right for the left

1. OPTIMAL TREATMENT SEQUENCE IN
LEFT SIDE RAS WT BRAF WT MCRC
DR. R. RAJKUMAR D.M.
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL SPECIALITY HOSPITALS

2. EPIDEMIOLOGY
- Incidence of colorectal cancer in India is 3.6 – 4.1 per
100,000
- Left sided tumors are more common
-Around 2/3
- ~ 25% of patients are < 40 years of age
- More proximal tumors

3. PREDICTION IS MORE WORRISOME

4. 1. Patients with resectable metastatic disease at presentation
2. Patients with unresectable disease at presentation that becomes
potentially resectable after downstaging (conversion) with systemic
therapy
3. Patients who have potentially resectable metastatic disease but
who are not candidates for resective surgery
4. Patients with unresectable metastatic disease
PATIENTS WITH METASTATIC DISEASE CAN BE
CLASSIFIED INTO 4 GROUPS:

5. Resection
Maximising OS, while maintaining QoL
Treatment
strategy
Treatment
goal
Curative
surgery
10%
Classification
Upfront
resectable
MOST PATIENTS WITH mCRC HAVE INITIALLY
UNRESECTABLE DISEASE AT FIRST PRESENTATION:
INCREASING OS IS THE PRIMARY TREATMENT GOAL
20–30% 60–70%
Potentially
resectable
Permanently
unresectable
CT +
biologic
CT +
biologic
Relapse
Initially unresectable

6. COLON CANCER: MORE THAN 1 DISEASE
MSI vs MSS RAS WT vs
mutant
Right vs left vs
rectal
Young vs old
Stool flora typesBRAF WT vs
mutant
HER2
Molecular Anatomic

7. RAS
MSI
BRAF
PIK3CA
PTEN
RAS
KRAS
HER2/NEU
APC
TP53
RAS
KRAS
HER2/NEU
APC
TP53
© 2017 The Ruesch Center for the Cure of GI Cancers

8. 19.92
Cetux +
FOLFIRI
20.31
Bev +
IFL
21.33
Bev +
XELOX/
FOLFOX
CRYSTAL NO16966AVF2107g
23.52
Cetux +
FOLFIRI
23.84
Pan +
FOLFOX
-4
28.75
Cetux +
FOLFIRI
FIRE-3*CRYSTAL PRIME
28.46
Cetux +
FOLFIRI
33.15
Cetux +
FOLFIRI
25.84
Pan +
FOLFOX
-4
CRYSTAL
32.57
Cetux +
FOLFOX
CALGB/
SWOG
80405†FIRE-3*
29.07
Bev +
FOLFOX
CALGB/
SWOG
80405†
32.07
Cetux +
FOLFIRI
CALGB/
SWOG
80405†
35.27
Bev +
FOLFIRI
CALGB/
SWOG
80405†PRIME
Biologics
(unselected patients)
MedianOS,months
30
20
9
Personalization
KRAS exon 2 wt‡ Expanded RAS wt
CT alone
Cetuximab-based therapy
Panitumumab-based therapy
Bevacizumab-based therapy
19.93
XELOX/
FOLFOX15.61
IFL
18.62
FOLFIRI
NO16966AVF2107g CRYSTAL
Chemotherapy
.
TREATMENT EVOLUTIONS HAVE LEAD TO
IMPROVED SURVIVAL RATES IN MCRC
Left Side tumor
40
28.79
Cetux +
FOLFIRI
30.39
Pan +
FOLFOX
-4
38.39
Cetux +
FOLFIRI
FIRE-3*
CRYSTAL
PRIME
39.39
Cetux +
CT
CALGB/
SWOG
80405†
How? Whom? Why?

9. ADCC, antibody-dependent cell-mediated cytotoxicity; CMS, consensus molecular subtypes.
1. Arnold D, et al. Ann Oncol 2017;28:1713–1729; 2. Bokemeyer C, et al. J Cancer 2012;48:1466–1475; 3. Lenz H-J, et al. J Clin Oncol 2019;37:1876–1885; 4. Erbitux EU SmPC, Jul 2008; 5. Erbitux EU SmPC, Dec
2013; 6. Holch JW, et al. Eur J Cancer 2017;70:87–98; 7. Yoshino T, et al. Ann Oncol 2018;29:44–70; 8. NCCN Colon Cancer Guidelines Version 2.2019; 9. Monteverde M, et al. Crit Rev Oncol Hematol
2015;95:179–90; 10. Lo Nigro, et al. World J Gastrointest Oncol 2016;8:222–30; 11. Santini D, et al. Ann Oncol 2012;23:2313–2318; 12. Cremolini C, et al. JAMA Oncol 2019;5:343–350; 13. Aderka D, et al.
Lancet Oncol 2019;20:e274–283; 14. García-Foncillas J, et al. Frontiers Oncol 2019;9:1–16.
mCRC is an evolving field and we are continuously re-evaluating
treatment practices
Tumor location1,6Molecular profiles1-3
Immune activity and the
microenvironment9,10
Dynamic mutation
status11,12
2012 2013 2014 2015 2016 2017 2018 20192004
Evolution of Cetuximab indication
(KRAS, RAS),4,5 changing landscape of
precision medicine; continuing evolution of
evidence about BRAF1,2 and CMS3
Santini rechallenge hypothesis11
and first prospective rechallenge
study (CRICKET)12
Efficacy of Cetuximab in
left-sided and right-sided
RAS wt mCRC;1,6 incorporation of
tumor location into guidelines7,8
NK cell-mediated ADCC identified as key
to Cetuximab antitumor activity9,10
…

10. THE LUXURY OF SO MANY OPTIONS: HOW DO
WE PERSONALIZE THERAPY?
Patient X
Patient Y
Patient Z
Oxaliplatin
Irinotecan
Bevacizumab
5-FU
5-FU
Oxaliplatin
BevacizumabOxaliplatin
Cetuximab
Capecitabine

11. WHAT INFLUENCES TREATMENT CHOICES
Quality
of life
Pt preference
Toxicity
profile
Tumor burden Resectability
Tumor location
Tumor characteristics
Pt characteristics
Age
Comorbidities
Prior adjuvant
treatment
Performance
status
Therapy tailored according to individual patient needs
Molecular
characteristics
RAS BRAF
MSI high HER2
1L
2L
3L
4L

