taxanes, gemcitabine and monoclonal antibodies anti- her-2 and their combined use: what is the...

TAXANES, GEMCITABINE AND MONOCLONAL ANTIBODIES ANTI-HER-2 AND THEIR COMBINED USE:

WHAT IS THE BENEFIT IN TERMS OF RESPONSE QUALITY AND

SURVIVAL?

PROF. FRANCESCO COGNETTIREGINA ELENA NATIONAL CANCER INSTITUTE, ROME

Rome, 16-18 December 2004

INTRODUCTION

• TAXANES (Paclitaxel and Docetaxel) are anticancer drugs that has shown significance efficacy against metastatic breast cancer.

• PACLITAXEL is an anticancer agent that stabilizes microtubules.

• Single-agent Paclitaxel: Response Rate ranges between 30 to 60% when given every three weeks and between 20 to 50% when given weekly.

Seidman AD, JCO 1998

Perez BA, JCO 2001

INTRODUCTION

• DOCETAXEL is a new semisintetic taxane with a significant antineoplastic activity and toxicity consisting in myelosuppression primarily.

• It acts by disruption of mitosis, promotion of microtubular assembly, and suppression of depolymerization of microtubular bundles to free tubulin.

• Single-agent Docetaxel: Response Rate of 59% in first-line treatment and 46% in second-line treatment in patients with metastatic breast cancer. Response rate of 41% in patients progressing after prior anthraciclines therapy.

Ravdin, Semin Oncol,1997

Bissery MC, Cancer Research 1991

INTRODUCTION • GEMCITABINE, a nucleotide analog, upon entering

the cells, is phosphorilated by deoxycytidine kinase and both diphosphate and triphosphate contribute to its citotoxicity.

• Diphospate is an inhibitor of ribonucleotide reductase, essential for the intracellular synthesis of deoxynucleotide triphosphates for normal DNA production.

• Triphosphate is a fraudolent base that, once incorporetad into the DNA, leads to halting of DNA chain enlogation.

Perez BA, JCO 2001

INTRODUCTION

• Single-agent Gemcitabine: Response Rate ranges between 14 to 37% in first and subsequent lines, with very low toxicity.

Perez BA, JCO 2001

COMBINATION DOC/GEM

REFERENCE SCHEDULE NRR

(CR)

MEDIAN TTP(mo)

Fountzilas et al., 2000

Q21(Gem 1000 gg 1, 8,

Doc 75 g1)39

36%(8%)

7

Mavroudis et al., 1999

Q21(Gem 900 gg 1, 8,

Doc 100 g8)52

54%(13%)

8

Brandi et al., 2001

Q21(Gem 1000 gg 1, 8,

Doc 80 g8)53

53%(9%)

7.5

COMBINATION DOC/GEM

SCHEDULE NRR

(CR)

MEDIAN TTP(mo)

REFERENCE

Q21(Gem 1000 gg 1, 8,

Doc 100 g8)36

72%(8%)

NDAlexopoulos et

al, 2001

Q28(Gem 800 gg 1, 8, 15, Doc 100 g1)

3979%(5%)

7.6Laufman et al.,

2002

Q28(Gem 1500 gg 1, 15,

Doc 50 gg1 e 15)34

59%(7%)

7Kornek et al.,

2001

Paclitaxel/gemcitabine background

In Non small cell lung camcer (NSCLC) cell lines the combination of Paclitaxel and Gemcitabine has at least additive cytotoxicity, with paclitaxel leading to the accumulation of difluorodeoxycytidine triphosphate (dFdCTP), the active metabolite of Gemcitabine.

Kroep JR, Br J Cancer 2000

Kroep JR, JCO 1999

Paclitaxel did not affect the pharmacokinetics of Gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increase dFdCTP accumulation.

Paclitaxel/gemcitabine background

In mouse model the maximum effect was obtained when paclitaxel was administered on day 1 and 15, with gemcitabine every three days.

Cividalli A, J Canc Res Clin Onc, 2000

In NSCLC cell lines, paclitaxel administered immediatly before gemcitabine, significantly improves dFdCTP accumulation, gemcitabine accumulation into RNA and apoptotic index.

