Ponencia en el CLOC19, Bogotá, 02.02.2019

1. 1
Alternativas al cáncer colo-rectal
metastático
Mauricio Lema Medina
Clínica de oncología Astorga, Clínica SOMA, Medellín02.02.2019

2. 2
Conflicts of interest for this talk
Mauricio Lema Medina
@Onconerd

3. Surgery

4. Adam R, Oncologist, 2012
Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus
guidelines for the management of patients with metastatic
colorectal cancer. Ann Oncol. 2016;27(8):1386-1422.
doi:10.1093/annonc/mdw235.

5. A UNICANCER phase III trial of Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) for Colorectal Peritoneal Carcinomatosis.<br /><br />Prodige 7 - ACCORD 15 trial. NCT00769405, N° EudraCT : 2006-
006175-20
Presented By Elin Sigurdson at 2019 Gastrointestinal Cancer Symposium

6. Unicancer Prodige 7 trial design
Presented By Elin Sigurdson at 2019 Gastrointestinal Cancer Symposium

7. HIPEC Arm (open or closed technique)
Presented By Elin Sigurdson at 2019 Gastrointestinal Cancer Symposium

8. Overall survival (ITT)
Presented By Elin Sigurdson at 2019 Gastrointestinal Cancer Symposium

9. Relapse-free survival (ITT)
Presented By Elin Sigurdson at 2019 Gastrointestinal Cancer Symposium

10. Conclusions
Presented By Elin Sigurdson at 2019 Gastrointestinal Cancer Symposium

11. 0
17.5
35
52.5
70
OS
42 41
PRODIGE7/ACCORD15 (2019),
ProcASCO-GI
Peritonectomy + HIPEC vs
Peritonectomy
-

12. Chemotherapy

13. FULV
Capec
Iri
Bev Targeted
Surgery
Ablative
Rx
Ox
Other
anti VEGF
Anti-PD1
Cet
Pan

14. 0
17.5
35
52.5
70
OS PFS ORR G3/4Tox
14
4
22
5
FU Douillard (2000), Lancet1L

15. 0
17.5
35
52.5
70
OS PFS ORR G3/4Tox
16
9
50
18
DeGramont (2000), JCOFOLFOX 1L

16. 0
17.5
35
52.5
70
OS PFS ORR
21
9
54
Tournigard (2003), JCOFOLFIRI-FOLFOX 1L-2L

17. 0
17.5
35
52.5
70
OS PFS ORR
21
8
50
Tournigard (2003), JCOFOLFOX-FOLFIRI 1L-2L

18. Falcone A Ricci S Brunetti I Pfanner E Allegrini G et. al. Journal of Clinical Oncology. 2007 vol: 25 (13) pp: 1670-1676
Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared
with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for
metastaticcolorectal cancer: the Gruppo Oncologico Nord Ovest.
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI
FOLFIRI
60*
22.0*
9.8*
6.9*
16.7*
34*
R0 resection (%)
n=244
* Statistically significant
6*15*

19. 0
17.5
35
52.5
70
OS PFS ORR R0 resection
22
10
60
1517
7
34
6
Falcone (2007), JCOFOLFOXIRI vs
FOLFIRI
1L

20. Souglakos J Androulakis N Syrigos K Polyzos A Ziras N et. al. British Journal of Cancer. 2006 vol: 94 (6) pp: 798-805
FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil
and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised
phase III trial from the Hellenic Oncology Research Group (HORG).
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI
FOLFIRI
43.0
21.5
8.4
6.9
19.5
33.6
n=283
* Statistically significant

