Andrés Cervantes

Cáncer de Colon: Resultados de los estudios CRYSTAL, FIRE3 y CALGB-80405

R

CRYSTAL study design

Presented by: Eric Van Cutsem

FOLFIRI + cetuximab

n=599(KRAS codon 12/13 WT, n=316)

Stratification factors:ECOG performance status Region

Treatment until disease progression, unacceptable toxicity, withdrawal of consent

Irinotecan

5-FU

LV

FOLFIRI (q2w)

400 mg/m2 initial dose then

250 mg/m2 weekly

180 mg/m2, day 1

400 mg/m2 bolus, then

2400 mg/m2 infusion over 46 h

200 mg/m2*, day 1

Cetuximab

n=1198(KRAS codon 12/13 WT, n=666:PCR clamping and melting curve

analysis)

R

FOLFIRIn=599

(KRAS codon 12/13 WT, n=350)

EGFR-expressing, previously untreated,

mCRC

*L-form; 400 mg/m2, racemic. 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; LV, leucovorin; PCR, polymerase chain reaction; R, randomization; WT, wild-type

Van Cutsem E, et al. N Engl J Med 2009;360:1408-17Van Cutsem E, et al. J Clin Oncol 2011;29:2011-9

RAS mutation analysis: BEAMing

Presented by: Eric Van Cutsem

• KRAS and NRAS codons screened for particular missense* mutations:

– KRAS exon 3; codons 59, 61

exon 4; codons 117, 146– NRAS exon 2; codons 12, 13

exon 3; codons 59, 61

exon 4; codons 117, 146

• In line with other techniques which may be used clinically to determine RAS mutation status, a cutoff of ≥5% mutant to wild-type alleles was selected

– Tumors were scored as RAS mutant if mutant alleles were detected at a prevalence of ≥5% of total amplified sequences, regardless of whether all loci were evaluable

– Tumors were scored as RAS wild-type only if all 26 mutation assays were evaluable and prevalence of mutations was <5%

*Resulting in a change in the specified amino acid

Study profile

Presented by: Eric Van Cutsem

Tumors evaluable for KRAS codon 12/13 status

n=530

FOLFIRI alonen=599

Randomized and treated;full analysis population

n=1198

FOLFIRI + cetuximabn=599

KRAS codon 12/13 wild-type

n=316

KRAS codon 12/13 mutant

n=214

Tumors evaluable for KRAS codon 12/13 status

n=533

KRAS codon 12/13 mutant

n=183

KRAS codon 12/13 wild-type

n=350

RAS wild-type

n=189

Other RAS mutant

n=31

Evaluable forRAS status

n=220

RAS wild-type

n=178

Other RAS mutant

n=32

Evaluable forRAS status

n=210

Any RAS mutant n=214

Any RAS mutant n=246

Other RAS mutations: CRYSTAL

Presented by: Eric Van Cutsem

KRAS

NRAS

3.3% 5.6%

EXON 3 EXON 4EXON 2

11759 61

2.8% 0.9%

EXON 2 EXON 3 EXON 4

12 13 11759 61

12 13

WT

3.5%

146

146

In 5 tumors with KRAS mutations, an NRAS mutation also detected (low prevalence, 0.1%–<5%, in 4/5 samples)In 1 tumor, 2 NRAS mutations detected (1 with low prevalence)

Percentages relate to fraction of RAS evaluable patients with mutations in particular exons

430/666 patients with KRAS codon 12/13 wild-type tumors evaluable for tumor RAS statusOther RAS mutations: 63/430 (14.7%) patients

RAS mutation rates: first-line studies

Study Evaluable patients*

Method Other RAS mutations, %

CALGB/SWOG 80405

670 BEAMing†† 15.3

OPUS 118 BEAMing† 26.3

CRYSTAL 430 BEAMing† 14.7

FIRE-3‡ 407 Pyrosequencing 16.0

PRIME§ 620 Dideoxy sequencing/WAVE 17.4

PEAK 221 Dideoxy sequencing/WAVE 23.1

*For other tumor RAS mutations†5% mutant/wild-type alleles diagnostic cutoff† †1% mutant/wild-type alleles diagnostic cutoff‡KRAS codons 59 and 117 not considered§KRAS and NRAS codon 59 not considered

Patients with KRAS codon 12/13 wild-type tumors

Van Cutsem E, et al. J Clin Oncol 2015; 33: ahead of print.

