Metastatic Colon CA Flashcards Preview

Medical oncology > Metastatic Colon CA > Flashcards

Flashcards in Metastatic Colon CA Deck (142):
1

What is the advantage of CI 5FU>Bolus 5FU?

Better RR
Better Survival
Less toxicity
- loading Bolus: stomatitis, myelosupprssion
- weekly plus: diarrhea
- continuous infusion: PPE

2

What is Irinotecan metabolized into?

Irinotecan --> SN38

SN38 - active compound
Metabolized by UGT1A1

If there is UGT1A1*28 polymorphism, there is increased risk of neutropenia

3

What is the evidence for Irinotecan >BSC?

Cunningham Lancet 1998

Irinotecan+BSC > BSC
Survival is better

4

What is the evidence for IFL 1st line?

1) Saltz et al NEJM 2000

3 arms:
A) q6weeks each given weekly for 4 weeks
- Irinotecan (125) IV over 90min
- Leucovorin (20) IV Bolus
- 5FU (500) Bolus
B) Daily X 5 days, Q4w
- Leucovorin (20) IV Bolus
- 5FU (425) IV Bolus
C) weekly X 4weeks Q6w
- Irinotecan alone (125) over 90min

IFL vs 5FU/LV
- PFS 7m vs 4m
- RR 40% vs 20%
- OS 15m vs 13m


2) Douillard Lancet 2000
N=400
Tx-naive
2 arms:
- Irinotecan + 5FU + LV
- FU/LV
RESULTS:
- RR 35% vs. 20% (ITT arm)
- TTP 7m vs 4m
- OS 17m vs 14m

3) EORTC 40986, Kohne et al
N=430
2 arms:
- FA (500)/5FU (2.6g/m2 over 24h) weekly x6, Q8w = AIO arm
- Irinotecan (80) --> FA (500)/5FU (2.6g/m2/24h)
Results:
MPFS 8.5m vs 6.5m (AIO)
Med OS 17m to 20m (p not sig)
ORR 60% vs 30%

5

FOLFOX vs CAPOX

Equivalent

Arkenau et al JCO 2008, meta-analysis

N=3500, 6RCTs PH II and III
CAPOX vs FOLOFX

Lower RR with CAPOX, but similar PFS and OS

FOLFOX:
- lesser G3/4 HFS, thrombocytopenia, diarrhea

CAPOX:
- less G3/4 neutropenia

6

What are the Fluorouracil regimens?

1) MAYO clinic regimen
- Q4w to Q5w
- 5FU (425) D1-5
- Leucovorin (20) D1-5

2) Roswell Park
- Q8weeks, 6 weeks on/2 weeks off
- FU(500)
- Leucovcorin (500)

3) de Gramont --> French LV5FU2
- q2weeks
- Leucovorin (200) over 2 hours --> Bolu 5FU(400) -->5FU (600) over 22 hours X 2 days
- De Gramont with Oxaliplatin added on ?

4) German AIO
- 5FU as protracted infusion for 24 hours
- FU (425) + Leu (20) D1-5 Q28days
- FU (2600) as 24 hour infusions +/- Leu (500) weekly x6
- 6 weeks on, 2 weeks off

7

Any evidence for Bev in 2nd line?

E3200 Giantonio JCO 2007

Single agent Bev activity is 3%, little/no activity as a single agent.

Addition of Bev to FOLFOX improves survival of those refractory to Irinotecan.

8

How about Bev beyond progression?

Tell me about ML18147

ML18147 Arnold ASCO 2012

N=800
Bev+ Standard 1st line chemo
1st line chemo = Ox- or Iri-based

Upon progression, randomized to 2 arms:
A) standard 2nd line chemo until PD
B) Bev (2.5mg/kg/week) + standard 2nd-line chemo
** CT switch upon PD: Ox--> Iri, Iri-->Ox)

Results:
- PFS in favor of Bev+CT: HR 0.7 5.7m vs 4m
- OS HR 0.8 11m vs 10m

9

What are the studies supporting Bev beyond progression?

ML18147
BRiTE
BEBYP

10

Tell me about the GONO-BEBYP study:

1st line chemo +Bev
Chemo: FOLFIRI/FOLFOX/FOLFOXIR/Fluoropyrimidine mono-tx

Randomized to 2 arms:
A) Second-line CT
B) Second-line CT + Bev
2nd-line CT = FOLFIRI/mFOLFOX-6

Results:
- PFS 7m vs 5m (CT); HR 0.65

11

Tell me about the BRiTE study:

Axel Grothey JCO 2008
An observational study

After 1st PD, physician decision with no random assignment into 3 arms:
A) No post-PD treatment
B) PostPD Tx w/o Bev
C) PostPD Tx with Bev

Results:
BBP (Bev beyond PD) > No BBP> No Tx
~ 1 yr: 75% > 50% > 25%

12

Any evidence to back up using Bev in the elderly?

Pooled analysis by Cassidy ESMO 2008

4 RCTs
NO16966: 1st line FOLFOX4/XELOX + Bev
AVF2108g: 1st line IFL + Bev
AVF2192g: 1st line FL +Bev
E4300: 2nd line FOLFOX4 = Bev

Results:
Bev provides consistent PFS benefit in those >65 and those 65, Bev provided a similar OS benefit to young and old

13

What are the 3 VEGF receptor functions?

VEGF-R1:
(Flt-1)
- Migration, invasion, survival

VEGF-R2:
(KDR/Flk-1)
Proliferation, survival, Permeability

VEGF-R3:
(Flt-4)
- lymphangiogenesis

14

What are the 3 general mechanisms of angiogenesis inhibitors ?

Intracellularly:
- Block VEGF expression
- Erlotinib, Cetuximab Panitumumab

Intracellularly:
- Neutralize VEGF
- Aflibercept, Bevacizumab

Extracellularly:
- Block VEGF Receptor (VEGFR-2)
- Anti-VEGFR-2 TKIs: Sunitinib, Sorafenib, Pazopanib

15

Tell me about the evidence for Aflibercept?

Aflibercept is a VEGF-TRAP, and works extracellularly to neutralize the activity of VEGF

Evidence for its usage comes from the VELOUR trial
Phase III study

Met CRC after failure of an Ox-based regimen. Randomized into 2 groups:
A) Aflibercept 4mg/kg + FOLFIRI Q2weeks
B) Placebo + FOLFIRI Q2 weeks

N=600
30% with prior Bev

Results:
OS: 12m vs 13.5m (with Alfibercept) HR 0.8
PFS: 4.7 m vs 7m HR 0.75

16

What about evidence for Regorafenib ?

CORRECT study by Grothey et al ASCO GI 2012

N=760
Met CRC after standard therapy, randomized into 2 groups:
A) Regorafenib 160mg OM 3w/1w +BSC
B) Placebo + BSC

RESULTS:
OS = 6.5m vs 5m (Placebo) HR 0.8
PFS = 1.9m vs 1.7 (Placebo) HR 0.5

17

Any evidence for Cetuximab alone?

