TAXANES, GEMCITABINE AND MONOCLONAL ANTIBODIES ANTI-HER-2 AND THEIR COMBINED USE: WHAT IS THE BENEFIT IN TERMS OF RESPONSE QUALITY AND SURVIVAL?

1
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
2
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.

Perez BA, JCO 2001
Seidman AD, JCO 1998
3
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.

Bissery MC, Cancer Research 1991
Ravdin, Semin Oncol,1997
4
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
5
INTRODUCTION

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

Perez BA, JCO 2001
6
COMBINATION DOC/GEM
REFERENCE SCHEDULE N RR (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
7
COMBINATION DOC/GEM
SCHEDULE N RR (CR) MEDIAN TTP (mo) REFERENCE
Q21 (Gem 1000 gg 1, 8, Doc 100 g8) 36 72 (8) ND Alexopoulos et al, 2001
Q28 (Gem 800 gg 1, 8, 15, Doc 100 g1) 39 79 (5) 7.6 Laufman et al., 2002
Q28 (Gem 1500 gg 1, 15, Doc 50 gg1 e 15) 34 59 (7) 7 Kornek et al., 2001
8
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 difluorodeoxycytidi
  ne triphosphate (dFdCTP), the active metabolite
  of Gemcitabine.

Kroep JR, Br J Cancer 2000
Paclitaxel did not affect the pharmacokinetics of
Gemcitabine, nor did gemcitabine affect the
pharmacokinetics of paclitaxel, but paclitaxel
increase dFdCTP accumulation.
Kroep JR, JCO 1999
9
Paclitaxel/gemcitabine background
In NSCLC cell lines, paclitaxel administered
immediatly before gemcitabine, significantly
improves dFdCTP accumulation, gemcitabine
accumulation into RNA and apoptotic index.
Kroep JR, JCO 1999

• 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
10
PHASE II TRIALS OF PTX/GEM

• 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
  Oncol264-268, 2001.
• Sanchez F., RESULTS FROM A PHASE II STUDY OF
  GEMCITABINE IN COMBINATION WITH PACLITAXEL IN
  METASTATIC BREAST CANCER. Ann Oncol 916, 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)

11
PHASE II TRIALS OF PTX/GEM

• J. OShaughnessy 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 15201-206, 2004.

12
GEMCITABINE PLUS PACLITAXEL (GT) VERSUS
PACLITAXEL (T) AS FIRST-LINE TREATMENT FOR
ANTHRACYCLINE PRE-TREATED METASTATIC BREAST
CANCER (MBC).

• 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-CSF NEUROTOXICITY
5(18.5) 6 (5,4) G3 8 G4 FEBRILE 2 (in febrile neutropenia) G1 5 G3 2
A. M. Murad et al, Am J Clin Oncol264-268, 2001
13
GEMCITABINE PLUS PACLITAXEL (GT) VERSUS
PACLITAXEL (T) AS FIRST-LINE TREATMENT FOR
ANTHRACYCLINE PRE-TREATED METASTATIC BREAST
CANCER (MBC).
RESULTS
ORR () CR () PR () SD () MEDIAN RESPONSE DURATION MEDIAN OS
55 17 38 20.5 8 (4-26) 12 MONTHS
A. M. Murad et al, Am J Clin Oncol264-268, 2001.
14
RESULTS FROM A PHASE II STUDY OF GEMCITABINE IN
COMBINATION WITH PACLITAXEL IN METASTATIC BREAST
CANCER.

• SECOND OR SUBSEQUENT LINES (93PRIOR
  ANTHRACICLINES AND 20PRIOR 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.

Sanchez F., et al, Ann Oncol 916, 1998 (abs 77P)
15
RESULTS FROM A PHASE II STUDY OF GEMCITABINE IN
COMBINATION WITH PACLITAXEL IN METASTATIC BREAST
CANCER.
RESULTS
ORR () CR () PR () MEDIAN RESPONSE DURATION MEDIAN OS
45 16 30 8 (4-26) 12 MONTHS (4-28)
Sanchez F., et al, Ann Oncol 916, 1998 (abs 77P)
16
BIWEEKLY PACLITAXEL/GEMCITABINE (P/G) AS SALVAGE
TREATMENT IN BREAST CANCER PATIENS PRELIMINARY
RESULTS.

• 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-CSF NEUROTOXICITY G1-G2
4 11 37
P Vici et al., Proc Am Soc Clin Oncol 2002 (abs
2054)
17
BIWEEKLY PACLITAXEL/GEMCITABINE (P/G) AS SALVAGE
TREATMENT IN BREAST CANCER PATIENTS PRELIMINARY
RESULTS.
RESULTS
ORR () CR () PR () SD () MEDIAN TTP MEDIAN OS
45 10 35 20.5 8 MONTHS NA
P Vici et al., Proc Am Soc Clin Oncol 2002 (abs
2054)
18
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.
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).
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
19
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).

