mCRC – Treatment options of unresectable dis

ease

DR RAJAT BAJAJ
 Metastatic Colon Cancer

• Resectable Metastatic disease

• Potentially Resectable Metastatic disease

• Unresectable Disease
 Resectable Metastatic disease

• Comprises patients with R0 resectable Liver/L

ung metastasis.

Upfront
Resection

Neoadjuvant CT
Resectable
f/b Resection Adjuvant CT
Metastasis

Colectomy f/b
CT f/b
Metastasis
resection
Potentially Resectable Metastatic
disease
Liver disease which is initially unresectable or R
0 resection not feasible

Preoperative Chemotherapy
(to downsize the tumor for resection)

R0 Resection
• Goal of preoperative CT:
– Maximum tumor shrinkage
– Eradication of micrometastases

• Advantages of preoperative CT:

– Earlier Rx of micrometastasis
– Determination of responsiveness to CT

• Dis-advantages of preoperative CT:

– Progression of disease
– Achievement of complete response
 Recommended preoperative CT

• Most active agents should be used.

Cytotoxic Doublet/Triplet
(FOLFOX/FOLFIRI/FOLFOXIRI)
±
Targeted agents
(Bev/Cetuximab/Panitumumab)
 Unresectable Metastatic Disease

• Goal of Treatment
– Palliation or Control of symptoms
– Control of tumor growth
– To prolong PFS & OS
– To maintain QOL
 Active agents

Cytotoxic Agents Targeted Agents

• 5-FU • Anti angiogenesis:
• Capecitabine – Bevacizumab (VEGF mAb)
• Irinotecan – Ziv-Aflibercept (Decoy receptor,
Recombinant fusion protein)
• Oxaliplatin
• Anti EGFR mAb:
– Cetuximab (Chimeric) – IgG1
– Panitumumab (Human) – IgG2
Regorafenib (multi TKI)
Advances in the Treatment of Stage IV CRC

1980 1985 1990 1995 2000 2005

Best supportive care (BSC)

5-FU
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
30 Bevacizumab
Panitumumab
O S (m o n th s )

25

20

15

10

5 median overall survival

0
1980 1985 1990 1995 2000 2005
 Efficacy of Various Regimens

Regimen RR (%) OS (mo)

5-FU Bolus 12 11

5-FU/LV bolus 23 11.5

5-FU/LV biweekly Infusion 37 14.3

IFL 39 14.8

FOLFOX 54 15 to 20.6

FOLFIRI 56 15.6 to 21.5

FOLFOXIRI 60 16.2 to 22.6

 Regimen recommended

1st Line Regimens

• FOLFOX
• FOLFIRI
• CapeOx ± Bevacizumab / ziv-
• Infusional 5-FU/LV aflibercept / Cetuximab/
• Capecitabine Panitumumab
• FOLFOXIRI
 Regimen recommended

2nd Line Regimens

• FOLFOX
± Bevacizumab / ziv-
• FOLFIRI aflibercept / Cetuximab/
• Irinotecan Panitumumab
SINGLE AGENT THERAPY IN mCRC – ERA BEF
ORE FOLFOX

13
1

2
 Infusional 5FU/LV was better than conven
tional 5FU
• Short-term infusional FU/LV – Response rates with
FU/LV have been further improved by the use of shor
t-term infusional schedules of FU.
• A trial of 448 patients who were randomly assigned to
a monthly regimen of LV (20 mg/m2) plus bolus FU (4
25 mg/m2) on days one to five every four weeks - V
S - a bimonthly regimen (the de Gramont regimen) o
f LV (200 mg/m2 over two hours) followed by bolus F
U (400 mg/m2) and a 22-hour infusion of FU (600 mg/
m2); both drugs are given daily for two consecutive d
ays every two weeks.

15
• The infusional regimen was associated with a
significantly better response rate (33 versus 1
4 percent) and median progression-free survi
val (28 versus 22 weeks), and a trend toward
longer median survival (62 versus 57 weeks,
p = 0.067).

16
Name of
Author (Ref.) Schedule (All Agents Administered Intravenously)
Regimen

LV 20 mg/m2 bolus, followed by 5-FU 425 mg/m2/d as

Mayo’s clinic Poon et al., 1989
bolus, D1-5 x Q 4 weekly for 5 courses

Protracted Lokich et al.,

5-FU 300 mg/m2/d by continuous infusion.
venous infusion 1989

Low-dose weekly LV 20 mg/m2 over 5–15 min, followed by bolus 5-FU 500 mg/
Jager et al., 1996
LV m2; weekly for 6 consecutive wk, repeated every 8 wk.

LV 200 mg/m2 over 2 hr days 1 and 2, followed by bolus 5-

de Gramont et
LV5FU2 FU 400 mg/m2/day 1 and 2, followed by 5-FU 600
al., 1997
mg/m2 over 22 hr days 1 and 2; cycle repeated every 14 d.

AIO (weekly 24- Kohne et al., LV 500 mg/m2 over 2 hr, followed by 5-FU 2,600 mg/m2 over
hr infusion) 1998 24 hr, repeated weekly.

LV 500 mg/m2 over 2 hr  5-FU 500 mg/m2 by bolus 1 hr.

Haller et al.,
Roswell Park Treatments given weekly for 6 consecutive wk, repeated
1998
every 8 wk.