Kroep JR, JCO 1999

•A. M. Murad et al., PHASE II TRIAL OF THE USE OF PACLITAXEL AND GEMCITABINE AS A SALVAGE TREATMENT IN METASTATIC BREAST CANCER. Am J Clin Oncol:264-268, 2001.

•Sanchez F., RESULTS FROM A PHASE II STUDY OF GEMCITABINE IN COMBINATION WITH PACLITAXEL IN METASTATIC BREAST CANCER. Ann Oncol 9:16, 1998 (abs 77P)

•P Vici et al., BIWEEKLY PACLITAXEL/GEMCITABINE (P/G) AS SALVAGE TREATMENT IN BREAST CANCER PATIENS : PRELIMINARY RESULTS. Proc Am Soc Clin Oncol: 2002 (abs 2054)

PHASE II TRIALS OF PTX/GEM

•J. O’Shaughnessy et al, GEMCITABINE PLUS PACLITAXEL (GT) VERSUS PACLITAXEL (T) AS FIRST-LINE TREATMENT FOR ANTHRACYCLINE PRE-TREATED METASTATIC BREAST CANCER (MBC). Proc Am Soc Clin Oncol: 2003 (abs 25)

•C. Delfino et al, GEMCITABINE PLUS PACLITAXEL AS FIRST-LINE CHEMOTHERAPY FOR PATIENTS WITH ADVANCED BREAST CANCER. Oncology 2004, 66 (1): 18-23.

•R. Colomer et al., BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED BREAST CANCER: PHASE II TRIAL AND PREDICTIVE VALUE OF HER2 EXTRACELLULAR DOMAIN. Annals of Oncology 15:201-206, 2004.

PHASE II TRIALS OF PTX/GEM

GEMCITABINE PLUS PACLITAXEL (GT) VERSUS PACLITAXEL (T) AS FIRST-LINE TREATMENT FOR

ANTHRACYCLINE PRE-TREATED METASTATIC BREAST CANCER (MBC).

A. M. Murad et al, Am J Clin Oncol:264-268, 2001

•SECOND OR SUBSEQUENT LINES•T (135 mg/mq) g1, G (1000 mg/mq) gg 1, 8, (15* in the first 5 patients, interrupted because of inacceptable thrombocitopenia). Cycles every 3 weeks.•29 PATIENTS.•137 MEDIAN CYCLES.

THROMBOCITOPENIA GRADE III AND IV

NEUTROPENIA G-CSFNEUROTO

XICITY

5(18.5%)*6 (5,4%)

G3: 8G4 FEBRILE: 2

+ (in febrile

neutropenia)

G1: 5 G3: 2

GEMCITABINE PLUS PACLITAXEL (GT) VERSUS PACLITAXEL (T) AS FIRST-LINE TREATMENT FOR

ANTHRACYCLINE PRE-TREATED METASTATIC BREAST CANCER (MBC).

A. M. Murad et al, Am J Clin Oncol:264-268, 2001.

ORR (%)

CR(%)

PR(%)

SD(%)

MEDIAN RESPONSE DURATION

MEDIANOS

55 17 38 20.58

(4-26)12

MONTHS

RESULTS

RESULTS FROM A PHASE II STUDY OF GEMCITABINE IN COMBINATION WITH PACLITAXEL IN METASTATIC

BREAST CANCER.

Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)

•SECOND OR SUBSEQUENT LINES (93%PRIOR ANTHRACICLINES AND 20%PRIOR PACLITAXEL)•T (135 mg/mq) g1, G (2500 mg/mq) gg 1, 15. Cycles every 4 weeks.•44 PATIENTS.•137 MEDIAN CYCLES.•EMATOLOGIC TOXICITY IN 15% OF PATIENTS, WITH 34% REQUIRING G-CSF.

RESULTS FROM A PHASE II STUDY OF GEMCITABINE IN COMBINATION WITH PACLITAXEL IN METASTATIC

BREAST CANCER.