12. CASE DETAILS
•38yrs/ F
•CA RECTUM
•STAGE IV (2017)
•LIVER METS
•HPE- ADENOCARCINOMA

13. CASE DETAILS
QUESTION ?
1. SURGERY
2. PALLIATIVE CHEMO
3. CONVERSION CHEMO

14. 1. Saltz L, et al. J Clin Oncol 2008;26:2013–2019; 2. Lenz H-J, et al. Ann Oncol 2014;25 (suppl 4) (Abstract No. 501O); 3. Pericay C, et al. Ann Oncol 2012;23 (suppl 4)
(Abstract No. O-0024); 4. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240–2247; 5. Langer C, et al. Ann Oncol 2008;19 (suppl 8) (Abstract No. 385P); 6. Peeters M, et al. J
Clin Oncol 2014;32 (suppl 3) (Abstract No. LBA387); 7. Hecht JR, et al. Clin Colorectal Cancer 2015;14:72–80; 8. Grothey A, et al. Lancet 2013;381:303–312; 9. Price T, et al.
Lancet Oncol 2014;15:569–579; 10. Hess G, et al. J Oncol Pract 2010;6:301–307; 11. Erbitux SmPC Dec/2016.
• *Range of results for the targeted treatment arms of key Phase II/III trials RAS wt except where indicated; ‡KRAS (exon 2) wt; †unselected; Cetuximab is approved in
patients with EGFR-expressing, RAS wt mCRC: in combination with irinotecan-based CT, or in 1st line in combination with FOLFOX, or as a single agent in patients who
have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan;11 §Refers to US-specific real-world practice patterns (n=1655).
• ORR, objective response rate; PFS, progression-free survival.
1st line treatment decision in mCRC is paramount
100%
45%
~20%
1st line1–4 2nd line5–7 3rd line8,9
ORR, %*
Median PFS,
months*
38†–69
8†–12
10†–41
4†–9†
1†–22‡
2†–4‡
100% received
1st line therapy10
~45% received
2nd line therapy10
~20% received
3rd line therapy10

15. 1. Biomarker status
2. Tumor sidedness
3. Treatment sequence
4. Patient characteristics
5. All of the above
1. Factors considered for selecting 1st-line treatment for
patients with mCRC?
1L

16. National Comprehensive Cancer Network
(NCCN) 20201
Proposed ESMO
consensus 2015/162
“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”
“The appropriate molecular analyses are to be carried
out at the time of initial diagnosis of mCRC and
should comprise a full analysis of tumour RAS
mutational status (KRAS: exon 2, 3 and 4 and NRAS:
exon 2, 3 and 4) with a simultaneous analysis of tumour
BRAF mutational status, conducted in a validated
laboratory/testing centre, to facilitate the best
diagnostic and prognostic decision making possible.”
“Turnaround time for RAS testing (expanded RAS
analysis) should be ≤7 working days from the time of
receipt of the specimen by the testing laboratory to the
time of issuing of the final report, for >90% of
specimens”
ESMO
consensus 20162
1. NCCN clinical practice guidelines; Colon Cancer, Version 1.2020;
2. Van Cutsem E, et al. Ann Oncol 2016;27:1386–1422;
3. Erbitux® SmPC June 2014; 4. Vectibix® SmPC February 2015.
RAS testing has become integral to 1st line treatment
decision making

17. • The predominant BRAF mutation in mCRC is V600E (~10% mCRC cases)1
• V600E BRAF mutations are strongly associated with microsatellite instability and CpG island
methylator phenotypes, and are linked to unfavourable outcomes1–6
Testing for BRAF mutation is recommended by international
guidelines at diagnosis of mCRC
1. Saletti P, et al. Gastrointestinal Cancer: Targets and Therapy 2015:5 21–38; 2. Tie J, Desai J. Target Oncol 2015;10:179–88;
3. Yuki S, et al. ASCO 2015 (Abstract No. 11038); 4. Hall RD, Kudchadkar RR. Cancer Control 2014;21:221–30;
5. Atlasgeneticsoncology.org [accessed July 2015]; 6. Chen D, et al. PLoS One 2014;9:e90607;
7. Van Cutsem E, et al. Ann Oncol 2016;27:1386–1422; 8. NCCN clinical practice guidelines; Colon Cancer, Version 2. 2017; 9. Yoshino T, et al. Ann Oncol 2018; 29:44–70.
International guidelines
ESMO Pan-Asia 20179
“Tumor BRAF mutation (V600E) status should be
assessed alongside the assessment of tumor RAS
mutational status for prognostic assessment (and/or
potential selection for clinical trials)”
X
NCCN 20178
“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”
X
ESMO consensus 20167
“The appropriate molecular analyses are to be carried out at the
time of initial diagnosis of mCRC and should comprise a full
analysis of tumour RAS mutational status (KRAS: exon 2, 3 and
4 and NRAS: exon 2, 3 and 4) with a simultaneous analysis of
tumour BRAF mutational status, conducted in a validated
laboratory/testing centre, to facilitate the best diagnostic and
prognostic decision making possible”
X

18. *Includes patients with rectal cancer. CMS, Consensus Molecular Subgroups; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; TMB, tumor mutational burden.
1. Gallois C, et al. Drugs 2018;78:789–798; 2. Maus MK, et al. Pharmacogenomics J 2015;15:354–362; 3. Lee GH, et al. Eur J Surg Oncol 2015;41:300–308; 4. Tejpar S, et al. JAMA Oncol 2017;3:194–201; 5. Lievre A, et al.
Cancer Res 2006;66:3992–3995; 6. Samowitz WS, et al. Cancer Res 2005;65:6063–6069; 7. Barault L, et al. Cancer Res 2008;68:8541–8546; 8. Tran B, et al. Cancer 2011;117:4623–4632; 9. Innocenti F, et al. J Clin Oncol
2019;37:1217–1227; 10. Lenz H-J, et al. J Clin Oncol 2019;37:1876–1885.
We consider tumor location is the master prognostic factor?1
Left-sided CRC
Affects 60–80% of
patients2–4*
Right-sided CRC
Affects 20–40% of
patients2–4
Right
colon
Worse
prognosis
RAS mt5
BRAF mt6
CIMP-High7
MSI-High8
LowTMB9
CMS110
CMS310
Better
prognosis
RAS wt5
BRAF wt6
CIMP-Low7
MSI-
Stable8
HighTMB9
CMS410
CMS210
Left
colon

19. Guidelines and experts acknowledge tumor location as a key
decision factor for treatment of RAS wt mCRC1–5
Tumor location is predictive of treatment outcomes1–5
Update in
progress:
expected this year,
to include
recommendations
based on tumor
location
2020
European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network.
1. Venook AP, et al. Oral presentation at ESMO 2016; 2. Holch JW, et al. Eur J Cancer 2017;70:87–98; 3. Arnold D, et al. Ann Oncol 2017;28:1713–1729; 4. NCCN Colon Cancer Guidelines
Version 1.2020; 5. Yoshino T, et al. Ann Oncol 2018;29:44–70.