LV 400 mg/m2 over 2 hr, followed by bolus 5-FU 400 mg/m2,

Simplified Andre et al.,
followed by 5-FU 1,200 mg/m2/d times 2 d (2,400
LV5FU2 1999
mg/m2 over 46–48 hr); cycles repeated every 14 d.
CAPECITABINE in Metastatic CRC

18
Some data of other drugs in metastatic C
RC

19
Search of other active agents…….

20
 Search of other active agents…….

• Key developments in the early 2000s include

d the introduction of the topoisomerase I inhib
itor irinotecan and the platinum-containing ag
ent oxaliplatin as components of cytotoxic co
mbination therapy for mCRC.

21
 • Saltz et al found that treatment with bolus 5-F
U/leucovorin and irinotecan (IFL) resulted in s
ignificantly longer PFS (7.0 vs. 4.3 months; P
= .004), greater RR (39% vs. 21%; P < .001),
and longer OS (14.8 vs. 12.6 months;P = .04)
than 5-FU/leucovorin alone as first-line therap
y for patients with mCRC

Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan
Study Group. NEJM 2000 Sep 28;343(13):905-14
Saltz LB1, Cox JV, Blanke C, Rosen LS, Fehrenbacher L,

22
23
Entry trial of FOLFOX

24
25
26
• The FOLFOX regimen was also associated wi
th significantly lower rates of severe nausea,
vomiting, diarrhea, and febrile neutropenia th
an was the IFL regimen (all P < .001).
• The unfavorable toxicity profile of the IFL regi
men led to the development of a regimen com
prised of infusional IFL (FOLFIRI).

27
Evolution of various FOLFOX regimen
 From FU/LV to FOLFOX and FOLFIRI
Oxaliplatin 400 400 Irinotecan

FOLFOX4 600 600 “Douillard”

x LV5FU2 q2wks
85 180
400
FOLFOX6 2400 FOLFIRI
100 (m85) x sLV5FU2 q2wks 180
400
FOLFOX7 2400
130 (m85/100) x vsLV5FU2 q2wks

FUFOX 2000
2600
x FUFIRI
50 AIO weekly 80
 FOLFOX4 Maintains Efficacy/ Safety R
atio in Elderly Patients
• Retrospective analysis of pts. receiving FOLFOX4

• 3,742 patients; 614 aged >70 years

• Grade 3/4 AEs (TCP/Neutropenia) more frequent in older pa

tients

• No difference in 60-day mortality

• No difference in FOLFOX4 efficacy

Goldberg RM, et al. 2006 ASCO GI. Abstract 228.

Is FOLFOX and FOLFIRI equal?

33
 FOLFIRI Equivalent to FOLFOX4

• Phase III randomized trial compared FOLFIRI to F

OLFOX4 in first-line advanced CRC
• Survival, response rates similar between groups
• Toxicity mild but differed by treatment
– FOLFOX
• Thrombocytopenia
• Neurosensory toxicities
– FOLFIRI
• Alopecia
• GI disturbances

Colucci G, et al. J Clin Oncol. 2005;23:4866-4875 (GOIM Study).

 Phase III GERCOR Study: FOLFOX6/FO
LFIRI Sequence

R
Folinic acid, FU, Folinic acid, FU,
A irinotecan oxaliplatin
N=220 N (FOLFIRI) (FOLFOX6)
•Previousl (n=109) (n=81)
y
D
untreate O
d mCRC M
I Folinic acid, FU, Folinic acid, FU,
oxaliplatin irinotecan
Z (FOLFOX6) (FOLFIRI)
E (n=111) (n=69)

Tournigand C, et al. J Clin Oncol. 2004;22:229-237.

 FOLFOXIRI vs FOLFIRI

R FOLFIRI
Irinotecan (180 mg/m2 d1)
A I-LV (100 mg/m2 d1,2);
N=244
N bolus 5FU (400 mg/m2 d1,2);
Previousl 5FU (600 mg/m2 22 h inf on d1,2)

y
D (n=122)
untreated O Repeat q2 wk until progression

mCRC M FOLFOXIRI
I Irinotecan (165 mg/m2 d1)
Oxaliplatin (85 mg/m2 d1)
Z I-LV (200 mg/m2 d1);
E 5FU (3200 mg/m2 48 h inf starting on d1)
(n=122)

Falcone A, et al. ASCO GI 2006. Abstract 227.

 FOLFOXIRI More Effective Than
FOLFIRI
• ORR significantly higher with FOLFOXIRI
– 66% vs 41% with FOLFIRI (P=0.0002)

• At median FU of 14.0 months, PFS longer with FO

LFOXIRI
– Median PFS, 9.8 vs 6.8 months; P=0.0003)

• FOLFOXIRI associated with significantly more gra

de 2/3 neurotoxicity (20% vs 0%; P<0.0001)

Falcone A, et al. ASCO GI 2006. Abstract 227.

• There were higher rates of secondary surgica
l resection of liver metastases in the FOLFOX
IRI arm.

42
• Although similar high rates of objective respo
nse and significantly better median overall sur
vival (29.8 versus 25.8 months) were noted wi
th FOLFOXIRI plus Bevacizumab as compare
d to FOLFIRI plus bevacizumab in a second tr
ial of 508 patients, the TRIBE trial, this trial di
d not confirm higher rates of secondary surgic
al resection of liver metastases with an initial t
hree-drug chemotherapy backbone

43
Can we give sequential therapy, rather th
an combined?

44
• In the United Kingdom Medical Research Cou
ncil's FOCUS trial, patients were randomly as
signed to one of the following groups:
• The control arm (strategy A) received sequent
ial single agent therapy (FU/LV followed by iri
notecan monotherapy at the time of progressi
on).