Yes
NCI-CO.17 study by Cunningham NEJM 2004 and Jonker NEJM 2007

Cetuximab showed single agent activity of 10% in BOND1

Improved OS (6.1m can 4.6m) when compared against BSC in pretreated met CRC (CO.17)

18

What is the EPIC study?

Cetuximab/Irinotecan vs Irinotecan
Sobrero JCO 2008

Failed 1st line FU/OX

Results:
Improved RR and PFS

19

How about Cetuximab in 1st line ?

CRYSTAL study by Van Cutsem NEJM 2009

Untreated met CRC n=1200
2 arms:
A) FOLFIRI
B) FOLFIRI+Cetuximab

Results:
- Improved RR and PFS
>> RR 50% vs 40%
>> PFS 9m vs 8m
- In wt-KRAS patients:
>> RR 60% vs 40%
>> PFS 10m vs 9m
- In those undergoing surgery with curative intent, more had successful resection
- KRAS-mutated:
>> mPFS 7.4 vs 7.7 (FOLFIRI alone)
>> mOS 16.2m vs 16.7m

20

What are the factors that increase the risk of colon cancer?

A) Polyposis Syndromes
- Familial Polyposis
- Peutz-Jeghers Syndrome
- Juvenile polyposis
B) Non-Polyposis syndromes
- HNPCC
C) Other medical conditions
- Inflammatory bowel disease
- Hx of colon cancer
- prior polyps
- 1st degree relative Dx

21

What are the genetic aberrations in the development of colon cancer ?

5q loss --> APC, Beta-Catenin --> Adenoma

18q loss--> KRAS --> Late adenoma

17q loss --> BAT-26, p53 --> Early cancer

8q loss --> late cancer

** 5q, 18q,17q, 8q

22

What is the RR for the following?
1) FU+Leu
2) addition of Ox or Irinotecan to FU+Leu

1) 20%, median survival 1 year
2) 24 months

23

What is the evidence for bi-monthly high-dose Leucovorin + FU + CI5FU in advanced Ca?

De Gramont study, JCO 1997 French study

N=400
Advanced CLR Ca

2 arms:
A) IV LV (20) + Bolus 5FU (425) D1-5 q28days
B) IV LV (200) + Bolus 5FU (400) + 22hr CI 5FU (600) D1-2 q2weeks

Results:
RR 15% (A) vs 30% (B)
PFS 22w (A) vs 28w
Med survival 57w vs 62 weeks (not sig)
G3/4 tox 24% vs 10%

24

What is the evidence for Cape = 5Fu/Leu

1) 2001 JCO Hoff et al

N=600
Met CLR CA, 1st line tx

2 arms:
A) Oral Cape D1-14 q21days
B) 5FU/LV Bolus D1-5 q28days

Results:
RR 25% vs 15% (5FU/LV)
Med TTP 4.3m vs 4.7m
Med OS 12.5m vs 13m (non-sig)

Cape with lower diarrhea, stomatitis, nausea and alopecia.
But has higher HFS and G3/4 hyperbilirubinemia

============
2) Van Cutsem JCO 2001
Cape (2500/d) vs Mayo regimen
RR 19 vs 15%
OS 12m vs 13m (5FU)

25

What are the options for patients with symptomatic primary in CLR CA?

Surgical:
- primary resection
- Defunctioning stoma
Non-surgical:
- stents
- RT

26

Chemo vs BSC in Stage IV CRC?

Chemo if fit.

Simmonds BJC 2000, colorectal cancer collaborative group.
Meta-analysis

7 trials, 850 pts

Results:
35% reduction in risk of death
Absolute improvement in survival of 16%, median survival of 3.7m

27

What do you know about chemotherapy timing in asymptomatic adv CLR CA? Earlier better?

In asymptomatic patients, one study for earlier, one study negative.

1) Positive study: JCO 1992, Nordic group
N=180
2 groups:
- MTX/5FU/LV early
- MTX/5FU/LV only when symptomatic

Results:
- earlier treatment a/w improved OS 14m vs 9m
- earlier treatment a/w improved med PFS (8vs 3m) and symptom-free interval (10vs 2m)

2) Negative trial: BJC 2005 Australasian group
- Meta-analysis 2 RCTs n= 170
- early vs late 5FU
- suspended early due to low accrual
- results did not show difference in median survival, PFS nor QoL

CAVEAT: old chemo regimens

28

What can be used in patients with DPD deficiency?

Raltitrexed
Lancet 2002

Pure Thymidylate synthetase inhibitor
Raltitrexed vs deGramont vs Lokich regimen

Real tittered has increased treatment-related deaths due to combined GI and haem toxicities. also has inferior QoL

29

What is the Mayo Regimen?

Leucovorin (20) Bolus
FU (425) Bolus

D1-5
Q28days

30

IFL better or Mayo regimen better?

Saltz NEJM 2000

IFL better
PFS 7m vs 4m
OS 15m vs 13m
ORR 40% vs 20%

31

FOLFIRI better or 5FU better as first line?

Doulliard Lancet 2000
FOLFIRI>5FU as 1st line

Results:
RR 40% vs 20% (5FU)
TTP 7m vs 4m
OS 17m vs 14m

32

What is S-1?

1) Tegafur
2)Gimeracil (5-Chloro-2,4 dihydropyridine)
- inhibits DPD activity
3) Oteracil

DPD = Dihydropyrimidine Dehydrogenase

33

What is UFT?

UFT = UFUR = Tegafur-uracil

UFT is a 1st generation DPD inhibitory Fluoropyrimidine drug
UFT is an oral agent = Uracil + Tegafur in 4:1 ratio

Uracil = Competitive inhibitor of DPD
excess uracil competes with 5FU for DPD, thereby inhibiting 5FU Catabolism.
Tegafur is hence taken up by cancer cells and breaks Down into 5FU that kills cancer cells
Uracil causes more 5FU to stay inside the cells and kill them

34

What is the evidence of 2nd-line Irinotecan>CI 5FU?

2nd line
Met CLR CA, failed FU

N=250

2 groups:
- Irinotecan (300-350) q3weeks
- infusion all 5 FU

Results:
1y Survival 30% vs 45%(Irinotecan)
OS 11m vs 8.5m (Irinotecan)
PFS 4m vs 3m

35

What is the standard AIO FU/FA regimen?

FA (500) as 2-Hr infusion + CI-5FU (2.6g) over 24hours
weekly x 6 weeks, then 2 week rest
Q8weeks

36

What are the side-effects of Oxaliplatin?

1) Acute
- cold-triggered sensory neuropathy that is temporary and rapidly reversible
- no structural nerve damage
2) Chronic
- dose-related, dose-limiting s/e

No neuroprotective effect of IV Ca/Mg

37

What is the NCCTG/Intergroup N9741 trial?

Goldberg JCO 2004

Met CLR CA, tx-naive
N=800
3 groups:
1) IFL (control arm)
2) IROX
3) FOLFOX

Results:
TTP: 6.9m vs 6.5m vs 8.7m
RR 30% vs 35% vs 45%
Med survival 15m vs 17m vs 19.5m

FOLFOX with lower rates of severe n/v, diarrhea, FN, diarrhea

CONCLUSION = FOLFOX emerged as new standard 1st-line therapy.