20. Biomarker status of this patient
• RAS WT
• BRAF WT
• Microsatellite stable (MSS)

21. Recommendations are based on global tumor location data (EU and US)
Agreement with ESMO consensus meta-analysis2
ESMO pan-Asian guidelines 20181
Left-sided RAS wt
mCRC tumors
Right-sided RAS wt
mCRC tumors
Disease control Anti-EGFR + doublet CT Bevacizumab + doublet CT
Cytoreduction Anti-EGFR + doublet CT
Anti-EGFR + doublet CT
Bevacizumab + doublet/triplet CT
1. Yoshino T, et al. Ann Oncol 2018;29:44–70; 2. Arnold D, et al. Ann Oncol 2017;28:1713–1729.
Irrespective of treatment goal for this patient?

22. 1. Wainberg ZA, Drakaki A. Expert Opin Biol Ther 2015;15:1205–1220.
Does treatment sequence matters?1
Treatment sequence is important
1st line 2nd line 3rd line
Previously, key clinical trials have not been designed to investigate
treatment sequence, so how do we determine the optimal sequence?

23. Which targeted therapy has greatest evidence in 1L
left-sided RAS wt BRAF WT mCRC?
• Cetuximab
• PanitumumabAnti-EGFR
• Bevacizumab
Anti-VEGF

24. CALGB/SWOG 80405: FIRST-LINE CT +
BEVACIZUMAB OR CETUXIMAB IN
KRAS-WT mCRC
• Multicenter, randomized, open-label phase III trial
• Primary endpoint: OS; secondary endpoints: PFS, TTF, DoR
• Conclusion: no difference in first line
Pts ≥ 18 yrs of age with KRAS-WT
(codons 12, 13), locally advanced
or mCRC; ECOG PS 0/1; no prior
systemic treatment
(N = 1137)
FOLFOX or FOLFIRI
+ Bevacizumab IV Q2W
(n = 559)
FOLFOX or FOLFIRI
+ Cetuximab IV Q1W
(n = 578)
29.0
29.9
10.8
10.4
mOS,
Mos
mPFS,
Mos
Stratified by CT (FOLFOX vs FOLFIRI), prior adjuvant
chemotherapy (yes vs no), prior pelvic radiotherapy (yes vs no)

25. 100
80
60
40
20
0
0 12 24 36 48 60 72 84 96 108
Mos From Study Entry
EventFree(%)
CALGB/SWOG 80405 (FOLFIRI/FOLFOX + BEV OR
CETUXIMAB): OS BY TUMOR LOCATION (RAS WT)
Bevacizumab
(n = 152 vs 78)
32.6
(28.3-36.2)
29.2
(22.4-36.9)
0.88
(0.62-1.25)
.50
OS, Mos (95% CI) HR
(95% CI)
P Value
Left Right
Cetuximab
(n = 173 vs 71)
39.3
(32.9-42.9)
13.7
(11.3-19.0)
0.55
(0.39-0.79)
.001
.

26. CETUXIMAB IS THE 1ST LINE THERAPY THAT DEMONSTRATES
SIGNIFICANT SURVIVAL BENEFIT OVER BEVACIZUMAB IN
LEFT-SIDED RAS WT MCRC IN THE PHASE III FIRE-3 TRIAL
38.3
Bevacizumab
+ FOLFIRI
(n=149)
Cetuximab
+ FOLFIRI
(n=157)
40
30
20
0
MedianOS(months)
Phase III FIRE-3
)
28.0
10
+10.3
months
HR=0.63
(p=0.002)

27. 2014.
CETUXIMAB IS THE 1ST LINE THERAPY THAT DEMONSTRATES
SIGNIFICANT SURVIVAL BENEFIT OVER BEVACIZUMAB IN
LEFT-SIDED RAS WT MCRC IN THE PHASE III
CALGB/SWOG 80405 TRIAL
40
30
20
0
MedianOS(months)
Phase III CALGB/SWOG 804051–3
10
39.3
32.6
+6.7
months
HR=0.77
(p=0.04)
Bevacizumab
+ FOLFOX/FOLFIRI
(n=152)
Cetuximab
+ FOLFOX/FOLFIRI
(n=173)

28. Two independent sequencing meta-analyses support starting with
anti-EGFR before anti-VEGF in patients with RAS WT mCRC1,2
1. Khattak M, et al. Clin Colorectal Cancer 2015;14:81–90; 2. Li J, et al. ASCO GI 2019
(Abstract No. 679); 3. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075; 4. Venook A, et
al. JAMA 2017;317:2392–2401.
FE, fixed effect. *FIRE-3 did not meet its primary endpoint of significantly improving overall response rate (ORR)
based on investigators’ read in patients with KRAS (exon 2) wt mCRC. Primary endpoint for FIRE-3 was ORR in
patients with KRAS wt mCRC.3 †CALGB/SWOG 80405 did not meet its primary endpoint of significantly improving
overall survival in the Cetuximab + CT arm vs bevacizumab + CT arm in patients with KRAS (exon 2) wt mCRC.
Primary endpoint for CALGB/SWOG 80405 was OS in patients with KRAS wt mCRC.4
Khattak meta-analysis1 Li meta-analysis2
OS: 1st-line anti-EGFR vs 1st-line anti-VEGF
0.5 0.75 1 1.5
Favors Anti-EGFR Favors Anti-VEGF
Study ID
FIRE-3*
PEAK
CALGB/SWOG
80405†
Overall
p=0.016
0.70
(0.53–0.92)
37.01
0.63
(0.39–1.02)
15.87
0.90
(0.70–1.10)
47.12
0.77
(0.63–0.95)
100.00
Hazard Ratio
(95% CI) Weight (%)
Anti-EGFR
Anti-EGFRAnti-VEGF
Anti-VEGF
Anti-EGFR Anti-VEGF
Anti-VEGF Anti-VEGF
Group B‡:
Three studies (n=432)
Group A†:
Three studies (n=318)
PFS: HR=0.85; p=0.0081
OS: HR=0.94; p=0.0022
PFS: HR=1.43; p=0.1962
OS: HR=0.95; p=0.6897
1st line
2nd line
Significant benefit of
anti-EGFR  anti-VEGF
vs reverse sequence
No benefit of anti-
VEGF TML strategy
✓ ✗

