Malattia HER-2 positiva Terapia per la fase metastatica Cosa sapremo presto: nuovi farmaci U.O. di...

Malattia HER-2 positivaMalattia HER-2 positivaTerapia per la fase metastaticaTerapia per la fase metastatica

Cosa sapremo presto: nuovi farmaciCosa sapremo presto: nuovi farmaci

U.O. di Oncologia Medica “Sandro Pitigliani”Dipartimento di Oncologia

USL 4 Prato

Angelo Di Leo

Ongoing – Future strategies

• Complete HER-2 receptor blockade

• Inhibiting HER-2 dimerization

• Multi-targeted bio-therapy without chemotherapy

• A more potent trastuzumab : TDM-1

Lapatinib 1000 mg qd +

continuation of trastuzumab 2 mg/kg qw

(n=148)

MBC HER2-positive (IHC 3+ / FISH positive) Progression on prior Herceptin-based regimena

(n=296)

Lapatinib 1500 mg qd(n=148)

R

EGF104900: study design

aPatients received a median of 3 prior lines of trastuzumabor 4-5 prior lines of chemotherapy; IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; qd, every day; qw, every week; PD, progression of disease

Crossover if PD after 4 weeks of therapy(77 patients)

Blackwell K et al, J Clin Oncol 28: 1124-30, 2010

Probability of PFS

0 2 4 6 8Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

10 12

EGF104900: PFS

2.8a1.9a

trastuzumab+ lapatinib (n=146)

Lapatinib (n=145)

HR=0.73; p=0.008

aMedian PFS in months

148148

7353

4221

2713

85

20


EGF104900: Updated OS (SABCS2009)

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 25Time (months)

5 15 30 35

148148

8865

4328

12513

6447

121102

Probability of survival

14.0a 9.5a

aMedian OS in months

trastuzumab+ lapatinib (n=146)

Lapatinib (n=145)

HR=0.74; p=0.026


EGF104900: results

ORR, %

CBR, %

Median PFS, months

Median OS, months

Lapatinib

6.9

12.4

1.9

9.5

Lapatinib + Herceptin

10.3

24.7

2.8

14.0

p value

0.46

0.01

0.008

0.026

HR

0.73

0.74


EGF104900: safety profile

Grade 3/4, diarrhoea, n (%)

Symptomatic LVEF decline (LV dysfunction ≥ grade 3 or LVEF decrease ≥20% and below LLN), n (%)

Cardiac-related deaths, n (%)

Lapatinib

10 (7)

3 (2)

0 (0)

Lapatinib + Herceptin

12 (8)

10 (7)

1 (0.7)a

LLN, lower limit of normalaDeath due to pulmonary thromboembolism


Complete HER-2 receptor blockade : key message

Concomitant inhibition of the HER-2 external domain and the HER-2 tyrosine kinase more active than single inhibition either as upfront or as a further-line treatment

BO17929: A multicentre Phase II trial of trastuzumab + pertuzumab in HER2-positive MBC that progressed during trastuzumab-based therapy

• Primary endpoint:– Response rate and clinical benefit rate (response rate + disease stabilisation)

HER2-positive MBC progressing on trastuzumab

+ chemotherapy (Cohort 1, n=24; Cohort 2, n=42)

Pertuzumab+ trastuzumab

16 patients receivedpertuzumab + trastuzumab


+ chemotherapy (n=29)

PertuzumabPD

MBC = metastatic breast cancer; PD = progressive disease1. Baselga et al. J Clin Oncol 2010;28:1138–1144;

2. Baselga et al. SABCS 2009. Abstract 5114

Cohorts 1 and 21

Cohort 3 (added after protocol amendment)2

Inhibiting HER-2 / HER-3 dimerization: Pertuzumab

BO17929 (cohorts 1 and 2): The combination of pertuzumab and trastuzumab demonstrates

encouraging efficacy

Response n (%)(n=66)

Complete responsea,b 4 (6.1)

Partial responsea,b 12 (18.2)

Objective response rate 16 (24.2)

Stable disease for 8 cycles or ~6 months 17 (25.8)

Clinical benefit rate (CR + PR + SD ≥6 months) 33 (50.0)

Progressive disease 33 (50.0)

Baselga et al. J Clin Oncol 2010;28:1138–1144Cortes J et al. J Clin Oncol 2010;28(7S):Abstract 1066

aMedian duration of response was 5.8 months (2.9–15.3 months);bOne patient was reclassified from a CR to a PR CR = complete response; PR = partial response; SD = stable disease

