1. Nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer: a clinical experience
Silvia Vecchiarelli
Istituto di Ematologia e Oncologia “L.& A. Serágnoli”, Policlinico S.Orsola-Malpighi,
Bologna

2. Background
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy. For many years there has been immobility in the medical treatment field of patients with PDAC
The high mortality rate is a result of multiple factors including late diagnosis, early systemic spread and a poor response to chemo- and radiotherapy
CA Cancer J Clin Jan-Feb;65(1):5-29.

3. Primary endpoint: Clinical benefit response
Background
Treatment Schedule
GEM 1000mg/m2/wk
5FU 600mg/m2/wk
Primary endpoint: Clinical benefit response
Pz=126
OS: 5.65 (GEM) vs (5-FU)
TTP: 9 week (GEM) vs. 4 week (5-FU)

4. …clinically irrelevant
Background
Gemcitabine (1000 mg/m2) +
Erlotinib (100 or 150 mg/die)
vs Gemcitabine (1000 mg/m2) +
Placebo
…clinically irrelevant
Pz=569
OS 6.24 (GEM+ERL) vs (GEM)
(p=0.038)

5. Background
nel 2010…. Many phase II studies demonstrated the efficacy of gemcitabine combination treatments, but none of the randomized phase III trials confirmed the improvement in OS of gemcitabine-based doublets compared to gemcitabine alone

6. Background Pz=342 FOLFIRINOX vs. GEM
OS: 11.1 (FOLFIRINOX) vs. 6.8 (GEM)
PFS: 6.4(FOLFIRINOX) vs. 3.3 (GEM)

7. Background Phase III MPACT trial
NAB-P + GEM
vs GEM
Pz=861
Phase III MPACT trial
Gemcitabine plus nab-paclitaxel showed a significant improve in overall survival, progressione-free survival and response rate over Gemcitabine alone
in the median overall survival in metastatic pancreatic cancer patients with nab- paclitaxel plus gemcitabine when compared to gemcitabine only (8.5 months vs 6.7 months, respectively).
OS: 8.5 (NAB-P+GEM) vs. 6.7 (GEM)
PFS: 5.5(NAB-P+GEM) vs. 3.7 (GEM)

8. Background

9. Background ma quale scegliere?
Actually Standard chemotherapy for metastatic PDAC:
• Gemcitabine monotherapy:
no longer the standard for all patients
• FOLFIRINOX
- has demonstrated a significant improvement in OS in an academic national multicentre phase II/III trial
- Toxicity concerns have led to regimen modifications in clinical practice: same efficacy results?
• nab-Paclitaxel + gemcitabine
- has demonstrated a significant improvement in OS in an international multicentre phase III trial
- Tolerability profile and administration schedule superior to FOLFIRINOX?
Differences between trial designs & patient populations limit cross-trial comparisons
ma quale scegliere?
Quello che possiamo dire è che oramai gemcitabina non può più essere lo standard di trattamento
Folfirinox ha dimostrato efficacia in uno studio di fase tre multicentrico nazionale, ma su una popolazione selezionata con ottimo PS
nab.P e gemcitabina hanno dimostrato un significativo beneficio in termini di overall survival in uno studio multicentrico internazionale

10. Background Grade 3/4 AE n/N (%) FOLFIRINOX (n=171) nab-P + gem (n=421)
Haematological
Neutropenia
75/164 (46)
153/405 (38)
Febrile neutropenia
9/166 (5)
14 (3)
G-CSF administration
43%
26%
Thrombocytopenia
15/165 (9)
52/4015 (13)
Anemia
13/166 (8)
53/405 (13)
Non-Hematological
Fatigue
39/165 (24)
70 (17)
Vomiting
24/166 (15) -
Diarrhoea
21/165 (13)
24 (6)
Sensory neuropathy *
15/166 (9)
Increased ALT
12/165 (7)
Thromboembolism
11/166 (7)
* Oxaliplatin-induced sensory neuropathy is a long term outcome that persists after treatment; nab-Paclitaxel peripheral neuropathy was cumulative and rapidly reversible
1 Conroy et al. New Engl J Med 2011
2 Von Hoff et al. New Engl J Med 2013
NB: Cross-trial comparisons should be interpreted with caution!!!