PFS

OS

EFFICACCY ACCORDING TO RAS SUBGROUPS

Progression-free survival

Presented by: Eric Van Cutsem

KRAS codon 12/13 wild-type* RAS wild-type

178 153 114 75 31 8 4 0 0189 154 92 44 11 5 3 0 0

Pro

bab

ility

of

PF

S0 3 6 9 12 15 18 21 24

FOLFIRI + cetuximabFOLFIRI

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Number of patients at risk

Months

HR (95% CI) 0.56 (0.41–0.76)

No. of eventsMedian, months95% CI

7311.410.0–14.6

998.47.4–9.4

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 4 8 12 16 20

Pro

bab

ility

of

PF

S

Months

316 227 128 40 8350 237 111 22 4

Number of patients at risk

10

HR (95% CI) 0.70 (0.56–0.87)

No. of eventsMedian, months95% CI

1469.99.0–11.3

1898.47.4–9.2

FOLFIRI + cetuximabFOLFIRI

*Van Cutsem E, et al. J Clin Oncol 2011;29:2011-9

Overall survival

Presented by: Eric Van Cutsem

RAS wild-type

Pro

bab

ility

of

OS

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

178 174 163 155 142 140 128 108 97 89 73 66 56 52 45 29 16 5 3 0

189 182 171 160 135 115 98 85 79 70 58 47 38 32 28 20 10 6 2 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Number of patients at risk

Months

FOLFIRI + cetuximabFOLFIRI

HR (95% CI) 0.69 (0.54–0.88)

No. of eventsMedian, months95% CI

13028.424.7–31.6

15420.217.0–24.5

KRAS codon 12/13 wild-type*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ility

of

OS

Months

HR (95% CI) 0.80 (0.67–0.95)

No. of eventsMedian, months95% CI

24223.521.2–26.3

28820.017.4–21.7

0 6 12 18 24 30 36 42 48 54

316 281 237 198 144 108 82 65 21 4

350 311 246 179 132 92 64 48 18 2

Number of patients at risk

FOLFIRI + cetuximabFOLFIRI

*Van Cutsem E, et al. J Clin Oncol 2011;29:2011-9

Conclusions

Presented by: Eric Van Cutsem

• This retrospective subgroup analysis supports the use of FOLFIRI + cetuximab as first-line treatment in patients with RAS wild-type mCRC

– Significant improvements in PFS (HR 0.56), OS (HR 0.69) and ORR (odds ratio 3.11) associated with addition of cetuximab to FOLFIRI

– No benefit nor deleterious effect seen in patients with RAS mutations

• The safety profile in the RAS wild-type and RAS mutant subgroups is similar and in line with expectations

• Exclusion of patients with other RAS mutations from the KRAS codon 12/13 wild-type treatment population improves the benefit-risk ratio associated with the addition of cetuximab to FOLFIRI

• Molecular testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment for patients with mCRC

FIRE-3 study design

FOLFIRI + CetuximabCetuximab: 400 mg/m2 i.v. 120min initial dose

250 mg/m2 i.v. 60min q 1w

FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w

mCRC1st-line therapyKRAS wild-type

Randomize 1:1

• Primary endpoint: Overall response rate (RECIST 1.0)

• Amendment in October 2008 to include only KRAS wild-type patients

• 150 active centers in Germany and Austria

FOLFIRI q2w: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2 irinotecan: 180 mg/m2

5-FU: 2,400 mg/m2 (i.v. 46h)

Heinemann V, et al. Lancet Oncol Lancet Oncol. 2014 Sep;15(10):1065-75

Cetuximab + CT Bevacizumab + CT p value

Overall response rate (primary endpoint not met)

62% 58% 0.183

Progression-free survival 10.0 months 10.3 months 0.547

Cetuximab + CT (FOLFIRI) (n=297)

Bevacizumab + CT (FOLFIRI) (n=295)