21. Falcone A Ricci S Brunetti I Pfanner E Allegrini G et. al. Journal of Clinical Oncology. 2007 vol: 25 (13) pp: 1670-1676
Souglakos J Androulakis N Syrigos K Polyzos A Ziras N et. al. British Journal of Cancer. 2006 vol: 94 (6) pp: 798-805
FOLFOXIRI vs FOLFIRI.
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI
FOLFIRI
43.0
21.5
8.4
6.9
19.5
33.6
n=283
* Statistically significant
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI
FOLFIRI
60*
22.0*
9.8*
6.9*
16.7*
34*
R0 resection (%)
6*15*
n=244
* Statistically significant

22. 0
17.5
35
52.5
70
OS PFS ORR R0 resection
22
10
60
15
Falcone (2007), JCOFOLFOXIRI 1L

23. Access to Chemotherapy Improves
Survival
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
22
20
18
16
14
12
MedianOS(Mos)
0 20 40 60 80
Patients With 3 Drugs (%)
LV5FU2
Bolus 5-FU/LV
Infusional 5-FU/LV
+ irinotecan
Infusional 5-FU/LV
+ oxaliplatin
Bolus 5-FU/LV
+ irinotecan
Irinotecan
+ oxaliplatin
First-line therapy

24. Bevacizumab +
Chemotherapy

25. 0
17.5
35
52.5
70
OS PFS ORR G3/4Tox
31
12
64
10
30
11
62
22
Yamazaki (2016), Annals OncolBev+FOLFIRI vs
Bev+FOLFOX
1L

26. 0
17.5
35
52.5
70
OS PFS ORR Diarrhea
25
12
56
16
24
10
53
22
Schmiegel (2013), Annals OncolBev+CapOX vs
Bev+CapIRI
1L

27. Bevacizumab 7.5 mg/kg with
CapOx: Oxaliplatin 130 mg/m(2)/day 1 plus
capecitabine 1000 mg/m(2) bid/days 1-14
CapIri: Irinotecan 200 mg/m(2)/day 1 plus capecitabine
800 mg/m(2) bid/days 1-14 both every 21 days
Schmiegel (2013), Annals Oncol

28. 0
17.5
35
52.5
70
OS PFS ORR Neutropenia
29
12
65
20
26
10
53
50
TRIBE (2015), Lancet OncolBev+FOLFOXIRI vs
Bev+FOLFIRI
1L

29. 0
17.5
35
52.5
70
OS PFS ORR Neutropenia
29
12
65
50
TRIBE (2015), Lancet OncolBev+FOLFOXIRI 1L

30. Elderly

31. Phase 3 trial,
Patients aged 70 years and older with
previously untreated, unresectable,
metastatic colorectal cancer, who
were not deemed to be candidates
for oxaliplatin-based or irinotecan-
based chemotherapy regimens, were
randomly assigned in a 1:1 to
capecitabine alone or with
bevacizumab
Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly
patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial.
Lancet Oncol. 2013;14(11):1077-1085. doi:10.1016/S1470-2045(13)70154-2.
Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated
metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial.
OS (mo)
PFS (mo) – Primary endpoint
ORR (%)
Capecitabine - Bevacizumab
Capecitabine
19*
20.7
5.1*
16.8
10*
Grade ¾ toxicity (%)
22*40*
n=280
* Statistically significant
9.1*

32. 0
17.5
35
52.5
70
OS PFS ORR G3/4Toxi
20
9
19
40
17
5
10
22
AVEX (2013), Lancet OncolBev+Capecitabine
vs Capecitabine
1L

33. 0
17.5
35
52.5
70
OS PFS ORR G3/4Toxi
20
9
19
40
AVEX (2013), Lancet OncolBev+Capecitabine 1L

34. Anti EGFR
RAS wild-type

35. 0
17.5
35
52.5
70
OS PFS ORR
24
10
57
20
8
39
CRYSTAL (2011), JCOCet+FOLFIRI vs
FOLFIRI
1L

36. 0
17.5
35
52.5
70
OS PFS ORR
24
10
57
CRYSTAL (2011), JCOCet+FOLFIRI 1L

37. 0
17.5
35
52.5
70
OS PFS ORR G3/4 Tox
24
10
57
10
20
9
48
8
PRIME (2014), Annals OncolPanit+FOLFOX vs
FOLFOX
1L