45
• Experimental strategy B was FU/LV initially fol
lowed by combination chemotherapy (FU plus
either Irino or Oxali) at progression.
• Experimental strategy C was initial combinati
on therapy with either FOLFOX or FOLFIRI.

46
 FOCUS - Results

• Only the comparison of initial FOLFIRI versus

sequential single agent therapy was statisticall
y significant (16.7 versus 13.9 months), althou
gh the survival in both groups was low by mod
ern standards (median 20 to 22 months).

• The authors concluded that sequential single a

gent therapy did not compromise overall surviv
al.

47
Iriniotecan and Oxaliplatin with 5FU oral c
ongeners

66
• Irinotecan plus capecitabine or S-1 —
Capecitabine and irinotecan have partially over
lapping toxicity profiles, particularly with regard
to diarrhea.
• The potential for greater toxicity reduces the th
erapeutic advantage of an irinotecan/capecitab
ine combination.
• Six trials have compared the safety and efficac
y of CAPIRI and FOLFIRI regimens, either with
or without bevacizumab

67
• The irinotecan doses in the XELIRI arms rang
ed from 200 to 250 mg/m2 on day 1 of each 2
1-day cycle, and all trials used capecitabine 1
000 mg/m2 twice daily on days 1 to 14.

• A meta-analysis of all six trials concluded that

both regimens had similar efficacy and similar
adverse event profiles

68
• But since XELIRI is not well tolerated, the effi
cacy seems to get compromised.

69
 Different ways to administer Irinotecan
• In the phase III BICC-C trial, which compared three different appro
aches to combining irinotecan with a fluoropyrimidine (infusional F
U [FOLFIRI], bolus FU [modified IFL], or capecitabine [XELIRI] usi
ng the standard European doses of irinotecan [250 mg/m2 day 1] a
nd capecitabine [1000 mg/m2 twice daily, on days 1 to 14 of every
three-week cycle])

• FOLFIRI emerged as the undisputed winner of the head-to-hea

d comparison of all three regimens in terms of efficacy and tolerab
ility. XELIRI was associated with a higher rate of grade 3/4 advers
e events, in particular, diarrhea (48 versus 14 percent), nausea (1
8 versus 9 percent), vomiting (16 9 percent), and dehydration (19
versus 6 percent). Higher rates of grade 3 and 4 diarrhea with XE
LIRI as compared to FOLFIRI have been seen in other trials as we
ll .

70
• Where S-1 is available, irinotecan plus S-1 repre
sents a reasonable alternative to FOLFIRI, at lea
st for second-line treatment after failure of first-lin
e FOLFOX

• [A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinote

can/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated
results of the FIRIS study. Yasui H, Muro K, Shimada Y, Tsuji A, Sameshima S, Baba
H, Satoh T, Denda T, Ina K, et al , J Cancer Res Clin Oncol. 2015 Jan;141(1):153-60.
Epub 2014 Aug 9.
• The FIRIS study previously demonstrated non-inferiority of IRIS (irinotecan plus S-1) t
o FOLFIRI (5-fluorouracil/leucovorin with irinotecan) for progression-free survival as th
e second-line chemotherapy for metastatic colorectal cancer (mCRC) as the primary e
ndpoint.]

71
OXALIPLATIN

74
 CAPOX = FOLFOX
• Capecitabine plus oxaliplatin — In three separat
e phase II studies in previously untreated patients,
ORR using oxali (130mg/m2 day one) f/b by xeloda
(1000 mg/m2 twice daily for 14 of every 21 days) w
ere 36, 42, and 55 percent, respectively.
• Multiple randomized trials have explored whether X
ELOX provides similar efficacy and tolerability as o
therfluoropyrimidine/oxali combinations

87
• Multiple randomized trials have explored whether XELOX prov
ides similar efficacy and tolerability as other fluoropyrimidine/o
xali combinations, all suggest comparable efficacy, but a differ
ent toxicity profile. As examples:
• The phase II TREE-1 trial randomly assigned 150 patients to
modified FOLFOX6, CAPOX (xeloda 1000 mg twice daily for 1
4 of every 21 days plus oxali 130 mg/m2 on day one), or bFOL
(bolus FU 500 mg/m2, and LV 20 mg/m2 weekly for three of ev
ery four weeks plus oxaliplatin 85 mg/m2 on days 1 and 15). T
he differences between FOLFOX and CAPOX in response rat
es, TTP and median survival were not significant

88
 TREE 2 trial …Bev was added
• After bevacizumab was approved in February 2004, the trial was a
mended to include bevacizumab in all arms (223 patients, TREE-
2).
• The primary objective of the studies was to determine the safety an
d feasibility of these different oxaliplatin-fluoropyrimidine combinatio
ns.
• Early in the trial, the capecitabine dose used in the CapeOx arm ha
d to be reduced from 1000 mg/m2 twice a day on days 1-14 every 3
weeks to 850 mg/m2 due to excess toxicity (adverse events include
d diarrhea and hand-foot-syndrome).
• Subsequently, reduced-dose CapeOx was well tolerated. In the fina
l toxicity analysis of TREE-2, bFOL appeared to have the worst toxi
city/efficacy ratio with a 30% incidence of grade 3/4 diarrhea.

