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

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. 2015 Jan-Feb;65(1):5-29.

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. 4.41 (5-FU) TTP: 9 week (GEM) vs. 4 week (5-FU)

…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. 5.91 (GEM) (p=0.038)

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

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

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)

Background

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

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!!!

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

Methods Retrospective analysis Metastatic ductal pancreatic adenocarcinoma Treated with nab-paclitaxel (125 mg/m2) + gemcitabine (1.000 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

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.

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

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

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

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

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.

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