Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona Toxicities of molecularly targeted agents in combination with chemotherapy

Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche

Ancona

Toxicities of molecularly targeted agents in combination with chemotherapy

Tossicita’ dei nuovi agenti biologici

Trastuzumab– Cardiotossicita’

Bevacizumab– ipertensione– Proteinuria– Malattia tromboembolica

Cetuximab– Tossicita’ cutanea

Sunitinib– Diarrea– astenia

Imatinib– Astenia– diarrea

I farmaci biologici modificano o incrementano la tossicita’ dei chemioterapici ?

Trastuzumab– Antracicline

Bevacizumab– Oxaliplatino– irinotecan– Taxani– carboplatino

Cetuximab– Irinotecan– taxani

La differenza della incidenza degli eventi cardiaci (scompensi e morti) tra terapie con H e senza è inferiore al 4%.

Analisi a 9 mesi: 500 pz per braccio con diminuzione della LVEF 15% dal basale (dopo AC) - 0,0% (95% CI, 0,0-0,7%) per il braccio di controllo - 2,2% (95% CI, 2.0-5.1%) per il controllo vs sequenziale - 3,3% (95% CI, 2.0-5.1%) per il controllo vs terapia concomitante con paclitaxel * * a 9 mesi questi pazienti hanno ricevuto ulteriori cicli di H rispetto al gruppo sequenziale.

Perez et al ASCO 2005

NCCTG N9831Effetti della introduzione di H

sulla tollerabilità cardiaca

SAFETY ANALYSIS POPULATIONSAFETY ANALYSIS POPULATIONCardiotoxicityCardiotoxicity

0.5%0.5%

(95% CI: 0.25(95% CI: 0.25 --1.02)1.02)0.5%0.5%

(95% CI: 0.25(95% CI: 0.25 --1.02)1.02)

0 %0 %

(95% CI: 0.00(95% CI: 0.00 --0.21)0.21)

0 %0 %

(95% CI: 0.00(95% CI: 0.00 --0.21)0.21)

Same LVEF criteriaSame LVEF criteriaandandsymptomatic symptomatic CHF NYHA class CHF NYHA class III/IV, confirmed III/IV, confirmed

by cardiologist by cardiologist

Cardiac deathCardiac death

Same LVEF criteriaSame LVEF criteriaandandsymptomatic symptomatic CHF NYHA class CHF NYHA class III/IV, confirmed III/IV, confirmed

by cardiologist by cardiologist

Cardiac deathCardiac death

7.1 %7.1 %7.1 %7.1 %2.2 %2.2 %2.2 %2.2 %Decrease by Decrease by 10 EF points 10 EF points

and LVEF < 50% and LVEF < 50%

Decrease by Decrease by 10 EF points 10 EF points

and LVEF < 50% and LVEF < 50%

1 year trastuzumab1 year trastuzumab

N=1677N=16771 year trastuzumab1 year trastuzumab

N=1677N=1677ObservationObservation

N=1736N=1736ObservationObservation

N=1736N=1736

0.1% 0%

HERA TRIAL

Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer. Buzdar et al JCO 2005Event P>FEC alone

n = 19

P>FEC +H

n = 23

Grade 4 neutropenia 11 21

Neutropenic fever 8 8

Neutropenic infections 3 5

Hospitalization 1 3

Chemotherapy dose reduction as a result of neutropenia

5 10

Cardiac safety dataCHF10% decrease in ejection fractionDecrease on PDecrease on FEC

0505

0743

Improvement in ejection fraction on follow-up evaluation

2 3

Abnormal troponin-T 0 1

LVEF Declines by NYHA Class

1181Grade 3/4 CHF

4256>15%, <LLN

7349>10%, <LLN

TCHAC- THAC- T

1181Grade 3/4 CHF

4256>15%, <LLN

7349>10%, <LLN

TCHAC- THAC- T

I mplication: Trastuzumab per se is not cardiotoxic; it becomes so when it keeps company with DOX

CAN DOXORUBI CI N BE ELI MI NATED?