BO17929 (cohorts 1 and 2): Adverse events were generally grade 1/2

• The most frequent adverse events were grade 1/2 and included diarrhoea, fatigue, nausea, and rash

• Only 4 of 66 patients had treatment-related adverse events grade 3

• Grade 3 adverse events were:

Adverse event n (%) Outcome Treatment continued

Diarrhoea 2 (3) Resolved Yes

Central line infection

1 (2) Resolved Yes

Pruritic rasha 1 (2) Resolved Yes

aOne patient had a grade 3 pruritic rash following injection of contrast before receiving pertuzumabSAE = serious adverse event; NR = Not reported Baselga et al. J Clin Oncol 2010;28:1138–1144

BO17929: A multicentre Phase II trial of trastuzumab + pertuzumab in HER2-positive MBC that progressed during trastuzumab-based therapy

• Primary endpoint:– Response rate and clinical benefit rate (response rate + disease stabilisation)

1. Baselga et al. J Clin Oncol 2010;28:1138–1144;2. Baselga et al. SABCS 2009. Abstract 5114MBC = metastatic breast cancer; PD = progressive disease


+ chemotherapy (Cohort 1, n=24; Cohort 2, n=42)

Pertuzumab+ trastuzumab

16 patients receivedpertuzumab + trastuzumab


+ chemotherapy (n=29)

PertuzumabPD

Cohorts 1 and 21

Cohort 3 (added after protocol amendment)2

BO17929: Pertuzumab plus trastuzumab demonstrated encouraging efficacy

Response, n (%)Cohorts 1 and 21,2

(n=66)

Cohort 32 (pertuzumab)

(n=29a)

Cohort 32

(pertuzumab + trastuzumab)

(n=16b)

Complete response 4 (6.1)c 0 (0.0) 0 (0.0)

Partial response 12 (18.2)c 1 (3.4) 3 (21.4)

Objective response rate 16 (24.2) 1 (3.4) 3 (21.4)

Stable disease for 8 cycles (6 months)

17 (25.8) 2 (6.9) 3 (21.4)

Clinical benefit rate 33 (50.0) 3 (10.3) 6 (42.8)

Progressive disease 33 (50.0) 24 (82.8) 8 (57.1)

aOnly 27 patients are evaluable: 1 patient did not progress on pertuzumab monotherapy before moving on to combination therapy and 1 patient’s tumour was unassessable after Cycle 2bn=14 as at data cut-off; 1 patient had not reached overall best response endpoint (8 cycles of assessment during this phase) and 1 patient died before efficacy assessmentcOne patient was reclassified from a CR to a PR

1. Baselga et al. J Clin Oncol 2010;28:1138–1144;2. Cortes J et al. J Clin Oncol 2010;28(7S):Abstract 1066

3. Baselga et al. SABCS 2009. Abstract 5114

BO17929 (cohort 3): Pertuzumab monotherapy and combination therapy with trastuzumab were both well tolerated

Pertuzumab (n=29)n (%)

Pertuzumab + trastuzumab (n=16)n (%)

Adverse event Any gradea Grade 3/4 Any gradea Grade 3/4

Diarrhoea 14 (48) 1 (3) 5 (31) 1 (6)

Nausea 10 (34) - 5 (31) -

Vomiting 7 (24) - 4 (25) -

Fatigue 5 (17) 1 (3) 4 (25) 1 (6)

Asthenia 5 (17) - 2 (13) -

Back pain 5 (17) - 2 (13) 1 (6)

Rash 3 (10) - 3 (19) -

Chills - - 3 (19) -

Weight decrease - - 3 (19) -

Baselga et al. SABCS 2009. Abstract 5114aAdverse event occurring in 15% patients

BO17929: Conclusions

• The combination of trastuzumab and pertuzumab is active in patients with HER2-positive breast cancer who have experienced progression during:

– Prior trastuzumab therapy1

– Prior sequential treatment with single-agent trastuzumab and pertuzumab2

• Pertuzumab monotherapy and combination therapy with trastuzumab were well tolerated and there were no significant cardiac events1,2

• The partnership of pertuzumab and trastuzumab may offer an effective new treatment option for patients with HER2-positive MBC

1. Baselga et al. J Clin Oncol 2010;28:1138–1144; 2. Baselga et al. SABCS 2009. Abstract 5114MBC = metastatic breast cancer

• Trastuzumab-DM1 (T-DM1) is a novel anti-HER2 antibody drug–conjugate in development for the treatment of HER2-positive metastatic breast cancer (MBC)1,2

– Combines the HER2-targeting properties of trastuzumab3 with targeted delivery of a highly potent anti-microtubule derivative, DM13-5

– After binding to HER2, T-DM1 undergoes receptor-mediated internalization,6 resulting in intracellular release of DM1

1. Krop I, et al. J Clin Oncol 2008. 28:2698-27042. Burris HA, et al. J Clin Oncol, 2010, in press 20103. Lewis Phillips, et al. Cancer Res. 2008. 68:9280-90.