29. Benefit of 1st-line Anti-EGFR vs anti-VEGF + CT in left-sided
RAS wt mCRC is supported by independent pooled and meta-analyses1,2
Holch meta-analysis of 1st-line anti-EGFR vs anti-VEGF in left-sided RAS wt mCRC1
Trial OS HR (95% CI) p-value
CALGB/SWOG 80405† (n=325) 0.77 (0.59–0.99)
FIRE-3‡ (n=306) 0.63 (0.48–0.85)
PEAK (n=107) 0.84 (0.22–3.27)
Summary (fixed effects) 0.71 (0.58–0.85) 0.0003
Summary (random effects) 0.71 (0.58–0.85) 0.0003
Heterogeneity: I2=0% (95% CI: 0–95.1)
p=0.575 (chi-squared test)
Supported by the Arnold pooled analysis: (OS HR 0.75 [0.67–0.84], p<0.001)2
Favors
anti-EGFR
0.25 1.0 3.0
OS HR (95% CI)
Favors
anti-VEGF
86%
of patients treated
with anti-EGFR
agents received
Cetuximab
Figure adapted from Holch JW, et al.
Eur J Cancer 2017;70:87–98.
*CT regimens were FOLFOX/FOLFIRI. †The CALGB/SWOG 80405 study did not meet its primary endpoint of significantly improving OS in the Cetuximab + CT arm vs bevacizumab + CT arm in patients with KRAS (exon 2) wt
mCRC.3 ‡FIRE-3 did not meet its primary endpoint of significantly improving ORR based on investigators’ read in patients with KRAS (exon 2) wt mCRC.4 Cetuximab is indicated for the treatment of patients with EGFR-expressing,
RAS wt mCRC in combination with irinotecan-based CT,
in 1st line in combination with FOLFOX and as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.5
1. Holch JW, et al. Eur J Cancer 2017;70:87–98; 2. Arnold D, et al. Ann Oncol 2017;28:1713–1729; 3. Venook A, et al. JAMA 2017;317:2392–2401; 4. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075; 5. Erbitux EU SmPC,
May 2019

30. *CT regimens were FOLFOX/FOLFIRI. †The CALGB/SWOG 80405 study did not meet its primary endpoint of significantly improving OS in the Cetuximab + CT arm vs bevacizumab + CT arm in
patients with KRAS (exon 2) wt mCRC.3 ‡Cetuximab is approved in patients with EGFR-expressing, RAS wt mCRC: in combination with irinotecan-based CT, or in 1st line in combination with
FOLFOX, or as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.4 §Treatment specified by trial protocol.
LS, left-sided; RS, right-sided.
1. Modest DP, et al. Oncotarget. 2017;8:105749–105760; 2. Venook AP, et al. Oral presentation at ESMO 2016; 3. Venook AP, et al. JAMA 2017;317:2392–2401;
4. Erbitux EU SmPC, May 2019.
Starting with Cetuximab + CT* can provide benefit over
bevacizumab + CT that extends beyond 1st line1,2†‡
39.3 mo2†
Cetuximab + CT‡ Bevacizumab + CT / other 3rd line
32.6 mo2†Cetuximab/panitumumab
+ CT/other‡
Bevacizumab + CT 3rd line
Median OS,
CALGB/SWOG
80405:
100%1 ~70%1 ~40%1
1st line 2nd line 3rd line
RAS wt
LS mCRC
RAS wt
LS mCRC
Bevacizumab + CTBevacizumab + CT 3rd line
All RAS
LS and RS
mCRC 23.9 mo2‡
Median OS,
ML18147:

31. 2. Are two anti-EGFR agents (Cetuximab and
Panitumumab) same?
• Yes
• No
No Head to Head trials between 2 anti-EGFR’s
in 1st line mCRC

32. EGFR
binding
NK cell
ADCC
Macrophage
& dendritic
cell activation
T cell
recruitment
Tumor cell
targeting
NK cell
ADCC
Macrophage
& dendritic
cell activation
T cell
recruitment
Tumor cell
targeting
Cetuximab is approved in patients with EGFR-expressing, RAS wt mCRC: in combination with irinotecan-based CT, or in 1st-line in combination with FOLFOX, or as a single agent in patients who
have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.1 *Based on in vitro data. †Based on in vitro studies, panitumumab did not appear to induce NK cell-
mediated ADCC above negative control.6,7
1. Erbitux EU SmPC, May 2019; 2. Vectibix EU SmPC, February 2018; 3. Monteverde M, et al. Crit Rev Oncol Hematol 2015;95:179–190; 4. Lo Nigro, et al. World J Gastrointest Oncol
2016;8:222–230; 5. García-Foncillas J, et al. Frontiers Oncol 2019;9:1–16; 6. Schneider-Merck T, et al. J Immunol 2010;184:512–520; 7. Trivedi S, et al. Clin Cancer Res 2016;22:5229–5237.
Only Cetuximab can trigger a ‘domino effect’ immune
cascade through NK cell-mediated ADCC, leading to changes
in the tumor microenvironment*†1–5
In vitro data indicate that panitumumab does not induce NK cell-mediated ADCC6,7
Panitumumab2,5Cetuximab1,5
Adapted from García-Foncillas J, et al. Frontiers Oncol 2019;9:1–16.
EGFR
binding