Criticisms:
- did not directly compare Ox and Irinotecan
- compared 2 diff combination regimens with diff FU/Leu backbones
- higher efficacy and better tolerability with infusion all FU/Leu may have contributed to differences in efficacy

38

FOLFOX = FOLIRI. Evidence?

A) 2005 JCO Colucci
n=360
Tx-naive met CLR CA
2arms:
- FOLFIRI
- FOLFOX4
Results:
- ORR 30%~
- TTP 7m~
- Duration of response 9-10m~
- OS 14m s 15m


B) 2004 JCO Tournigand
Met CLR CA treatment-naive, n=200
2arms:
- FOLFIRI--> FOLFOX6
- FOLFOX6-->FOLFIRI
Results:
- Med survival 22m vs 21m
- PFS 14m vs 11m
- RR 56% vs 54%
- Med PFS (1st line) 8.5m vs 8m
- RR (2nd line) 15% vs 4%
- med PFS (2nd line) 2.4m vs 2.5m
--> If you use FOLFIRI as 2nd line after FOLFOX6, the 2nd PFS & RR is shorter, but OS similar.

39

What is the FOLFOX4 regimen?

Oxaliplatin (85) D1 + LV5FU2 regimen.

LV5FU2 = Leucovorin (100) over 2 hours, Bolus FU (400), CI5FU (600) over 22hours D1-2

40

What is the FOLFIRI Regimen?

Irinotecan (180) D1 + LV5FU2 regimen

LV5FU2:
Leucovorin (100) over 2 hours D1
FU (400) Bolus
FU (600) CI over 22 hours

41

What is the FOLFOX6 regimen?

2-hour infusion of Leucovorin
FU Bolus (400)
46hr CI5FU (2400-3000)
Oxaliplatin (100)

Q2weeks

42

What is FOLFOXIRI and what is the evidence?

5FU
Leucovorin
Irinotecan
Oxaliplatin

High activity, increased toxicity

Reserved for specific situations eg. Substantial tumor shrinkage

Falcone JCO 2007

N=250
treatment-naive
Unresectable met CLR CA
2 groups:
- FOLFOXIRI
- FOLFIRI

Results:
CR 8% vs 6%
PR 60% vs 40%
ORR 70% vs 50%
R0 resection rate 15% vs 6%
MPFS 10m vs 7m
MOS 23m vs 17m

Tox:
G2/3neurotox 20% vs 0%
G3/4 neutropenia 50% vs 30%

43

What are the side-effects of Bevacizumab?

Hypertension
Bleeding
GI Perforations (1-2%)
Arterial thrombotic events (4-5%)
?Venous thrombotic events

44

Any evidence for Capecitabine + Bev?

Yes
AVEX trial Cunningham Lancet Onco 2013

N=300
Elderly pts, >70yo
Treatment-naive, Unresectable, met CLR CA
Deemed not candidates for Ox-based or Irinotecan-based chemo
2 groups:
A) Cape (1000) BD D1-14
B) Cape (1000) BD D1-14 + Bev (7.5mg/kg) D1
Q21 days

Results:
- PFS 9m vs 5m (cape alone)
- ARE 40% vs 20%
- med OS 21m vs 17m (Cape alone)

* study underpowered to demonstrate stat significant improvement in OS

45

Any evidence for EGFR Ab + Bev + chemo?

Yes, negative and in fact harmful.

A) JCO 2009 Hecht et al
1st line tx, met CRC
2 arms:
- Panitumumab + Bev + Chemo
- Bev + Chemo
Chemo = Ox- and Irinotecan-based
Results:
- med PFS 10m (Pani) vs 11m
- med survival 19m vs 24.5m
- G3/4 adverse events 36% vs 1% (no pani)


B) NEJM 2009 Tol et al
Treatment-naive, met CLR Ca
N=750
2 arms:
- Cape + Ox + Bev
- Cape + Ox + Bev + Cetuximab
Results:
- med PFS 11m s 9m (Cetuximab)
- QoL scores lower in CBC group
- OS and RR ~
- those with KRAS mutation + Cetuximab had decreased PFS

46

Tell me some common side effects of Cetuximab

Acne-like rash, predominantly on face, upper tors
Asthenia
Fatigue
Malaise
Lethargy

47

Any evidence for Cetuximab as onto therapy?

Yes. Saltz et al. JCO 2004
Phase II

Aim: to evaluate the anti-tumor activity and toxicity of single-agent Cetuximab in chemo-refractory CLR cancer whose tumor express EGFR

S/p Irinotecan (either alone or in combination), with demonstrated clinical failure
N=60

Cetuximab weekly
- 1st dose 400 mg/m2 over 2 hours
- subsequent weekly tx at 250mg/m2 over 1 hour

Results:
10% with PR (5 patients)
21 patients with SD/minor responses
Median survival 6months

48

Any role in continuing Irinotecan beyond PD with Cetuximab?

Yes
NEJM 2004 Cunningham

N=300
Met CLR CA
Refractory to tx with Irinotecan

2 arms:
A) Cetuximab + Irinotecan
B) Cetuximab
If PD, addition of Irinotecan to Cetuximab mono therapy was permitted.

Results:
RR 20% vs 10% (monotherapy)
TTP 4m vs 1.5m (monotherapy)
Median survival 9m vs 7m - Trend

49

What is the evidence for Panitumumab?

JCO 2007 Van Cutsem

Met CLR CA
PD after std tx
N=450
1% or more EGFR staining
Measurable dz
Radiologic PD during or within 6m of most recent chemo

2 arms:
- Panitumumab + BSC
>> Panitumumab 6mg/kg Q2w
- BSC

RESULTS:
PFS 8w vs 7w (BSC)
ORR 10% vs 0%
OS~ (likely contributed by cross-over)

50

How about Cetuximab in chemo-refractory CLR CA?

Jonker NEJM 2007

N=575
CLR CA
EGFR+
S/p Fluoropyrimidine, Irinotecan, Oxaliplatin OR had contraindications to tx with these drugs

2 groups:
A) Cetuximab (400) 1st dose; 250mg/m2+BSC 2nd dose onwards weekly
B) BSC alone

RESULTS:
OS HR 0.77, in favor of Cetuximab
PFS HR 0.7 in favor of Cetuximab
Med OS 6m (Cetuximab) vs 4.5m (BSC alone)

51

What is Cetuximab

IgG1 chimeric monoclonal Antibody against Epidermal growth factor receptor

52

What do you know about Panitumumab vs Cetuximab?

ASPECCT trial
Price et al, Lancet Onco 2014
N=1000

Chemo refractory wt KRAS exon2
Met CLR CA
2 arms:
A) Panitumumab 6mg/kg Q2weeks
B) Cetuximab 400 mg /m2 --> 240mg/me Qweekly

Results:
OS ~ 10.4m (Pani) vs 10m

53

Tell me about KRAS

KRAS is a homolog of the transforming gene Kirsten rat sarcoma-2 virus

Pts with advanced CLR CA must have wt KRAS for EGFR Ab to be effective

KRAS is a phosphorylated signal transducer that self-inactivates via intrinsic GTPase activity

Several KRAS oncogene mutations result in the production of proteins with reduced GTPase activity and hence unable to self-inactivate.

