1. Dr. Carles Pericay Pijaume
“Enfermedad limitada al hígado en cáncer colorrectal metastásico RAS WT: ¿qué aporta Panitumumab?”. 
Dr. Carles Pericay Pijaume
Oncología Médica,
Hospital Universitari de Sabadell,
Corporació Sanitària Parc Taulí (Sabadell)
Madrid, 12 de Febrero de 2015

2. CRC liver metastases are common and predict a poor prognosis if untreated
In 2012, CRC was the 2nd most common cancer in Europe:1
447,000 new cases
215,000 deaths
~ 50% of CRC patients develop liver metastases2
Liver metastases responsible for 2/3 of CRC patient deaths2
0-6% 5 year survival for untreated CRC liver metastases3
From an estimated 3.45 million new cases of cancer (excluding non-melanoma skin cancer) in Europe in 2012, the most common sites were female breast (464,000 cases), followed by colorectal (447,000), prostate (417,000) and lung (410,000).1
The most common causes of death from cancer were cancers of the lung (353,000 deaths), colorectal (215,000), breast (131,000) and stomach (107,000).1
Hepatic metastases develop in 50% of patients and are responsible for two thirds of colorectal cancer patient deaths.2
A 5-year survival rate of 90.3% was reported for localised cancer of the colon and rectum for the period in 18 regions of the USA by the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.3
A median 5-year survival of 0% (range 0–6%) for patients with colorectal hepatic metastases who did not undergo resection was concluded from a review of six relevant studies in a systematic review that aimed to include all relevant prospective and retrospective series reporting the outcomes of surgical resection with curative intent of colorectal hepatic metastases.4
REFERENCES
1. Ferlay J, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in Eur J Cancer 2013;49:1374–403.
2. Van den Eynde M, Hendlisz A. Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials 2009;4:56–62.
3. Howlader N, et al. SEER Cancer Statistics Review (CSR), Natl. Cancer Inst (accessed 19 Mar2014).
4. Simmonds PC, et al. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006;94:982–99.
1. Ferlay J et al. Eur J Cancer. 2013;49(6):1374–403; 2. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 3. Simmonds PC et al. Br J Cancer. 2006;94(7):982–99.
CRC, colorectal cancer.

3. Resection of liver metastases improves survival70 60 50 40 30 20 10
R0 resected (16 studies)
Median 5-year survival, %
Resected, R0/R1 unclear (19 studies)
Non-radical resection (11 studies)
Not resected (6 studies)
30%
32% 7% 0%
This slide shows results from a qualitative systematic review reporting the available evidence for the effectiveness of surgical resection of colorectal liver metastases.1
Out of 529 independent studies, 30 met all eligibility criteria for the review, which included surgical series published after 1980 reporting the outcomes of at least 100 patients who underwent surgical resection of colorectal liver metastases with curative intent.1
Median 5-year survival in 16 studies of patients undergoing R0 resection of colorectal liver metastases with curative intent was 30% (range 15–67%).1
In contrast, patients with colorectal liver metastases who did not undergo resection in 6 studies had a median 5-year survival of 0% (range 0–6%).1
A more recent systematic review of 142 studies published between 1999 and 2010 revealed a median 5-year survival for patients with liver metastases after resection of 38% (range of 16%–71%).2
Results from the LiverMetSurvey, involving 14,774 patients from 330 centres in 58 countries, who underwent surgery for liver metastases, reported a 5-year survival of 42% in patients who underwent liver resection, compared with 8% in unresected patients.3
REFERENCES
1. Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006;94:982–99.
2. Kanas GP, Taylor A, Primrose JN, et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol 2012;4:283–301.
3. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist 2012;17:1225–39.
Surgical series published after 1980
Simmonds PC et al. Br J Cancer. 2006;94(7):982–99
Error bars indicate range.

4. Current definition of liver metastases resectability
The criteria for liver metastasis resectability have not been standardized1-3
Medical fitness for surgery
Resectability1-5
Oncological considerations
Technical considerations
e.g.
Resectable extrahepatic disease
Number of lesions ≥ 5
Tumour progression
R0 with ≥ 25%–30% FLR
Complex procedure
Until recently, the classic contraindications for resection of CRC liver metastases have been: 4 metastases, disease outside the liver; metastatic nodes in the liver pedicule; a resection margin of <1 cm; the presence of co-morbid disease; incomplete resection; the involvement of more than 2 sushepatic veins.1
However, these limitations for resectability are currently now outdated since advances in surgery and chemotherapy have increased the feasibility of liver metastases resection. However, there remains no consensus regarding which factors have the best prognostic value.1–5
In addition to the definition of resectability in the NCCN Guidelines6, other example definitions include:
“The potential for complete resection with tumour-free margins (R0 resection) with preservation of at least two disease-free liver segments with viable vascular inflow, outflow, and biliary drainage and an FLR volume of 30%.”4
“After confirmation of medical fitness for general anaesthesia and major abdominal surgery, [...] eligibility is determined by two domains: oncological and technical. From an oncological perspective, evaluation for extrahepatic disease and the response to pre-operative systemic therapy are the main considerations. From a technical perspective, resection is the preferred treatment option if all viable tumours can be removed with negative margins, while leaving an adequate functional liver remnant.”5
The R classification denotes absence or presence of residual tumour after treatment.7
R0 corresponds to resection for cure or complete remission with microscopically negative margins; R1 to microscopic residual tumour; R2 to macroscopic residual tumour.3,7 
REFERENCES:
1. Van den Eynde M, Hendlisz A. Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials 2009;4:56–62.
2. Schmoll HJ, Van Cutsem E, Stein A, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol 2012;23:2479–516.
3. Spolverato G, Ejaz A, Azad N, et al. Surgery for colorectal liver metastases: The evolution of determining prognosis. World J Gastrointest Oncol 2013;5:207–21.
4. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist 2012;17:1225–39.
5. Adams RB, Aloia T a, Loyer E, et al. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB 2013;15:91–103.
6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer [v ]. (accessed 20 Feb2014).
7. Hermanek P, Wittekind C. The pathologist and the residual tumor (R) classification. Pathol Res Pr 1994;190:115–23.
NCCN Guidelines criteria for resection suitability6
“... the likelihood of achieving complete resection of all evident disease with negative surgical margins and maintaining adequate liver reserve”
1. Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 2. Spolverato G et al. World J Gastrointest Oncol. 2013;5(12):207–21; 3. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 4. Adams RB et al. HPB. 2013;15(2):91–103; 5. Adam R et al. Oncologist. 2012;17(10):1225–39; 6. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer [v ]. (accessed 20/02/2014).
FLR, functional liver remnant; R0, resection with microscopically negative margins

5. ESMO 2012 Clinical Guidelines Stratification of mCRC patients for 1st-line treatment
Metastatic colorectal cancer
Group 0
Group 1
Group 2
Group 3
Yes
Initially R0 resectable No
Potentially R0 resectable with CT & patient can tolerate CT and surgery
Yes No
Yes
Symptomatic or aggressive disease
As described in ESMO 2012 Guidelines, mCRC patients can be divided into four clinical groups, by a hierarchy of parameters describing localization, extent, and resectability of the disease, tumour dynamics, co-morbidity, potential of the patient to tolerate chemotherapy and secondary surgical treatment.
Treatment strategy, aim and intensity for each of these groups is described in the guidelines.
REFERENCE:
Schmoll HJ, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23: No
Yes
Yes
Far advanced/bulky disease
Patient can tolerate CT No No
Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516
CT, chemotherapy; R0, resection with microscopically negative margins.