89
• Bevacizumab substantially improved the resp
onse rates of all of the regimens.
• Median overall survival was 23.7 months for t
he combined groups receiving Bevacizumab
(versus 18.2 months for the combined non-be
vacizumab-treated groups)

90
OXALIPLATIN PLUS IRINOTECAN

97
• High rates of successful resection and favora
ble long-term survival rates for patients with i
nitially unresectable liver metastases have be
en reported for the FOLFOXIRI

98
• Two phase III trials comparing FOLFOXIRI with the Douillard irinotecan/FU/LV regim
en have come to opposite conclusions, while a third phase III trial comparing FOLFO
XIRI plus bevacizumab versus FOLFIRI plus bevacizumab suggests superiority for F
OLFOXIRI in terms of response rate and progression-free survival (PFS), but compa
rable rates of subsequent complete resection of liver metastases:

• An Italian trial comparing a six-month course of FOLFOXIRI versus FOLFIRI sugges

ts significantly better outcomes with FOLFOXIRI.

• Benefits of a six-month course of FOLFOXIRI included a significantly higher respons

e rate (the primary end point, 66 versus 41 percent), and a greater number of patient
s able to undergo complete secondary surgical resection of liver metastases (36 ver
sus 12 percent).

99
• In the latest report, at a median follow-up of over 60 months, FO
LFOXIRI was associated with significantly longer median PFS
(9.8 versus 6.8 months), and overall survival (23.4 versus 16.7
months), with a five-year survival rate of 15 versus 8 percent.

• Compared with FOLFIRI, FOLFOXIRI was associated with signif

icantly higher rates of grade 2 or 3 peripheral neuropathy (19 ve
rsus 0 percent) and of grade 3 or 4 neutropenia (50 versus 28 p
ercent), but the incidence of febrile neutropenia (5 versus 3 perc
ent) and of grade 3 or 4 diarrhea (20 versus 12 percent) were n
ot significantly different .

100
 TRIBE study

• A second phase III trial comparing

bevacizumab plus either FOLFOXIRI or FOLF
IRI (the TRIBE trial) did not confirm these hig
h rates of secondary surgical resection of live
r metastases with FOLFOXIRI plus bevacizu
mab, although it did confirm higher response
rates and a significantly longer progression-fr
ee survival with this regimen as compared to
FOLFIRI plus bevacizumab.

101
• At a median follow-up of 32.2 months, FOLFOXIRI-bevacizuma
b was associated with a significantly better overall response rat
e (65 versus 53 percent) and progression-free survival rate (me
dian 12.1 versus 9.7 months). In the most recent update, at 48-
month median follow-up, median overall survival was significantl
y better with FOLFOXIRI/bevacizumab (29.8 versus 25.8 month
s), and estimated five-year overall survival rates were twice as h
igh (24.9 versus 12.5 percent).

• However, the rate of secondary complete (R0) resections in pati

ents with liver metastases was not higher with FOLFOXIRI (15 v
ersus 12 percent

102
STEAM study – FOLFOX vs FOLFOXIRI

• The phase III STEAM trial randomly assigned

280 patients with previously untreated mCRC
to bevacizumab plus FOLFOX, or concurrent
FOLFOXIRI or sequential FOLFOXIRI, which
consisted of alternating courses of FOLFOX a
nd FOLFIRI every four weeks.

103
• In a preliminary report presented at the 2016 AS
CO Gastrointestinal Cancers Symposium, the O
RR were higher for concurrent FOLFOXIRI/beva
cizumab (60 versus 47 percent for FOLFOX), me
dian PFS was modestly but significantly better (1
1.7 versus 9.3, hazard ratio [HR] 0.672, 95% CI
0.489-0.922), and twice as many patients were a
ble to undergo secondary liver resection (15.1 ve
rsus 7.4 percent).

104
• Regimens that contain both irinotecan and
oxaliplatin with or without bevacizumab have not
yet replaced standard doublet regimens such as
FOLFOX or FOLFIRI with or without bevacizuma
b as a standard approach for first-line therapy or
salvage treatment after failure of an irinotecan- or
oxaliplatin-based regimen. Toxicity is greater than
with a two-drug chemotherapy backbone with or
without bevacizumab

105
106
TARGETED THERAPY

107
• Avastin is a humanized monoclonal antibody
(MoAb) targeting VEGF. Adding bevacizumab
to a variety of first-line regimens used for met
astatic colorectal cancer (mCRC) improves o
utcomes.

108
 Phase III Trial: Bevacizumab + IFL

R
A IFL + bevacizumab q2 wk
N=813 N (n=402)
Previously D
untreated O Stratified by study center, ECOG PS, colon vs
rectal disease, no. metastatic sites
mCRC M
I
IFL + Placebo
Z (n=411)
E

Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

 Survival Benefit When Bevacizumab Adde
d to IFL

BEV + IFL IFL

(n=402) (n=411) P-value
Median OS (mo) 20.3 15.6 <0.001

Median PFS (mo) 10.6 6.2 <0.001

Response rate (%) 44.8 34.8 0.004

Median duration 10.4 7.1 0.001

response (mo)

Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

 Bevacizumab + IFL: Safety

BEV + IFL IFL

Adverse Event (n=393) (n=397) P-value
Any grade 3/4 event 84.9 74.0 <0.01
Any hypertension 22.4 8.3 <0.01
Grade 3/4 hypertension 11.0 2.3 <0.01
Any thrombotic event 19.4 16.2 NS
Any proteinuria 26.5 21.7 NS

Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

 Bevacizumab related SE

• Hypertension:
– 1.6% developed HTN that needed hospitalisation
– Temporarily stop if HTN
– If Hypertensive crisis  permanently stop
• Thromboembolic events (arterial):
– More common in >65 years
– If severe TE  permanently stop
 Bevacizumab related SE

• GI perforation/ wound dehiscence:

– Incidence - 2%
– Permanently stop if wound dehiscence/ GI perforat
ion
• Hemorrhage:
– Usually mild
– If Severe bleeding  permanently stop
– h/o recent  Bev should not be started
• Proteinuria
 E3200: High-dose
BEV + FOLFOX4: Study Design

FOLFOX4 + Bevacizumab
R (BEV 10 mg/kg q2 wk)
A (n=289)
N=822 N
Previousl D
FOLFOX4
y treated O (n=290)
mCRC M
I
Bevacizumab
Z (10 mg/kg q2 wk)
E (n=243)
Stratified by study center, ECOG PS, prior XRT

Giantonio BJ, et al. ASCO 2005. Abstract 2.

