1. 8th Mucscat International Oncology conference. Muscat, Oman
« Navigating Guidelines in The Management of mCRC Closer look in the new ESMO guidelines
Fadi Farhat, MD, MHHM
8th Mucscat International Oncology conference. Muscat, Oman
2-3 November 2016

2. Some Comments concerning the new guidelines
ESMO has released new consensus guidelines for the management of metastatic CRC
Some Comments concerning the new guidelines
“Management of mCRC is becoming more complex, requiring a strategic approach & evidence-based patient selection for the best treatment options”
Eric Van Cutsem (Chair of ESMO Consensus Conference)
With these long awaited guidelines, the management of mCRC officially enters the personalized era, addressing the role of existing & emerging biomarkers & their role in clinic
Dr Fotios Loupakis, the Ospedale Civile - Istituto Toscano Tumori and member of the ESMO Faculty for Gastro-Intestinal Tumors

3. Major innovations in the guidelines
Detailed therapeutic algorithm:
Patient’s condition and fitness
Therapeutic goals such as tumour shrinkage or slowing disease progression
Molecular markers
Questions:
Use of chemo & radio-embolization
Imaging
Surgical resection
RAS & BRAF mutation testing/MSI/ EGFR, HER2/Others
I. Development of a detailed therapeutic algorithm taking into account
II. Address questions such a
III. RAS and BRAF mutation testing at diagnosis for all patients with metastatic colorectal cancer.
IV. Growing evidence for more frequent testing for Microstaelite Instability
V. Testing emerging biomarkers (EGFR or HER2) not recommended as routine 

4. ESMO consensus guidelines
Molecular pathology & biomarkers
2012: First set of ESMO consensus guidelines for mCRC
2014: International panel of experts - to update the existing ESMO Consensus Guidelines
Pre-formulated topics
Three working groups
The first set of ESMO consensus guidelines for metastatic colorectal guidelines was published in 2012.
In 2014, an international panel of experts in the management of patients with CRC was convened to update the existing ESMO Consensus Guidelines for the management of patients with CRC
A set of pre-formulated topics was prepared and three working groups convened in the areas of:

5. LAT (+surgery) & management of OMD
Molecular pathology & biomarkers

6. ESMO consensus guidelines
Treatment of metastatic disease
LAT (+surgery) & management of OMD
Molecular pathology & biomarkers
Set of pre-formulated topics; 3 working groups convened in areas:
Molecular pathology and biomarkers [1-9]
Local and ablative treatment (LAT) (including surgery and the management of patients with oligometastatic disease) [10-17]
The treatment of metastatic disease [18-…]
5FU or Cape ?
Oxali or Irino ?
Bev or Cetux/Vec ?
Bev or Afliber ?
OR ??????????

7. New ESMO consensus guidelines for the management of metastatic CRC
Recommendations from each group were then presented to the entire panel of experts, where they were discussed and modified as required until consensus was reached.
(i) molecular pathology and biomarkers;
(ii) local and ablative treatment (LAT) [including surgery and the management of patients with oligometastatic disease (OMD)];
(iii) the treatment of metastatic disease.
1.Tissue handling
2.Selection of specimens for biomarker testing
9.Emerging technologies

8. 3.Tissue selection
Tissue from either the primary tumour or a liver metastasis may be used for RAS mutation testing [III, A].
Other metastatic sites such as lymph node or lung metastases may be used only if primary tumour or liver metastases samples are not available [II, B].