OS

est

imat

e

HR=0.77p=0.017

28.7months

25.0 months

Overall survival

0.75

1.0

0.50

0.25

0.012 24 36 48 60 72

Months since start of treatment

FIRE-3 study results

ITT KRAS exon 2 wild-type population

Tumor samples

N= 488 (82.4%)tumor material available of

KRAS wild-type ITT

• DNA of insufficient quality: 13

N= 475 (80.2%)RAS mutational analyses

successful in all RAS locations

• not KRAS wild-type ITT: 115

• redundant tumor samples:14

• no tumor on block:20

N= 637tumor samples

KRAS exon 2 WTn=592 (100%)

Final RAS wild-type populationN=400

New RAS mutantN= 75 (15.8%)

ORR and PFSFinal RAS* wild-type population

Eventsn/N (%)

Median(months)

95% CI

― FOLFIRI + Cetuximab 164/199(82.4%)

10.3 9.5 – 11.8

― FOLFIRI + Bevacizumab 169/201(84.1%)

10.2 9.3 – 11.7

HR 0.97 (95% CI: 0.78 – 1.20)p (log-rank)= 0.77

* KRAS and NRAS exon 2, 3 and 4 wild-type

0.75

1.0

0.50

0.25

12 24 36 48 60 72months since start of treatment

199201

No. at risk

7070

1611

104

51

3

0.0

Pro

ba

bil

ity

of

su

rviv

al

N=400Cetuximab + FOLFIRI

(N=199) Bevacizumab + FOLFIRI

(N=201)OR/

(95% CI)p-value

ORR, % (95% CI)65.3

(58.3–51.6)58.7

(51.6–65.6)1.33

(0.88–1.99)0.18

Overall survivalFinal RAS* wild-type population

Eventsn/N (%)

Median(months)

95% CI

― FOLFIRI + Cetuximab 107/199(53.8%)

33.1 24.5 – 39.4

― FOLFIRI + Bevacizumab 133/201(66.2%)

25.0 23.0 – 28.1

HR 0.697 (95% CI: 0.54 – 0.90)p (log-rank)= 0.0059

0.75

1.0

0.50

0.25

12 24 36 48 60 72months since start of treatment

199201

No. at risk

147147

7982

4634

2311

71

0.0

Pro

ba

bil

ity

of

su

rviv

al

* KRAS and NRAS exon 2, 3 and 4 wild-type

Δ = 8.1 months

Independent radiological review

An independent, centralized radiological review (blinded to treatment arms) was performed to evaluate:

• Tumor response according to RECIST 1.1

• Early tumor shrinkage (ETS) (-20% diameter change) measured at 1st CT after baseline (6 weeks)

• Depth of response defined as the percentage of maximal tumor shrinkage observed at the nadir compared with baseline

p = Fisher´s exact test (two-sided)

CT evaluable population

FOLFIRI + Cetuximab

FOLFIRI + Bevacizumab

ORR % 95%-CI % 95%-CI Odds ratio

p

KRAS exon 2 wtn= 493

66.5 60.1 – 72.5 55.6 49.3 – 61.8 1.58(1.10-2.28) 0.016

Final RAS wtn= 330

72.0 64.3 – 78.8 56.1 48.3 – 63.6 2.01(1.27-3.19) 0.003

Independent evaluation of response

Evaluation of ETS Rate(Early Tumor Shrinkage)

p = Fisher´s exact test (two-sided)

Rate of Early Tumor Shrinkage*

CT evaluable population

FOLFIRI + Cetuximab

FOLFIRI + Bevacizumab Odds

ratio p

% 95%-CI % 95%-CI

KRAS exon 2 wtn= 493

62.3 55.8 – 68.5 47.9 41.6 – 54.2 1.80(1.26-2.58) 0.0015

Final RAS wtn= 330

68.2 60.3 – 75.4 49.1 41.5 – 56.8 2.22(1.41-3.47) 0.0005

*ETS: early tumor shrinkage ≥20% at 6 weeks

Evaluation of Depth of Response (DpR*)