6. Metastatic colorectal cancer
mCRC patient distribution between ESMO guideline first-line treatment stratification groups
Metastatic colorectal cancer
~15%1,2
~85%1,2
Initially R0 resectable
Non-resectable at clinical presentation
10-30%2
70-90%2
The only potentially curative standard treatment in CRC patients with liver metastases is liver resection or local ablative treatment (e.g., radiofrequency, cryoablation).1
Unfortunately, approximately 85% of patients with stage IV CRC, referred to specialist centres, have metastatic liver disease which is considered to be unresectable at presentation.1,2
However, up to 30 % of initially unresectable patients may become resectable following preoperative, neoadjuvant, combination chemotherapy.2
REFERENCES:
1. Van den Eynde M, Hendlisz A. Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials 2009;4:56–62.
2. Nordlinger B et al. Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer. 2007;43(14):2037–45.
3. Schmoll HJ, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23:
Potentially resectable
Never resectable
Group 2*
Group 1
Group 3
Group 0
Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Nordlinger B et al. Eur J Cancer. 2007;43(14):2037–45.
*Some patients may become resectable following exceptional response to treatment. CT, chemotherapy; R0, resection with microscopically negative margins.

7. Metastatic colorectal cancer
mCRC patient distribution between ESMO guideline first-line treatment stratification groups
Metastatic colorectal cancer
~15%1,2
~85%1,2
Initially R0 resectable
Non-resectable at clinical presentation
10-30%2
70-90%2
The only potentially curative standard treatment in CRC patients with liver metastases is liver resection or local ablative treatment (e.g., radiofrequency, cryoablation).1
Unfortunately, approximately 85% of patients with stage IV CRC, referred to specialist centres, have metastatic liver disease which is considered to be unresectable at presentation.1,2
However, up to 30 % of initially unresectable patients may become resectable following preoperative, neoadjuvant, combination chemotherapy.2
REFERENCES:
1. Van den Eynde M, Hendlisz A. Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials 2009;4:56–62.
2. Nordlinger B et al. Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer. 2007;43(14):2037–45.
3. Schmoll HJ, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23:
Potentially resectable
Never resectable
Group 2*
Group 1
Group 3
Group 0
Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Nordlinger B et al. Eur J Cancer. 2007;43(14):2037–45.
*Some patients may become resectable following exceptional response to treatment. CT, chemotherapy; R0, resection with microscopically negative margins.

8. What is conversion chemotherapy?
Resection
mCRC with initially non-resectable liver metastases
Tumour shrinkage
In patients with unresectable liver metastases, emerging data have shown that neoadjuvant chemotherapy can render some metastases resectable, hence opening up the possibility of prolonged survival.1
Chemotherapy given to convert unresectable liver metastases to resectable is referred to as “conversion chemotherapy.”2
Note: the term “neoadjuvant chemotherapy” is reserved for chemotherapy for resectable and potentially resectable disease prior to surgery with or without adjuvant chemotherapy after surgery.2
The goal of conversion chemotherapy is not specifically the eradication of micrometastatic disease, but rather optimal size regression of visible metastases.3
When chemotherapy is initiated to achieve resectability, the aim should be for as short a treatment course as possible and surgery performed as soon as the metastases become resectable.2,4
REFERENCES:
1. Nordlinger B, Benoist S. Benefits and risks of neoadjuvant therapy for liver metastases. J Clin Oncol 2006;24:4954–5.
2. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist 2012;17:1225–39.
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer [v ]. (accessed 20/02/2014).
4. Nordlinger B, Vauthey J-N, Poston G, et al. The timing of chemotherapy and surgery for the treatment of colorectal liver metastases. Clin Color Cancer 2010;9:212–8.
1. Adam R, et al. Oncologist 2012;17:1225–39; 2. Nordlinger B, Benoist S. J Clin Oncol 2006;24:4954–5;
3. Nordlinger B, et al. Clin Colorectal Cancer 2010;9:212–8; 4. Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516.
*Chemotherapy to convert unresectable liver metastases to resectable.

9. unresectable liver metastases
Conversion CT + surgery for treatment of mCRC with unresectable liver metastases
Single centre study of consecutive patients F O L W - U P
mCRC with
unresectable liver metastases
(n = 184)
Conversion
chemotherapy*
Surgery
Response evaluated every 2 months
Minimum follow-up 5 years
The aim of this study was to evaluate long-term outcome after combining downsizing chemotherapy and rescue surgery in patients with initially unresectable colorectal liver metastases (CLM) and to define prognostic factors of cure.
Inclusion: all patients with unresectable CLM at the time of diagnosis who underwent rescue surgery after conversion chemotherapy and had a minimum follow-up of 5 years from surgery were included.
Definition of technically unresectable disease: when complete resection of all metastases would leave < 30% of liver remnant, or < 40% when patients received intensive preoperative chemotherapy.
Definition of cure: a disease-free interval of ≥ 5 years after the last hepatectomy or last resection of extrahepatic metastases. Furthermore, patients had to be free of disease at last follow-up.
Patients who died of not curatively resected metastases or disease recurrence were defined as “noncured.”
Response to chemotherapy was evaluated every 2 months by a multidisciplinary team according to the WHO guidelines during the initial study period and to RECIST (Response Evaluation Criteria in Solid Tumours) during the final period.
Patients responding to chemotherapy were reconsidered for surgery when the overall strategy could achieve complete clearance of intra- and extrahepatic metastases.
However, when tumour-free margins were not possible owing to major vascular or biliary contact, resection was still indicated provided that all tumours could be macroscopically resected.
REFERENCE:
Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 2009;27:
Study objectives: evaluation of possibility of cure, determination of predictive factors of disease cure
Adam R, et al. J Clin Oncol 2009; 27:
*Last preoperative regimen, FL (18%), FOLFOX (62%),
FOLFIRI (6%), FOLFOXIRI (9%), Other (5%)

10. An oncosurgical approach offers the chance of cure to a subgroup of initially non-resectable patients
1.0
OS (n = 184)
DFS (n = 184)
0.8
0.6
5-year survival
10-year survival
Survival probability
0.4
33%
27%
0.2
19%
15%
Graph shows overall and disease-free survival curves of patients with initially unresectable disease who underwent resection after downsizing chemotherapy.
184 patients with liver metastases considered potentially resectable after downsizing.
55% were male and median age was 56.9 years.
Patients had a median of 5 (range 1-22) metastases and median size at diagnosis was 50mm (range 6-160mm).
Metastases were bilobar in 76% of cases.
Surgery was possible after one line of chemotherapy in 88% of cured patients.
Noncured patients more often received two or more lines of chemotherapy before hepatectomy could be reconsidered (33% v 13%; P = 0.05).
Patients who achieved cure were administered a median number of 8 cycles (range, 4-29 cycles) and a last preoperative regimen that most often consisted of fluorouracil, leucovorin, and oxaliplatin (75%).
148 patients (80%) had a follow-up of 5 years or more after hepatectomy.
Of these, 24 patients (16%) were considered cured.
112 patients (76%) died of disease and formed the non-cured patient group.
12 patients (8%) were excluded because of a disease-free interval of < 5 years after last resection (n = 3), the presence of disease recurrence at last follow-up (n = 8), or death from a nontumoral cause (n = 1; 9 months after hepatectomy).
REFERENCE:
Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 2009;27: 1 2 3 4 5 6 7 8 9 10
Cure was achieved in 16% of CRC patients with liver metastases who became eligible for surgery after response to conversion chemotherapy
Time (years)
Adam R, et al. J Clin Oncol 2009; 27:
Cure = disease-free ≥ 5 years after last hepatectomy / last resection of extrahepatic metastases; CRC, colorectal cancer; DFS, disease-free survival; OS, overall survival.