HER2 +FISH

4 x AC60/ 600 mg/ m2

4 x Docetaxel100 mg/ m2

6 x Docetaxel and Platinum salts75 mg/ m2 75 mg/ m2 or AUC 6

1 Year Trastuzumab

N=31501 Year Trastuzumab

ACT

ACTH

TCH

BCI RG 006

Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Administered As First-Line Treatment: Results of a Randomized Phase II Trial by the M77001 Study Group Marty et al, JCO 2005

Toxicity Trastuzumab + Docetaxel

(n=92)

Docetaxel alone (n=94)

Anemia 1 1

Thrombocitopenia 0 0

Leukopenia 20 15

Neutropenia 32 22

Febrile neutropenia / Neutropenic sepsis 23 17

Alopecia 10 6

Astenia 10 6

I farmaci biologici modificano o incrementano la tossicita’ dei chemioterapici



Cetuximab– Irinotecan– taxani

Patients (%)

IFL + placebo (n=397)

IFL + bevacizumab (n=393)

Bleeding Grade 3/4

2.5

3.1

Any thromboembolic event Arterial Venous

16.2 1.0

15.2

19.4 3.3

16.1 Deep thrombophlebitis Grade 3

6.3

8.9

Pulmonary embolus Grade 4

5.1

3.6

Any hypertension Grade 3

8.3 2.3

22.4* 11.0*

Any proteinuria Grade 2 Grade 3

21.7 5.8 0.8

26.5 3.1 0.8

Unusual chemotherapy-related toxicity

NB: not adjusted for different time on therapy*p<0.05

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Hypertension: incidence

Trial

Regimen

All grades

Grade 3/ 4

Grade 3

Grade 4

E32001 FOLFOX NR NR 2 <1

FOLFOX + bevacizumab (10mg/ kg)

NR NR 5 1

Bevacizumab (10mg/ kg) NR NR 6 0

AVF07802 5-FU/ LV 3 0 NR NR

5-FU/ LV + bevacizumab (5mg/ kg)

11 8.6 NR NR


28 25 NR NR

AVF21073 IFL 8.3 NR 2.3 0

IFL + bevacizumab (5mg/ kg) 22.4 NR 11 0

AVF21924 5-FU/ LV 4.8 NR 2.9 0


32.0 NR 16.0 0

NR = not reported

Proteinuria: incidence Trial

Regimen

All grades

Grade 3/4

Grade 3

Grade 4

E32001 FOLFOX NR NR 0 0

FOLFOX + bevacizumab (10mg/kg)

NR NR <1 0

Bevacizumab (10mg/kg) NR NR <1 0

AVF07802 5-FU/LV 11.4 NR NR NR

5-FU/LV + bevacizumab (5mg/kg)

22.8 NR NR NR


28.1 NR NR NR

AVF21073 IFL 21.7 NR 0.8 0

IFL + bevacizumab (5mg/kg) 26.5 NR 0.8 0

AVF21924 5-FU/LV 19.2 NR 0 0


38.0 NR 1.0 0

Thromboembolic events during first-line therapy (AVF2192)

No. of patients (%)

5-FU/LV + placebo (n=104) 5-FU/LV + bevacizumab (n=100)

All Grades

Grade 3

Grade 4

All

Grades

Grade 3

Grade 4

Total venous and arterial events

19 (18.3)

14 (13.5)

5 (4.8)

18 (18.0)

10 (10.0)

6 (6.0)

All venous events 14 (13.5) 12 (11.5) 2 (1.9) 9 (9.0) 5 (5.0) 3 (3.0)

Select venous events Pulmonary embolism Deep thrombophlebitis

9 (8.7) 2 (1.9)

9 (8.7)

0

0

2 (1.9)

6 (6.0) 3 (3.0)

6 (6.0)

0

0

3 (3.0)

All arterial events 5 (4.8) 2 (1.9) 3 (2.9) 10 (10.0) 5 (5.0) 4 (4.0)

Select arterial events Myocardial infarction Arterial thrombosis Cerebrovascular accident Cerebral infarction Cerebral ischaemia

2 (1.9) 1 (1.0) 1 (1.0)

0 1 (1.0)

0

1 (1.0) 0 0

1 (1.0)

2 (1.9)

0 1 (1.0)