In CLR Ca, mainly in exon 2, codons 12 and 13.

54

What is the frequency of KRAS exon 2 mutations in CLR CA?

~40%

55

What is the PRIME Study about?

JCO 2010
Doulliard et al
PRIME: Panitumumab Randomized trial In combination with chemotherapy for Metastatic Colorectal cancer to determine Efficacy


Treatment naive
Met CLC CA
N=1200

2 arms:
A) Panitumumab + FOLFOX4
B) FOLFOX4

Results:
Non-significant increase in OS 24m vs 20m (FOLFOX4)
PFS 9.6m vs 8m
IF mutant KRAS:
- PFS reduced significantly in Pani-folfox4 arm HR 1.29
- med OS 15.5m vs 19m

56

Tell me about the FIRE-3 trial

Lancet Oncol 2014 Heinemann

Aim: compare Cetuximab + FOLFIRI vs Bev+ FOLFIRI

N=600
KRAS Exon2 wt
Metastatic treatment naive

2 arms:
A) FOLFIRI + Cetuximab
B) FOLFIRI + Bevacizumab

Results:
Objective response ~ 62% (Cetuximab) 58% (Bev)
Med PFS ~ 10m
OS 29m (Cetuximab) vs 25m (Bev) HR 0.8 p significant

** Updated analysis accounted for additional mutations in KRAS Exon3 and NRAS. This demonstrated an even larger difference in OS of 33m (Cetuximab) vs 26m

Toxcities:
Hematotoxicities 20%~
Skin reactions 26% vs 2%(Bev)
Diarrhea 10% ~

57

Are BRAF mutually exclusive with KRAS?

Yes

Mutations of BRAF (5-10%) of patients with advanced CLR CA, are mutually exclusive with KRAS mutations

58

Tell me about BRAF-associated advanced CLR CA

Patients with BRAF mutations in Adv CLR CA are mutually exclusive with KRAS mutations

A/w very poor prognosis
Median survival 12-14m

Aggressive 1st line approach may at least partially counteract the poor prognosis
Think if pt can take FOLFOXIRI+Bev

59

Tell me what you know about the scheduling of Irinotecan?

Fuchs et al JCO 2003

FU-refractory CLR CA
N=300

2 arms:
A) Weekly x4, off 2 week
- 125m/2
B) Q3weekly
- 350mg/m2
- 300mg/m2 in those 70 and older, ECOG 2, prior pelvic RT

RESULTS:
Med f/u 16m
1y OS similar 40-50%
Med OS 10m
Med TTP 3-4m
QoL not statistically different

Toxicities:
G3/4 diarrhea in 40% of weekly pts vs 20% in Q3w tx.
Tx-related mortality in 5% of the weekly regimen vs 2% of those in Q3weekly

60

Tell me about Irinotecan

Camptothecin derivative
Also known as CPT-11
Topoisomerase-I inhibitor

Single agent activity in adv CLR CA and other solid tumors ~10%-15%, median survival ~8m

Active metabolite = SN-38
SN-38 binds to and stabilizes the Top-I DNA complex, preventing the re-ligation of DNA during replication and transcription.
Subsequent collision between this stable complex and an advancing replication fork results in dsDNA breaks and apoptosis

61

Are there any treatment options beyond 5FU/Irinotecan/Oxaliplatin?

Yes. Trifluridine-Tipiracil

Mayer NEJM 2015 RECOURSE Study

Tx-refractory with previous exposure to 5FU/Irinotecan/Oxaliplatin
N=800

2arms:
A) Trifluridine-Tipiracil
- 35mg/m2 BD 5 days a week with 2 days rest X 2weeks --> 2 week rest
B) Placebo

Results:
Med OS 5m vs 7m
Med time to worsening PS 5.7m (TAS) vs 4m

62

What is Folinic Acid?

Leucovorin

63

What is Leucovorin

Folinic Acid

64

Why is Leucovorin added to Fluorouracil?

FU has been combined with Folinic Acid to enhance the capacity of FU to bind to thymidylate synthase.

65

What is TAS-102?

Orally administered combination of:
- Trifluridine
- Tipiracil Hydrochloride

Trifluridine = active cytotoxic component of TAS-102
- It is a thymidine-based nucleic acid analogue
- Triphosphate forms gets incorporated into the DNA, resulting in anti-tumor effects.

Tipiracil Hydrochloride = Thymidine phosphorylase inhibitor
- Prevents the rapid degradation of Trifluridine
- allows for maintenance of adequate plasma levels of the active drug.

66

What is the evidence for TAS-102?

RECOURSE Study by Mayer et al NEJM 2015

N=800
Known KRAS status
Prior chemo with Fluoropyrimidine ,Oxaliplatin, Irinotecan, Bevacizumab, +/- Cetuximab/Panitumumab

RESULTS:
Med OS 5m (Placebo) vs 7m (HR 0.7)
Med time to worsening PS 4m (placebo) vs 6m
Med PFS ~ 2m
ORR 1.6% (TAS-102) vs 0.4% (Placebo)

67

What is Grothey's 3-Drug hypothesis?

JCO 2004 by Grothey
7 phase III trials in adv CRC

Median OS is strongly correlated with exposure to all 3 active chemo drugs.

Only exposure to all 3 drugs but not to initial doublet chemo was significantly a/w OS
Pts who received doublet chemo as 1st line have higher chances of receiving all 3 active agents

Use of combination protocols a/w sig improvement in med survival of 3.5months

68

Tell me about Desmoid tumors

Second only to colorectal cancer as a common cause of death among patients with FAP

Heterogeneous presentation
- asymptomatic abdominal mass to bowel obstruction or urethral obstruction

Sporadic Desmoid tumors also occur

Possible palliative options include:
- Chemotherapy
- Hormonal therapy
- Targeted therapy such as imatinib

69

Describe Muir-Torre syndrome

Multiple colon cancers
Multiple cutaneous neoplasia, including sebaceous adenomas

70

FAP is characterized by...?

Chromosomal instability due to mutations in the APC tumor suppressor gene

71

What is HNPCC characterized by?

MSI caused by mutations in the DNA MMR genes

Most common hereditary syndrome predisposing to CLR CA
Lifetime risk for developing colon cancer among patients with HNPCC approaches 80%

Also a/w other malignancies:
- endometrial
- gastric
- ampullary
- biliary
- urinary tract cancers

72

What are the other associated cancers with HNPCC?

Colon cancers
Endometrial cancers
Gastric cancers
Ampullary cancers
Biliary cancers
Urinary tract cancers

73

How can HNPCC be confirmed by?

Demonstration of MSI-H phenotype +
Germline mutation in any of the DNA MMR genes:
- MLH1 on chr 3p
- MSH2 on chr 2p
- MSH6 on chr 2p
- PMS1 on 2q
- PMS2 on 7q

Germline mutations involving MSH2 and MLH1 genes account for >60% of the known mutations present in HNPCC

NCCN recommends:
1) Tumor screening with MSI
2) Lack of expression of MMR protein expression by IHC
3) MMR mutation testing

74

How is 5FU eliminated?