11. Response to CT correlates with liver resectability
Rate of liver resection following CT
Response rate
0.3
0.4
0.6
0.5
0.7
0.8
0.0
0.2
0.1
Selected patients, r = 0.96 P = 0.002
Non-selected patients, r = 0.74 P <
Phase III trial data, r = 0.67 P = 0.024
Resection rate
This study reviewed reviewed the literature to explore the relationship between tumour response and resectability following chemotherapy.
Studies and reports of retrospective analyses and prospective trials (phases I–III) in patients with CRC cancer treated with systemic chemotherapy were divided into:
Studies that included only patients that have liver limited metastases (‘selected’ patients); 5 prospective phase II trials and 1 retrospective study
Studies that included all mCRC patients (‘non-selected’ patients); 9 phase II studies and 5 phase III studies.
The slide shows the correlation between objective response and resection rate.
For selected patients (filled squares):
A strong and highly significant correlation between the rates of liver resection and the tumour response to chemotherapy was found (r = 0.96, P = 0.002).
The rate of R0 resection did not significantly correlate with the response rate (r = 0.43).
For non-selected patients (triangles) a positive correlation between the response rate and the resection rate of liver metastases. This was true for the analysis of:
all trials combined, open triangles, (r = 0.74, P <0.001), or
phase III trials only, filled triangles, (r = 0.67, P = 0.024).
A non-significant trend toward correlation was observed for R0 resections (r = 0.62, P = 0.08).
The correlation in selected patients was not only steeper but also on a higher level than in unselected patients, meaning that a higher number of patients could be rendered potentially resectable.
REFERENCE:
Folprecht G, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005;16:1311–9.
0.9
Patient selection and efficacy of pre-operative CT were strong predictors for resectability of liver metastases
Folprecht G, et al. Ann Oncol 2005;16:1311–9.
CT, chemotherapy

12. Placebo + FOLFOX4/XELOX
NO16966: BEV + CT significantly improves PFS but not RR or OS in combination with XELOX/FOLFOX4 (ITT)
Response rate (%) 10 20 30 40 50 60 70
Placebo + FOLFOX4/XELOX
BEV +
FOLFOX4/XELOX 38
p=0.99 RR
AVF2107g: Bevacizumab significantly improves RR, PFS and OS in combination with IFL (ITT)
Response rate (%) 10 20 30 40 50 60 70
Placebo + IFL
BEV + IFL 45 35
p=0.004 RR
Saltz LB, et al. Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study
J Clin Oncol 2008;26(12): Reprinted with permission. © American Society of Clinical Oncology.  All rights reserved
Months
Months 12

13. CRYSTAL: Cetuximab + FOLFIRI significantly improves RR, PFS and OS vs FOLFIRI (KRAS wt)
Response rate (%) 10 20 30 40 50 60 70
FOLFIRI
Cetuximab + FOLFIRI 57
p<0.001 RR
OPUS: Cetuximab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt)
Response rate (%) 10 20 30 40 50 60 70
FOLFOX4
Cetuximab + FOLFOX4 57 34
p=0.0027 RR
Van Cutsem E, et al. Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status. J Clin Oncol 2011;29 (15):2011–2019
Reprinted with permission. © (2011) American Society of Clinical Oncology.  All rights reserved

14. PRIME: Panitumumab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt)
Response rate (%) 10 20 30 40 50 60 70
FOLFOX
Pani + FOLFOX 57 48
p=0.018 RR
Douillard JY, et al. Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study. J Clin Oncol 2010;28(31):4697–4705. Reprinted with permission. © (2010) American Society of Clinical Oncology.  All rights reserved.

15. CRYSTAL y OPUS (KRAS WT)n
RR (%)
R0 resections (%)
CRYSTAL FOLFIRI + ERBITUX FOLFIRI
p<0.001
p=0.03
OPUS FOLFOX + ERBITUX FOLFOX
82 97
p<0.003
p=0.22
FOLFIRI + ERBITUX FOLFIRI
68 72
p=0.002
p=0.15
FOLFOX + ERBITUX FOLFOX
25 23
p=0.018
p=0.35
All patients
Liver limited
Van Cutsem ASCO-GI 2011

16. PRIME: Increased R0 resection rate in LLD
KRAS wt
KRAS wt: LLD
Patients (%)
Patients (%)
Douillard J-Y, et al. J Clin Oncol 2010;28:4697–4705;
Petrelli F, et al. Int J Colorectal Dis 2012;27:997–1004

17. Conceptualizing the relevance of DpR for survival
OS
Lethal tumor load
No tumor shrinkage
Baseline tumor load
PFS
Tumor shrinkage
PFS
PFS
Time under treatment
Mansmann UR, et al. ASCO GI 2013 (Abstract no. 427)

18. CRYSTAL and OPUS: More patients demonstrate ETS when treated with cetuximab
Cetuximab + FOLFIRI
CRYSTAL
<20%* (n=115)
≥20%* (n=184)
Cetuximab + FOLFIRI
1.0
Probability of OS
0.8
mOS 30.0 mo
0.6
38%
62%
<20%* (n=115)
≥20%* (n=184)
0.4
HR p<0.001
0.2
mOS 18.6 mo
0.0
n=299 10 20 30 40 50 60
(months)
OPUS
Cetuximab + FOLFOX4
Cetuximab + FOLFOX4
1.0
≥20%* (n=54)
<20%* (n=24)
Probability of OS
0.8
31%
69%
mOS 26.0 mo
≥20%* (n=54)
<20%* (n=24)
0.6
HR 0.43
p=0.006
0.4
mOS 15.7 mo
0.2
n=78
0.0 10 20 30 40
*Radiologic evaluation reported by the investigator and reviewed by an IRC
(months)
Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)

19. Patients with RECIST response
PRIME: More patients had RECIST response or ETS at week 8 with panitumumab + CT than with CT alone
Patients with RECIST response
Patients with ETS 39 51 10 20 30 40 50 60 70 80 38 39 69 10 20 30 40 50 60 70 80 56
Patients (%)
Patients (%)
FOLFOX
(n = 298)
Pani + FOLFOX (n=286)
FOLFOX
(n = 298)
Pani + FOLFOX (n=284)
Douillard J-Y, et al. ESMO 2012 (Abstract No. 558P)

20. OS was significantly longer in patients achieving RECIST response or ETS in both arms
FOLFOX
FOLFOX + pani
ETS
<20% (n=130)
≥20% (n=158)
<20% (n=87)
≥20%
(n=197)
Median OS, months
(95% CI)
16.6
(12.4–18.8)
25.1
(22.1–32.8)
10.7
(9.4–16.1)
30.0
(27.2–33.1)
HR, p-value
HR=0.52, p<0.0001
HR=0.43, p<0.0001
Patients demonstrating ETS who received pantitumumab plus FOLFOX showed a greater OS benefit compared with those receiving FOLFOX alone (30.0 vs months)
FOLFOX
FOLFOX + pani
RECIST response
<30% (n=130)
≥30% (n=112)
<30% (n=141)
≥30%
(n=145)
Median OS, months
(95% CI)
17.6
(15.4–20.2)
29.5
(22.5–34.5)
18.0
(14.0–21.7)
30.3
(26.6–36.8)
HR, p-value
HR=0.54, p<0.0001
HR=0.53, p<0.0001
Douillard J-Y, et al. ESMO 2012 (Abstract No. 558P)

