Colorectal cancer

(1)

Recent advances in treatment

Colorectal cancer

순천향대학교 부천병원

종양혈액내과 윤진아

(2)

Early-Stage CRC

(3)

Case 1.

• M/50

• ECOG 0

• Sigmoid colon cancer, pT3N1M0

• Adenocarcinoma, MD

(4)

• 다음 중 어떤 치료를 선택하시겠습니까?

① Cetuximab + FOLFOX/XELOX

② Bevacizumab + FOLFOX/XELOX

③ FOLFOX/XELOX

④ FOLFIRI

⑤ Capecitabine/FL

⑥ 경과관찰

(5)

Case 2.

• M/50

• ECOG 0

• Sigmoid colon cancer, pT3N0M0

• Adenocarcinoma, MD

(6)

• 다음 중 어떤 치료를 선택하시겠습니까?

① Cetuximab + FOLFOX/XELOX

② Bevacizumab + FOLFOX/XELOX

③ FOLFOX/XELOX

④ FOLFIRI

⑤ Capecitabine/FL

⑥ 경과관찰

⑦ 생각 좀 더 해 봐야겠다

(7)

Case 3.

• M/75

• ECOG 1

• Sigmoid colon cancer, pT3N1M0

• Adenocarcinoma, MD

(8)

• 다음 중 어떤 치료를 선택하시겠습니까?

① Cetuximab + FOLFOX/XELOX

② Bevacizumab + FOLFOX/XELOX

③ FOLFOX/XELOX

④ FOLFIRI

⑤ Capecitabine/FL

⑥ 경과관찰

(9)

2010 2015

(10)

Clinical Trial about Adjuvant chemotherapy in CRC

Study N Standard

arm

Experimental arm

DFS OS

HR P HR P

MOSAIC 1347 Infusional

5FU FOLFOX 0.78 0.005 0.80 0.023

NSABP C-07 1714 Bolus 5FU FLOX 0.78 <0.001 0.85 0.052(NS) NO 16968 1886 Bolus 5FU CapeOx 0.80 0.0038 0.83 0.0367

Study Stage Standard

arm

Experimental

arm Benefit

CALGB89803 III Bolus 5FU IFL NO

PETACC-03 II/III Infusional 5FU

/Bolus 5FU FOLFIRI/FUFIRI NO

ACCORD III/II(high) Infusional 5FU FOLFIRI NO

(11)

Adjuvant Therapy Options for Stage III Colon Cancer

– Oxaliplatin-based chemotherapy: standard

adjuvant treatment of stage III colon cancer in good performance patients ^[1]

• FOLFOX/XELOX (CapeOx)

• FLOX

– Fluoropyrimidine monotherapy: considered for patients who cannot tolerate more aggressive oxaliplatin-based regimens

• 5-FU/LV

• Capecitabine

NCCN. Clinical practice guidelines in oncology: colon cancer. v.3.2013.

(12)

Recent advance of adjuvant therapy

(13)

NSABP C-08

• 2672 pts

• Stage II = 24.9%

• Primary endpoint : DFS

Allegra CJ, et al. J Clin Oncol. 2011;29:11-16

(n=1334)

(14)

NSABP C-08

• Positive effect of bevacizumab over the 15 first months on RFS, not maintained afterwards

Allegra CJ, et al. J Clin Oncol. 2011;29:11-16 Allegra CJ, et al. J Clin Oncol. 2013;31:359-364

(15)

AVANT

• 3451 pts

• Stage II = 17%

• Primary endpoint : DFS

(n=1334)

Aimery de Gramont, et al. LANCET. 2012;13:1225-1233

(16)

AVANT

• Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer.

Aimery de Gramont, et al. LANCET. 2012;13:1225-1233

(17)

NCCTG N-0147

• 2686 pts

• Primary endpoint : DFS

(n=1297)

NCCTG N0147

III Cetuximab – 6 m

(n=1283)

JAMA. 2012 Apr 4; 307(13):1383-93.

(18)

NCCTG N-0147

JAMA. 2012 Apr 4; 307(13):1383-93.

• All subsets of patients treated with cetuximab

experienced increased in grade ¾ adverse events.

(19)

Agents Currently Not Recommended for Adjuvant Therapy in Localized CRC

• Irinotecan

– Similar DFS and OS but increased toxicity with 5-FU/LV + irinotecan vs

5-FU/LV alone in stage III colon cancer

• Bevacizumab

– Similar DFS with FOLFOX + bevacizumab vs FOLFOX alone in stage II/III colon cancer

• Cetuximab

– Similar DFS and OS but increased toxicity with FOLFOX + cetuximab vs FOLFOX alone in stage III colon cancer

• Worse DFS in KRAS mutant disease

(20)

Case 1.