>80% eliminated via the DPD enzyme

DPD enzyme deficiencies are at high risk of 5FU toxicities

75

What are the 5FU Toxicities, esp related to DPD enzyme deficiencies

Severe neutropenia
FN
Diarrhea, mucositis
Cerebellar ataxia, neurotoxicity
Death

Most common mutation = IVS14 + 1G>A, DPYD*2A mutation

76

What is TSER *3/*3 genotype a/w ?

TSER *3/*3 genotype is a/w higher levels of thymidine synthase and Lower tumor response to 5FU therapy

77

Tell me about MYH-associated Polyposis

AR disease
MYH Gene, a base-excision repair Gene
Deficiency in MYH leads to somatic mutations in APC Gene
- not Germline
Clinical features similar to FAP

78

Tell me about MYH-associated Polyposis

AR disease
MYH Gene, a base-excision repair Gene
Deficiency in MYH leads to somatic mutations in APC Gene
- not Germline
Clinical features similar to FAP

79

Which genetic change is a/w resistance to treatment with Cetuximab?

KRAS mutation
BRAF V600E mutation

80

Tell me about the MRC FOCUS study

Matthew Seymour Lancet 2007
One of the trials that showed sequential chemotherapy was a viable option as cf to combination chemo in treatment naive met colorectal cancer

N=2000
Advanced CLR CA
3 arms:
A = control group = CI FU/LV 48hr q2w --> Irinotecan
B = FU --> Combination chemo
C = Combination chemo

Combination chemo = FU/Iri or FU/Ox
= B-ir and C-ir
= B-Ox and C-ox

Results:
Median survival = 14m (A); B-ir 15m, B-Ox 15m, C-ir 17m C-Ox 15m

81

What are the 3 trials that support sequential use over combination use of chemo agents in met CLR CA?

1) CAIRO-1
2) MRC-FOCUS
3) FFCD-2000-05

82

Tell me about the FFCD 2000-05 trial

Ducreux Lancet Oncol 2011

Aim: to evaluate if combination Tx > Sequential Tx in adv CLR CA

N=400
Advanced CLR CA
Treatment-naive

2arms:
A) Simplified LV5FU2 regimen --> FOLFOX6 --> FOLFIRI
- Bolus 5FU (400) + CI 5FU(2400)+ Leucovorin (400) --> L5FU2+Ox (100) --> LV5FU2+Iri (180)
B) FOLFOX6-->FOLFIRI
Both Q2w

RESULTS:
Med PFS after 2lines 10.5m (Sequential) vs 10.3m (Comb)
6 deaths due to toxic effects of treatment occurred in combination go up
Fewer G3/4 SE significantly in sequential groups for hematological and non-hematological.

Conclusion --> Upfront Combination chemo more toxic and not more effective than sequential

83

Re: Sequencing of agents, which trials tell us what?

FOLFOX, FOLFIRI largely comparable

1) JCO Colucci 2005
2) JCO Tournigand 2004

84

What are the studies that discuss re: maintenance vs intermittent chemo?

OPTIMOX-1
OPTIMOX-2
MRC COIN
CAIRO3

85

What is the OPTIMOX-1 study?

Tournigand JCO 2006
Aim: To evaluate the efficacy of intermittent Oxaliplatin Tx as opposed to continuous Tx.

N=600
+ exploratory cohort of 100 elderly/poor prognosis

2arms:
A) FOLFOX4
- Leucovorin + FU Bolus (400) + 22hr CI5FU (600) D1-2
- Ox (85) D1
- q2weeks
B) 6 FOLFOX7 -->12# (s)LV5FU2 --> 6FOLFOX7
- FOLFOX7= 2hr Leucovorin + CI5FU (2400) 46hours + Ox (130) on D1 q2w
- (s)LV5FU2 = Leucovoin/Bolus 5FU(400) + CI5FU(3000) over 46hr q2w

RESULTS:
Med PFS 9m (A) vs 9m (B)
Med OS 20m (A) vs 21m (B)
RR ~60%
G3 sensory neuropathy 18% (A) vs 13% (B)

Conclusion: Ox can be safely stopped after 6# in a FOLFOX regimen

86

Tell me about the OPTIMOX2

Chibaudel JCO 2009

Aim: To compare chemo discontinuation vs maintenance therapy after 6#FOLFOX

N=200
Met CLR CA
Tx-naive

2arms:
1) Arm 1 = maintenance arm = 6mFOLFOX7 --> Leucovorin+Bolus & Infusional 5FU until PD -->mFOLFOX7
2) Arm 2 = CFI arm = 6#mFOLFOX7--> complete Stop --> reintroduction of mFOLFOX7 after tumor PD

RESULTS:
Median duration of disease control (DDC) 13m v 9m (CFI)
Med PFS 9m (maintenance) vs 7m (CFI)
Med OS 24m (maintenance) vs 20m (CFI)
ORR ~60%

87

Tell me about the MRC COIN trial

Richard Adams Lancet Oncol 2011

Aim: assess if OS on intermittent Tx was non-inferior to that of continuous chemo

N=1600
Txt naiive

3 arms:
A): Continuous Ox+5FU
B): Continuous Tx + Cetuximab
C): Intermittent chemotherapy
- Chemo x12 weeks---> CFI until PD --> Chemo

RESULTS:
Median survival ITT: 16m (A) vs 14m (C)
Raised baseline platelet a/w poor survival with intermittent chemo
G3/worse hematological Toxic effect 15% vs 12%
N/V more common on intermittent therapy
G3/worse peripheral neuropathy 30% vs 5%
G3/worse HFS 4% vs 3%

Conclusion:
- did not show non-inferiority of intermittent tx
- but remains a Tx option as it decreases time on chemo, reduced cumulative toxic effects and improved QoL.

88

Tell me about the CAIRO3

Simkens Lancet 2015

Aim: to determine the efficacy of maintenance txt with Cape+Bev vs observation

N=550
Previously untreated met CLR Ca with stable disease or better after induction treatment
Induction Tx: 6#Cape/Ox/Bev q21days

2arms:
A) Maintenance : Cape/Bev
B) Observation group

On 1st PD = PFS1, patients then receive CAPOX-B until 2nd PD = PFS2

RESULTS:
- median f/u 4 years
- PFS2 better with maintenance 12m vs 9m
- Med OS 18m vs 22m (maintenance) - trend

89

What is the evidence for Irinotecan as first-line in met CLR CA?

Douillard et al Lancet 2000

Aim: To investigate the efficacy of Irinotecan+FU as first-line tx.

N=400
Met CLR CA, treatment-naive

2 arms:
A) Irinotecan + 5FU/Leu
B) 5FU/Leu

Results:
RR 50% (Iri) vs 30%
TTP 7m vs 4m
OS 17m vs 14m

90

Why is an Infusional-based schedule of 5FU is preferred when using with Irinotecan?