21. Initially non-resectable
Downsizing initially unresectable metastases offers similar 5-year survival as initially resectable patients
CRC liver metastases
Initially resectable
Initially non-resectable
Conversion CT
Resection
Resection
Untreated
The long-term survival rates for those patients with unresectable metastases brought to surgery thanks to a response to chemotherapy are similar to those of patients with initially resectable metastases.1
Kanas et al. conducted a systematic review of 142 studies published between 1999 and 2010 of patients with colorectal liver metastases who underwent surgical liver resection.2
Median 5-year survival after resection for all patients with liver metastases was 38% (range 16%–71%; data from 86 studies).
Median 5-year survival after resection for patients with initially resectable liver metastases was 38% (range 30%–68%; data from 10 studies).
Median 5-year survival after resection for patients with initially unresectable liver metastases, who required pre-operative chemotherapy, was 37% (range 7.8%–79%; data from 13 studies).
Simmonds et al. conducted a systematic review of studies published between 1999 and 2010 reporting the outcomes of at least 100 patients who underwent surgical resection of colorectal liver metastases with curative intent.3
Of the 30 studies that met eligibility criteria, 6 studies reported patients who did not undergo resection; these patients had a median 5-year survival of 0% (range 0-6%).
16 studies presented 5-year survival for patients undergoing R0 resection; median 5-year survival for these studies was 30% (range 15–67%).
REFERNCES:
1. Van den Eynde M, Hendlisz A. Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials 2009;4:56–62.
2. Kanas GP, et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol 2012;4:283–301.
3. Simmonds PC, et al. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006;94:982–99.
5-year survival* (range)
38% (30-68%)2
37% (8-79%)2
0% (0-6%)3
1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Kanas GP, et al. Clin Epidemiol 2012;4:283–301; 3. Simmonds PC et al. Br J Cancer. 2006;94(7):982–99.
*median; CRC, colorectal cancer; CT, chemotherapy.

22. A meta analysis of resectability and outcomes with anti-EGFR mAb therapy (KRAS exon 2 WT, LLD)
Comparison of first-line CT + / - cetuximab or panitumumab
KRAS WT initially unresectable liver-limited mCRC
Meta analysis of RCTs:
Primary outcome: rate of R0 resection
Secondary outcomes: PFS, OS and ORR
Four RCTs involving 484 KRAS WT patients were included:
PRIME, Douillard 2010
COIN, Maughan 2011
CRYSTAL, Van Cutsem 2011
OPUS, Van Cutsem 2011
This slide describes a systematic review that compared the performance of chemotherapy plus an anti-EGFR monoclonal antibody to that of chemotherapy alone in permitting R0 resection of liver-confined CRC metastases in a KRAS wild-type population.
Publications (prior to August 2011) were identified that reported RCTs of patients with unresectable, liver-only, KRAS WT colorectal metastases, treated with or without cetuximab or panitumumab.
Studies were selected if they reported: (1) total number of patients with KRAS wild-type, liver confined disease, (2) number of R0 resected patients, (3) number of responses (if available) and (4) hazard ratio (HR) for PFS and/or OS (if available).
REFERENCE:
Petrelli F, Barni S. Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis. Int J Colorectal Dis 2012;27:
Petrelli F, Barni S. Int J Colorectal Dis 2012;27:
CT, chemotherapy; mCRC, metastatic colorectal cancer; LLD, liver limited disease; mAb, monoclonal antibody; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

23. Impact of anti-EGFR mAb therapy on outcomes (KRAS exon 2 WT, LLD)
Response rate
R0 resection rate
P = 0.001
P = 0.04
This slide shows the results of a systematic review and meta analysis comparing the performance of chemotherapy plus an anti-EGFR mAb to that of chemotherapy alone in permitting R0 resection of liver-confined CRC metastases in a KRAS wild-type population.
The results show that chemotherapy plus cetuximab or panitumumab increases the likelihood of obtaining a disease response by 70% (from 43% to 72%) and a R0 liver resection by 60% (from 11% to 18%) in an unselected population with liver-only disease enrolled in four randomized trials.
These data confirm the notion that a strong correlation exists between ORR and the resection rate in patients with isolated liver metastases.
This meta-analysis confirmed that in a selected CRC population with unresectable liver-limited disease, the addition of an anti-EGFR mAb to 5-fluorouracil + oxaliplatin (or irinotecan-based) chemotherapy confers a significant benefit in terms of resectability and PFS compared to standard multi-agent chemotherapy alone.
REFERENCE:
Petrelli F, Barni S. Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis. Int J Colorectal Dis 2012;27:
CT alone
CT+ EGFR mAb
CT alone
CT + EGFR mAb
Meta-analysis indicates EGFR inhibitors increase R0 resection rate by 60% in mCRC patients with unresectable liver-limited disease
Petrelli F, Barni S. Int J Colorectal Dis 2012;27:
CT, chemotherapy; mAb, monoclonal antibody;
R0, resection with microscopically negative margins.

24. 20060314 Trial FOLFIRI + panitumumab in 1st-line mCRCD O F T R A M F O L W - U P S A E T Y S T U D Y E N O F
mCRC
(n = 150)
FOLFIRI (Q2W) +
panitumumab 6 mg/kg (Q2W on day 1 of each cycle)
Disease assessment every 8 weeks until week 48, then every 3 months until disease progression
8 weeks after end of treatment
This was a first-line, single-arm phase 2 study prospectively evaluating the relationship between KRAS status and response to combination therapy with panitumumab and FOLFIRI.
Eligible patients received panitumumab (6 mg/kg; intravenous infusion [IV]) on day 1 of a 14-day cycle with the initial dose administered over 60 minutes ± 15 minutes prior to chemotherapy. If the first dose was well tolerated subsequent infusions were given over 30 minutes ± 10 minutes prior to chemotherapy. No panitumumab-specific pre-medication was given before administration.
Treatment was to be given until progression or unacceptable toxicity.
All analyses were descriptive.
REFERENCE:
Köhne CH, Hofheinz R, Mineur L, et al. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol 2012;138:65-72.
Study endpoints: ORR (1°), PFS, disease control rate, DoR, TTP, DoSD, TTF, safety
The incidence of R0 resection was also reported
protocol ID: ; ClinicalTrials.gov ID: NCT
Köhne C-H, et al. J Cancer Res Clin Oncol 2012; 138:65-72.
DoR, duration of response; PFS, progression-free survival; TTP, time to progression; DoSD, duration of stable disease; TTF, time to treatment failure; ORR, overall response rate.

25. KRAS WT tumours were more likely to respond to treatment with panitumumab plus FOLFIRI
Objective response rate
R0 resection rate, patients with LLD
This study involved 154 patients, enrolled at 36 study centres in Austria, Belgium, France, Germany, and Sweden, during 2007 and 2008.
KRAS data were available for 145/154 (94%) patients: 59% were KRAS WT and 41% were KRAS MT.
Objective responses occurred in 49% of patients: 56% versus 38% in the KRAS WT versus MT groups [(18% difference (95% CI 1–35%); odds ratio 2.1 (95% CI 1.0–4.4)].
Median duration of response was 13.0 versus 7.4 months.
More patients in the KRAS WT group underwent R0 resection (8% vs. 5%).
Overall, 11 patients (7%; 95% CI 4–12%) had a R0 resection.
In patients with liver-only metastases at baseline (n = 52), R0 resections were performed in 8 patients (15%) overall and 6/31 patients (19%) versus 1/16 patients (6%) in the KRAS WT and MT groups, respectively.
Median progression-free survival also favoured the KRAS WT group (8.9 vs. 7.2 months).
The most common adverse events (any grade) were integument toxicities (98%), diarrhoea (79%) and stomatitis/oral mucositis (51%).
REFERENCE:
Köhne CH, Hofheinz R, Mineur L, et al. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol 2012;138:65-72
KRAS MT
KRAS WT
KRAS MT
KRAS WT
A higher proportion of patients with KRAS WT than with KRAS MT had an objective response and R0 resection
Köhne C-H, et al. J Cancer Res Clin Oncol 2012; 138:65-72.
CT, chemotherapy; R0, resection with microscopically negative margins.