33. *Retrospectiveanalysesof Phase III trials.†FIRE-3 didnot meet its primaryendpoint of significantlyimprovingORR basedon investigators’read in patientswithKRAS (exon 2) wt mCRC.7 ‡CALGB/SWOG80405 did not meet its primaryendpointof significantlyimprovingOS in the cetuximab+ CT arm vs bevacizumab+ CT arm in patientswithKRAS (exon 2) wt mCRC.8 §Phase III RCTs in 1st-linevs CT ± bevacizumab available
via clinicaltrials.govas of August 2019. Cetuximabis approved in patientswith EGFR-expressing,RAS wt mCRC: in combinationwithirinotecan-basedCT, or in 1st line in combinationwithFOLFOX,or as a single agent in patientswho have failed oxaliplatin- and irinotecan-based therapyand who are intolerantto irinotecan.9 RCT, randomizedcontrolled trial.
1. Holch JW, et al. Eur J Cancer 2017;70:87–98; 2. StintzingS, et al. ASCO2018 (AbstractNo. 3508); 3. Qin S, et al. ASCO2018 (Abstract No. 3521); 4. Van Cutsem E, et al.
J Clin Oncol 2015;33:692–700; 5. Douillard J-Y,et al N Engl J Med 2013;369:1023–1034; 6. García-FoncillasJ, et al. Frontiers Oncol 2019;9:1–16; 7. HeinemannV, et al.
Lancet Oncol 2014;15:1065–1075; 8. Venook AP, et al, JAMA2017;317:2392–2401;9. ErbituxSmPC, May 2019.
Cetuximab is the only anti-EGFR therapy with multiple Phase III RCTs in 1st-line RAS
wt mCRC in combination with FOLFOX/FOLFIRI vs
CT ± bevacizumab1–5*†‡
Size of bricks approximately reflects RAS wt
sample size (including control and
comparator arms)
Patients with RAS wt mCRC
in panitumumab Phase III
randomized controlled trials in
1st line vs CT ± bevacizumab§
Patients with RAS wt mCRC
in cetuximab Phase III
randomized controlled trials
in 1st line vs CT ± bevacizumab§
Cetuximab + FOLFOX Cetuximab + FOLFIRI Panitumumab + FOLFOX
CRYSTAL*4
(n=367)
FIRE-32*†
(n=400)
CALGB/
SWOG
804051*†‡
(n=526)
TAILOR3
(n=393)
PRIME*5
(n=512)
“Cetuximab has been shown to pair well with either FOLFOX or FOLFIRI vs FOLFOX or
FOLFIRI alone, whereas all available phase 3 data for panitumumab efficacy in
first-line mCRC are in combination with FOLFOX”6

34. Cetuximab bi-weekly administration is non-inferior to
weekly administration patients with RAS wt mCRC*1
1. Lamy FX, et al. ASCO 2019 Abstract e15087 2. Kasper S, et al. ESMO 2019 (Abstract No. 584P)
*Recommended dosage for Cetuximab is every weekly

35. 3. Does choice of CT backbone (FOLFOX/FOLFIRI)
drive your choice of Anti-EGFR?
• 1. Stintzing S, et al. ASCO 2018 (Abstract No. 3508); 2. Venook AP, et al. ESMO 2016. Special session; 3. Qin S, et al. J Clin Oncol 2018;36:3031–3039.
• Yes
• No

36. CT backbone does not impact efficacy of Cetuximab in left-
sided RAS wt mCRC
• 1. Stintzing S, et al. ASCO 2018 (Abstract No. 3508); 2. Venook AP, et al. ESMO 2016. Special session; 3. Qin S, et al. J Clin Oncol 2018;36:3031–3039.
+ FOLFOX + FOLFIRI
TAILOR*3
vs CT alone
(n=393)
Cetuximab arm: 74% FOLFOX, 26% FOLFIRI13
CRYSTAL‡1
vs CT alone
(n=280)
FIRE-3§1
vs bevacizumab + CT
(n=307)
HR: 0.69;
95% CI: 0.54–0.89
p=0.004
% reduction
in risk of
death
HR: 0.77;
95% CI: 0.59–0.99
p=0.04
HR: 0.65;
95% CI: 0.50–0.86
p=0.002
HR: 0.70;
95% CI: not reported
p=0.004
CALGB/SWOG 80405†2
vs bevacizumab + CT
(n=325)
23%31% 35% 30%
*TAILOR met its primary endpoint of significantly improving PFS in the Cetuximab + FOLFOX4 arm vs FOLFOX4 alone in RAS wt mCRC;3 †CALGB/SWOG 80405 did not meet its primary endpoint of
significantly improving OS in the Cetuximab + CT arm vs bevacizumab + CT arm in patients with KRAS (exon 2) wt mCRC; ‡CRYSTAL met its primary endpoint of significantly improving PFS in the
Cetuximab arm vs FOLFIRI arm in KRAS wt mCRC; §FIRE-3 did not meet its primary endpoint of significantly improving ORR based on investigators’ read in patients with KRAS (exon 2) wt mCRC.
PFS, progression-free survival.

37. Cetuximab is the anti-EGFR agent with the strongest evidence
compared to bevacizumab + CT for patients with left-sided RAS
wt mCRC1–3*†‡
1. Stintzing S, et al. ASCO 2018 (Abstract No. 3508); 2. Venook AP, et al. Oral presentation at ESMO
2016; 3. Arnold D, et al. Ann Oncol 2017;28:1713–1729; 4. Heinemann V, et al. Lancet Oncol
2014;15:1065–1075.
*Retrospective subgroup analyses; †FIRE-3 did not meet its primary endpoint of significantly improving
ORR in patients with KRAS (exon 2) wt mCRC based on investigators’ read4; ‡CALGB/SWOG 80405 did not
meet its primary endpoint of significantly improving OS in the Cetuximab + FOLFOX/FOLFIRI vs
bevacizumab + FOLFOX/FOLFIRI arm in patients with KRAS (exon 2) wt mCRC.2
Panitumumab has not been evaluated
in a Phase III trial vs bevacizumab + CT
Difference in OS is
not significant
Cetuximab has data vs bevacizumab + CT from Phase III trials in
combination with both FOLFIRI and FOLFOX
Cetuximab +
FOLFIRI
(n=158)
Bevacizumab +
FOLFIRI
(n=149)
Phase III FIRE-31†
(retrospective analysis of patients with left-sided RAS wt mCRC)
40
30
20
10
0
MedianOS(months)
HR=0.70 (p=0.004)
+8.4 months
28.0
months
36.4
months
39.3
months
0
40
30
20
10MedianOS(months)
Cetuximab +
FOLFOX/FOLFIRI
(n=173)
Bevacizumab +
FOLFOX/FOLFIRI
(n=152)
Phase III CALGB/SWOG 804052‡
(retrospective analysis of patients with left-sided RAS wt mCRC)
HR=0.77 (p=0.04)
+6.7 months
32.6
months
39.3
months 0
40
30
20
10
MedianOS(months)
Pani + FOLFOX
(n=53)
Bevacizumab +
FOLFOX (n=54)
Phase II PEAK3
(retrospective analysis of patients with left-sided RAS wt mCRC)
32.0
months
43.4
months
HR=0.77 (p=0.31)
+11.4 months