Fuchs et al JCO 2007. BICC-C study

Aim: To compare 3 different Irinotecan-containing regimens in 1st line setting of previously untreated met CLR CA patients

N=400
3arms:
A) FOLFIRI
B) mIFL
C) CapeIRI
* initially a double-blind treatment with celecoxib/placebo
** Protocol amendment:
>> add Bevacizumab
>> CapeIRI arm discontinued, because of greater toxicity of CapeIRI + paucity of safety data for combination of CapeIRI+Bev.

RESULTS:
Med PFS 8m (FOLFIRI) vs 6m (IFL) vs 6m (CapeIRI)
Med OS 23m (FOFIRI) vs 18m (mIFL) vs 19m (CapeIRI)
ORR ORR~ 47% (FOLFIRI) 43%(mIFL) 29% (CapeIRI)

91

Tell me about the Arkenau pooled analysis

Arkenau JCO 2008
Pooled analysis of 6 randomized phase II and III trials
Aim: investigated role of Ox in combination with Capecitabine or Infusional FU in met CRC. Meta-analysis to compare the efficacy

N=3500

RESULTS:
Higher RR for FU-based regimens
PFS and OS similar

92

Any evidence AGAINST FOLFOXIRI?a

Yes.
HORG study by Souglakos in BJC 2006

N=280
2 arms:
A) FOLFOXIRI
B) FOLFIRI

RESULTS:
No difference in OS/TTP/RR
But observed med OS of 21.5m is one of the best ever reported

93

What is the difference in regimen of FOLFOXIRI in the Falcone study and HORG study?

FOLFOXIRI
A) HORG study
- Day 1: Irinotecan (150mg/m2 30min infusion)
- Day 2: Oxaliplatin (65) as 2h infusion at same time as LV
- Day 2+3: LV (200) +Bolus 5FU (400) +22h CI5FU (600)

B) FALCONE
- Day1: Irinotecan (165) over 1hour + Oxaliplatin (85) over 2 hours + LV (200) over 2 hours
- Day 1-3: CI5FU (3200)

94

What is Cetuximab?

Recombinant chimeric IgG1 monoclonal Ab to EGFR
Competitive inhibitor of EGFR
Binds specifically to EGFR and with greater affinity than EGF or other Ligands (eg. TGF alpha)

Possible IgG1 related ADCC anti-tumor effects shown in vitro

95

What are the trials with Cetuximab as 1st line?

1) Van Cutsem ASCO 2007 - CRYSTAL phase 3 study
N=1200, previously treated EGFR+patients
2arms:
- FOLFIRI + Cetuximab
- FOLFIRI
PFS 9m vs 8m
1yPFS 30% s 20%
RR 50% vs 40%

2)Tabenero JCO 2007 Phase 2
n=40 EGFR+
FOLFOX4 + Cetuximab
RR 70%, PFS 12m, OS 30m

3) Venook ASCO 2006 CALGB Phase 3
- Tx-naive, regardless of EGFR
- n=240
- 2 X 2 factorial:
>> FOLFOX or FOLFIRI
>> Cetuximab or no Cetuximab
- RR 50% vs 30%

4) OPUS Study by Bokemeyer ASCO 2007 2008
- randomized phase 2
- n=340 EGFR+
- 2 arms:
>> FOLFOX4 + Cetuximab
>> FOLFOX4
- RR 46% vs 36%

5) Borner Ann Oncol 2008
- phase 2 randomized, n=74 previously untreated, EGFR+
- XELOX +/- Cetuximab
- PR 40% vs 15%
- SD 35% vs 60%
- TTF 7m vs 6m
- OS 21m vs 17m

96

What are the 2nd line studies for Cetuximab?

1) JCO 2004 Saltz et al
- phase 2, EGFR+ who failed Irinotecan n=60
- PR 9%, SD 36% OS 6m

2) EPIC study Sobrero JCO 2008
- Phase 3, s/p 5FU and Ox failure
- n=1300 EGFR +
- 2 arms:
>> Cetuximab+ Irinotecan
>> Irinotecan
- OS 10.7m vs 10,
- PFS 4m vs 2.m
- CR 1.4% vs 0.2%
- 47% on Irinotecan arm go on to receive Cetuximab, this may explain lack of difference in OS

3) 2nd and 3rd Line Cunningham NEJM 2004
- s/p Irinotecan failure
- n=330 (regardless of EGFR status)
- 2 arms:
>> Cetuximab+ Irinotecan
>> Cetuximab alone
- PR 23% s 11% ; SD 30% vs 20%
- TTP 4m vs 1.5m
- OS 9m vs 7m

97

What are the 3rd Line evidence for Cetuximab?

1) Cunningham NEJM 2005
- Phase 3
- Cetuximab+Iri vs Cetuximab alone
- previous Irinotecan failure
N=330
- PR 23% vs 11%
- SD 30% vs 20%
- TTP 4m vs 1.5m
- OS 9m vs 7m

2) Jonker NEJM 2007- NCIC CTG phase 3
- n= 580 EGFR + patients
- prev tx with or contraindicated to 5FU, Irinotecan and Oxaliplatin
- Randomised to: Cetuximab vs BSC
- OS 6m vs 4.6m
- PR 8% vs 0%

3) Lenz JCO 2006
- Phase 2 n=350 EGFR positive patients refractory to 5FU/Oxaliplatin and Irinotecan,
- all patients received Cetuximab monotherapy
- PR 12%
- PFS 1.5m
- OS 6.6m

98

How common is K-RAS mutation?

Activating K-RAS mutations in exon 2 are found in 40-45% of met CLR Ca

99

What are the 2 conditions in which met CLR CA can be treated?

1) resectable mets
2) initially Unresectable disease rendered suitable for resection

100

What are the goals of treatment in Unresectable mCRC?

Treatment is seen as a continuum of care.

Prolongation of survival
Cure
Improving tumor-elated symptoms
Stopping tumor progression
Maintaining QoL

101

What is systemic treatment of mCRC comprised of?

1) Cytotoxic agents
2) Biological targeted agents
- Anti-VEGF strategies
- Anti-EGFR strategies
- Multi-kinase inhibitors

102

What is the benefit of combination chemo?

Higher RR
Longer PFS
Better OS

103

Tell me about Aflibercept

Anti-VEGF
A recombinant fusion protein
Blocks: VEGF-A, VEGF-B, Placenta Growth factor

Improves OS, PFS and RR when combined in 2nd line with FOLFIRI in Oxaliplatin-pretreated patients
- regardless of whether Bev was given in first line

Similar toxicity pattern as Bev:
- mucosal bleeding, Arterial thrombosis, hypertension, intestinal peforation, proteinuria, wound healing problems
- **unlike Bev, Aflibercept increases chemo-related side-effects such as diarrhea, neutropenia, Asthenia and stomatitis

104

What is the expanded RAS analysis?

Detection of mutations in:
Exon3 of KRAS Gene
Exon4 of KRAS Gene
Exon2-4 of NRAS Gene

In addition to KRAS Exon 2

105

Name me the side-effects of Regorafenib

Specific HFS
Fatigue
Transaminitis

106

What are the 4 clinically defined groups in deciding treatment strategy as per ESMO Guidelines?