26. panitumumab 6 mg/kg (Q2W)
PRIME study FOLFOX4 ± panitumumab in 1st-line treatment of metastatic CRC
FOLFOX4 (Q2W) +
panitumumab 6 mg/kg (Q2W) E N D O F T R A M F O L W - U P N G T E R M
mCRC
KRAS* WT
(n = 1183) R
FOLFOX4 (Q2W)
1:1
Disease assessment every 8 weeks
Patients were stratified by:1
Performance status (ECOG 0-1 vs. 2)
Geographic region: Western Europe, Canada, and Australia vs. rest of the world
The evaluation of changes in HRQoL using the EQ-5D was a tertiary objective.3
Patients were evaluated every 8 weeks until progression. Responses were confirmed at least 4 weeks after the criteria for response were first met.
Patients were followed for safety 30 days after the last study drug administration and for survival every 3 months.
Enrolment period was from Aug 2006 to Feb 2008.
Participating countries: Argentina, Australia, Belgium, Brazil, Canada, Chile, Costa Rica, Czech Republic, Estonia, France, Hungary, Italy, Latvia, Mexico, Poland, South Africa, Spain, Switzerland, United Kingdom.
Please refer to Douillard JY, et al. J Clin Oncol 2010;28: for further information.
REFERENCES:
1. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:
2. Douillard JY, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N Engl J Med 2013;369:
3. Bennett L, Zhao Z, Barber B, et al. Health-related quality of life in patients with metastatic colorectal cancer treated with panitumumab in first- or second-line treatment. Br J Cancer 2011;105:
Study endpoints: PFS (1°), OS, ORR, TTR, DoR, safety and tolerability
Primary Analysis: pre-specified; after >50% of KRAS exon 2 WT patients had died1,2
Updated OS Analysis: exploratory; after >80% of KRAS exon 2 WT & MT patients died2
*KRAS status was prospectively analysed; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin;
DoR, duration of response; ORR, objective response rate;
OS, overall survival; TTR, time to response; Q2W, every 2 weeks.
ID: ; ClinicalTrials.gov ID: NCT ;
1. Douillard JY, et al. J Clin Oncol 2010; 28: ; 2. Douillard JY, et al. N Engl J Med 2013; 369:

27. PRIME study RAS analysis Post-hoc analysis objective
Post-hoc analysis to evaluate tumour shrinkage, resection rates and PFS and OS outcomes for patients with RAS WT and LLD treated in
the 1st-line PRIME study
In PRIME, patients who had received no prior chemotherapy for mCRC and who had unresectable disease at baseline were randomised 1:1 to panitumumab + FOLFOX4 or FOLFOX4.1
In this exploratory analysis, data were analysed for the subgroup of patients with RAS WT mCRC2 and LLD to determine the following for each treatment:3
The proportion of patients achieving ≥30% tumour shrinkage/ response by week 8 and the ORR;
Rates of metastasectomy and complete resection;
Median PFS, OS and 3-year OS rates.
REFERENCES:
1. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:
2. Douillard JY, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N Engl J Med 2013;369:
3. Peeters M, et al. Resection Rates and Survival in Patients with Wild-Type KRAS/NRAS Metastatic Colorectal Cancer and Liver Metastases: Data from the Prime Study. EJC 2013; 49 (suppl 4):abstract MC (and poster).
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster).
RAS WT, KRAS & NRAS exons 2/3/4;
LLD, liver-limited disease

28. PRIME study RAS analysis Patient population and objective (RAS WT LLD patients, updated analysis)
LLD (n = 41)
LLD (n = 48)
Other only mets (n = 39)
Other only mets (n = 36)
Liver plus other mets (n = 172)
FOLFOX4 (n = 252)
First-line mCRC RAS WT (n = 505)
FOLFOX4 + Panitumumab (n = 253)
Liver plus other mets (n = 169)
In PRIME, patients who had received no prior chemotherapy for mCRC and who had unresectable disease at baseline were randomised 1:1 to panitumumab + FOLFOX4 or FOLFOX4.1
In this exploratory analysis, data were analysed for the subgroup of patients with RAS WT mCRC and LLD to determine the following for each treatment:3
The proportion of patients achieving ≥30% tumour shrinkage/ response by week 8 and the ORR;
Rates of metastasectomy and complete resection;
Median PFS, OS and 3-year OS rates.
These analyses included data from an exploratory analysis conducted when ≥ 80% of patients in PRIME had an OS event (updated OS analysis population).3
To determine those patients with RAS WT tumours, banked tumour samples from patients who had KRAS exon 2 WT mCRC were tested for mutations in KRAS and NRAS exon 2,3 and 4.2,3
The primary analysis population excluded patients with mutations in any of the following: KRAS and NRAS exons 2 (codons 12/13), 3 (codon 61) and 4 (codons 117/146).2
This updated exploratory analysis population also excluded patients with mutations at KRAS and NRAS exon 3 (codon 59).2,3
Data were summarised descriptively and tested for significance using Cox’s proportional hazards models and Wilcoxon two-sample test.3
REFERENCES:
1. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:
2. Douillard JY, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N Engl J Med 2013;369:
3. Peeters M, et al. Resection Rates and Survival in Patients with Wild-Type KRAS/NRAS Metastatic Colorectal Cancer and Liver Metastases: Data from the Prime Study. EJC 2013; 49 (suppl 4):abstract MC (and poster).
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster).
CLM, colorectal liver metastases; LLD, liver-limited disease;
RAS, KRAS & NRAS exons 2/3/4.

29. PRIME study RAS analysis Objective response and tumour shrinkage (RAS WT LLD patients, updated analysis)
Objective response
Tumour shrinkage ≥ 30% at wk 8#
Maximum tumour shrinkage§
FOLFOX4
Panitumumab + FOLFOX4
P = 0.231
P = 0.015
P = 0.270
In patients with RAS WT mCRC and LLD, addition of panitumumab to FOLFOX4 resulted in:
Numerically higher objective response
Greater reduction in tumour burden at week 8
Numerically greater maximum tumour shrinkage
REFERENCE:
Peeters M, et al. Resection Rates and Survival in Patients with Wild-Type KRAS/NRAS Metastatic Colorectal Cancer and Liver Metastases: Data from the Prime Study. EJC 2013; 49 (suppl 4):abstract MC (and poster).
n = 41
n = 48
n = 35
n = 43
n = 39
n = 46
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster).
#Patients assessed at baseline and week 8; §Patients assessed at baseline and at least one other time point; LLD, liver-limited disease; RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive.