9. What is the relevance of BRAF testing in 1st line mCRC?
RAS testing: An integral part of the current 1st line treatment decision-making process
Guidelines in 2014/2015
Appropriate Molecular analyses are to be performed at the time of diagnosis of mCRC and should comprise a full RAS analysis with simultaneous BRAF analysis
to provide the best diagnostic and prognostic decision making.
NCCN 20152
ESMO 20151
“The panel strongly recommends genotyping of tumor tissue (either primary tumor or metastasis) in all patients with metastatic colorectal cancer for RAS (KRAS exon 2 and non-exon 2; NRAS) and BRAF at diagnosis of stage IV disease”
What is the relevance of BRAF testing in 1st line mCRC?
Cetuximab and panitumumab are approved in patients with RAS wt mCRC.3,4
Cetuximab and panitumumab are not indicated for the treatment of patients with mCRC whose tumors have RAS mutations or for whom RAS tumor status is unknown3,4
1. The ESMO consensus on metastatic CRC – 2015 Eric Van Cutsem, MD, PhD, Dirk Arnold, MD, and Andrés Cervantes, MD, PhD 2. NCCN clinical practice guidelines; Colon Cancer, Version Available at (accessed April 2015) 3. Erbitux SmPC June/2014; 4. Vectibix SmPC February/2015

10. 4: RAS testing
RAS mutational status - negative predictive biomarker for therapeutic choices involving EGFR Ab therapies [I, A].
Should be carried out for m CRC [I, A].
Mandatory before EGFR- targeted MoAb [I, A].
Primary or metastatic tissue can be used
At least K & N RAS exons 2, 3 & 4 (codons 12, 13, 59, 61, 117) (& 146 – KRAS)
RAS mutational status is a negative predictive biomarker for therapeutic choices involving EGFR antibody therapies in the metastatic disease setting [I, A].
RAS testing should be carried out on all patients at the time of diagnosis of mCRC [I, A].
RAS testing is mandatory before treatment with the EGFR- targeted MoAb cetuximab and panitumumab [I, A].
Primary or metastatic colorectal tumour tissue can be used for RAS testing
RAS analysis should include at least KRAS exons 2, 3 & 4 (codons 12, 13, 59, 61, 117 & 146) & NRAS exons 2, 3 & 4 (codons 12, 13, 59, 61 and 117).

11. 5.BRAF testing Distribution of BRAF mutation vs other mutations
Retrospective consortium analysis of tumor samples from 747 patients with chemorefractory mCRC treated with Erbitux + CT1
BRAF mutations* occurred exclusively in RAS wt tumors
KRAS wt†
KRAS mt† 34 2
371
256 43 26 1 14
PIK3CA exon 9 mt
NRAS mt‡
Other studies have confirmed that RAS and BRAF mutations are largely mutually exclusive in CRC tumors2
*Comprising 35 tumors with BRAF V600E mt and one with D549G mt †KRAS exon 2 (codons 12 and 13), exon 3 (codon 61) and exon 4 (codon 146) ‡NRAS exon 2 (codons 12 and 13) and exon 3 (codon 61)
1. De Roock W, et al. Lancet Oncol 2010;11:753–762; 2. Chen D, et al. PLoS One 2014;9:e90607

12. Meta-analysis: BRAF mutation > than doubles the risk of mortality in patients with CRC1
Random effects meta-analysis of cohort studies and RCTs assessing the association between BRAF status and mortality in early stage or metastatic CRC
Study type
No. studies
Patients, n
Weight, %
OS log HR (95% CI)
Cohort 21
6888
76.9
0.88 (0.60–1.16)
RCT* 5
4433
23.1
0.61 (0.28–0.94)
Overall 26
11,321
100.0
0.81 (0.60–1.03)
Heterogeneity:
I2=74.3%; τ2=0.2058, p<0.0001 -1 1 2
OS log HR (95% CI)
Corresponds to HR=2.24 (95% CI: 1.82–2.83), i.e fold increased risk of death with BRAF mt vs wt
Favors mt
Favors wt
*Includes data from the pooled analysis of CRYSTAL and OPUS, COIN, FOCUS and CAIRO2 in mCRC, plus a pooled analysis of PETACC-3, EORTC 40993, SAKK in resected stage II/III colon cancer
1. Safaee Ardekani G, et al. PLoS One 2012;7:e47054

13. 5.BRAF testing & 6.MSI testing
Tumour BRAF mutation status should be assessed alongside the assessment of tumour RAS mutational status
for prognostic assessment
and/or potential selection for clinical trials [I, B]
6.MSI testing
MSI testing can assist clinicians in genetic counseling [II, B]
MSI testing has strong predictive value for the use of immune check-point inhibitors in the treatment of mCRC [II, B]