1) Group 0 - primarily technically R0-resectable liver/lung mets + no biological relative contraindications
- Upfront resection

2) Group 1 - Potentially resectable met disease with curative intention
- Downsize disease by chemo
- enable secondary surgery to allow disease-free status
--> most active induction chemo
- Anti-EGFR Ab appear to be more effective in tumor shrinkage than Bev-based combinations

3) Group 2 - disseminated disease, technically "never"/unlikely resectable intermediate intensive treatment
- Treatment intent is palliative largely
- in those who are symptomatic/more aggressive biology/extensive disease, very active 1st-line Tx with high likelihood to induce mets regression in short time
--> Consider cytotoxic doublet + Targeted agent
- In oligometastatic patients ablative methods should be additionally considered, as they may allow a progression-free interval even without systemic treatment.

4) Group 3 - Never-resectable metastatic disease - non-intensive/sequential treatment
- Maximal shrinkage of mets is NOT the primary aim
- Aim is prevention of tumor progression & prolongation of life with minimal treatment burden
--> Combination cytotoxic+/- biological targeted agent OR escalation strategy may start with FP+ Bev

107

What is considered sufficient remnant liver?

>30%

108

What is the 5-yr survival rates in R0-resectable colorectal liver mets?

20-45%

109

What is th 5-yr survival rates in R0-resectable colorectal lung mets?

25-35%

110

What are the 2 potential strategies for (neo)- adjuvant therapy in those with resectable liver mets?

1) Post-op adjuvant chemo with FOLFOX for 6 months
2) Peri-op chemo
- 3 months before and 3 months after resection of mets

111

What are the different histological changes in liver parenchyma that Oxaliplatin and Irinotecan may cause?

Oxaliplatin = sinusoidal liver lesions
Irinotecan - steatohepatitis

112

What are the high-risk factors for recurrence?


(Histology, Invasion, Perforation, Margins, Obstruction, LN)

poorly differentiated Histology
lymphatic / vascular / perineural Invasion
localized Perforation

Margins - close/indeterminate/positive
bowel Obstruction

113

On pathology review, what is considered as a Positive margin for endoscopic ally removed malignant polyps ?

No consensus as to the definition but:
1) Tumor

114

What is the minimum number of LN that needs to be evaluated?

12

115

What is hepatic artery infusion?

Placement of a hepatic arterial port or implantable pump during surgery for liver resection with subsequent infusion of chemo directed to the liver mets through the hepatic artery.

116

Tell me about the SIRFLOX trial

Aim: To assess efficacy and safety of adding SIRT to standard FOLFOX-based chemo in treatment-naive patients

Treatment-naive, liver mets +/- limited extra hepatic mets.
2x2 factorial design:
- mFOLFOX6 + SIRT +/- Bev
- mFOLFOX6 - SIRT

RESULTS:
- PFS (any site): no difference ~10-11m
- PFS (Liver): 13m vs 21m (in favor of FOLFOX+Bev+SIRT)
- ORR (any site): trend: 67% vs 72%
- ORR (Liver) 70% vs 80%

117

What're are the SIRT-associated events?

Gastric/duodenal ulcer (4%)
Ascites (3%)
Hepatic failure (1%)
aviation hepatitis (1%)

118

What is SIRT?

Selective Internal Radiation Therapy

Employs Yttrium-90 (Y-90) labeled resin microspheres as liver-directed therapy.

Hepatic artery injection
Delivers a single large radiation dose to liver tumors with radiation deposited over 3 weeks
FDA approved in 2002 for Unresectable CRCLMs

119

What are the liver-directed therapies that you know about in CLR CA?

1) Hepatic Arterial Infusion
2) Arterially Directed Embolic Therapy
- TACE
3) Liver-Directed Radiation
- Radioembolization
4) Tumor Ablation
- RFA
- Microwave ablation
- Cryoablation
- Percutaneous ethanol injection
- Electro-coagulation

120

When the remnant liver is insufficient in size based on cross-sectional imaging volume tricks, what can be done?

Pre operative portal vein embolization of the involved liver can be performed to expand the future live remnant

121

What are the advantages to pre-op chemo?

Earlier treatment of micro mets disease
Determination of responsiveness to chemotherapy (which can be prognostic, and help in planning postop therapy)
Avoidance of local therapy for those with early PD

122

Potential disadvantages of pre-op chemo

Missing "window of opportunity" for resection due to PD
Achieve tent of CR, making it difficult to identify areas for resection
Potential for development of liver steatohepatitis/sinusoidal injury

123

What syndromes are a/w deficiencies in UGT 1A1?

Crigler-Najjar Types I and II
Gilbert Syndrome

124

Any evidence for FOLFOXIRI + Bev?

Yes. TRIBE trial

Phase III
Unresectable met CLR CA
FOLFOXIRI/Bev vs FOLFIRI/Bev

RESULTS:
FOLFOXIRI/Bev significantly increase PFS 12m vs 10m HR 0.75
RR 65% vs 50%
Updated analysis : Median OS 30m vs 26m

Subgroup analysis:
60% had adjuvant Oxaliplatin. In this group, no benefit to addition of Ox

125

What is the Half-life of Bev?

3 weeks

126

What is Ziv-Aflibercept?

Recombinant protein that has part of the human VEGF Receptors 1 and 2 fused to the Fc portion of human IgG1

Designed to function as a VEGF trap to prevent activation of VEGF receptors and thus inhibit angiogenesis

127

What is the VELOUR trial

Tested 2nd-line Ziv-Alfibercept in met CLR CA who had PD after one Ox-containing regimen

2 arms:
- FOLFIRI-ziv-Aflibercept
- FOLFIRI/placebo

Results:
OS 13.5m vs 12m

128

What is Ramucirumab?

Anti-angiogenic agent
Human monoclonal antibody that targets the extracellularly domain of VEGFR-2 --> Blocking VEGF signaling.

129

What is the evidence for Ramucirumab in met CLR CA?

RAISE Study
Phase III=1000
Met CLR CA PD on 1st-line Tx: FU/Ox/Bev

Randomized to:
- FOLFIRI+Ramucirumab
- FOLFIRI+Placebo

Results:
- OS: 13m vs 12m HR 0.8
- PFS 6m vs 4.5m HR 0.8

130

What does Regorafenib inhibit

VEGFR
Fibroblast growth factor receptors (FGF)
PDGFR
BRAF
KIT
RET

131

What is the evidence of Regorafenib?

1) CORRECT
- n= 760, phase III
- PD on standard therapy
- 2 arms: Placebo or Regorafenib
- OS 6.4m vs 5m HR 0.8
- PFS 1.9m vs 1.7m

2) CONCUR trial
- China/HK/S.Korea/Taiwan/Vietnam
- progressive met CLR Ca, PD after 2 or more lines
- Regorafenib vs placebo
- OS 9m vs 6m HR 0.55

132

How does Pembrolizumab work?