30. Metastasectomy (all resections)
PRIME study RAS analysis Metastasectomy and complete resection rates (RAS WT, LLD patients, updated analysis)
Metastasectomy (all resections)
Complete resection*
P = 0.349
P = 0.216
In patients with RAS WT mCRC and LLD, addition of panitumumab to FOLFOX4 resulted in numerically higher rates of metastasectomy and complete resection..
Of the patients receiving Panitumumab + FOLFOX4 (n = 48), 15 underwent metastasectomy and 14 underwent complete resection.
Of the patients receiving FOLFOX4 only (n = 41), 9 underwent metastasectomy and 7 underwent complete resection.
Overall 20 patients (33%) with colon cancer and four patients (14%) with rectal cancer had metastasectomies.
REFERENCE:
Peeters M, et al. Resection Rates and Survival in Patients with Wild-Type KRAS/NRAS Metastatic Colorectal Cancer and Liver Metastases: Data from the Prime Study. EJC 2013; 49 (suppl 4):abstract MC (and poster).
FOLFOX4
(n= 41)
Panitumumab
+ FOLFOX4
(n= 48)
FOLFOX4
(n= 41)
Panitumumab
+ FOLFOX4
(n= 48)
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster).
*Subgroup of patients with metastasectomy; LLD, liver-limited disease; RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive.

31. PRIME study RAS analysis PFS, OS (RAS WT, LLD patients, updated analysis)
Months 20 40 60 80
100 90 70 50 30 10
Kaplan-Meier estimate 36 4 8 12 16 28 32 24 44 48 52 20 40 60 80
100 90 70 50 30 10
Kaplan-Meier estimate
Months 64 4 8 12 16 24 28 32 56 52 48 44 36
HR (95% CI) = 0.75 (0.48, 1.19)
P =
HR (95% CI) = 0.71 (0.43, 1.16)
P =
Median PFS was 1.4 months longer in patients with RAS WT mCRC and LLD receiving panitumumab + FOLFOX4 vs. FOLFOX4, but this difference was not statistically significant.
Similarly, median OS was 7.3 months longer in patients with RAS WT mCRC and LLD receiving panitumumab + FOLFOX4 vs. FOLFOX4, but this difference was not statistically significant.
The 3-year OS rates for patients with RAS WT mCRC and LLD receiving panitumumab + FOLFOX4 vs. FOLFOX4 were 55% vs. 44%, respectively.
Overall, 3-year OS rates for patients who did and did not have a metastasectomy were 78% and 41%, respectively
Overall, 3-year OS rates for patients who did and did not have a complete resection were 84% and 41%, respectively.
REFERENCE:
Peeters M, et al. Resection Rates and Survival in Patients with Wild-Type KRAS/NRAS Metastatic Colorectal Cancer and Liver Metastases: Data from the Prime Study. EJC 2013; 49 (suppl 4):abstract MC (and poster).
Events n (%)
Median OS months
Panitumumab + FOLFOX4 (n = 48)
38 (79)
11.3
FOLFOX4 (n = 41)
37 (90)
9.9
Events n (%)
Median OS months
Panitumumab + FOLFOX4 (n = 48)
32 (67)
40.7
FOLFOX4 (n = 41)
31 (76)
33.4
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC (and poster).
LLD, liver-limited disease; PFS progression-free survival; OS, overall survival; RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive.

33. NEOADJUVANT BEVACIZUMAB IN LIVER METASTASES
Study
Treatment
Selected patients n
TR (%)
R0 (%)
AVF 21071
B-IFL
IFL No
402 45
< 2 NO
B-FOLFOX
B-XELOX
700
701 38
6.3
4.9
First-BEAT3
B-CT (oxali/CPT)
1914 -
9 (12/7)
GONO4
B-FOLFOXIRI
No (LLD)
57 (30)
77 (80)
(26)
TRIBE5
b-FOLFOXIRI
FOLFIRI
252
256 65 53
15 (32)
12 (28)
LLD CRC patients
Gruenberger7
Resectable 56 73 92
BOXER6
B- XELOX
non-resectable and borderline 46 78
10-40
OLIVIA8
B-FOLFOX6
non- resectable disease 41 39 80 61
49%
23%
1- Hurwitz 2004, 2- Saltz 2008, 3- Okines 2009, 4- Masi 2010, 5- Falcone 2012, 6- Wong 2011, 7- Gruenberger 2008, 8- Gruenberger 2013 33

34. CELIM: Tasas de Respuesta y Resección R0
All patients
Cetuximab
+ FOLFOX6
Cetuximab + FOLFIRI
KRAS wt
KRAS mt
n=106
n=53
n=67
n=27
CR/PR
62%
68%
57%
70%
41%
95% CI
52–72%
54–80%
42–70%
58–81%
22–61%
R0 resections
34%
38%
30%
33%
25–44%
25–52%
18–44%
22–45%
14–50%
Resultados del estudio:
Los pacientes KRAS nativo tratados con Cetuximab + FOLFOX/FOLFIRI en el estudio CELIM obtuvieron una ORR del 70%, con una tasa de resecciones R0 del 33%
Folprecht G, et al. Lancet Oncol 2010; 11: 38–47
Folprecht G, et al. EMCC 2011 (Abstract-Poster No. 6009)

35. POCHER: Alta tasa de respuestas y resecciones
Response rate
R0 resection rate
2-year OS rate
Patients (%)
79% 80 70
Patients (%)
Patients (%) 60
68%
60% 50 40 30 20 10
Garufi C, Br J Cancer, 2010

36. ▼Panitumumab in 1st-line mCRC
Phase II trial of panitumumab plus FOLFOX4 or FOLFIRI in subjects with KRAS wild-type colorectal cancer and liver-limited disease: The PLANET study
A. Abad1*, B. Massuti2, C. Grávalos3, P. Escudero4, C. Guillén-Ponce5, J.L. Manzano1, A. Gomez6, Mª J. Safont7, J. Gallego8, J. Sastre9, C. Pericay10, R. Dueñas11, C. López- López12, F. Losa13, M. Valladares14, E. González15, A. Yuste2, A. Carrato5, Enrique Aranda6
On behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)
1.Germans Trias i Pujol Hospital –ICO, Badalona, Spain; 2. General Hospital, Alicante, Spain; 3. Doce de Octubre Hospital, Madrid, Spain; 4. Clínico Lozano Blesa Hospital, Zaragoza, Spain; 5. Universitario Ramón y Cajal Hospital, Madrid, Spain; 6. Maimonides Institute of Biomedical Research, IMIBIC, Spain, Reina Sofía Hospital, University of Córdoba. Spanish Cancer Network, (RTICC), Instituto de Salud Carlos III, Spain; 7. General Hospital, Valencia, Spain; 8. General Universitario de Elche Hospital, Alicante, Spain; 9. Hospital Clínico San Carlos, Madrid; Center affiliated to the Red Temática de Investigación Cooperativa, RD06/0020/0021, Spain, Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid; 10. Sabadell Hospital, Corporación Sanitaria Parc Taulí, Barcelona, Spain; 11. Complejo Hospitalario de Jaén Hospital, Jaén, Spain; 12. Marqués de Valdecilla Hospital, Santander, Spain; 13. General de L´Hospitalet Hospital, Barcelona, Spain; 14. Complejo Hospitalario Universitario Hospital, La Coruña, Spain; 15. Virgen de las Nieves Hospital, Granada, Spain; *actual address: Oncology Unit, Campus CIMA, Barcelona, Spain
▼ This medicinal product is subject to additional monitoring. All suspected adverse reactions should be reported

37. PLANET study Objectives
To evaluate the efficacy and safety of the addition of Pmab to standard CT regimens, either FOLFIRI or FOLFOX4, as first-line treatment in WT KRAS CCR patients with liver-only metastases.
To explore possible differences in outcomes according to other RAS mutations.