SE = standard error; p = two-sided Wilcoxon test p

FOLFIRI + Cetuximab FOLFIRI + Bevacizumab

pmedian

DpR % SE % SE

KRAS exon 2 wtn= 493

- 44.1 (±54.6%) - 32.9 (± 44.3%) 0.0003

Final RAS wtn= 330

- 48.9 (±54.8%) - 32.3% (± 42.3%) <0.0001

*DpR: percentage of maximal tumor shrinkage observed at the nadir compared with baseline

Depth of response correlated significantly with OS and PFS (two-sided Bravais Pearson test)

Depth of response correlates with overall survival

CRYSTAL study Cetuximab + FOLFIRI (n=315)

FOLFIRI (n=348) p

Median DpR (95% CI) 50.9 33.3 p<0.0001

Median OS (95% CI) 23.5 (21.2 - 26.3) 20.0 (17.4 - 21.7) P<0.0093

adopted from Mansmann et al, ASCO GI 2013 abstract #427

• ETS predicts sensitivity to treatment

• ETS predicts the potential DpR

• DpR predicts OS

Time under treatment

OS

ETS

DpR (smallest tumor size)

Model

Depth of response correlates with overall survival

FIRE-3 Study(AIO KRK-0306)

Cetuximab + FOLFIRI (n=157)

Bevacizumab + FOLFIRI (n=173) p

Median DpR (95% CI) 48.9 32.2 p<0.0001

Median OS (95% CI) 33.1 (24.5 – 39.4) 25.0 (23.0 – 28.1) P=0.0056

Time since start of treatment

OS

ETSTumor nadir

Fire-3 data

• ETS predicts sensitivity to treatment

• DpR predicts OS

PFS

Tumor load at Baseline

Lethal tumor load

Summary of RAS analyses

• Extended RAS testing was possible in >80% of FIRE-3 ITT.

• The RAS evaluable population was in all respects comparable to the ITT population.

• In patients with all-RAS wild-type tumors ORR and PFS were not significantly different between treatment arms

• Median OS was markedly superior (Δ = 8.1 months, HR 0.70) in all-RAS wild-type patients receiving 1st-line therapy with cetuximab

CALGB/SWOG 80405: PHASE III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with

bevacizumab (BV) or cetuximab (CET) for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum

(MCRC): Expanded ras analyses

Heinz-Josef Lenz, Donna Niedzwiecki, Federico Innocenti, Charles David Blanke, Michelle R.

Mahoney, Bert H. O'Neil, James Edward Shaw, Blase N. Polite, Wilbur Franklin, Wendy Frankel,

Howard Hochster, James Norman Atkins, Richard M. Goldberg, Robert J. Mayer, Richard L. Schilsky,

Monica M. Bertagnolli, Alan Venook

for the ALLIANCE and SWOG

RAS mutation analysis: BEAMing• KRAS and NRAS genes were screened for particular missense*

mutations:

– KRAS exon 2; codons 12, 13

exon 3: codon 59, 61

exon 4; codons 117, 146

– NRAS exon 2; codons 12, 13

exon 3; codons 59, 61

exon 4; codons 117, 146

• In line with other techniques which may be used clinically to determine

RAS mutation status, a cutoff of ≥1% mutant to wild-type alleles was used to discriminate patients

– Tumors were scored as RAS mutant if mutant alleles were detected at a prevalence of ≥1% of total amplified sequences, regardless of whether all loci were evaluable

– Tumors were scored as RAS wild-type only if all 26 mutation assays were evaluable and prevalence of mutant alleles was <1%

*Resulting in a change in the specified amino acid

Study profileKRAS WT codons 12/13

N=1137

Chemo + BevN=559

Evaluable for RAS analysis

N=324 (26 NA)

RAS mutN=42

Chemo + CetuxN=578

Evaluable for RAS analysis

N=346 (23 NA)

RAS WTN=270

RAS mutN=53

Efficacy: RAS SubgroupsSubgroup Chemo

+ BV

N

Chemo + CET

N

ResponseRate (%)*BV vs CET

p-value

PFS timeHazard ratio

95% CIp-value

OS timeHazard ratio

95% CIp-value

RAS evaluable**

324 346 56.0 vs 68.8

p<0.01

11.4 vs 10.9‡

1.1 0.9-1.3p=0.34

30.3 vs 30.8‡

0.90.8-1.1p=0.49

RAS wild-type

256 270 53.8 vs 68.6

p<0.01

11.3 vs 11.4‡

1.10.9–1.3p=0.31

31.2 vs 32.0‡

0.9 0.7–1.1p=0.40

*406 RAS evaluable and 319 RAS WT patients evaluable for response**Patients with KRAS codon 12/13 wild-type tumors for which tumor DNA samples were evaluable for other RAS mutations ‡Median, months

