse – No difference

• Secondary endpoints:

Bachelot T et al. Lancet Oncol 2013 Pivot X et al. JCO 2015

Neratinib and Brain Metastases

Freedman R et al. J Clin Oncol 2016.

Abemaciclib (CDK4/6 inhibitor)

ClinicalTrials.gov Identifier: NCT02308020

HER2-directed Metabolic Imaging

Gebhart G et al. Annals Of Oncology 2015.

[email protected]

Twitter: @aftimosp

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new drug development in her2+ breast cancer › pdf › 3. aftimos.pdf · the trastuzumab...

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