 Improved Survival with High-dose Bevacizumab
+ FOLFOX4

BEV +
BEV FOLFOX4 FOLFOX4
(n=243) (n=290) (n=289) P-value*
Median OS 10.2 10.8 12.9 0.0018
(mo)
Median PFS 2.7 4.8 7.2 <0.0001
(mo)
Overall RR, % 3.0 9.2 21.8 <0.001

*P-value compares BEV + FOLFOX4 vs FOLFOX4.

Giantonio BJ, et al. ASCO 2005. Abstract 2.
 TREE-1/2: Bevacizumab + Oxaliplatin + Fluor
opyrimidine

mFOLFOX6 + BEV q2 wk
Bevacizumab (5 mg/kg d1); Oxaliplatin (85 mg/m2)
N=213 R LV (fixed dose 350 mg)
5-FU (400 mg/m2 IV bolus followed by 2400 mg/m2 IV inf
•Previously A over 46 h d1)

untreated N (n=71)
mCRC D bFOL + BEV q28 d
•Unresecta Bevacizumab (5 mg/kg d1, 15)
O Oxaliplatin (85 mg/m2 d1, 15)
ble LV (20 mg/m2 IV bolus d1, 8, 15)

•Adequate M 5-FU (500 mg/m2 IV bolus d1, 8, 15)

I (n=71)
organ
Z CapeOx + BEV q21 d
function Bevacizumab (7.5 mg/kg d1)
E Oxaliplatin (130 mg/m2 d1)
Capecitabine (850 mg/m2 bid d1-15; d1 PM only, d15 AM only)
(n=71)
Hochster H, et al. ASCO 2006. Abstract 3510.
 Addition of Bevacizumab Improves Efficacy of Al
l Three Regimens

mFOLFOX bFOL CapeOx

-BEV +BEV -BEV +BEV -BEV +BEV

(n=49) (n=71) (n=50) (n=70) (n=48) (n=72)

Median TTP* (mo) 8.7 9.9 6.9 8.3 5.9 10.3

Overall RR, % 41 52 20.0 39 27 46

Median OS (mo) 19.2 26.0 17.9 20.7 17.2 27.0

*TTP, time from randomization to objective tumor progression or death.

Hochster H, et al. ASCO 2006. Abstract 3510.
 TREE-2 Conclusions

• No significant additive toxicities when bevacizuma

b combined with any regimen

• Bevacizumab improved RR, TTP, OS of all regime

ns (over TREE-1 results)

• CapeOx tolerability improved when CAPE dose re

duced to 850 mg/m2 bid

Hochster H, et al. ASCO 2006. Abstract 3510.

124
125
126
127
128
 OPUS: Study design

Cetuximab +
FOLFOX4
N=168
EGFR-detectable
mCRC R

Primary endpoint FOLFOX4

• Overall confirmed response rate
(as assessed by independent review) N=169
Secondary endpoints
• PFS time
• OS time
• Rate of curative surgery for metastases
• Safety Stratification by:
ECOG PS 0/1, 2
Bokemeyer et al. JCO 2008
 OPUS - Relating KRAS status to efficacy
Secondary endpoint: PFS – KRAS wild-type

1.0
mPFS
0.9
Cetuximab + FOLFOX: 7.7 mos
Progression-free survival estimate

0.8 FOLFOX: 7.2 mos

0.7 HR=0.57; p=0.016
0.6

0.5

0.4

0.3

0.2
Cetuximab + FOLFOX
0.1 FOLFOX

0.0
0 2 4 6 8 10 12
Months
Bokemeyer et al. JCO 2008
 OPUS - Relating KRAS status to efficacy
Secondary endpoint: PFS – KRAS mutant
1.0
mPFS
0.9
Cetuximab + FOLFOX: 5.5 mos
Progression-free survival estimate

0.8
FOLFOX: 8.6 mos
0.7 HR=1.83; p=0.019
0.6

0.5

0.4

0.3

0.2
Cetuximab + FOLFOX
0.1 FOLFOX

0.0
0 2 4 6 8 10 12
Months
Bokemeyer et al. JCO 2008
CRYSTAL study design FOLFIRI +
cetuximab
n=599
EGFR-expressing, (KRAS codon 12/13 WT, n=316)
previously untreated, R
mCRC
FOLFIRI
Stratification factors: n=599
ECOG performance status n=1198
(KRAS codon 12/13 WT, n=350)
Region (KRAS codon 12/13 WT, n=666:
PCR clamping and melting curve
analysis)

FOLFIRI FOLFIRI+Cet P value

ORR 38.7% 46.9% 0.004
ORR (WT Kras) 39.7% 57.3% 0.001
OS 18.6 mo 19.9 mo 0.31
OS (WT Kras) 20 mo 23.5 mo 0.01
PFS 8 mo 8.9 mo 0.048
PFS (WT Kras) 8.4 mo 9.9 mo 0.001
Resection Rate 2.5% 6% <0.05
R0 Resection rate 1.5% 4.3% 0.0034
KRAS-dependent RR in First-Line Trials

OPUS CRYSTAL PACCE

(Oxali) (Irino) (Irino/BEV)
134
135
136
137
 Chemo-Holidays
• Types of treatment breaks
– Treatment break with maintenance regimen
• OPTIMOX-1
• CONcePT
– Complete Chemotherapy-free intervals (CFI)
• OPTIMOX-2

Goldberg. Oncologist. 2007;12:38; Grothey. ASCO 2007 Educational Book.