38. Anti EGFR vs
Bevacizumab
RAS wild-type

39. PEAK: A Randomized, Multicenter Phase II Study of Panitumumab Plus Modified Fluorouracil,
Leucovorin, and Oxaliplatin (mFOLFOX6) or Bevacizumab Plus mFOLFOX6 in Patients With Previously
Untreated, Unresectable, Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer
OS (mo)
ORR (%)
Serious Adverse Event
(%)
n=285
* Statistically significant
PFS (mo) – Primary endpoint
3020103366100
33
66
100
12
8
4
Schwartzberg LS, J Clin Oncol. 2014 Jul 20;32(21):2240-7
FOLFOX – Panitumumab
FOLFOX – Bevacizumab
34.2*
10.9
44
57.8
24.3*
10.1
38
53.5

40. 0
17.5
35
52.5
70
OS PFS ORR G3/4 Tox
34
11
58
44
24
10
54
38
PEAK (2014), JCOPanit+FOLFOX vs
Bev+FOLFOX
1L

41. 0
17.5
35
52.5
70
OS PFS ORR G3/4 Tox
34
11
58
44
PEAK (2014), JCOPanit+FOLFOX 1L

42. Stintzing S, Modest DP, Rossius L, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer
(FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial.
Lancet Oncol. 2016;17(10):1426-1434. doi:10.1016/S1470-2045(16)30269-8.
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of
tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial.
OS (mo)
Secondary Endpoint
Depth of response (-%)
ORR (%) – Primary Endpoint
FOLFIRI - Cetuximab
FOLFIRI - Bevacizumab
72
33*
-32*
56
n=400
* Statistically significant
-48*
wtKRAS
25*

43. Phase III 80405 Trial: First-line CT +
Either Cetux or Bev in KRAS-WT mCRC
▪ Primary endpoint: OS
▪ Secondary endpoints: ORR, PFS, TTF, duration of response
Patients with
mCRC
and KRAS WT
(codons 12, 13),
ECOG PS 0/1
(N = 1137)
FOLFOX or FOLFIRI +
Bevacizumab q2w
(n = 559)
ClinicalTrials.gov. NCT00265850. Venook AP, et al. ASCO 2014. LBA3..
FOLFOX or FOLFIRI +
Cetuximab q1w
(N = 578)
A third arm with CT + bevacizumab +
cetuximab was closed to accrual in
September 2009

44. CALGB/SWOG 80405: OS in the ITT
Population
mOS (95% CI), mos
CT + Cetux 29.9 (27.0-32.9)
CT + Bev 29.0 (25.7-31.2)
HR 0.925 (0.78-
1.09)
P = 0.34
Venook AP, et al. ASCO 2014. Abstract LBA3.
0
12 24 36 48 60 72
Mos
80
10
0
60
40
0
OS(%)
20
84

45. Venook AP, et al. ASCO 2014, Abstract LBA3.
Phase III 80405 Trial: First-Line CT + Either Cetuximab or Bevacizumab
in KRAS-WT mCRC
OS (mo)
PFS (mo)
CT – Cetuximab (n=559)
CT – Bevacizumab (n=578)
29.9
10.8
29.0
* Statistically significant
wtKRAS
10.4

46. 0
17.5
35
52.5
70
OS PFS
30
10
29
11
CALGB 80405 (2014), ProcASCOCetuxi+Chemo vs
Bev+Chemo
1L

47. Right or Left?
Carlos Alberto Ortiz

48. Right-sided
tumors do not
appear to
respond well to
anti-EGFR +
Chemo
Most of the benefit
of anti EGFR +
Chemo is in Left-
sided tumorsrs
Bev + Chemo,
the option
wtKRAS