0 0

2 (2.0) 1 (1.0) 2 (2.0) 2 (2.0) 3 (3.0)

0

1 (1.0) 0 0

3 (3.0)

2 (2.0)

0 2 (2.0) 1 (1.0)

0

Novotny W, et al. J

Thromboembolic events during first-line therapy (AVF2107)

No. of patients (%)

IFL + placebo (n=396) IFL + bevacizumab (n=392)

All Grades

Grade 3

Grade 4

All Grades

Grade 3

Grade 4

Total venous and arterial events

64 (16.2)

34 (8.6)

23 (5.8)

76 (19.4)

47 (12.0)

22 (5.6)

All venous events 60 (15.2) 34 (8.6) 20 (5.1) 65 (16.6) 45 (115) 14 (3.6)

Select venous events Pulmonary embolism Deep thrombophlebitis

25 (6.3) 20 (5.1)

25 (6.3)

0

0

20 (5.1)

35 (8.9) 14 (3.6)

35 (8.9)

0

0

14 (3.6)

All arterial events 4 (1.0) 0 3 (0.8) 13 (3.3) 3 (0.8) 9 (2.3)

Select arterial events Myocardial infarction Arterial thrombosis Cerebrovascular accident Cerebral ischaemia

3 (0.8) 1 (0.3)

0 0

0 0 0 0

3 (0.8)

0 0 0

6 (1.5) 3 (0.8) 2 (0.5) 1 (0.3)

0

2 (0.5) 0

1 (0.3)

6 (1.5)

0 2 (0.5)

0

Novotny W, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3529

Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer

surgery

ComplicationIFL/placebo(n=155) (%)

IFL/bevacizumab (n=150) n (%)

5-FU/LV/bevacizumab

(n=37) (%)

Abscess 0 0 0

Perforatedlarge intestine 0 1 (0.67) 0

Perforated stomach ulcer 0 1 (0.67) 0

All types (total) 0 2 (1.3) 0

Wound healing complications

Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer

surgery (cont’d)

Haemorrhage

IFL/placebo

(n=155)

n (%)

IFL/bevacizumab

(n=150)

n (%)

5-FU/LV/bevacizumab

(n=37) (%)

GI 1 (0.65) 0 0

Rectal 0 1 (0.67) 0

All types 1 (0.65) 1 (0.67) 0

Bleeding complications

Bleeding: incidence

Trial Regimen All grades Grade 3/4 Grade 3 Grade 4

E32001 FOLFOX NR NR 0 0

FOLFOX + bevacizumab (10mg/kg)

NR NR 2.0 0

Bevacizumab (10mg/kg) NR NR 2.0 0

AVF07802 5-FU/LV 11* 0* NR NR


52* 0* NR NR


69* 9.4* NR NR

AVF21073 IFL NR 2.5 NR NR

IFL + bevacizumab (5mg/kg) NR 3.1 NR NR

AVF21924 5-FU/LV NR 2.9 1.9 1.0


NR 5.0 3.0 2.0

*Epistaxis + GI haemorrhage

I farmaci biologici modificano o incrementano la tossicita’ dei chemioterapici



EGFR inibitori (Cetuximab/TKI)– Irinotecan– gemcitabina– taxani

CRYSTAL trial:Safety: Grade 3/4 AE

FOLFIRI

n=602, %

Cetuximab + FOLFIRI

n=600, %

Any 59.5 78.0

Neutropenia 23.3 26.7

- Febrile neutropenia 2.2 2.7

Diarrhea 10.5 15.2

Vomiting 5.0 4.5

Fatigue 4.5 5.0

Skin reactionsa 0.2 18.7

Hypomagnesemiab 0.2 1.8

Infusion-related reactions 0 2.3

aThere were no grade 4 skin reactions

bAvailable only from a subset of patients (at least one measurement in 20% of population)

Tossicita’ dei nuovi agenti biologici

Trastuzumab– Cardiotossicita’

Bevacizumab– ipertensione– Proteinuria– Malattia tromboembolica

Cetuximab– Tossicita’ cutanea

Sunitinib– Diarrea– astenia

Imatinib– Astenia– diarrea

Documents

Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona Toxicities of molecularly targeted agents in combination with chemotherapy