Francesco Di Costanzo
Direttore SC Oncologia Medica
Azienda Ospedaliero Universitaria Careggi Firenze
La strategia terapeutica per il trattamento del carcinoma del colon-retto metastatico
VI Corso Nazionale
Eventi Formativi AIOM-SIAPEC
Roma,15 Giugno 2016
ITALY 2015
Incidence: 52,000
Mortality:19,202
The Goal of Palliative Therapy
J Clin Oncol, 1992
CALGB/S WOG
80405
Colorectal Cancer:
~20 Years after meta-analysis 1992
Old & New“
Drugs
5FU+FA
Irinotecan
Oxaliplatin
Anti-EGFR
Anti-VEGF
Regorafenib
(Aflibercept) P
r
o
b
a
b
i
l
i
t
y
o
f
O
S
Improved use of medical treatment
Kopetz S et al, J Clin Oncol 2009
*Compared with irinotecan use in 1998 and
normalized by yearly patient volume
La resezione delle metastasi epatiche
nei centri specializzati migliora la sopravvivenza a lungo termine
o Landmark analysis della sopravvivenza dei pazienti vivi a 12 mesi dalla diagnosi (70% della popolazione iniziale)
Kopetz S et al. J.Clin.Onc. 2009;27:3677-3683 6
La resezione delle metastasi epatiche incrementa sensibilmente la sopravvivenza a lungo termine e offre reali possibilità di cura
“ ”
OS mediana
(mesi)
OS a 5 anni Pazienti
resecati 65,3 55%
Pazienti
non resecati 26,7 19,5%
HR 0,35
Although OS Continues to Improve, PFS Has Been Mostly Stable With First-line Therapy in the Chemobiologic Era
Although OS Continues to Improve, PFS Has Been Mostly Stable With First-line Therapy in the Chemobiologic Era
Tools for Treatment Selection
Accesso alle linee successive alla 1a
1. Abrams TA, et al. J Natl Cancer Inst 2014;106:djt371 2. Modest D, et al. J Clin Oncol 2015 [epub ahead of print]
0 10 20 30 40 50 60 70 80 90 100
1a linea 2a linea 3a linea 4a linea
Pe rc entuale di pazienti (% )
Coorte US (n=4877) FIRE-3 (n=592)
Registro tedesco Italy (Observer)
Example of Decision Matrix
Presented By Axel Grothey at 2016 ASCO Annual Meeting
RAS and BRAF distribution in mCRC
Fakih et al, J Clin Oncol ‘15
EXON 2 EXON 3 EXON 4 EXON 1
KRAS
12 13 61 117 146
Prevalence of Mutations*
*The KRAS exon 2 data is from the overall population. The remaining data are within the wild-type KRAS exon 2 subset and based on samples that yielded a result.
5.8% (36/620) 4.5% (29/638)
40.1% (440/1096)
EXON 2 EXON 3 EXON 4
EXON 1
NRAS
12 13 61 117 146
0.0% (0/629) 4.4% (28/636)
3.5% (22/637)
59
59
Douillard et al., NEJM 2013
BRAF Mutation in CRC- 1st and 2nd Line Phase III Studies
TRIBE: benefit of more intensive treatment for patients with BRAF-mutated mCRC
Loupakis, et al. ASCO 2014. Abstract 3519
Time (months)
OS esti mate
0 1.0
0.75
0.50
0.25
10 20 30 40 60
0 50
Treatment with a chemotherapy triplet plus bevacizumab may be an appropriate treatment for patients with BRAF mutations
10.8 19.1 HR=0.55
(95% CI: 0.24–1.23)
FOLFIRI + bevacizumab (n=12) FOLFOXIRI + bevacizumab (n=16)
mOS (months) FOLFOXIRI +
bevacizumab 31.0
HR=0.79 0.63–1.00 FOLFIRI +
bevacizumab 25.8
Overall trial
Stintzing S, ASCO GI 2014
FOLFIRI + cetuximab (N=23): mOS 12.3 FOLFIRI + bevacizumab (N=25): mOS 13.7
FIRE-3: OS in BRAF mutant
There is no role for biological therapy in the neoadjuvant therapy in resectable metastatic CRC
No Role for anti-EGFR in resectable metastatic KRAS-WT CRC
No proven role for bevacizumab in resectable metastatic CRC
Both Anti-EGFR and Angiogenesis Inhibitors improve the outcome of metastatic CRC
Anti-EGFR Therapy in the 1st Line Treatment of MCRC
Anti-EGFR Therapy in the 2nd Line Treatment of MCRC
Anti-EGFR Therapy in MCRC: Chemotherapy- Refractory Disease
Anti-EGFR Therapy in MCRC
Bevacizumab Improves Clinical Outcome When Added to 1st Line Combination Therapies
Anti-Angiogenic Strategies Result in Limited Improvements When Combined with 2nd Line Chemotherapy
Metastatic Colorectal Cancer
Is there an optimal
sequence for biological
therapy (Ras WT) ?