RESULTS

ORR (%)

CR(%)

PR(%)

MEDIAN RESPONSE DURATION

MEDIANOS

45 16 308

(4-26)

12 MONTHS

(4-28)

BIWEEKLY PACLITAXEL/GEMCITABINE (P/G) AS SALVAGE TREATMENT IN BREAST CANCER PATIENS :

PRELIMINARY RESULTS.

P Vici et al., Proc Am Soc Clin Oncol: 2002 (abs 2054)

•T (150 mg/mq) g1, G (1500 mg/mq) gg 1, 15. Cycles every 4 weeks.•27 PATIENTS HEAVILY PRETREATED.•137 MEDIAN CYCLES.

ANEMIA G3

NEUTROPENIA G3 - G4

G-CSFNEUROTOXICITY

G1-G2

4% 11% + 37%

BIWEEKLY PACLITAXEL/GEMCITABINE (P/G) AS SALVAGE TREATMENT IN BREAST CANCER PATIENTS :

PRELIMINARY RESULTS.

P Vici et al., Proc Am Soc Clin Oncol: 2002 (abs 2054)

RESULTS

ORR (%)

CR(%)

PR(%)

SD(%)

MEDIANTTP

MEDIANOS

45 10 35 20.5 8 MONTHS NA

GEMCITABINE plus PACLITAXEL (GT) versus PACLITAXEL (T) as first-line treatment for

anthracyclne pre-treated metastatic breast cancer (MBC): Quality of life (QoL) and pain palliation

results from the global phese III study.

Oshaughnessy J, C. Moinpour, ASCO 2003-2004

RANDOMI

ZE

GT (G 1250mg/mq d 1, 8; T 175 g/mq d1)

T (175 mq/mq d1 q 21)

END POINT: OVERALL SURVIVAL (os), Progression free-survival (PFS), overall response rate (ORR), QoL, Palliation of pain, time to progressive disease (TTP).

Paclitaxel/gemcitabine•529 patients randomized: 267 GT arm and 262 T arm.•Median cycles: 6 for GT (range 0-20) 5 for T (range 0-16).

TTPmo

ORR(%)

GT5.4

(95% CI, 4.6-6.1 mos)

39.3(95% CI, 33.5-

45.2 mos)

T

3.5(95% CI, 2.9-

4.0 mos)

25.6(95% CI, 20.3-

30.9 mos)

P= 0.0013

P= 0.0007



Time to disease progression

GTGT

TT

% P

rog

ress

ion

-fre

e%

Pro

gre

ssio

n-f

ree

TTP (months)TTP (months)

Log-rank test p-value 0.0013Log-rank test p-value 0.0013

Hazard ratio 0.73 (0.61-0.89) Hazard ratio 0.73 (0.61-0.89)

00

2020

4040

6060

8080

100100

00 33 66 99 1212 1515 1818 2121 2424

Paclitaxel/Gemcitabine•EMATOLOGIC TOXICITY CTC GRADE 4

NEUTROPENIA ANEMIATHROMBOCYTO

PENIA

GT 17.7% 1.1% 0.4%

T 6.6% 0.4% 0%


Paclitaxel/gemcitabine


•The Rotterdam Symptoms checklist (RSCL) global QoL score for patients receiving GT was significantly and significantly better than that reported by T arm patients.

•This difference was clinically significant.

•Of patients requiring analgesic at baseline, more GT pts were able to reduce analgesic level for >1 cycle (25 vs 15%)

Rotterdam Symptoms checklist: overall evaluation of

life item

*Statistical improvement within the GT arm, as compared to baseline

Mea

n S

core

Mea

n S

core

6060

6565

7070

7575

8080

CycleCycle00 11 22 33 44 55 66

** **

GT (n=152)GT (n=152)

T (n=162)T (n=162)


BETTER QoL

WORSE QoL

Paclitaxel/gemcitabine


•The Rotterdam Symptoms checklist (RSCL) global QoL score for patients receiving GT was significantly and significantly better than that reported by T arm patients.

•This difference was clinically significant.