 Stop and Go concept - OPTIMOX
1
FOLFOX4

R
6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7
620 pts
Cum. Oxaliplatin 780 1560
FOLFOX4 FOLFOX7
RR (%) 58.5 58.3
PFS (mos) 9.0 8.7
DDC (mos) 9.0 10.6 Primary
OS (mos) 19.3 21.3 endpoint
G3/4 sNT 17.9 13.3
(%) Tournigand et al, JCO 2006
 OPTIMOX 1: neurotoxicity FOLFOX4 vs 7

25 FOLFOX4
Grade 3 neurotoxicity
FOLFOX7
Percentage of patients

20

15

10

0
1 3 5 7 9 11 13 15 17 19 21 23

Cycles
Tournigand et al, JCO 2006
 CONcePT: Continuous Oxaliplatin Ne
urotoxicity Prevention Trial

R mFOLFOX7 + bevacizumab
A (continuous)
+/- IV Calcium/magnesium
N
• Previously D
untreated
mCRC
O
M mFOLFOX7 + bevacizumab
(intermittent oxaliplatin)
(initiated 2/05) I
+/- IV Calcium/magnesium
Z
E

Study Director, Gilbert Jirau-Lucca, MS, Bridgewater, NJ: Sanofi-Aventis.

 CONcePT study: IO arm
5-FU

LV 200 2400 Cumulative Months

OX 85 oxaliplatin
BEV 5
x8

200 2400 680 mg/m2 4

5

x8

200 2400 680 mg/m2 8

85
5
x8
1360 mg/m2 12
 CONcePT: Results
TTF PFS
1.0 1.0 CO
0.9 0.9
0.8
IO
0.8

Proportion of Patients
Proportion of Patients

0.7 0.7
0.6 0.6
0.5 0.5
0.4 P=0.002 0.4 P=0.044
0.3 0.3
0.2 0.2
0.1 4.2 5.6 0.1 7.3 12
0.0 0.0
0 2 4 6 8 10 12 1416 0 2 4 6 Months
8 10 12 14 16
Months

Censored data.

Grothey. ASCO. 2008 (abstr 4010).

 OPTIMOX2:
Maintenance vs Chemotherapy-free intervals

R mFOLFOX7
A No maintenance until baseline progression
mFOLFOX7 reintroduction
N (n=102)

N=202 D
Previously O
untreated
mCRC
M mFOLFOX7
I sLV5FU2 until baseline progression
mFOLFOX7 reintroduction
Z (n=100)

Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.

 Chemotherapy-free Intervals Feasible in
Some Patients after FOLFOX
CFI Maintenance
Outcome (n=102) (n=100)
ORR, % 61 61
ORR at reintroduction, % 31 13
Median PFS, mo 6.9 8.7
Median duration disease control, 11.7 12.9
mo
Median PFS of reintroduction, mo 4.1 3.7

• Suggests break in therapy feasible in patients responding t

o first- line FOLFOX
Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.
 ECOG 3200 Trial

• In the ECOG E3200 trial, 828 patients with ad

vanced CRC who had failed first-line therapy
(mainly bolus irinotecan + 5-FU + LV [IFL]) we
re randomized into 3 treatment arms: FOLFO
X4 (control arm), FOLFOX4 plus high-dose b
evacizumab (10 mg/kg every 2 weeks), and a
high-dose bevacizumab monotherapy arm

146
147
• The bevacizumab/FOLFOX4 group had a sig
nificantly better PFS (7.3 versus 4.7 months)
and median overall survival (12.9 versus 10.8
months) compared to FOLFOX4 alone, and th
e bevacizumab alone arm was inferior to bot
h.

148
149
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
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170
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172
173
174
175
176
Results of a multicenter, randomized, double-blin
d, phase III study of TAS-102 (Trifluridine tipiracil)
plus best supportive care (BSC) versus placebo pl
us BSC in patients with metastatic colorectal canc
er (mCRC) refractory to standard therapies (RECO
URSE)
 TAS-102; Mechanism of Action
TPase
F3dThd (FTD)
FTY Inhibition of
tumor growth
(inactive form)
TPI F3dTMP

F3dTDP DNA dysfunction

TAS-102
(Oral Combination Drug)

FTD TPI F3dTTP

FTD incorporation
into DNA

Molar ratio = 1 : 0.5

FTD ： Trifluridine
TPI ： Tipiracil-HCl
 Differentiation between 5-FU and TAS-102
5-FU TAS-102
5-FU
FTD

FdUMP F3dTMP
Phosphorylation
F3dTDP
F3dTTP
Inhibit

TS Incorporation into DNA

DNA
dUMP dTMP duplication

dTTP

Inhibit DNA duplication DNA damage

FTD
T
Thymidine （ T ）
T
 Preclinical Results with TAS-102

• In an animal study, co-administration with TPI increased the plas

ma AUC of FTD by 100-fold 2

• In Xenograft Models, the anti-tumor effect of TAS‑102 appeared t

o occur through FTD incorporation into DNA 3 ; incorporation of
FTD into DNA was 700-fold greater than that of 2’-deoxy-5-fluoro
uridine (FdUrd) 4