38. *Cetuximab is indicated in RAS wt mCRC in combination with irinotecan-based CT, or in first-line in combination with FOLFOX.3 CI, confidence interval; mOS, median overall survival.
1. Samalin E, et al. WCGC 2019. (Abstract No. P-099); 2. Vectibix EU SmPC, February 2018; 3. Erbitux EU SmPC, May 2019.
Cetuximab with triplet CT:* providing an opportunity to
maximize ORR, conversion to resectability and OS in RAS
wt mCRC1
Retrospective analysis of three clinical trials and a patient database:
Cetuximab + FOLFIRINOX in patients with initially unresectable RAS wt mCRC
(n=70)*1
85.7%
95% CI:
75.3–92.9
months mOS
(95% CI: 36.2–56.4)
48.5
ORR
Figure created from data presented by Samalin E, et al. WCGC 2019 (Abstract No. P-099).
57.4% of the patients with initially
unresectable disease were able to
undergo surgery, and almost 80% of
these were able to benefit from a R0
resection1

39. • 1. Peeters M, et al. Br J Cancer 2018;119:303–312
In a recent pooled analysis of Phase II/III trials the median
OS achieved with panitumumab + FOLFOX appears to be
~33 months in patients with left-sided RAS wt mCRC1
Impact of primary tumor location and treatment on OS in RAS wt mCRC (retrospective, pooled analysis of PEAK and PRIME)1
0
0 68
100
Kaplan-Meierestimate
1684
20
40
60
80
Overall survival (months)
12 20 24 28 32 36 40 44 48 52 56 60 64
222
213
61
63
215
202
57
54
196
185
44
45
182
164
31
39
168
146
28
30
148
126
25
26
133
111
21
18
119
95
18
14
109
82
14
10
97
65
11
8
81
49
9
7
63
37
7
6
52
31
6
5
36
24
5
4
19
14
3
1
13
8
1
1
3
1
1
0
0
1
0
–
Left
Left
Right
Right
FOLFOX + panitumumab
FOLFOX (159)/FOLFOX + bev (54)
FOLFOX + panitumumab
FOLFOX (49)/FOLFOX + bev (14)
Left-sided RAS wt mCRC (pani + CT)
Right-sided RAS wt mCRC (pani + CT)
Left-sided RAS wt mCRC (CT alone)
Right-sided RAS wt mCRC (CT alone)
HR (95% CI)
0.71 (0.57–0.89)
0.90 (0.61–1.32)
~33 mOS

40. 40
Difference in affinity and distribution
1. Kim GP et al. Biologics. 2008;2(2):223–28
2. 2. Van Osdol W, et al. Cancer Res 1991;51:4776–84

41. Cetuximab and panitumumab have different adverse
event profiles1–3
• 1. Petrelli F, et al. Oncology 2018;94:191–199; 2. Erbitux SmPC Oct/2018; 3. Vectibix SmPC, Jan/2015.SAE, serious adverse event, OR, odds ratio.
Meta-analysis of randomized controlled Phase II/III studies in mCRC in any treatment line (± CT)
Grade 3-4 reactions, SAE and fatal SAE associated with anti-EGFR agents
OR=0.62;
p<0.001
Patients(%)
0
10
30
40
50
20
60
15.7
23.2
OR=1.24;
p=0.04
16.2
13.3
OR=0.34;
p<0.001
OR=7.1;
p<0.001
3
8.3
3
0.4
22.5
26.3
5.1
3.1
4.5
3.2
14.5
11.4
28.4
35.6
8.4
5.6
6.2
4.9
3
0.5
3.5
2.9 2.4
7.5
5.6
6.3
4.2 4
10
13.7
6.9
13.5
2.9
4.5
OR=0.82;
p=0.004
OR=1.65;
p=0.004
OR=1.42;
p=0.05
OR=1.3;
p=0.001
OR=0.62;
p=0.001
OR=1.6;
p=0.001
OR=1.28;
p=0.21
OR=5.95;
p=0.001
OR=1.2;
p=0.44
OR=1.12;
p=0.8
OR=0.88;
p=0.5
OR=1.05;
p=0.52
OR=0.7;
p=0.005
OR=0.47;
p=0.001
OR=0.64;
p=0.004
Preliminary discontinuation of
treatment may impact efficacy
Panitumumab-
based therapy
(n=2941)
Cetuximab-
based
therapy
(n=7438)
(OR=0.64;
p=0.004)
(OR=0.62;
p<0.001)
(OR=0.62;
p<0.001)
Cetuximab + CT has significantly lower rates of Grade 3/4
skin toxicity, SAEs, treatment discontinuations and fatal
SAEs than panitumumab + CT1
(OR=0.47;
p=0.001)
(OR=0.34;
p<0.001)