11. Aim
To report our retrospective experience with nab- paclitaxel plus gemcitabine in the treatment of metastatic PDAC patients.

12. Methods Retrospective analysis
Metastatic ductal pancreatic adenocarcinoma
Treated with nab-paclitaxel (125 mg/m2) + gemcitabine ( mg/m2) [days 1, 8 and 15 of a 28-day cycle]
TC scan was performed baseline, after 3 and 6 months
Progression-free survival (PFS) and overall survival (OS) were calculated from the start of gemcitabine plus nab-paclitaxel and were analyzed using the Kaplan-Meier method.
Toxicities was evaluated

13. Patients characteristic
Total patients
(N = 22)
Age — yr
Median
Range 63
33-77
Sex — no. (%)
Female
Male
12 (54.5)
10 (45.5)
ECOG — no. (%) 1 2
9 (41.0)
1 (4.5)
Site of primary tumor — no. (%)
Head
Body
Tail
13 (59.1)
5 (22.7)
4 (18.2)
Site of metastatic disease — no. (%)
Liver
Lung
Peritoneum
Other
15 (68.2)
3 (13.6)
Follow-up — months
11.9
A total 22 patients treated with nab- paclitaxel plus gemcitabine at Istituto di Ematologia e Oncologia “L. & A. Seràgnoli”- Ospedale S.Orsola- Malpighi.
Metastatic PDAC patients
A total of 22 patients were reviewed (Table 1).
All of them had metastatic disease. Principal metastatic sites were liver (68,2%), lung (13,6%) and peritoneum (4,5%). Median age was 63 years (range 33-77) and 54,5% were female. Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 54,5%, 1 in 40,9% and 2 in 4,5% of patients.

14. Results TC scan was performed baseline, after 3 and 6 months
Characteristic
Total patients
(N = 22)
Response — no. (%)
Complete response
Partial response
Stable disease
Progressive disease
Could not be evaluated *
*(who did not have an assessment after the baseline visit: treatment underway)
0 (0)
6 (27.3)
4 (18.2)
8 (36.3)
TC scan was performed baseline, after 3 and 6 months
Median time of therapy was 2,3 months.
8 pts (36,3%): treatment still underway at time of analysis

15. Adverse Events There were no febrile neutropenia
Common Adverse Events of Grade 3 or Higher
Event
Total pts
(N = 22)
Adverse events of Grade 3 or 4 — no. (%)
9 (41.0)
Haematologic adverse events — no. (%)
Febrile neutropenia
Neutropenia
Thrombocytopenia
0 (0)
8 (36.3)
1 (4.5)
Grade ≥3 nonhematologic adverse events — no. (%)
Gastrointestinal toxicities
Peripheral neuropathy
Fatigue
3 (13,6)
1 (4,5)
8 (36,3)
The most frequently occurring Grade 3/4 toxicities were neutropenia (36,3%), gastrointestinal toxicities (13,6%), fatigue (36,3%) and neuropathy (4,5%). There were no deaths due to the treatment (Table 2).
There were no febrile neutropenia
There were no deaths due to the treatment

16. Progression-free survival
Median PFS 3,68 months (95% CI 3,22-4,14)

17. Median OS 11,60 months (95% CI 8,00-15,19)
Overall survival
Median OS 11,60 months (95% CI 8,00-15,19)

18. Conclusions
In our experience, efficacy and tolerability of nab- paclitaxel plus gemcitabine in metastatic PDAC patients was similar to what has been reported in the MPACT trial.
New strategies are needed to reduce the overall dismal prognosis and to increase survival of pancreatic cancer patients; for this purpose nanomedicines seems to offer great potential.

19. Grazie per l’attenzione…
Conclusions
Grazie per l’attenzione…
Istituto di Ematologia e Oncologia “L. & A. Seragnoli”
SSD Oncologia Medica
Direttore Prof. Guido Biasco