Algoritmo terapeutico nell’adenocarcinoma del pancreas metastatico
Dr.ssa Chiara Alessandra Cella Istituto Europeo di Oncologia Tutor: Dr. Roberto Bordonaro
mOS (months)
6
6,24 8,5
11,1 FOLFIRINOX G-Nab G-Erlotinib GEM
GEM + 5FU GEM + pemetrexed GEM + OXA GEM + CAP GEM + CDDP
PEXG, Reni 2005
Burris, JCO 1997 Moore, JCO 2007 Conroy, NEJM 2011 Von Hoff, NEJM 2013 Wang-Gillam, Lancet 2016
BAYPAN: GEM + Sorafenib CALGB (III): GEM + beva vs GEM SWOG (III): GEM + Cetux vs GEM GEM + Erlotinib +/- Beva
…
Metastatic Pancreatic Cancer
Months 11,1 6,8
OS
GEM FOLFIRINOX
Conroy, NEJM 2011
N= 342
48 French centers
Concerns:
- Highly selected pts (ECOG 0-1) - Low number of head tumors
- >50% had normal or low CA 19-9 level - biliary stents 14.3%
mOS (months)
6
6,24 8,5
11,1 FOLFIRINOX G-Nab G-Erlotinib GEM
5 months
Burris, JCO 1997 Moore, JCO 2007 Conroy, NEJM 2011 Von Hoff, NEJM 2013 Wang-Gillam, Lancet 2016
BAYPAN: GEM + Sorafenib CALGB (III): GEM + beva vs GEM SWOG (III): GEM + Cetux vs GEM GEM + Erlotinib +/- Beva
…
Metastatic Pancreatic Cancer
GEM + 5FU GEM + pemetrexed GEM + OXA GEM + CAP GEM + CDDP
PEXG, Reni 2005
Months 11,1 6,8
OS
GEM FOLFIRINOX
Months 8,5
6,7
OS
GEM G-Nab
Von Hoff, NEJM 2013 N= 342
PS ECOG 0-1 French study
N= 861
PS ECOG 0-2 Multicentric
Conroy, NEJM 2011
II linea GEM based ChT or
5FU based ChT 5FU based mono-ChT or BSC
III linea BSC BSC
I linea
FOLFIRINOX
GEM + Nab-Paclitaxel Gem/5FU-based ChT
Gem-Erlotinib (USA)
GEM or 5FU
Monotherapy
Fit patient Non Fit patient
Considerations regarding 1st-line treatment choice
PS
Age
Comorbidity (pre-existing sensory neurophaty)
Liver function
Patient preference (need for central venous catheter)
Gem-Nabpaclitaxel VS FOLFIRINOX
Should nab-paclitaxel/GEM be considered in PS ECOG 2?
Von Hoff, NEJM 2013
Should nab-paclitaxel/gemcitabine be considered in a patient >75 years old?
• pts ≥75 years higher risk of serious AEs that led to treatment discontinuation
• Age ≥75 was not significantly associated with OS MPACT study was not powered to show difference
Von Hoff, NEJM 2013
Improving tolerance of long-term use of
GEM-Nab
….learning how to manage the toxicity of these multidrug regimens
may further improve their feasibility.
Considerations regarding 1st-line treatment choice
PS 0-1 for triplet vs 0-2 for G-Nab
Age range 25-76 for triplet vs 27-88 for G-Nab
Comorbidity (pre-existing sensory neurophaty) 17% vs 9% in favor to triplet
Liver function
Patient preference (need for central venous catheter)
Clinical trials
Nab-paclitaxel/GEM
FOLFIRINOX
CHT platform for current clinical practice favors GEM-based regimen rather than triplets.
Frequency of 2° line treatment in metastatic PDAC
Nagrial et al CROH 2015
CONKO Study: FF vs OFF
NAPOLI-1: MM-398 vs 5-FU/LV vs. MM-398 + 5-FU/LV
Second-line OFF significantly extended
duration of OS
compared with FF alone
MM-398 + 5-FU/LV extends survival compared to
5-FU/LV alone with a manageable safety profile
No difference in MM-398 monotherapy vs. 5-FU/LV
Wang Gillam, Lancet 2016 Pelzer, EJC 2011
2° line therapies in metastatic PDAC
After Failed GEM-Based Therapie:
- FOLFIRINOX - Cap + ruxolitinib
- Nab-paclitaxel monotherapy - FOLFIRI
After Failed FOLFIRINOX or 5FU-based Therapies:
- GEM Nab-paclitaxel (several retrospective analises show feasibility)
Evolving treatment algorythm
Combine strategies and fight it better!
Adopted from The Economist – June 2015
PEGPH20 Ibrutinib
PARP inhibitor PAK inhibitors
Tumor microenvironment
CCR2 inhibithors
Phase 2/3 Randomized Double-blind Study of Bruton’s Tyrosine Kinase inhibitor in the first line treatment of metastatic PDAC
Ibrutinib
exerts its effect on tumoral microenvironment
:
- mast cells disruption - Antiangiogenic effect
- shift Th1/Th2 immune response enhanced antitumor activity of CD8+ cytotoxic T cells
- Direct inhibition of ikinase of EGFR
PEGPH20 is a PEGylated version of the human recombinant PH20 hyaluronidase (rHuPH20), which removes HA from the extracellular matrix (ECM) by
depolymerizing the substrate.
Hereditary PDAC
Hereditary component in 10% of PDAC
Multiple gene panels for PDAC include : BRCA1, BRCA2, PALB2, CDKN2A, MLH1, MSH2, MSH6, PMS2, EPCAM, ATM, APC, STK11, PRSS1 and TP53 genes.
BRCA2 gene mut --> most frequent inherited risk factor for PDAC.
The prevalence of PALB2 among families with PDAC aggregation is estimated in a range from 3% to 4%.
The role of PARP inhibitor in BRCA mutated PDAC
Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation
A phase I/II study of the PARP inhibitor, ABT-888 plus 5-fluorouracil and oxaliplatin (modified FOLFOX-6) in patients with metastatic pancreatic cancer.
M. J. Pishvaian
The trial opened in January, 2011 and has accrued the first cohort.
Bella Kaufman. JCO 2017
RUCAPANC: An open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation.
S.Domchek
Poly (ADP-ribose) polymerase inhibitor, an effective radiosensitizer in lung and pancreatic cancers.
Kedar Hastak, Oncotarget 2017
Immunotheraphy in PDAC
Checkpoint inhibitors Vaccines
Monoclonal antibodies Adoptive cell transfer Viruses
Citokines
Poor antigenicity
Dense desmoplastic stroma
Immunosuppressive microenvironment BUT…
Conflicting results
Take home messages
CHT platform for current clinical practice favors GEM-based regimen rather than triplets even in frail patients.
Improving outcomes with 1° line treatments has increased the frequency of 2° line treatments.
Little is known about molecular mechanisms underlying chemoresistance of PDAC.
Greater attention should be paid also to hereditary cancers.
Immunotherapy does not play a major role probably because of tumor micronenvironment immunosuppression
Adopted from The Economist – June 2015
Thank you!
Chiara A. Cella
Istituto Europeo di Oncologia