14. 7.Biomarkers of chemo sensitivity & toxicity 8.Emerging biomarkers
7.Biomarkers of chemotherapy sensitivity and toxicity
DPD before 5-FU: an option but not routinely [II, D].
TS activity & TSER genotyping –not in clinical practice [II, D].
8.Emerging biomarkers not for routine management
Detection of mutations in PIK3CA, exon 20 [II, D].
Levels of the EGFR ligands amphiregulin, epiregulin and TGF-α [II, D].
Levels of EGFR protein expression [II, E].
7.Biomarkers of chemotherapy sensitivity and toxicity
DPD testing before 5-FU administration remains an option but is not routinely recommended [II, D].
TS activity & TSER genotyping -not recommended for use in clinical practice [II, D].
8.Emerging biomarkers not recommended for routine patient management outside of a CTs
Detection of mutations in PIK3CA, exon 20 [II, D].
Levels of the EGFR ligands amphiregulin, epiregulin and TGF-α [II, D].
Levels of EGFR protein expression [II, E].

15. Local and ablative treatment (LAT) “including surgery & the management of patients with oligometastatic disease”
Recommendations [10-17]

16. 12.perioperative treatment in Clearly resectable disease & favorable prognostic criteria
May not be necessary & upfront resection is justified [I, C; consensus >75%]
Unclear Prognosis or probably unfavorable, perioperative (FOLFOX or CAPOX) [I, B; consensus >75%]
Targeted agents should not be used [II, E]
If no perioperative chemotherapy - no strong evidence to support adjuvant [II, C]
1. Van Cutsem E, et al. Ann Oncol 2016; epub Jul 7

17. 1st line therapy options? On-treatment management?
CLINICIAN perspective: HOW do i choose the best 1st line treatment for this patient?
Diagnosis?
Biomarker testing?
Treatment goal?
What can I expect?
1st line therapy options?
Treatment sequence?
On-treatment management?

18. Possible treatment goals
Extend OS
What can I expect?
Tumor shrinkag e
Disease control
Surgery

19. Van Cutsem Ann Oncol (2016) 27 (8): 1386-1422.

20. Van Cutsem Ann Oncol (2016) 27 (8): 1386-1422.

21. ESMO clinical consensus guidelines
Drivers for decision-making in 1st line
Clinical presentation; tumor burden; tumor localization
Tumor biology
RAS/BRAF status
Age
Performance status
Organ function
Comorbidities
Toxicity profile
Flexibility
Socioeconomic factors
QoL, patient expectations and preferences
Tumor
Clinically fit
Patient
Clinically unfit
Treatment
Van Cutsem Ann Oncol (2016) (8):

22. Surgical resection as goal
Van Cutsem Ann Oncol (2016) (8):

23. Choosing first-line – Use your biomarkers!
Van Cutsem Ann Oncol (2016) (8):

24. 13.Conversion therapy In potentially resectable high RRs Shrinkage
[II, A].
RAS-mutant:
cytotoxic doublet or
FOLFOXIRI + BEV
In potentially resectable patients (if conversion is the goal), a regimen leading to high RRs and/or a large tumour size reduction (shrinkage) is recommended [II, A].
There is uncertainty surrounding the best combination to use as only few trials have addressed this specifically:
In RAS WT disease, a cytotoxic doublet + an anti-EGFR antibody seems to have the best benefit risk/ratio, although the combination of FOLFOXIRI + BEV. may also be considered and, to a lesser extent, a cytotoxic doublet + BEV. [II, A].
In RAS-mutant disease: a cytotoxic doublet or FOLFOXIRI + BEV [II, A].
≥1 of the following
• Candidate for conversion therapy
• Impending clinical threat or organ dysfunction
• Severe symptoms
1. Van Cutsem E, et al. Ann Oncol 2016; epub Jul 7