• 5-FU, capecitabine, S-1, and UFT work primarily by inhibiting thy

midylate synthase whereas TAS-102, while structurally similar, a
cts as an antimetabolite (i.e., incorporated into DNA)

1. Emura T, et al., Int J Mol. Med. 2004:545-49

2. Emura T, et al., Int J Oncol. 2005;27:449-55
3. Tanaka N, et al., AACR 2012 (Abstr 1783)
4. Data on file
 Clinical Rationale for TAS-102 in mCRC:
Phase I and Phase II Experiences
• Japanese Randomized Phase II trial for Patients with mCRC 1:
– Total 172 patients, who received all of prior fluoropyrimidine, irinotecan
and oxaliplatin, were randomized
– The median OS was 9.0 vs. 6.6 months (HR=0.56 p=0.0011)
– The most common grade 3 or 4 toxicity was hematological toxicity

The recommended dose (RD)

was determined to be 35 mg/
m2/dose orally twice daily 2,3

1. Yoshino T, Ohtsu A, et al., Lancet Oncol. 2012;13(10):993-1001

2. Doi T, Ohtsu A, Yoshino T, et al., Br J Cancer 2012;107(3):429-34
3. Patel M, Bendell J, Mayer RJ, et al., J Clin Oncol 2012; 30 (suppl; abstr 3631)
 Global Randomized Phase III study
RECOURSE: Refractory Colorectal Cancer Study
(NCT01607957)

R
Metastatic colorectal cancer (mCRC) A
TAS-102 + BSC
• 2 or more prior regimens N (n = 534)
• Refractory / Intolerable
D 35 mg/m22 b.i.d. p.o.
– fluoropyrimidine
O d1-5, 8-12 q4wks Endpoints Primary: OS
– irinotecan
M Secondary: PFS, Safety,
– oxaliplatin
I 2:1 Tolerability, TTF, ORR, DCR,
– bevacizumab
Z DoR, Subgroup by KRAS (OS
– anti-EGFR if wild-type KRAS
A and PFS)
• ECOG PS 0-1
• Age ≥ 18 T Placebo + BSC
(target sample size: 800) I (n = 266)
O
N d1-5, 8-12 q4wks

• Treatment continuation until progression, intolerant toxicity or patient refusal

• Multicenter, randomized, double-blind, placebo-controlled, phase III
– Stratification: KRAS status, time from diagnosis of metastatic disease,
geographical region
• Sites: 13 countries, 114 sites
• Enrollment: June 2012 to October 2013
 RECOURSE: Endpoints
Primary Endpoint: Overall Survival (OS)
– OS comparison between the two treatment arms are based
on the intent-to-treat (ITT) population
– Designed to detect an OS hazard ratio of 0.75 (25% risk red
uction), with a 1-sided type I error of 0.025, 90% power
– A target of 571 events was required
– Planned sample size was 800

Key Secondary Endpoints

– Progression Free Survival (PFS)
– Overall Response Rate (ORR)
– Disease Control Rate (DCR)
– Safety
 RECOURSE: Key Eligibility
• Histologically or cytologically confirmed adenocarcinoma of t
he colon or rectum
• Received at least 2 prior regimens of standard chemotherapie
s for mCRC and is refractory to or failing those chemotherapi
es
– Patients who have progressed based on imaging during or
within 3 months of the last administration of each standard
chemotherapy, including fluoropyrimidines, irinotecan, ox
aliplatin, bevacizumab, and cetuximab/panitumumab for wi
ld-type KRAS patients
– Patients who discontinued a treatment due to intolerance t
o that therapy were also eligible
• ECOG performance status 0-1
 Patient Demographics and Characteristics
(Intent-to-treat population)

TAS-102 Placebo
N=534 N=266
Age, median (range) 63.0 (27-82) 63.0 (27-82)
Gender, % Male 61.0 62.0
Female 39.0 38.0
Race, % White 57.3 58.3
Asian 34.5 35.3
Black 0.7 1.9
Geographic Region, % Japan 33.3 33.1
Western 66.7 66.9
Europe 50.7 49.6
US 12.0 13.2
Australia 3.9 4.1
ECOG PS, % 0 56.4 55.3
1 43.6 44.7
 Patient Disease Characteristics
(Intent-to-treat population)
TAS-102 Placebo
N=534 N=266
Primary site, % Colon 63.3 60.5
Rectum 36.7 39.5
KRAS mutational status, % Wild-type 49.1 49.2
Mutant 50.9 50.8
Time since diagnosis of < 18 months 20.8 20.7
metastasis, % > 18 months 79.2 79.3
Number of prior regimens for 1-2 25.8 25.6
metastatic, %
3 28.8 25.6
>4 45.3 48.9
All prior systemic cancer Fluoropyrimidine 100 100
therapeutic agents, % Irinotecan 100 100
Oxaliplatin 100 100
Bevacizumab 100 99.6
Anti-EGFR (if wild KRAS*) 99.6 99.3
Regorafenib 17.0 19.9

*Based on historical patient record

 Patient Disease Characteristics (cont’d)
(Intent-to-treat population)

TAS-102 Placebo
N=534 N=266
Patient receiving prior 5-FU, % 100 100
Refractory to Fluoropyrimidine at any time it was given 97.6 99.6
Refractory to Fluoropyrimidine last time it was given 92.7 89.8
Patients receiving 5-FU as last Regimen Prior to
61.4 58.6
Randomization, %
Refractory to Fluoropyrimidine 91.8 89.7
 Overall Survival
TAS-102 Placebo
N=534 N=266