38. PLANET study Study design
FOLFOX4 (Q2W) + panitumumab 6 mg/kg (Q2W)
FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W))
WT KRAS liver-only mCRC
not suitable for initial surgery
Response Rate,
Resectability Rate,
Safety, PFS,OS R
1:1
N=80
Sponsor: Spanish Cooperative Group for Digestive Tumour Therapy (TTD)
Principal investigators: Dr. Albert Abad & Dr. Alfredo Carrato
ClinicalTrials.gov identifier: NCT

39. PLANET study Endpoints
Primary Endpoint:
Objective response rate (ORR) over the entire Pmab+CT treatment period
Secondary Endpoints:
Resection rate (R0+R1) of liver metastases
Time to resection
Progression-free survival (PFS)
Overall survival (OS)
Adverse Events (AEs) and peri-operative safety
Exploratory Endpoints:
Response according to molecular biomarkers (RAS status)

40. PLANET study Key eligibility criteria
>18 years of age
WT KRAS CRC
Synchronous or metachronous liver-only metastases deemed resectable or unresectable, meeting one of the following criteria
≥4 liver metastases
≥1 metastasis >10 cm in diameter
Liver metastases not resectable
No prior anti-EGFR therapy
Karnofsky performance status ≥70%
Adequate haematologic, renal and metabolic function
Key inclusion criteria:
>18 years of age
WT KRAS CRC with at least one unidimensionally measurable lesion ≥20 mm with the conventional techniques (computed tomography (CT), magnetic resonance imaging) or >10 mm with spiral CT, according to the modified RECIST criteria (Version 1.1).
Synchronous or metachronous liver-only metastases deemed resectable or unresectable, including those patients who had undergone complete resection (R0) of the primary tumour at least 4 weeks before randomisation, fulfilling one of the following criteria:
≥4 liver metastases
at least 1 metastasis >10 cm in diameter
Liver metastases technically not resectable (vascular compromise and/or location in which complete resection is impossible and/or 25-30% of healthy liver would not remain functional after resection)
Patients with either:
Recurrence after adjuvant treatment with 5- fluorouracil/folinic acid or capecitabine +/- radiotherapy with a disease-free interval >6 months; or after oxaliplatin containing adjuvant treatment with a disease-free interval >12 months
Recurrence after surgical treatment and/or radiotherapy with no adjuvant systemic treatment.
De novo diagnosis
No major contra-indication to liver surgery
Karnofsky performance status ≥70%
Adequate bone marrow function: neutrophils ≥1.5 x109/ L; platelets ≥100 x109/L; hemoglobin ≥9 g/dL
Hepatic and metabolic function as follows:
Total bilirubin count ≤1.5 x upper limit of normal (ULN) and not increasing >25% within the last 4 weeks; ALT and AST <5 x ULN
Renal function, calculated as creatinine clearance or 24-hour creatinine clearance ≥50 mL/min
Magnesium > lower limit of normal
Key exclusion criteria:
Prior anti-EGFr antibody therapy (e.g., cetuximab) or treatment with small molecule EGFr tyrosine kinase inhibitors (e.g., erlotinib).Subjects who have experienced an infusion reaction to their first dose of anti-EGFR therapy (cetuximab) may participate in this clinical trial
Hormonal therapy, immunotherapy or experimental or approved proteins/antibodies (e.g., bevacizumab) ≤ 30 days before inclusion
Surgery (not including diagnostic biopsy or central venous catheter placement) and/or radiotherapy in the 4 weeks prior to inclusion
Metastasis on any site other than the liver, including extrahepatic lymph nodes.
Active disease or treatment for prior malignant tumour in the last 5 years, except a history of basal cell carcinoma or cervical carcinoma in situ
Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or a history of ventricular arrhythmia
Known positive test for human immunodeficiency virus infection, hepatitis C virus, chronic active hepatitis B infection
Reference:
Abad A, Massuti B, Grávalos C, et al. Phase II trial of panitumumab plus FOLFOX4 or FOLFIRI in subjects with KRAS wild-type colorectal cancer and liver-limited disease: The PLANET study. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster).
Abad A, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster).
EGFR, epidermal growth factor receptor

41. PLANET study Patient disposition and characteristics
77 patients were analyzed
38 received Pmab-FOLFOX4
39 received Pmab-FOLFIRI
Pmab-FOLFOX4
(N = 38)
Pmab-FOLFIRI
(N = 39)
TOTAL
(N = 77)
Male, n (%)
31 (81.6)
28 (71.8)
59 (76.6)
Median age, years (min, max)
65 (32, 79)
63 (37, 83)
64 (32, 83)
Mean body mass index, kg/m2 (SD)
27.4 (4.4)
25.9 (3.6)
26.7 (4.0)
Median time since CCR diagnosis, months (Q1, Q3)
3.4 (1.3, 22.7)
1.6 (0.6, 11,5)
1.9
(0.6, 22.2)
Technically resectable liver metastases, n (%)
12 (31.6)
12 (30.8)
24 (31.2)
Prior surgery for primary tumor, n (%)
26 (68.4)
22 (56.4)
48 (62.3)
Prior adjuvant/neoadjuvant CT and/or radiotherapy, n (%)
6 (15.8)
4 (10.3)
10 (13.0)
Prior FOLFOX, n (%)
3 (7.9)
3 (7.7)
6 (7.8)
Abad et al. Presented at the 16th World Congress on Gastrointestinal Cancer, June 25-28, 2014, Barcelona (Spain); Abstract nº PD-0006

42. PLANET study Response rate and resectability – presented a ESMO
Preliminary median OS in WT KRAS (exon 2) was 32.5 and 42.4 months (p = 0.848).
Median OS in WT RAS was 39.0 months with pmab + FOLFOX4 and 45.8 months withp+ FOLFIRI.
Reference:
Abad A, Massuti B, Grávalos C, et al. Phase II trial of panitumumab plus FOLFOX4 or FOLFIRI in subjects with KRAS wild-type colorectal cancer and liver-limited disease: The PLANET study. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster).

43. PLANET study OS WT KRAS exon 2 WT RAS Median, months (95% CI)
100
100 90 90 80 80 70 70 60 60
Proportion event-free (%) 50
Proportion event-free (%) 50 40 40 30 30 20
P log rank = 0.848
P Wilcoxon = 0.915 20
P log-rank = 0.935
P Wilcoxon = 0.634 10 10 10 20 30 40 50 60 10 20 30 40 50
Months
Months
Preliminary median OS in WT KRAS (exon 2) was 32.5 and 42.4 months (p = 0.848).
Median OS in WT RAS was 39.0 months with pmab + FOLFOX4 and 45.8 months withp+ FOLFIRI.
Reference:
Abad A, Massuti B, Grávalos C, et al. Phase II trial of panitumumab plus FOLFOX4 or FOLFIRI in subjects with KRAS wild-type colorectal cancer and liver-limited disease: The PLANET study. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster).
Median, months
(95% CI)
Panitumumab + FOLFOX4
32.5 (20.6–NA)
Panitumumab + FOLFIRI
42.4 (17.8–51.5)
Median, months
(95% CI)
Panitumumab + FOLFOX4
39.0 (26.4–NA)
Panitumumab + FOLFIRI
45.8 (32.8–51.5)
Abad A, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster).
WT RAS, WT KRAS & NRAS exons 2/3/4;
NA, not achieved

44. ESMO Clinical Groups for 1st-line treatment Definition of Group 0 (initially resectable) patients
Initially R0 resectable
Non-resectable at clinical presentation
Group 2
Group 1
Group 3
Group 0
Metastases are:
Limited to liver and / or lung
Clearly R0-resectable, even without preoperative chemotherapy
Treatment aim is curative and to decrease risk of relapse
Group 0:
This group comprises those patients in whom metastases are limited to liver/lung metastases, which are clearly R0 resectable even without preoperative chemotherapy
This group is different from Group 1, where upfront resection has a high likelihood for a R ≥ 1 resection
REFERENCE:
Schmoll HJ, Van Cutsem E, Stein A, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23:
Schmoll HJ, et al. Ann Oncol 2012; 23:
R0, resection with microscopically negative margins.