Progression Free Survival By Arm(All RAS Wild Type Patients)

ArmN

(Events)Median (95% CI)

HR(95% CI)

p

Chemo + Bev

256(221)

11.3(10.3-12.6) 1.1

(0.9-1.3) 0.31

Chemo + Cetux

270(241)

11.4(9.6-12.9)

Overall Survival By Arm(All RAS Wild Type Patients)

ArmN

(Events)Median (95% CI)

HR(95% CI)

p

Chemo + Bev

256(178)

31.2(26.9-34.3)

0.9(0.7-1.1)

 

0.40

 Chemo + Cetux

270(177)

32.0(27.6-38.5)

Overall Survival by Arm(All RAS Wild Type FOLFOX Patients)

ArmN

(Events)

Median

(95% CI)

HR

(95% CI)p

Chemo + Bev

192

(137)

29.0

(24.0-32.8) 0.86

(0.6-1.1)0.2 

Chemo + Cetux

198

(129)

32.5

(26.1-40.4)

Overall Survival by Arm(All RAS Wild Type FOLFIRI Patients)

ArmN

(Events)Median (95% CI)

HR(95% CI)

p

Chemo + Bev

64(41)

35.2(28.3-41.3) 1.1

(0.7-1.6)0.7 

Chemo + Cetux

72(48)

32.0(25.6-42.9)

Conclusions

• All patients with newly diagnosed mCRC should be tested for RAS

• Overall Survival > 30 months in both arms sets a new benchmark for patients with mCRC which was achieved across a broad clinical trials network and suggests that the results apply in a variety of practice settings.

• First line therapy should reflect treatment goal and concern for potential side effects.

• With additional data such as dose intensity, treatment duration, location, tumor shrinkage, second line therapies and additional biomarker for anti-EGFR and anti VEGF AB we might understand better the differences between FIRE3 and 80405

Venook AP and Tabernero J. J Clin Oncol 2015; 33:4-6

Venook AP and Tabernero J. J Clin Oncol 2015; 33:4-6

Venook AP and Tabernero J. J Clin Oncol 2015; 33:4-6

Shi Q, et al. J Clin Oncol 2015; 33:22-28.

CALGB/SWOG 80405: Baseline CharacteristicsResected Patients

Characteristic

Kras WT codons 12/13n=1137

Resected Ptsn=180

Chemo + Bev

n=559

Chemo + Cetuxn=578

Chemo + Bevn=75

Chemo + Cetuxn=105

Age, years

Median (range) 59 (21–85) 59 (20–89) 55 (24–82) 55 (21–79)

Male, % 62.3 60.4 64.0 60.0

Non-Caucasian, % 14.6 16.5 9.3 20.0

FOLFOX, %* 73 74 77 81

Prior Radiation, %* 14.5 13.7 8.0 6.7

Prior Adjuvant Chemotherapy, %*

8.9 9.0 6.7 9.5

Palliative intent, % 86.4 82.5 62.7 60.0

Primary in place, % 28 27 30 20

Liver metastases only, % 29.3 39.8 53.3 50.0

*Stratification Factor

Achieve NED: 132 /180

CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132)

ArmN

(Events)Median (95% CI)

HR(95% CI)

p

Chemo + Bev

50(15)67.4

(50.6-NA) 1.2(0.6-2.2)

0.56

 Chemo + Cetux

82(30)64.1

(51.1-78.9)

CALGB/SWOG 80405: Patients undergoing surgery and rendered NED

• Subset of patients survive > 5 years• Patients likelier to have “curative” surgery

on cetuximab-containing regimen• Outcomes similar between arms• Expanded RAS may distinguish prognosis

in this already select group of patients• Opportunity to interrogate clinical and tumor

factors related to curability