Post on 06-Aug-2020
Innovación en oncología: Nanotecnología dirigida al tumor. Nuevos paradigmas en el melanoma
Javier CortésMarzo/2013
Oncology DepartmentVall d´Hebron University Hospital
Barcelona. Spain
• Chemotherapy – Dacarbazine or temozolomide– Cisplatin, dacarbazine, vinblastine (CVD)– Carboplatin +paclitaxel
• Interferon-alfa
• Interleukin-2 (high-dose)
• Biochemotherapy– CVD + IL-2+ interferon-alfa
Standard Systemic Treatment for Metastatic Melanoma
Multi-agent chemotherapy/biochemotherapy is not substantially better than dacarbazine, although RR may be higher
Survival Outcome is Consistent In Large Trials
Self-sufficiency in growth signals Insensitivity to antigrowth signals Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Tumor invasion and metastases Avoidance of immunosurveillance
Dunn GP et al. Ann. Rev. Immunology 2004; 22: 329-360
Immunoselection or Immunoediting
Immunosubversion
HALLMARKS OF CANCER
1009080706050403020100
Ove
rall
surv
ival
(%)
No. of patients in follow upDacarbazineVemurafenib
0 1 2 3 4 5 6 7 8 9 10 11 12
Vemurafenib (N=336)Est 6 mo survival 84%
Months
336336
283320
192266
137210
98162
64111
3980
2035
16
11
Dacarbazine (N=336)Est 6 mo survival 64%
914
Hazard ratio 0.37 (95% CI; 0.26 - 0.55)Log-rank P<0.0001
Overall survival (BRIM 3)
Chapman PB, NEJM 2011
1009080706050403020100
Prog
ress
ion-
free
sur
viva
l (%
)
No. of patients in follow upDacarbazineVemurafenib
0 1 2 3 4 5 6 7 8 9 10 11 12
Hazard Ratio 0.26 (95% CI; 0.20 - 0.33)Log-rank P<0.0001
Months274275
213268
85211
48122
28105
1650
1035
616
34
03
Dacarbazine (N=274)
Vemurafenib (N=275)
Progression-free survival (BRIM 3)
Median 1.6 mos Median 5.3 mos
Chapman PB, NEJM 2011
Self-sufficiency in growth signals Insensitivity to antigrowth signals Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Tumor invasion and metastases Avoidance of immunosurveillance
Dunn GP et al. Ann. Rev. Immunology 2004; 22: 329-360
Immunoselection or Immunoediting
Immunosubversion
HALLMARKS OF CANCER
Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma
Evan M. Hersh,1 Michele Del Vecchio,2 Michael P. Brown,3 Richard Kefford,4 Carmen Loquai,5 Alessandro Testori,6 Shailender Bhatia,7 Ralf Gutzmer,8 Andrew Haydon,9 Caroline Robert,10 Alicia Clawson,11 Ileana
Elias,11 Markus F Renschler,11 Axel Hauschild12
1 Arizona Cancer Center, Tucson, AZ, USA; 2 Istituto Nazionale Tumori, Milano, Italy; 3 Royal Adelaide Hospital, Australia; 4 Westmead Hospital and Melanoma Institude, Australia; 5 Universitätsmedizin Mainz, Germany; 6 Istituto Europeo di Oncologia, Milano, Italy; 7 Seattle Cancer Care Alliance, USA; 8 Medizinische Hochschule Hannover, Germany; 9 Alfred Hospital, Melbourne, Australia; 10 IGR Centre de Lutte Contre le Canc, Villejuif, France; 11 Celgene, Summit, NJ, USA; 12 Universitätsklinkum Schleswig-Holstein, Kiel, Germany
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
nab-Paclitaxel Distinct Pharmacokinetics and Biodistribution
Compared with solvent-based paclitaxel, nab-paclitaxel exhibits:– Linear pharmacokinetics [1]– ~10-fold increase in Cmax and ~3-fold higher AUC of unbound paclitaxel [2]– Potential binding to albumin-binding proteins– Enhanced transport across endothelial cell monolayers [3]– 33% higher paclitaxel concentration in tumor xenografts [3]
1. Nyman, JCO, 2005 2. Gardner, CCR, 2008 3. Desai, CCR, 2006
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Aleatorización (1:1)n = 460
Cáncer de mama
nab-Paclitaxel 260 mg/m2
c/3 semanas
Paclitaxel 175 mg/m2
c/3 semanas
Aleatorización (1:1)n = 1052
Cáncer de pulmón
nab-Paclitaxel 100 mg/m2/semanalCarboplatino AUC 6 c/3 semanas
Paclitaxel 200 mg/m2 c/3 semanasCarboplatino AUC 6 c/3 semanas
Aleatorización (1:1)n = 460
Cáncer de Páncreas
nab-Paclitaxel 125 mg/m2 d1, 8, 15Gemcitabina 1000 mg/m2 d1, 8, 15
c/4 semanas
Gemcitabina 1000 mg/m2 d1, 8, 15c/4 semanas
Aleatorización (1:1)n = 514
melanoma
nab-Paclitaxel 150 mg/m2 d1, 8, 15c/4 semanas
Dacarbacina 1000 mg/m2
c/3 semanas
*
•Durante las primeras 8 semanas, los pacientes recibirán gemcitabina1000 mg/m2 semanalmente durante las primeras 7 semanas, seguido de una semana de descanso
nab-Paclitaxel Randomized Phase III Trials
nab-Paclitaxel: Phase I and II Studies
nab-Paclitaxel, 30-min IV infusion, weekly 3 of 4 weeksPhase 1, Advanced Solid Tumors [4] (14 Melanoma pts)
80-200 mg/m2 weeklyN = 39
DCR, % 38
The 150 mg/m2 dose level was well tolerated in lightly pretreated patients
Phase 2, Metastatic Melanoma [5] 150 mg/m2
Chemo-naïve N = 37
PR, %DCR, %PFS, median monthOS, median month
22494.59.6
• No premedication; No special tubing; No acute toxicities typical of taxanes• While cremophor-paclitaxel [1,2] or docosahexaenoic acid-paclitaxel [3]
produced limited clinical benefit, nab-paclitaxel produced promising efficacy:
1. Walker, Melanoma Res, 2005 2. Pfugfelder, Plos Once, 2011 3. Bedikian, Ann Oncol, 2011 4. Nyman, JCO, 2005 5. Hersh, Cancer. 2010
DCR, disease control rate; OS, overall survival; PFS, progression-free survival; PR, partial response
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Phase III Study Design
1:1 randomization stratified by:• metastatic stage (M1a, M1b, and M1c)• region (Australia, North America, Western Europe)• baseline LDH (< 0.8 x ULN, 0.8–1.1 x ULN, >1.1-2 x ULN)
Planned N = 514
Chemo-naïveECOG PS 0-1Stage IV cutaneousMeasurable diseaseLDH levels ≤2.0 x ULNNo current brain mets
nab-Paclitaxel (nab-P) 150 mg/m2 IV
days 1, 8, and 15, 28-day cycle
Dacarbazine (DTIC)1000 mg/m2 IV, day 1, 21-day cycle
• CT scan every 8 weeks in both arms• Enrollment period April 2009 – June 2011; Data cut-off – June 30, 2012• Treatment until disease progression or unacceptable toxicity, patient/investigator discretion
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; ULN, upper limit of normal
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Study Endpoints• Primary Efficacy Endpoint
PFS per blinded radiology assessment, RECIST v1.0
• Secondary Efficacy Endpoint
OS
• Other Endpoints Included
ORR, DCR
• Safety/tolerability using NCI CTCAE v3
• For PFS, 514 with 379 events patients provided ≥80% power to detect a HR of 0.750 (two sided alpha of 0.049)
• Interim survival analysis was planned at PFS final analysis• Treatment differences in PFS and OS were tested using stratified log-rank; ORR
and DCR were tested using chi-squared test• The ITT population was evaluated for efficacy, the treated population for safety
Statistical Analyses
ITT, intent-to-treat; NCI CITCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; HR, hazard ratio; ORR, objective response rate; RECIST, Response Evaluation Criteria In Solid Tumors
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Baseline Characteristics
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
PFS by Independent Radiology Review
CI, confidence interval
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
OS: Planned Interim Analysis
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Some thoughts…
Some thoughts…
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
PFS and Interim OS by BRAF Status
BRAF Status nab-Paclitaxel(n = 264)
Dacarbazine(n = 265)
HR(nab-P/DTIC)
P-value
Wild TypeNMedian PFS, monthsMedian OS, months
1165.4 12.7
1082.5 11.1
0.715 0.845
0.0880.330
V600E Mutation
NMedian PFS, monthsMedian OS, months
655.316.9
673.511.2
0.8830.688
0.6560.132
Unknown NMedian PFS, monthsMedian OS, months
833.711.1
902.29.9
0.6840.837
0.0660.381
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Other Efficacy Endpoints
Blinded Radiology Assessment
nab-Paclitaxel(n = 264)
Dacarbazine(n = 265)
Response Rate Ratio
(Pnab-P/PDTIC)P-value
ORR, % (95% CI) 15 (10.5, 19.1) 11 (7.5, 15.1) 1.305 (0.837, 2.035) 0.239
DCR, % (95% CI) 39 (32.8, 44.5) 27 (21.5, 32.1) 1.442 (1.123, 1.852) 0.004PR, % 15 11SD ≥16 weeks, % 24 15
Best Response 0.0017*PR, % 15 11SD, % 25 16PD, % 35 48 0.005**Not Evaluable, % 25 25
P, proportion of improved patients; PD, progressive, disease; SD, stable disease
* Includes confirmed PR + SD + PD** Comparison of PD rate between arms
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
PFS by Independent Review – Subgroups
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
OS Interim Analysis – Subgroups
Target Tumor Responses by Patient
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Treatment Exposure, Dose Reductions
Variable nab-Paclitaxel(n = 257)
Dacarbazine(n = 258)
Planned Protocol Dose , median %Min, Max
97.749.9, 105.0
100.048.0, 105.0
Dose Intensity, median mg/m2/weekMin, Max
146.574.9, 157.5
333.3160.1, 350.0
Duration of Treatment, median weeks*Min, Max
11.10, 88
6.40, 106
Patients with at least 1 Dose Reduction, % 32 20
* nab-paclitaxel: 28-day cycle; dacarbazine: 21-day cycle
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Preferred Termnab-Paclitaxel
(n = 257)Dacarbazine
(n = 258)Patients with at least 1 TRAE, %Patients with at least 1 serious TRAE, %
509
287
Hematologic Adverse events, %*NeutropeniaLeukopeniaLymphocytopeniaThrombocytopeniaAnemia
2012802
1071165
Nonhematologic Adverse Events, %*Peripheral Neuropathy**FatigueAlopecia
2585
020
Neuropathy, median daysTime to OnsetTime to Improvement by 1 gradeTime to Improvement to grade ≤1
1012867
---
Grade ≥3 Treatment-related Adverse Events (TRAEs) in ≥ 5% Patients
* Except for lymphocytopenia, all events P < 0.05** All but 2 neuropathy cases were grade 3
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Summary
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Conclusions I
• IN MY OPINION…
… nab-Paclitaxel is a new standard of care!!!
Conclusions II
PEOPLE EDUCATION