Pembrolizumab is a humanized, IgG4 monoclonal Ab
Binds to PD-1 with high affinity
This prevents PD-1 from interacting with PD-L1 and PD-L2, allowing immune recognition and response

133

What did the BICC-C study conclude?

Fuchs et al JCO 2007
N=400
Treatment-naive

3 arms:
1) FOLFIRI
2) mIFL
3) CapeIRI
Protocol amendment : additional 100 pts added and randomized to FOLFIRI+ Bev vs mIFL+Bev, CapeIRI stopped

RESULTS:
med PFS 7.5m FOLFIRI, 6m mIFL, 6m CapeIRI
Med OS 23m FOLFIRI, 17.5m mIFL, 19m CapeIRI
CapeIRI a/w higher rates of vomiting/diarrhea/dehydration
After amendment, med survival time for FOLFIRI+Bev not reached, but 19m for mIFL+Bev

Conclusion:
- FOLFIRI and FOLFIRI+Bev offered superior activity to comparators, and were safe
- Infusional schedule of 5FU should be the preferred Irinotecan-based regimen in first-line met CLR CA

134

Any evidence to show Bevacizumab improves OS and PFS?

Yes
Hurwitz NEJM 2004

Untreated met CLR CA, n=800
2 arms:
- IFL + Placebo
- IFL + Bev

RESULTS:
- med OS 20m vs 15.5m (Placebo)
- med PFS 10.5m vs 6m
- RR 45% vs 35%

135

What is the evidence to show the antagonistic effect of EGFR Ab and Bevacizumab when used concurrently?

1) Hecht et al JCO 2008
2 arms, n=1000:
- Chemo/Bev/Pani
- Chemo/Bev
RESULTS:
- Med PFS 10m vs 11.5m(control)
- Med survival 19.5m vs 24.5m
- Increased toxicity in Panitumumab of Irinotecan cohort.

20 NEJM 2009 Tol et al
N=750
2 arms:
- Chemo/Bev/Cetuximab
- Chemo/Bev
RESULTS:
- med PFS 11m (CB) vs 9m (CBC)
- QoL lower in CBC group, more G3/4 events

136

What has anaphylaxis to Cetuximab been correlated to?

Presence of pre-existing serum IgE Ab to oligosaccharide, galactose-alpha-1,3-galactose

137

What is the Bethesda Criteria?

1) Cancer in the family tt fulfills the Amsterdam criteria
- FAP excluded
- 3 or more family members with CLR CA, at least 2 of whom must be 1st degree relatives.
- At last 2 successive generations affected
- Development of CLR Ca must occur before 50yo
2) CLR Ca or endometrial Ca Dx before 45 yo
3) R sided colon CA it's an undifferentiated pattern on histo evaluation, Dx 45 yo
4) Signet ring cell-type colorectal cancer Dx before 45 yo
5) Adenoma diagnosed before 40yo
6) Development of 2 HNPCC-related extracolonic cancers in one individual (I.e. Endometrial, small intestine, ovarian, gastric)
7) Development of CLR ca in an individual who has a first-deg relative with CLR ca and/or HNPCC-related extracolonic cancer and/or colorectal Adenoma.
- Ca Dx before 45 yo and Adenoma before 40

138

Tell me about the CRYSTAL Study

Van Cutsem JCO 2011 (update)
Original NEJM 2009
Aim: Invx efficacy of FOLFIRI+Cetuximab as 1st line treatment for mCLR CA
- Also to check associations between KRAS mutation status and clinical response to Cetuximab.

N=1200


2 arms:
1) FOLFIRI
2) FOLFIRI + Cetuximab

RESULTS:
(a) 2009: No Significant differences in OS btwn the 2 groups
- HR for PFS among wtKRAS = 0.7 in favor of the Cetuximab group.
- med OS in wtKRAS group 25m vs 21m
- med OS in mtKRAS group 17.5 ad 17.7m (FOLFIRI)
(b) Median OS 23.5m (Cetuximab) vs 20m
PFS 10m vs 8.5m
RR 57% vs 40%

CONCLUSIONS:
KRAS mutation status was confirmed as a powerful predictive bio marker for Cetuximab+FOLFIRI efficacy.
BRAF tumor mutation was a strong indicator of poor prognosis

The CRYSTAL study results are consistent with the updated data from the OPUS study which confirmed that:
KRAS tumor mutation status as an effective bio marker for the efficacy of Cetuximab + Oxaliplatin/LV/CI 5FU in first-line TC of patients with KRAS wtype mCRC

139

Tell me about the OPUS study

JCO 2008, Bokemeyer
Update Ann Onco 2011

N= 300
Met CLR Ca treatment-naive

2 arms:
1) FOLFOX4 + Cetuximab
2) FOLFOX4

RESULTS:
- ORR 46% vs 36% (FOLFOX4)
- wtKRAS: ORR 60% vs 37% (FOLFOX4)
- wtKRAS: lower risk of disease progression HR 0.57
- ITT population: OS not different. Median survival 18m~
- wtKRAS group:
>> RR 60% vs 35%
>> med PFS 8m vs 7m
>> OS 23m vs 18.5m (trend)
- mtKRAS group:
>> RR 35% vs 55%(FOLFOX)
>> Med PFS 5.5 vs 8.5m
>> Med OS 17.5m vs 13.5m
- Comparing wt vs mt + received Cetuximab
>> OS 23m vs 13.5m
- Comparing wt vs mt + NO Cetuximab:
>> OS 18.5m vs 17.5m

140

Tell me about the EPIC study

Alberto Sobrero JCO 2008

N=1300
Met CLR CA
Previously s/p Fluoropyrimidine+Oxaliplatin

2arms:
1) Cetuximab + Irinotecan
2) Irinotecan (350 mg/m2 Q3w)

RESULTS:
- Med OS comparable 10.7m vs 10m (Iri)
>> 45% of those assigned to Irinotecan alone eventually received Cetuximab
- Med PFS 4m vs 2.5m
- RR 16.5% vs 4%
- improve QoL

141

Tell me about the PRIME study

Douillard et al JCO 2010

Aim: To evaluate efficacy and safety of Panitumumab + FOLFIRI in First line setting for met CLR CA.
- Panitumumab already approved as monotherapy for chemo-refractory met CLR CA

N=1200

2 arms:
1) Panitumumab + FOLFOX4
2) FOLFOX4

RESULTS:
(A) wt KRAS:
- improved PFS 9.6m vs 8m HR 0.8
- OS 24m vs 20m (Trend)
(B) mt KRAS:
- med OS 15.5m vs 19m (no Pani)

142

Tell me about the New EPOC study

Primrose Lancet Oncology 2014

B/g:
Surgery for liver met result in OS of 40% at 5 years.
Aim: To assess benefit of adding Cetuximab to standard chemotherapy in those with resectable CLR liver met

N=250
KRAS exon 2wt
Resectable or sub optimally resectable CLR Liver met

2 arms:
1) Chemo
2) Chemo+ Cetuximab before and after liver liver resection

Chemo: FOLFOX or XELOX or FOLFIRI (if adjuvant Ox given)

RESULTS:
PFS: 14m vs 20.5m(without Cetuximab)