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 COGNETTI REGINA ELENA NATIONAL CANCER INSTITUTE, ROME Rome, 16-18 December 2004
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.
Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)
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
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
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%
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
Paclitaxel/gemcitabine
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
•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)
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
BETTER QoL
WORSE QoL
Paclitaxel/gemcitabine
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
•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
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
TOXICITY
THROMBOCYTOPENIA
G3
NEUTROPENIA G3 - G4
G-CSFNEUROTOXICITY
G3
4%29%
(2% G3 febrile)- 8%
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
ORR (%)
CR(%)
PR(%)
MEDIANTTP
MEDIANOS
71 26 45 16.6 MONTHS NA
RESULTS
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
RESULTS: Response Rate according to baseline HER-2 ECD level (n=41)
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
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
Tyrosine Kinase Domain
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
Miller KD, Oncology, 2001
GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN METASTATIC BREAST
CANCER
•TOXICITY
THROMBOCYTOPENIA NEUTROPENIA G3
- G4ANEMIA
CONGESTIVE HEART FAILURE
G3 : 34%G4: 28 %
G3 : 11%G4: 28%
G3 : 6%G4: 2%
2% (1 PT)
Miller KD, Oncology, 2001
GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN METASTATIC BREAST
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..
Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)
•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
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..
Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)
•CLINICAL RESPONSE(available only for 26 pts)
CR PR
9(34.6%)
15(57.7%)
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.
Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)
•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.