25. The treatment of metastatic disease
13.Conversion therapy
RAS WT:
doublet + an anti-EGFR - best benefit risk/ratio,
FOLFOXIRI + BEV- may be considered
doublet + BEV- to a lesser extent
[II, A].
In potentially resectable patients (if conversion is the goal), a regimen leading to high RRs and/or a large tumour size reduction (shrinkage) is recommended [II, A].
There is uncertainty surrounding the best combination to use as only few trials have addressed this specifically:
In RAS WT disease, a cytotoxic doublet + an anti-EGFR antibody seems to have the best benefit risk/ratio, although the combination of FOLFOXIRI + BEV. may also be considered and, to a lesser extent, a cytotoxic doublet + BEV. [II, A].
In RAS-mutant disease: a cytotoxic doublet or FOLFOXIRI + BEV [II, A].
The treatment of metastatic disease
1. Van Cutsem E, et al. Ann Oncol 2016; epub Jul 7

26. Biologicals are indicated in the first-line treatment of most patients unless contraindicated [I, A].
1. Van Cutsem E, et al. Ann Oncol 2016; epub Jul 7

27. 18. First line therapy combinations
EGFR Ab - combination with FOLFOX/FOLFIRI [I, A]
Capecitabine-based & bolus 5-FU based: NO!!! [I, E].
VEGF antibody BEV should be used in combination with:
doublets FOLFOX/CAPOX/FOLFIRI,
triplet FOLFOXIRI in selected fit patients (cytoreduction & potentially BRAF mutations) [II, B],
fluoropyrimidine monotherapy in patients unable to tolerate aggressive treatment [I, B].

28. Test for resectability again and again!
1. Van Cutsem E, et al. Ann Oncol 2016; epub Jul 7

29. 19. Maintenance therapy Patients receiving FOLFOX or CAPOX + BEV therapy as induction therapy should be considered for maintenance therapy after 6 cycles of CAPOX & 8 cycles of FOLFOX
Optimal maintenance treatment is a combination of a Fp + BEV.
BEV as monotherapy is not recommended [I, B]
1. Van Cutsem E, et al. Ann Oncol 2016; epub Jul 7

30. 20. second-line combinations with targeted agents
Patients who are Bev naïve should be considered for treatment with an antiangiogenic (Bev. or aflibercept) 2nd line [I, A]
The use of aflibercept should be restricted to combination with FOLFIRI for patients progressing on an oxaliplatin-containing regimen [I, A].

31. 20: second-line combinations with targeted agents -2
Patients who received Bev. first line should be considered for treatment with:
Bev. post-continuation strategy [I, A].
Aflibercept or ramucirumab (in combination with FOLFIRI) when treated in first line with oxaliplatin [I, A].
EGFR antibodies in combination with FOLFIRI/irinotecan for patients with RAS wild-type (BRAF wild-type) disease
Relative benefit of EGFR antibodies is similar in later lines compared with second line [II, A]

32. 21: third-line therapy
In RAS WT & BRAF WT patients not previously treated with EGFR antibodies, cetuximab or panitumumab therapy should be considered:
Cetuximab and panitumumab are equally active as single agents [I, A].
The combination of cetuximab with irinotecan is more active than cetuximab alone, in irinotecan refractory patients [II, B].
There is no unequivocal evidence to administer the alternative EGFR antibody, if a patient is refractory to one of the EGFR antibodies [I, C].

33. 21: third-line therapy
Regorafenib is recommended in patients pre-treated with fluoropyrimidines, oxaliplatin, irinotecan, BEV & in RAS-WT patients with EGFR antibodies [I, B]
Regorafenib is superior to placebo in terms of OS, although there are toxicity concerns in frail patients.

34. ESMO consensus guidelines
Set of pre-formulated topics; 3 working groups convened in areas:
Molecular pathology and biomarkers [1-9]
Local and ablative treatment (LAT) (including surgery and the management of patients with oligometastatic disease) [10-17]
The treatment of metastatic disease [18-…]