•Of patients requiring analgesic at baseline, more Gt pts were able to reduce analgesic level for >1 cycle (25 vs 15%)

GEMCITABINE PLUS PACLITAXEL AS FIRST-LINE CHEMOTHERAPY FOR PATIENTS WITH ADVANCED

BREAST CANCER

C. Deflfino et al., Oncology 2004, 66 (1): 18-23

•FIRST LINE (60% PATIENTS PRIOR ADJUVANT).•T (175 mg/mq) g1, G (1200 mg/mq) gg 1, 8. Cycles every 3 weeks.•45 PATIENTS.

GEMCITABINE PLUS PACLITAXEL AS FIRST-LINE CHEMOTHERAPY FOR PATIENTS WITH ADVANCED

BREAST CANCER

C. Delfino et al., oncology 2004, 66 (1): 18-23

RESULTS

ORR (%)

CR(%)

PR(%)

MEDIAN TTP

MEDIANOS

66.7 22.2 44.4 11 MONTHS 19 MONTHS

•Grade3/4 leukopenia, neutropenia and thrombocitopenia developed in 13.3%, and 15.5% developed mucositis grade 3/4.

BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED BREAST CANCER: PHASE II TRIAL AND

PREDICTIVE VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD).

R. Colomer et al, Annals of Oncol 2004, 15: 201-206

•FIRST LINE (51% PATIENTS PRIOR ADJUVANT, 32% WITH ANTHRACICLINES)

•T (150 mg/mq) g1, 14; G (2500 mg/mq) gg 1, 14.

•43 PATIENTS

•ASSESSEMENT OF HER2 ECD SERUM LEVELS BY ELISA




TOXICITY

THROMBOCYTOPENIA

G3

NEUTROPENIA G3 - G4

G-CSFNEUROTOXICITY

G3

4%29%

(2% G3 febrile)- 8%




ORR (%)

CR(%)

PR(%)

MEDIANTTP

MEDIANOS

71 26 45 16.6 MONTHS NA

RESULTS




RESULTS: Response Rate according to baseline HER-2 ECD level (n=41)




RESPONSE DURATION stratified by HER2 ECD status

CONCLUSIONS

• The combination Ptx/Gem is higly active and well tolerated regimen as first-line therapy.

•HER2 ECD levels correlated inversely with objective response (p=0.02) and with response duration (p=0.04).

• A Study with Gem/Tax/Herceptin is ongoing.

Colomer R, Ann Onc 2004

TRASTUZUMAB IN BREAST CANCER

•HER-2

•Discovered in 1980•Member of EGFR family•Overexpressed in 25 to 30% of breast cancers•Shortened survival and relative resistance to therapies.

•TRASTUZUMAB

•Binds to the EC domain of HER2•FDA approved (1998)•Only in IHC 3+ or FISH +

erbB Receptor Family

HeregulinsEGF

TGF-AmphiregulinBetacellulin

HB-EGF

NRG2NRG3

HeregulinsBetacellulin

Fernandes et al, 1999. Moghal et al, 1999.

Tyrosine Kinase Domain



erbB-1 (EGFR)

erbB-2 (HER2/neu)

erbB-3 (HER3)

erbB-4 (HER4)

HERCEPTIN MONOTHERAPY

STUDY “LINE OF THERAPY”

RR TTP(mo)

Cobleigh MA et alJ Clin Oncol 1999;17:2639-2648N= 222

Prior Chemo 15% 9.1

Vogel CL et alJ Clin Oncol 2002;20:719-726

1st line

26%IHC 3+

(35%vs 0%)FISH +

(34%vs 7%)

18.8

HerceptinInteractions with Cytotoxic

Agents

Synergistic Additive Antagonistic

Cisplatin/CarboplatinDocetaxel

Docetaxel + platinumEtoposide

VinorelbineThiotepaIonizing radiation

DoxorubicinPaclitaxel

VinblastineMethotrexateGemcitabine

5-FluorouracilCapecitabine

Pegram et al. Oncogene 1999:18:2241.

Konecny et al. Breast Cancer Res Treat 1999;57:114a.

HERCEPTIN AND TAXANES

Paclitaxel/Gemcitabine/Trastuzumab

Sledge GW, Sem Onc, 2003

•The addition of Trastuzumab to chemotherapy improves response rate as well as duration of response and overall median survival. The combination is well tolerated.