42. Anti-EGFR agents are not the same: Cetuximab and Panitumumab
are different1–12
1. Erbitux SmPC, June/2014; 2. Vectibix SmPC, February 2015; 3. Ferris RL. Cancer Treatment Reviews 2018;63:48–60; 4. Stintzing S, et al. Lancet Oncol 2016;17:1426–1434; 5. Van Cutsem E, et al. J Clin Oncol
2015;33:692–700; 6. Qin S, et al. J Clin Oncol 2018; epub Sep 10; 7. Douillard JY, et al. N Engl J Med 2013;369:1023–1034;
8. Tejpar S, et al. JAMA Oncol 2017;3:194–201; 9. Venook AP, et al. Oral presentation at ESMO 2016; 10. Boeckx N, et al. Ann Oncol 2017;28:1862–1868; 11. Petrelli F, et al. Oncology 2018;94:191–199; 12.
Merck data on file Oct 2018; 13. Schneider-Merck T, et al. J Immunol 2010;184:512–20; 14. Trivedi S, et al. Clin Cancer Res 2016;22:5229–37; 15. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075; 16.
Venook AP, et al. JAMA 2017;317:2392–2401.
AE, adverse event; LA, locally advanced; R/M, recurrent/metastatic; SCCHN. squamous cell carcinoma of the head and neck.
*Based on in vitro data; †Based on in vitro studies, panitumumab did not appear to induce NK cell-mediated ADCC above negative control13,14; ‡Retrospective subgroup analyses; §FIRE-3 did not meet its primary endpoint of significantly improving
ORR in patients with KRAS (exon 2) wt mCRC based on investigators’ read15; ¶CALGB/SWOG 80405 did not meet its primary endpoint of significantly improving OS in the Cetuximab + FOLFOX/FOLFIRI vs bevacizumab + FOLFOX/FOLFIRI arm in
patients with KRAS (exon 2) wt mCRC16;
**Based on a systematic review for randomized trials in PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, and EMBASE using the terms (“Cetuximab” or “panitumumab”) AND (“colorectal cancer” OR “colorectal
carcinoma”). A total of 38 studies were included for analysis.
Key differences between Cetuximab and panitumumab Cetuximab Panitumumab
MOA Activates innate and adaptive anti-tumor immunity1–3*† ✓ ✗
Indication Indicated for both RAS wt mCRC and LA or R/M SCCHN1,2 ✓ ✗
Weight of
evidence
Superior OS in combination with CT vs bevacizumab + CT in RAS wt
mCRC in a Phase III trial4‡§ ✓ ✗
Significant efficacy with both FOLFIRI and FOLFOX in RAS wt mCRC in
randomized Phase III trials vs CT alone5,6,7‡ ✓ ✗
Unprecedented OS benefit in combination with CT vs
bevacizumab + CT in left-sided RAS wt mCRC in Phase III trials8–10‡§¶ ✓ ✗
Safety
Significantly fewer grade 3/4 skin reactions, SAEs and fatal AEs
compared with the other approved anti-EGFR antibody11**
✓ ✗
Wealth of
experience
>563,000 patients with mCRC treated to date12 ✓ ✗
✓

43. Treatment selection- 1L
• Therefore, considering the biological characteristics and the primary
site of the tumor in March 2017  1st-line Cetuximab + FOLFIRI
with 400mg/m2 followed by 250mg/m2 weekly started
• Prophylactic management of skin reactions was also initiated with 1%
hydrocortisone cream, oral doxycycline 100 mg daily and moisturizer
1st line 2nd line 3rd line

44. Response assessment
• First response assessment at (May 2017) shows early tumor shrinkage
(46%)
1st line 2nd line 3rd line
PR achieved

45. Follow-up
• Grade 1 acneiform rash observed over the torso from the second week
of treatment
• Patient reported no impact on QoL/daily activities
• Prophylactic management with oral doxycycline 100 mg daily,
hydrocortisone 1% cream and moisturizer switched to fluocinonide
0.05% cream twice daily for reactive management of rash
• Cetuximab monotherapy continued for 4 months

46. How long do you continue cetuximab treatment in
your patients?

47. • Patient underwent a left
hepatectomy and two
metastasectomy in the right
liver in Nov 2017, surgery
was well tolerated and liver
function remained stable
Management of liver metastases
MRI and CT scan after liver metastases resection
• Post-operative assessments showed a CEA at 3 ng/ml and no evidence of disease
on Computed Tomography of Thorax, Abdomen and Pelvis scans.

48. • Adjuvant treatment with 5FU(with folinic acid 400 mg/m2, followed by
fluorouracil 400 mg/m2 IV bolus, then fluorouracil 2400 mg/m2 IV infusion) was
started 4 weeks after surgery for 3 months
• Treatment was stopped in Mar 2018
Follow-up

49. Follow-up
• Progression documented in DEC 2018
• CA 19.9=76.06 U/m; CEA=40.34 ng/mL
• CT scan: multiple lung metastases
1st line 2nd line 3rd line

50. What should be 2nd line treatment in this patient?
• Bevacizumab+CT
• Cetuximab+CT
• Panitumumab+CT
• Regorafenib
• CT alone
• Immunotherapy
1st line 2nd line 3rd line

51. VEGF Inhibition in second or later line Therapy RAS MT
plus RAS WT disease
Second-line VEGF
TML 18147 E3200 VELOUR RAISE
BEV in 1st line All pts No pts Yes / No All pts
2nd line
Chemotherapy
FOLFIRI or FOLFOX FOLFOX FOLFIRI FOLFIRI
VEGF inhibitor Bevacizumab Bevacizumab Aflibercept Ramucirumab
OS
11.2 v 9.8 mo
HR 0.81
P = .0062
12.9 v 10.8 mo
HR 0.75
P = .0011
13.5 v 12.1 mo
HR 0.82
P = .003
11.7 vs. 13.3 mo
HR 0.84
P = .022
Bennouna J, et al. Lancet Oncol. 2013;14(1):29-37. Giantonio BJ, et al. J Clin Oncol. 2007;25(12):1539-1544. Van Cutsem E, et al. J Clin Oncol.
2012;30(28):3499-3506. Grothey A, et al. Lancet. 2013;381:303-312.

52. Superior 2nd-line survival outcomes for patients with RAS wt mCRC initially treated with
Cetuximab + CT (arm A) vs bevacizumab + CT (arm B) during FIRE-3*1
OS, overall survival;
*FIRE-3 did not meet its primary endpoint of significantly improving ORR in patients with KRAS (exon 2) wt mCRC based on
investigators’ read.2 Kaplan-Meier estimates for RAS wt populations according to FIRE-3 study arm including all patients receiving 2nd
line therapy.
OS-2
0.2
0
Overallsurvivalfromstart
of2ndlinetherapy
120 24 36 60
Time (months)
0.6
0.8
1.0
48
17.6 (15.0–21.7)
14.8 (10.3–16.8)
A
B
88/138
106/137
63.8
77.4
Months (95% CI) n %Arm
Events
Log-rank p=0.0021
HR=0.64 (0.48–0.85)
0.4
PFS-2
0.4
0.2
0
Progression-freesurvivalfrom
startof2ndlinetherapy
60 12 18 30
Time (months)
0.6
0.8
1.0
24
6.7 (5.8–7.4)
4.8 (4.2–5.8)
A
B
105/138
110/137
76.1
80.3
Months (95% CI) n %Arm
Events
Log-rank p=0.003
HR=0.67 (0.51–0.87)
1st -line use of anti-EGFRs may improve efficacy of 2nd
-line therapy
1. Modest D, et al. JCO 2015;33:3718–3726;
2. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075.