4 . Junttila TT, et al. Breast Cancer Res Treat, 2010, epub ahead of press5. Remillard S, et al. 1975. Science 189:1002–1005.3. 6. Austin CD, et al. 2004. Mol Biol Cell 15(12):5268–5282.

A more potent trastuzumab: TDM 1

TDM4258g TDM4374g

N=112 N=110

ORR, % 25.9% 32.7%

Clinical benefit rate, % 39.3% 48.2%Median Duration of Response (95% CI)

NR(6.2, NE)

NR (4.6, NE)

Median PFS (95% CI) 4.6 m(3.9, 8.6)

6.9 m(4.2, 9.5)

ORR in patients with retrospectively confirmed HER2+ 32.1% 40.3%

Studies TDM4374g and TDM4258g: Antitumor Activity by IRF Assessment

T-DM1 ISS AE Summary

• The majority of AEs were grade (Gr) 1−2 • Most common AEs (≥ 20% pts) of all grades were fatigue (63.3%), nausea (43.9%), and

headache (31.2%) • 109 pts (46.0%) experienced at least one Gr ≥ 3 AE

– Most common Gr ≥ 3 AEs: thrombocytopenia (7.6%), hypokalaemia (4.6%), fatigue (4.2%), cellulitis (3.4%)

• SAE were reported in 61 pts (25.7%)– Most common SAEs : cellulitis (3.4%), convulsion (2.5%), pneumonia (2.5%), and

dyspnoea (1.7%)• 20/237 (8%) patients discontinued treatment for adverse events• 5 total deaths within 30 days of last protocol therapy

– 4 patients attributable to progressive disease or underlying disease

– 1 due to Grade 5 AE (Hepatotoxicity)

• Randomized, phase II, international, open-label study• HER2+, measurable disease required• Stratification factors:

– World region, prior adjuvant trastuzumab therapy, disease-free interval • Key Primary endpoint: PFS by INV• Key Secondary endpoints: ORR, CBR, OS

TDM4450g: Study Design

HER2-positive, recurrent locally advanced BC or MBC (n=137)

Previously untreated

T-DM13.6 mg/kg Q3W until PD

Trastuzumab 8 mg/kg loading dose; 6 mg/kg Q3W

+ Docetaxel 75 or 100 mg/m2 Q3W

CrossoverT-DM1PD

Hurvitz SA et al, proc. ESMO/ECCO 2011, abstr. 5.001

Objective Response by Investigator Patients With Measurable Disease at Baseline

Trastuzumab + docetaxel

(n=69)a

T-DM1 (n=67)

Patients with an objective response,b n (%) 40 (58.0) 43 (64.2)

95% CI 45.5–69.2 51.8–74.8

Objective responses, n (%)

Complete response 3 (4.3) 7 (10.4)

Partial response 37 (53.6) 36 (53.7)

Stable disease 23 (33.3) 13 (19.4)

Progressive disease 4 (5.8) 8 (11.9)

Unable to evaluate or missing 2 (2.9) 3 (4.5)

Patients with clinical benefit,c n (%) 56 (81.2) 50 (74.6)

95% CI 70.7–89.1 63.2–84.2

aOne patient was not included in the efficacy analysis due to study site withdrawal.bDefined as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4 weeks apart.cDefined as objective response any time during the study or maintained stable disease for at least 6 months from randomization.

Time (months)Time (months)

Progression-Free Survival by InvestigatorRandomized Patients

Pro

por

tion

prog

ress

ion

-fre

e P

rop

ortio

n pr

ogre

ssio

n-f

ree

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10 12 14 16 18 200 2 4 6 8 10 12 14 16 18 20

Number of patients at risk

T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0

Number of patients at risk

T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0

Hazard ratio and log-rank P value were from stratified analysis.