•Gemcitabine and Trastuzumab exhibit additive or sinergistic antitumor effect when combined in Her-2 positive human cancer cell lines.

Slamon D, JCO 2001

Miller KD, Oncology, 2001

•FIRST LINE (ADJUVANT TAXANES PERMITTED)

•HER-2 OVEREXPRESSION DETECTED BY IMMUNOHYSTOCHEMISTRY OR FLUORESCENCE IN SITU HYBRIDIZATION.

•T (175 mg/mq) g1, G (1200 mg/mq) gg 1, 8. Cycle every 3 weeks.

TRASTUZUMAB 4 mg/Kg loading dose and 2 mg/Kg once weekly after.

•46 PATIENTS ENROLLED.

•MEDIAN CYCLES ADMINISTERED: 6.

GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN METASTATIC BREAST

CANCER



CANCER

•TOXICITY

THROMBOCYTOPENIA NEUTROPENIA G3

- G4ANEMIA

CONGESTIVE HEART FAILURE

G3 : 34%G4: 28 %

G3 : 11%G4: 28%

G3 : 6%G4: 2%

2% (1 PT)



CANCER

•RESULTS (41 PATIENTS AVALUABLE)

ORR (%)

CR(%)

PR(%)

SD (%)

PD(%)

MEDIANTTP

MEDIAN DURATION RESPONSE

MEDIANOS

71 12 59 15 15

10 MONTHS

(1.5-16.5)

11MONTHS(4-16.5)

NA

NEOADJUVANT SETTING

•P. Sanchez-Rovira, DOSE-DENSE AND SEQUENTIAL COMBINATION OF EPIRUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL AND GEMCITABINE +-TRASTUZUMAB AS NEOADJUVANT CHEMOTHERAPY IN STAGE II AND III BREAST CANCER. Proc Am Soc Clin Oncol: 2004 (abs 608)

•A. Schneeweiss et al., DOSE DENSE GEMCITABINE AND EPIRUBICIN (GE) FOLLOWED SEQUENTIALLY BY DOSE DENSE DOCETAXEL (Doc) AS PRIMARY SISTEMIC THERAPY OF PATIENTS WITH EARLY BREAST CANCER: FIRST RESULTS OF A PHASE I/II TRIAL. Proc Am Soc Clin Oncol: 2004 (abs 734)

DOSE-DENSE AND SEQUENTIAL COMBINATION OF EPIRUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL AND

GEMCITABINE +-TRASTUZUMAB AS NEOADJUVANT CHEMOTHERAPY IN STAGE II AND III BREAST CANCER..


•EPIRUBICIN (90 mg/mq) and CYCLOPHOSPHAMIDE (600 mg/mq) for III cyclesPACLITAXEL (150 mg/mq) and GEMCITABINE (2500 mg/mq) for VI Cycles (with profilactic G-CSF).•In patients with HER2-neu overexpression: weekly TRASTUZUMAB concomitant with GT.•30 PATIENTS.

•TOXICITY

NAUSEA VOMITING

G3

NEUTROPENIA G3 - G4

CONGESTIVE HEART FAILURE

12 % 3% none


GEMCITABINE +-TRASTUZUMAB AS NEOADJUVANT CHEMOTHERAPY IN STAGE II AND III BREAST CANCER..


•CLINICAL RESPONSE(available only for 26 pts)

CR PR

9(34.6%)

15(57.7%)


GEMCITABINE +-TRASTUZUMAB AS NEOADJUVANT CHEMOTHERAPY IN STAGE II AND III BREAST CANCER.


•PATHOLOGICAL RESPONSE (available only for 21 pts)

CR(%)

6 (28.6)

Of 5 pts overexpressing HER2, 1 pCR and 1microscopical residual disease

CONCLUSIONS

Combination of taxanes, especially paclitaxel and gemcitabine are:

•Safe : Haematologic toxicity is common (ANC) but mild.

•Active : RR – 40-70%, with durable responses with high level complete remissions

•Combination of both with trastuzumab is promising. Randomized trial are needed to test this combination.

taxanes, gemcitabine and monoclonal antibodies anti- her-2 and their combined use: what is the...

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