45. initially resectable LLD
EORTC intergroup study [EPOC] Surgery ± FOLFOX4 for resectable liver metastases from colorectal cancer
Open label, phase 3 study
FOLFOX4
6 cycles S U R G E Y
FOLFOX4
6 cycles
mCRC with
initially resectable LLD
(n = 364) R
1:1
None
None
Study objectives:
To compare the progression-free and overall survival of patients with resectable colorectal liver metastases treated with surgery with or without neoadjuvant and adjuvant oxaliplatin, fluorouracil, and leucovorin calcium.
To compare the percentage of patients with total resection with these two treatments.
Selected inclusion criteria:
WHO ≤ 2
1-4 resectable liver metastases
No detectable extra-hepatic tumours
Primary tumour either already (R0) resected or judged to be resectable (in case of synchronous metastases).
No previous chemotherapy with oxaliplatin.
REFERENCE:
Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371:
Study endpoints: PFS (1°), OS, resectability, tumour response, safety
ClinicalTrials.gov identifier: NCT
Nordlinger B, et al. Lancet 2008; 371: ; Nordlinger B, et al. Lancet 2013; 14:
mCRC metastatic colorectal cancer; LLD, liver limited disease; OS, overall survival; PFS, progression free survival.

46. EORTC intergroup study 40983 [EPOC] Progression free survival
All eligible patients
All resected patients
100
100
HR (96% CI) = 0.77 (0.60, 1.00)
P = 0.041
HR (96% CI) = 0.73 (0.55, 0.97)
P = 0.025 80 80 60 60
Proportion event-free (%)
Proportion event-free (%) 40 40 20 20 1 2 3 4 5 6 1 2 3 4 5 6
3-year PFS, %
Surgery + FOLFOX4 (n = 171)
36.2
Surgery (n = 171)
28.1
3-year PFS, %
Surgery + FOLFOX4 (n = 151)
42.4
Surgery (n = 152)
33.2
Years
Years
This slide represents the trial’s final data for PFS, which were published1 while overall survival was still being monitored.2
The combination of perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) and surgery increased progression-free survival (PFS) compared with surgery alone for patients with liver-only metastases from colorectal cancer deemed resectable on preoperative imaging.
For all patients eligible for analysis (ie, those who were assessed by the study coordinator to fulfil eligibility criteria as defined in the protocol) the absolute difference in 3-year PFS was 8·1% (28·1% [95·66% CI 21·2 – 36·6] in the surgery-only group vs 36·2% [28·7 – 43·8] in the perioperative chemotherapy group; HR 0·77 [0·60 – 1·00]; p=0·041).
Data from a median follow-up of 8.5 years reported the estimated 3-year PFS in all eligible patients to be:2
29.9% [95% CI 23·2 – 36·9] in the surgery-only group vs.
39.0% [95% CI 31.7 – 46.3] in the perioperative chemotherapy group;
HR 0·78 [0·61 – 0·99]; p=0·035).
REFERENCES:
1. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371:
2. Nordlinger B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet 2013; 14:
Perioperative FOLFOX4 reduced the risk of PFS events by ~25%
Nordlinger B, et al. Lancet 2008; 371:
PFS, progression free survival.

47. 20100086 EORTC BOS-2 study Patients with resectable liver metastases
Open label, phase 2 study
6 cycles
mFOLFOX6
mFOLFOX6 +
bevacizumab
panitumumab S U R G E Y
6 cycles
mFOLFOX6
mFOLFOX6 +
bevacizumab
panitumumab F O L W - U P
KRAS WT mCRC
with resectable LLD
(n = 360)
CRC with ≤8 resectable metachronous or synchronous liver metastases from CRC
KRAS wild-type R
The addition of targeted agents to standard FOLFOX chemotherapy in the perioperative strategy for mCRC might increase the ORR and R0 resectability, without significant increase in toxicity, therefore translating to a better outcome.
To test this, the European Organisation for Research and Treatment of Cancer (EORTC) has designed an open label, randomized, multi-centre, 3-arm late phase II study.
Selected inclusion criteria:
WHO 0 or 1
Histologically proven CRC with 1 to 8 metachronous or synchronous liver metastases considered to be completely resectable.
No detectable extra-hepatic tumours.
Primary tumour either already (R0) resected or judged to be resectable at the same time as the liver metastases (in case of synchronous metastases).
Primary tumour (or liver metastasis) of CRC must be KRAS status "wild type".
No previous chemotherapy for metastatic disease or surgical treatment for liver metastases.
No exposure to EGFR or VEGF/VEGFR targeting therapy in the last 12 months.
REFERENCE:
ClinicalTrials.gov identifier: NCT
Study endpoints: PFS (1°), pathological response rate, resection rate, OS, safety
ClinicalTrials.gov identifier: NCT
BOS, biologics, oxaliplatin and surgery, OS, overall survival.

48. Conclusiones El CCRm tiene mal pronóstico si no se trata.
La cirugía hepática ofrece posibilidad de curación (15%)
Hasta un 30% de los tumnores inicialmente irresecables se convierten en resecables tras QT de conversión
Las combinaciones de quimioterapia con tratamientos biológicos ofrecen tasas de respuestas superiores a 50% en pacientes no seleccionados, y superiores a 70% en pacientes con enfermedad limitada al hígado.
Los datos de los estudios fase III (PRIME), y los estudios de los estudios fase II con pacientes seleccionados (PLANET), permiten emular los resultados de otras combinaciones
REFERENCES:
1. Van den Eynde M, Hendlisz A. Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials 2009;4:56–62.
2. Nordlinger B et al. Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer. 2007;43(14):2037–45.
3. Schmoll HJ, Van Cutsem E, Stein A, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23:
4. Peeters M, et al. Resection Rates and Survival in Patients with Wild-Type KRAS/NRAS Metastatic Colorectal Cancer and Liver Metastases: Data from the Prime Study. EJC 2013; 49 (suppl 4):abstract MC (and poster)

49. Conclusiones
Cuando hablemos del tratamiento de conversión en pacientes afectos de CCRm potencialmente resecables, las combinaciones con panitumumab han demostrado ser igualmente eficaces que otras combinaciones de tratamiento estudiadas con anterioridad.
REFERENCES:
1. Van den Eynde M, Hendlisz A. Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials 2009;4:56–62.
2. Nordlinger B et al. Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer. 2007;43(14):2037–45.
3. Schmoll HJ, Van Cutsem E, Stein A, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23:
4. Peeters M, et al. Resection Rates and Survival in Patients with Wild-Type KRAS/NRAS Metastatic Colorectal Cancer and Liver Metastases: Data from the Prime Study. EJC 2013; 49 (suppl 4):abstract MC (and poster)