TTP mo ORR ()
GT 5.4 (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
20
Time to disease progression
GT
100
T
80
Log-rank test p-value 0.0013 Hazard ratio 0.73
(0.61-0.89)
60
Progression-free
40
20
0
0
3
6
9
12
15
18
21
24
TTP (months)
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
21
Paclitaxel/Gemcitabine

• EMATOLOGIC TOXICITY CTC GRADE 4

NEUTROPENIA ANEMIA THROMBOCYTOPENIA
GT 17.7 1.1 0.4
T 6.6 0.4 0
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
22
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 gt1
  cycle (25 vs 15)

Oshaughnessy J, C. Moinpour, ASCO 2003-2004
23
Rotterdam Symptoms checklist overall evaluation
of life item
BETTER QoL
80
GT (n152)
T (n162)
75


Mean Score
70
65
60
0
1
2
3
4
5
6
WORSE QoL
Cycle
Statistical improvement within the GT arm, as
compared to baseline
Oshaughnessy J, C. Moinpour, ASCO 2003-2004
24
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 gt1
  cycle (25 vs 15)

Oshaughnessy J, C. Moinpour, ASCO 2003-2004
25
GEMCITABINE PLUS PACLITAXEL AS FIRST-LINE
CHEMOTHERAPY FOR PATIENTS WITH ADVANCED BREAST
CANCER

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

C. Deflfino et al., Oncology 2004, 66 (1) 18-23
26
GEMCITABINE PLUS PACLITAXEL AS FIRST-LINE
CHEMOTHERAPY FOR PATIENTS WITH ADVANCED BREAST
CANCER
RESULTS

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

ORR () CR () PR () MEDIAN TTP MEDIAN OS
66.7 22.2 44.4 11 MONTHS 19 MONTHS
C. Delfino et al., oncology 2004, 66 (1) 18-23
27
BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED
BREAST CANCER PHASE II TRIAL AND PREDICTIVE
VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD).

• 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

R. Colomer et al, Annals of Oncol 2004, 15
201-206
28
BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED
BREAST CANCER PHASE II TRIAL AND PREDICTIVE
VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD).
TOXICITY
THROMBOCYTOPENIA G3 NEUTROPENIA G3 - G4 G-CSF NEUROTOXICITY G3
4 29 (2 G3 febrile) - 8
R. Colomer et al, Annals of Oncol 2004, 15
201-206
29
BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED
BREAST CANCER PHASE II TRIAL AND PREDICTIVE
VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD).
RESULTS
ORR () CR () PR () MEDIAN TTP MEDIAN OS
71 26 45 16.6 MONTHS NA
R. Colomer et al, Annals of Oncol 2004, 15
201-206
30
BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED
BREAST CANCER PHASE II TRIAL AND PREDICTIVE
VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD).
RESULTS Response Rate according to baseline
HER-2 ECD level (n41)
R. Colomer et al, Annals of Oncol 2004, 15
201-206
31
BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED
BREAST CANCER PHASE II TRIAL AND PREDICTIVE
VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD).
RESPONSE DURATION stratified by HER2 ECD status
R. Colomer et al, Annals of Oncol 2004, 15
201-206
32
CONCLUSIONS

• The combination Ptx/Gem is higly active and well
  tolerated regimen as first-line therapy.
• HER2 ECD levels correlated inversely with
  objective response (p0.02) and with response
  duration (p0.04).
• A Study with Gem/Tax/Herceptin is ongoing.

Colomer R, Ann Onc 2004
33
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

34
erbB Receptor Family
erbB-1 (EGFR)
erbB-2 (HER2/neu)
erbB-3 (HER3)
erbB-4 (HER4)
EGFTGF-?AmphiregulinBetacellulinHB-EGF
NRG2NRG3HeregulinsBetacellulin
Heregulins
Tyrosine Kinase Domain
Tyrosine Kinase Domain
Tyrosine Kinase Domain
Fernandes et al, 1999. Moghal et al, 1999.
35
HERCEPTIN MONOTHERAPY
STUDY LINE OF THERAPY RR TTP (mo)
Cobleigh MA et al J Clin Oncol 1999172639-2648 N 222 Prior Chemo 15 9.1
Vogel CL et al J Clin Oncol 200220719-726 1st line 26 IHC 3 (35vs 0) FISH (34vs 7) 18.8
36
HerceptinInteractions with Cytotoxic Agents
Synergistic Additive Antagonistic
Cisplatin/Carboplatin Docetaxel Docetaxel platinum Etoposide Vinorelbine Thiotepa Ionizing radiation Doxorubicin Paclitaxel Vinblastine Methotrexate Gemcitabine 5-Fluorouracil Capecitabine
Pegram et al. Oncogene 1999182241. Konecny et
al. Breast Cancer Res Treat 199957114a.
37
HERCEPTIN AND TAXANES
38
Paclitaxel/Gemcitabine/Trastuzumab

• 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
Sledge GW, Sem Onc, 2003
39
GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN
METASTATIC BREAST CANCER

• 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.

Miller KD, Oncology, 2001
40
GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN
METASTATIC BREAST CANCER

• TOXICITY

THROMBOCYTOPENIA NEUTROPENIA G3 - G4 ANEMIA CONGESTIVE HEART FAILURE
G3 34 G4 28 G3 11 G4 28 G3 6 G4 2 2 (1 PT)
Miller KD, Oncology, 2001
41
GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN
METASTATIC BREAST CANCER

• RESULTS (41 PATIENTS AVALUABLE)

ORR () CR () PR () SD () PD () MEDIAN TTP MEDIAN DURATION RESPONSE MEDIAN OS
71 12 59 15 15 10 MONTHS (1.5-16.5) 11 MONTHS (4-16.5) NA
Miller KD, Oncology, 2001
42
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)

43
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 cycles?PACLITAXEL (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.

Sanchez F., et al, Ann Oncol 916, 1998 (abs 77P)
44
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..

• TOXICITY

NAUSEA VOMITING G3 NEUTROPENIA G3 - G4 CONGESTIVE HEART FAILURE
12 3 none
Sanchez F., et al, Ann Oncol 916, 1998 (abs 77P)
45
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.

• PATHOLOGICAL RESPONSE (available only for 21 pts)

• CLINICAL RESPONSE
• (available only for 26 pts)

CR PR
9 (34.6) 15 (57.7)
CR ()
6 (28.6)
Of 5 pts overexpressing HER2, 1 pCR and
1microscopical residual disease
Sanchez F., et al, Ann Oncol 916, 1998 (abs 77P)
46
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.