100 Events # (%) 364 (68) 210 (79)

HR (95% CI) 0.68 (0.58-0.81)
90
Stratified Log-rank test p<0.0001
80 Median OS, months 7.1 5.3
Survival Distribution function

Median follow-up: 8.4 months

70
Alive at, %
60 6 months 58 44

50
12 months 27 18

40

30

20

10

0 3 6 9 12 15 18
Months from Randomization
N at Risk:
TAS-102 534 459 294 137 64 23 7
Placebo 266 198 107 47 24 9 3
 Progression-free Survival
100
TAS-102 Placebo
N=534 N=266
90
Events # (%) 472 (88) 251 (94)
Progression-free Distribution function

80 HR (95% CI) 0.48 (0.41-0.57)

70 Stratified Log-rank test p<0.0001

Median PFS, months 2.0 1.7
60
Tumor assessments performed every 8 weeks
50

40

30

20

10

0 2 4 6 8 10 12 14 16
Months from Randomization
N at Risk:
TAS-102 534 238 121 66 30 18 5 4 2
Placebo 266 51 10 2 2 2 1 1 0
 Overall Response
(tumor response evaluable population, investigator assessment)

Best response, % TAS-102 Placebo

N=502 N=258
Complete response or Partial response* 1.6 0.4
Stable disease 42.4 15.9
Disease control rate** 44.0 16.3
Progressive disease 51.8 75.6

Per RECIST version 1.1

*Not significant
**CR, PR or SD, p<0.0001
 Key Subgroup Analysis of OS

Subgroup Favors TAS-102 Favors Placebo

HR Median (mos)
Events/N [95% CI] TAS-102 : PBO
All Subjects 574 / 800 0.68 [0.58, 0.81] 7.1 : 5.3

KRAS Status
Wild Type 280 / 393 0.58 [0.45, 0.74] 8.0 : 5.7
Mutant Type 294 / 407 0.80 [0.63, 1.02] 6.5 : 4.9

Geographic Region
Japan 227 / 266 0.75 [0.57, 1.00] 7.8 : 6.7
West (AU/EU/US) 347 / 534 0.64 [0.52, 0.80] 6.5 : 4.8

Refractory to 5-FU when 317 / 441 0.75 [0.59, 0.96] 6.8 : 4.9
given as last therapy prior
to randomization*

0 0.5 1 1.5 2
Hazard Ratio: TAS-102 versus Placebo (95% CI)

*Not prespecified subgroup

Non-Hematologic Adverse Events Occurring in >10% of Patients
(as-treated population)

Non-Hema Adverse events, % TAS-102 (N=533) Placebo (N=265)

All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4
Nausea 48.4 1.9 0 23.8 1.1 0
Decreased appetite 39.0 3.6 0 29.4 4.9 0
Fatigue 35.3 3.9 0 23.4 5.7 0
Diarrhea 31.9 2.8 0.2 12.5 0.4 0
Vomiting 27.8 2.1 0 14.3 0.4 0
Pyrexia 18.4 0.9 0.2 14.0 0.4 0
Asthenia 18.2 3.4 0 11.3 3.0 0
Constipation 15.2 0.2 0 15.1 1.1 0
Abdominal pain 14.8 2.1 0 13.6 3.4 0
Cough 10.7 0.4 0 11.3 0.8 0
Dyspnoea 10.5 2.1 0.4 12.8 2.3 0
Oedema peripheral 9.9 0.2 0 10.2 0.8 0
Weight decreased 7.7 0 0 10.2 0 0

One treatment-related death was observed in TAS-102

Hematologic Laboratory Abnormalities Occurring in >10% of Patients
(as-treated population)

Lab abnormalities, % TAS-102 (N=533) Placebo (N=265)

All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4
Hematology
Leukopenia 77.1 18.6 2.8 4.6 0 0
Anemia 76.5 18.2 0* 33.1 3.0 0
Neutropenia 66.9 26.5 11.4 0.8 0 0
Lymphocytopenia 64.6 18.2 3.3 39.7 9.2 0.8
Thrombocytopenia 42.2 4.5 0.6 8.0 0 0.4

*One case of grade 4 was reported in AE

Occurring in < 10% of Patients but Clinically Important Adverse Events
(as-treated population)

Adverse events, % TAS-102 (N=533) Placebo (N=265)

All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4
Febrile neutropenia 3.8 2.8 0.9 0 0 0
Stomatitis 7.9 0.4 0 6.0 0 0
Hand-foot syndrome 2.3 0 0 2.3 0 0
Cardiac ischaemia events, % 0.4 0.2 0 0.4 0 0.4
Acute myocardial infarction 0.2 0.2 0 0 0 0
Angina pectoris 0.2 0 0 0 0 0
Myocardial ischaemia 0 0 0 0.4 0 0.4
 Conclusions
• TAS-102 demonstrated a clinically relevant improveme
nt in OS and PFS compared with placebo in mCRC pts
refractory / intolerant to standard therapies
– TAS-102 prolonged overall survival across all major prespecifi
ed subgroups including KRAS and region, and across the sub
group with patients refractory to 5-FU
• TAS-102 was well tolerated
– The most frequently observed toxicities were gastrointestinal
and hematologic, the rate of febrile neutropenia was 3.8%
• The RECOURSE results support TAS-102 as a new tre
atment option for patients with refractory mCRC