Head-to-head trials of targeted agents in 1st line treatment of mCRC
1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506); 2. Naughton MJ, et al. ASCO 2013 (Abstract No. 3611);
3. NCT00265850; 4. Schwartzberg LS, et al. ASCO GI 2013 (Abstract No. 446);
5. Schwartzberg LS, et al. ASCO 2013 (Abstract No. 3631)
FIRE-3 1
CALGB 80405 2,3
PEAK 4,5
Patients with untreated KRAS 12/13 wt mCRC
N=592
R
Cetuximab + FOLFIRI
Bevacizumab + FOLFIRI
Patients with untreated KRAS 12/13 wt mCRC
N=1177
(after trial modification)
Cetuximab + FOLFOX/FOLFIRI
Bevacizumab + FOLFOX/FOLFIRI Bevacizumab + cetuximab +
FOLFOX/FOLFIRI*
*Arm closed to accrual as of 09/10/2009
R
Panitumumab + mFOLFOX6
Bevacizumab + mFOLFOX6 R
Efficacy data expected Q1/Q2 2014
Phas e II Phas e II I
Patients with untreated KRAS 12/13 wt mCRC
N=285
ORR
OS
PFS
1º endpoint
RR PFS OS
CET/PAN BEV CET/PAN BEV CET/PAN BEV
FIRE-3 N=400
RR 1 ° endpoint
65% 59% 10.3 10.2 33.1 25.0
P=0.18 HR=0.97 HR=0.70, P=.006
NEGATIVE NEGATIVE POSITIVE
CALGB 80405 N=526
OS 1 ° endpoint
69% 54% 11.4 11.3 32.0 31.2
P<0.01 HR=1.10 HR=0.90
POS/NEG NEGATIVE NEGATIVE
PEAK N=170
PFS 1 ° endpoint
64% 61% 13.0 10.1 41.3 28.9
NA 0.029 0.058
NA “POSITIVE” POS/NEG
Head to Head trials in RAS wt
Adapted from Stintzing et al., ESMO 2014
Lenz et al, ESMO 2014
Schwartzberg et al, JCO 2014
FIRE-3 STUDY
35
Heinemann V. et al Lancet Oncol. 2014 Sep;15(10):1065-75
% %
FOLFIRI
Cetuximab FOLFIRI
Bevacizumab 57.9 to 72.6 65%
60%
51.9 to 67.1 ORR, %
95% CI 0.14
p
Primary Endpoint not met !
FOLFIRI + Cetuximab
FOLFIRI + Bevacizumab
R
CALGB trial: overall survival by arm
All RAS Wild Type Patients
Lenz HJ, ESMO 2014
PEAK STUDY
37
Schwartzberg L.S. et al. J Clin Oncol. 2014 Jul 20;32(21):2240-7
% %
FOLFOX Panitumumab
FOLFOX Bevacizumab
Primary Endpoint exploratory
FOLFOX + Panitumumab
FOLFOX + Bevacizumab
R
A CLINICALLY MEANINGFUL DIFFERENCE IN OS:
POSSIBLE EXPLANATIONS?