50. MSI

51. Key Features of the Consensus Molecular Subtypes (CMS)
Presented By Scott Kopetz at 2019 Gastrointestinal Cancer Symposium

52. Sporadic dMMR
BRAF mutation (75%)
dMMR
Lynch syndrome
No BRAF mutation
15-20% mCRC
¾ dMMR ¼ dMMR
Sepulveda AR, Hamilton SR, Allegra CJ, et al. EARLY ONLINE RELEASE. Arch Pathol Lab Med.:2016-2554.
MLH1, MSH2, MSH6, PMS2
CpG Methyl-MLH1

53. Slide 11
Presented By Flavio Rocha at 2019 Gastrointestinal Cancer Symposium

54. PD-1/PD-L1 blockade in Advanced Colon Cancer
Presented By Flavio Rocha at 2019 Gastrointestinal Cancer Symposium

55. Slide 13
Presented By Flavio Rocha at 2019 Gastrointestinal Cancer Symposium

56. 0
25
50
75
100
1-yr OS 1-yr PFS ORR G3/4Toxi
87
71
55
32
CM 142 (2018), JCONivolumab + Ipilimumab in
MSI-mCRC
>2L

57. IO for MSS

58. Study Design
Presented By Michael Overman at 2019 Gastrointestinal Cancer Symposium

59. Efficacy Results
Presented By Michael Overman at 2019 Gastrointestinal Cancer Symposium

60. BRAF, Her2+, Fusions
mCRC

61. BRAF Mutations
Presented By Scott Kopetz at 2019 Gastrointestinal Cancer Symposium

62. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of
patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3
TRIBE study. Lancet Oncol. 2015;16(13):1306-1315. doi:10.1016/S1470-2045(15)00122-9.
FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with
metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label,
phase 3 TRIBE study

63. BRAF V600E: Impact on Treatment Options
Presented By Scott Kopetz at 2019 Gastrointestinal Cancer Symposium

64. Slide 7
Presented By Scott Kopetz at 2019 Gastrointestinal Cancer Symposium

65. HER2 Amplifications: Potential predictive information
Presented By Scott Kopetz at 2019 Gastrointestinal Cancer Symposium

66. Fusions
Presented By Scott Kopetz at 2019 Gastrointestinal Cancer Symposium

67. Larotrectinib FDA Approved for NTRK Fusions, Including in CRC
Presented By Scott Kopetz at 2019 Gastrointestinal Cancer Symposium

68. A word on sequence…

69. Adam R, Oncologist, 2012
Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus
guidelines for the management of patients with metastatic
colorectal cancer. Ann Oncol. 2016;27(8):1386-1422.
doi:10.1093/annonc/mdw235.

70. Incurable
mCRC
fit for chemotherapy
Extended RAS
BRAF status
MSI status
BRAF mutated
FOLFOXIRI+Bev
(TRIBE)
Vemurafenib + Irinotecan
+ Cetuximab
(SWOG S1406)
KRAS mutated
FOLFOX/FOLFIRI+Bev
FOLFIRI/FOLFOX+Bev
(TML)
Regorafenib
(Correct / ReDOS)
TAS-102?
TAS-102?

71. Incurable
mCRC
fit for chemotherapyElderly or
marginally fit
Bevacizumab +
Capecitabine (or FU)
(AVEX, Kabbinavar)

72. Incurable
mCRC
fit for chemotherapy
Extended RAS
BRAF status
MSI status
MSI high
FOLFOX/FOLFIRI+Bev
Anti PD1 +/- anti
CTLA4

73. FOLFOX/FOLFIRI+Bev
FOLFIRI/FOLFOX+Bev
(TML)
Regorafenib
(Correct / ReDOS)
Right-Sided Left-Sided
Cetuximab +/- Iri
OS imperativeQoL imperative
FOLFOX/FOLFIRI+A
nti EGFR
FOLFIRI/FOLFOX
+Bev
TAS-102?
RAS wt