Trastuzumab + docetaxel (n=70)T-DM1 (n=67)

Trastuzumab + docetaxel (n=70)T-DM1 (n=67)

Median

PFS, mos

Hazard ratio 95% CI

Log-rank P value

9.2

14.20.594

0.364– 0.968

0.0353

Incidence of Hematologic Adverse Events: ≥30% (All Grade) and/or ≥5% (Grade ≥3) of Patientsa

Green represents those AEs with ≥20% difference between treatment arms.

aIn either treatment arm.bNo adverse events listed were grade 5.cTwo patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses.dIncludes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel.e Neutropenia includes events classified as MedDRA preferred terms neutropenia or neutrophil count decreased; thrombocytopenia includes

events classified as MedDRA preferred terms thrombocytopenia, platelet count decreased or heparin-induced thrombocytopenia; leukopenia includes events classified as MedDRA preferred terms leukopenia or white blood cell count decreased.

fAll of these events were grade 3.


aIn either treatment arm.bNo adverse events listed were grade 5.cTwo patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses.dIncludes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel.e Neutropenia includes events classified as MedDRA preferred terms neutropenia or neutrophil count decreased; thrombocytopenia includes

events classified as MedDRA preferred terms thrombocytopenia, platelet count decreased or heparin-induced thrombocytopenia; leukopenia includes events classified as MedDRA preferred terms leukopenia or white blood cell count decreased.

fAll of these events were grade 3.

AE

All grade, n (%) Grade ≥3b, n (%)

Trastuzumab + docetaxel (n=66)c

T-DM1 (n=69)c,d

Trastuzumab + docetaxel (n=66)c

T-DM1 (n=69)c,d

Neutropeniae 42 (63.6) 12 (17.4) 40 (60.6) 4 (5.8)Febrile neutropenia 9 (13.6) 0 9 (13.6) 0Thrombocytopeniae 4 (6.1) 21 (30.4) 2 (3.0)f 6 (8.7)f

Leukopeniae 18 (27.3) 6 (8.7) 17 (25.8) 0

Incidence of Nonhematologic Adverse Events: ≥30% (All Grade) and/or ≥5% (Grade ≥3) of Patientsa


aIn either treatment arm.bNo adverse events listed were grade 5.cTwo patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses.dIncludes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel.eNational Cancer Institute Common Terminology Criteria for Adverse Events v.3 only categorizes alopecia as grade 1 or grade 2; there is no grade ≥3 for this AE.

AE

All grade, n (%) Grade ≥3b, n (%)

Trastuzumab + docetaxel (n=66)c T-DM1 (n=69)c,d

Trastuzumab + docetaxel (n=66)c T-DM1 (n=69)c,d

Alopecia 44 (66.7) 3 (4.3) e e

Fatigue 30 (45.5) 34 (49.3) 3 (4.5) 3 (4.3)

Nausea 29 (43.9) 33 (47.8) 0 2 (2.9)Diarrhea 30 (45.5) 11 (15.9) 2 (3.0) 0

Peripheral edema 29 (43.9) 7 (10.1) 3 (4.5) 0Increased AST 4 (6.1) 27 (39.1) 0 6 (8.7)

Pyrexia 15 (22.7) 27 (39.1) 1 (1.5) 0Headache 12 (18.2) 25 (36.2) 0 0

Back pain 20 (30.3) 18 (26.1) 3 (4.5) 1 (1.4)Increased ALT 4 (6.1) 16 (23.2) 0 6 (8.7)

Pneumonia 1 (1.5) 6 (8.7) 0 4 (5.8)

Cardiac Safety

• Cardiac function was assessed locally and centrally based on cardiac ECHO/MUGA

• Prior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectively

• Asymptomatic LV dysfunction

• There were no clinically significant cardiac events reported

LVEF assessment Trastuzumab + docetaxel T-DM1

Local assessment

Patients assessed 65 67

Patients with post-baseline LVEF ≤40% 2a 0

Central assessment

Patients assessed 60 65

Patients with post-baseline LVEF ≤40% 1b 0

aBoth patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting.bThis patient did not receive prior treatment with an anthracycline.

aBoth patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting.bThis patient did not receive prior treatment with an anthracycline.

The future: Do we need more anti-HER-2 compounds or more bio-markers driving our treatment choices?

• Anti-HER-2 sensitive population:

Trastuzumab alone vs. combination

• Anti-HER-2 partially sensitive/resistant population:

Trastuzumab in combination with agents such as

• Anti-HER-2 ± chemotherapy

• If Trastuzumab with chemotherapy

lapatinib

pertuzumab

PI3K inhibitors

HSP 90 inhibitors

anti IGF-1R inhibitors

which regimen

taxaneanthracyclines

TDM1

others (DNA damaging agents, vinorelbine,….)

Malattia HER-2 positiva Terapia per la fase metastatica Cosa sapremo presto: nuovi farmaci U.O. di...

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