Choice and duration of 2nd line therapy
Depth of response Change in
tumor biology during 1st line therapy
OS
Depth of response correlates with overall survival
adapted from Mansmann et al, ASCO GI 2013 abstract #427
Time under treatment
OS
ETS
DpR (smallest tumor size)
Correlation index Cetuximab + FOLFIRI Bevacizumab + FOLFIRI
PFS -0.53, p<0.0001 -0.52, p<0.0001
OS -0.38, p<0.0001 -0.35, p<0.0001
PFS
OS
ETS predicts longer PFS and OS
Petrelli et al., Eur J Canc ‘15
A CLINICALLY MEANINGFUL DIFFERENCE IN OS:
POSSIBLE EXPLANATIONS?
Depth of response Choice and
duration of 2nd line therapy
Change in tumor biology during 1st line therapy
OS
02.11.2016
Titel der Präsentation und Name des Redners
HER2 AMPLIFICATION IS A DRIVER OF RESISTANCE TO CETUXIMAB IN MCRC PATIENT-DERIVED XENOGRAFTS (XENOPATIENTS)
Presented By Salvatore Siena at 2015 ASCO Annual Meeting
ESTIMATED NUMBERS OF HER2+ MCRCS AND OTHER MALIGNANCIES WITH ACTIONABLE MOLECULAR TARGETS
Presented By Salvatore Siena at 2015 ASCO Annual Meeting
HERACLES CONSORT DIAGRAM
Presented By Salvatore Siena at 2015 ASCO Annual Meeting
REPRESENTATIVE CE-CT SCANS OF 2 RESPONDERS
Presented By Salvatore Siena at 2015 ASCO Annual Meeting
POTENTIAL EXPLANATORY FACTORS
Presented By Kimmie Ng at 2016 ASCO Annual Meeting
SLIDE 29
NOT EXACTLY A NEW STORY….
Presented By Kimmie Ng at 2016 ASCO Annual Meeting
80405: SIDEDNESS IS PROGNOSTIC<BR />PROGRESSION FREE SURVIVAL (PFS)
Presented By Alan Venook at 2016 ASCO Annual Meeting
80405: SIDEDNESS IS PROGNOSTIC<BR /> OVERALL SURVIVAL (OS)
Presented By Alan Venook at 2016 ASCO Annual Meeting
MEDIAN OS BY SIDEDNESS:<BR />80405 AND FIRE-3*
Presented By Alan Venook at 2016 ASCO Annual Meeting
OVERALL SURVIVAL BY SIDEDNESS AND BIOLOGIC
Presented By Alan Venook at 2016 ASCO Annual Meeting
PFS BY TREATMENT GROUP AND LOCATION OF <BR />PRIMARY TUMOR (RIGHT VS LEFT)
LEE ET AL: MAJOR FINDINGS
Presented By Kimmie Ng at 2016 ASCO Annual Meeting
NIVOLUMAB ± IPILIMUMAB IN TREATMENT OF PATIENTS WITH METASTATIC COLORECTAL CANCER WITH AND WITHOUT HIGH MICROSATELLITE INSTABILITY: <BR />CHECKMATE 142 INTERIM RESULTS
Presented By Michael Overman at 2016 ASCO Annual Meeting
INVESTIGATOR-ASSESSED BEST OVERALL RESPONSE IN <BR />PATIENTS WITH MSI-H RECEIVING NIVOLUMAB MONOTHERAPY
Presented By Michael Overman at 2016 ASCO Annual Meeting
INVESTIGATOR-ASSESSED PFS IN PATIENTS WITH MSI-H<BR />NIVOLUMAB ± IPILIMUMAB IN METASTATIC CRC
Presented By Michael Overman at 2016 ASCO Annual Meeting
CONCLUSIONS<BR />NIVOLUMAB ± IPILIMUMAB IN METASTATIC CRC
Presented By Michael Overman at 2016 ASCO Annual Meeting
NIVOLUMAB ± IPILIMUMAB IN TREATMENT OF PATIENTS WITH METASTATIC COLORECTAL CANCER WITH AND WITHOUT HIGH MICROSATELLITE INSTABILITY: <BR />CHECKMATE 142 INTERIM RESULTS
Presented By Michael Overman at 2016 ASCO Annual Meeting
SUMMARY