53. • FOLFOX (Oxaliplatin 85 mg/m2 IV, with folinic acid 400 mg/m2, followed by fluorouracil 400
mg/m2 IV bolus, then fluorouracil 2400 mg/m2 IV infusion, (over 46 hours)
• Bevacizumab, 5 mg/kg bi-weekly
• After 4 cycles, his CEA decreased to 40 ng/mL.
• Patient remained asymptomatic, and target lesions were stable
• Oxaliplatin was discontinued after 6 cycles of treatment, due to grade 2 neuropathy that
subsequently resolved
• Bevacizumab with 5FU were continued
A second line treatment with FOLFOX + Bevacizumab
was decided

54. Jun 2019
• Patient consulted for fatigue, dyspnea, and worsening performance status,
and the CEA increase to 90 ng/mL.
• CT scan revealed progressive disease, with increase in number and size of
metastatic liver and pulmonary lesions
Follow up

55. What should be 3rd line treatment in this case?
• Bevacizumab+CT
• Cetuximab+CT
• Panitumumab+CT
• Regorafenib
• CT alone
• Immunotherapy
1st line 2nd line 3rd line

56. Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Ann Oncol, July 2016
ESMO consensus guideline:
Third-line choice
Systemic therapy choices according to the Zurich treatment algorithm for patients with unresectable metastatic disease
(excluding those with oligometastatic disease)
Category Fit patients
Treatment goal Cytoreduction (tumor shrinkage) Disease control (control of progression)
Molecular profile RAS wt RAS mt BRAF mt RAS wt RAS mt BRAF mt
Third line
Preferred choice
(s)
CT doublet +
EGFR antibody
Or
Irinotecan +
Cetuximab
Regorafenib or
Trifluridine/
tipiracil
Regorafenib or
Trifluridine/
tipiracil
CT doublet +
EGFR antibody
Or
Irinotecan +
Cetuximab
Regorafenib or
Trifluridine/
tipiracil
Regorafenib or
Trifluridine/
tipiracil
Second choice EGFR antibody
monotherapy
EGFR antibody
monotherapy
Third choice Regorafenib or
Trifluridine/
tipiracil
Regorafenib or
Trifluridine/
tipiracil

57. *Cetuximab is indicated for use in RAS wt mCRC; Cetuximab is not indicated for the treatment of patients with mCRC whose tumors have RAS mutations or for whom RAS
tumor status is unknown.2
•
1. Santini D, et al. Ann Oncol 2012;23:2313–2318;
2. Erbitux SmPC June/2014.
Biological rationale for rechallenge in subsequent
lines: Regrowth of sensitive clones (Santini
hypothesis)1
Cetuximab-resistant cloneCetuximab-sensitive clone
Cetuximab +
FOLFIRI PD
PD Cetuximab +
irinotecan
rechallenge*
Baseline
Response
Response Response
≥3rd-line2nd-line1st-line
Without
Cetuximab

58. Clinical evidence supports Cetuximab rechallenge
• 1. Rossini D, et al. ASCO 2018; 2. Grothey A, et al. Lancet 2013;381:303–312; 3. Mayer RJ, et al. N Engl J Med 2015;372:1909–1919; 4.
Van Cutsem E, et al. Ann Oncol 2016;27:1386–1422; 5. Erbitux SmPC, June/2014.
BSC, best supportive care; ESMO, European Society for Medical Oncology
mOS, median overall survival; mPFS, median progression-free survival; ORR, overall response rate.
ESMO guidelines support the concept of rechallenge with a therapy used previously
in 1st-line treatment4
Phase III CORRECT
(RAS/BRAF-unselected)2
Phase III RECOURSE
(RAS/BRAF-unselected)3
Regorafenib
(n=505)
BSC
(n=255)
TAS-102
(n=534)
BSC
(n=266)
ORR, % 1.0 0.4 1.6 0.4
mPFS, months 1.9 1.7 2.0 1.7
mOS, months 6.4 5.0 7.1 5.3
Phase II CRICKET
(RAS/BRAF wt)1
Cetuximab +
irinotecan (n=28)
ORR, % 21.4
mPFS, months 3.4
mOS, months 9.8

59. • The ongoing randomized Phase III FIRE-4 trial will provide further evidence regarding Cetuximab rechallenge
• The primary endpoint is OS after the second randomization (i.e. after start of 3rd-line therapy)
• Liquid biopsy is being used to longitudinally assess RAS status across the treatment continuum
Ongoing studies are investigating Cetuximab rechallenge
in patients WITH RAS wt mCRC
• 1. https://clinicaltrials.gov/ct2/show/NCT02934529.
• FP, fluoropyrimidine; OS, overall survival.
Bevacizumab +
FOLFOX
Cetuximab +
irinotecan/FOLFIRI
Cetuximab + FOLFIRI
Bevacizumab +
FP maintenance
Cetuximab + FOLFIRI
(8–12 cycles)
RAS wt
mCRC
(n=550)
Physician’s choice
FIRE-4: Phase III, randomized controlled trial1
Liquid biopsy:
R R
1st line 2nd line 3rd line
Estimated primary
completion date:
2020

60. • After 4 cycles, disease was stabilized, with a decrease of less than 30% in liver
metastases
• His performance status was 1
• Treatment with FOLFIRI + Cetuximab was continued up to Jan 2020 (6
months)
Patient is alive and doing well after 3 years of
treatment
A Re-challenge strategy with FOLFIRI + Cetuximab was
opted again

61. Summary
• March 2017: FEMALE patient with left-sided RAS/BRAF wt mCRC
• Initiated on 1st-line Cetuximab + FOLFOX
• PR (-46%) observed from first assessment at Month 2
• Nov 2017: Underwent a left hepatectomy and two metastasectomy in the right liver
• Dec 2018: Progression documented. Initiated on 2nd-line FOLFIRI + bevacizumab
• Jun 2019: Progression documented. Rechallenged with Cetuximab+FOLFIRI in 3rd-line
• Patient alive after 3 years

62. Thank You!