innovación en oncología: nanotecnología dirigida al tumor. … · nab-paclitaxel distinct...

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


Aleatorización (1:1)n = 460

Cáncer de mama

nab-Paclitaxel 260 mg/m2

c/3 semanas

Paclitaxel 175 mg/m2

c/3 semanas


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


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


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


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


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


Baseline Characteristics


PFS by Independent Radiology Review

CI, confidence interval


OS: Planned Interim Analysis


Some thoughts…

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


Other Efficacy Endpoints

Blinded Radiology Assessment

nab-Paclitaxel(n = 264)


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


PFS by Independent Review – Subgroups



OS Interim Analysis – Subgroups

Target Tumor Responses by Patient


Treatment Exposure, Dose Reductions

Variable nab-Paclitaxel(n = 257)


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


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


Summary


Conclusions I

• IN MY OPINION…

… nab-Paclitaxel is a new standard of care!!!

Conclusions II

PEOPLE EDUCATION

innovación en oncología: nanotecnología dirigida al tumor. … · nab-paclitaxel distinct...

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