• M/50

• ECOG 0

• Sigmoid colon cancer, pT3N1M0

• Adenocarcinoma, MD

=> FOLFOX/XELOX

(21)

Recent advance of adjuvant therapy

Stage II Colon cancer, adjuvant therapy

(22)

• 75~80% cured with surgery alone

• Direct evidence from randomized controlled trial results do not support routine administration of adjuvant chemotherapy

• Indirect evidence of benefit for stage II disease (eg, relative benefit of therapy in stage III disease)

contributes to justification for use of adjuvant

chemotherapy, particularly for patients with high-risk stage II colon cancer

– Definition of high risk is clearly inadequate

– No data point to features that are predictive of benefit from adjuvant chemotherapy

– No data correlate risk features and selection of chemotherapy

Stage II colon cancer

NCCN

(23)

Biomarker of adjuvant chemotherapy

(24)

MMR-D Is a Favorable Prognostic Marker in Stage II Colon Cancer

Study Stage

Treatment Endpoint MMR-D vs MMR-P HR (95% CI; P Value)

Ribic et al

^[1]

II/III

Surgery alone OS 0.31 (0.14-0.72; .004)

Roth et al

(PETACC-3)

^[2]

II

5-FU/LV ± irinotecan

Relapse-free survival OS

0.27 (0.10-0.72; .0094) 0.14 (0.03-0.64; .011) Sargent et al

^[3]

II/III

Surgery alone

DFS OS

0.46 (0.22-0.95; .03) 0.51 (0.24-1.10; .06)

1. Ribic CM, et al. N Engl J Med. 2003;349:247-257.

2. Roth AD, et al. J Clin Oncol. 2010;28:466-474.

3. Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226.

(25)

Yrs Since Random Assignment

CRC Recurrence by MMR Status, colon stage II only: QUASAR

Hutchins G, et al. J Clin Oncol. 2011;29:1261-1270.

Percentage With Recurrence

0 1 3 4 6 9 10

0 10 20 30 40 50 60 70 80 90 100

8 7

5 2

2P < .00001 27%

10%

MMR deficient MMR proficient MMR deficient

MMR proficient

Patients, n 167 469

Obs 13 98

Exp 31.3 79.7 Events, n

MMR deficient MMR proficient Pts at Risk, n

167 469

149 363 158

431

136 321

81 111

34 82

26 55 54

126 71

167 111

258 154

387

(26)

Defective MMR as A Predictive Marker for Lack of Efficacy of Fluorouracil Adjuvant Therapy in Colon Cancer

- 5 completed, randomized clinical trial

Sargent DJ et al, J Clin Oncol 2010;28:3219-3226

Stage II Stage III

pMMR dMMR

(27)

PETACC3: Integration Analysis of Molecular and Clinical Prognostic Factors

Roth A D et al. JNCI J Natl Cancer Inst 2012;104:1635-1646

(28)

Genomic Tests for CRC Risk Stratification

Study Oncotype DX colon cancer test ¹ ColoPrint ²

Tissue specimen required Formalin-fixed, paraffin-embedded

tumor specimens Fresh frozen tumor specimens

Type of assay RT-PCR High density Agilent 44K

oligonucleotide array Validation Set Stage II colon cancer patients in

QUASAR trial

Primary Endpoint Recurrence risk (RR) at 3 years Distant-metastasis-free survival (DMFS)

Risk groups (incidence)

Low (43.7% of patients) Low (61% of patients) Intermediate (30.7% of patients)

High (39% of patients) High (25.6% of patients)

Risk according to group

Low risk: 12% RR at 3 years Low risk: 89 % of DMFS at 5 years Intermediate risk: 18% RR at 3 years

High risk: 62% DMFS at 5 years High: 22% RR at 3 years

1. Kerr D, et al. ASCO meeting, J Clin Oncol. 2009 2. Glas AM RP, et al. ASCO meeting, J Clin Oncol. 2009.

(29)

Genomic Tests for CRC Risk Stratification

• Gene signatures provide

prognostic, not predictive,

information

• 12-gene recurrence score assay validated for recurrence risk in Stage II patients

– QUASAR: 12% (low risk) vs 22%

(high risk) 3-yr recurrence risk

^[1]

– CALGB 9581: 13% (low risk) vs 21% (high risk) 5-yr recurrence in T3, MMR proficient disease

^[2]

• Other genomic tests in development (microarray based)^[3,4]

• CALGB 9581 validation

1. Gray RG, et al. J Clin Oncol. 2011;29:4611-4619.

2. Venook AP, et al. J Clin Oncol. 2013;31:1775-1781.

3. Rosenberg R, et al. ASCO GI 2011. Abstract 358.

4. Kennedy RD, et al. J Clin Oncol. 2011;29:4620-4626.

Risk of Recurrence at 5 Yrs (%)

Colon Cancer Recurrence Score 0 10 20 30 40 50 60 0

5 10 15 20 25 30 35

70 Risk

95% CI

(30)

Potential Prognostic Role of KRAS and BRAF in Stage II (and III) Colon Cancer

• Translational study on the PETACC-3,

EORTC 40993, SAKK 60-00 trial

• 912 stage III

(755 MS-L/S, 104 MSI-H)

• 409 stage II

(309 MS-L/S, 86 MSI-H)

Roth AD, et al. J Clin Oncol. 2010;28:466-474.

(31)

Case 2.

• M/50

• ECOG 0

• Sigmoid colon cancer, pT3N0M0

• Adenocarcinoma, MD

1) Clinicopathologic factors

2) Molecular factors

3) Genetic factors

4) 환자와 상의

(32)

Recent advance of adjuvant therapy

Stage II Colon cancer, adjuvant therapy

Old age, adjuvant therapy

(33)

Subset analysis by Age – NSABP C-07 trial

Yothers G, et al. J Clin Oncol 2011;29:3768-3774

(34)

Age related toxicities – NSABP C-07 trial

Yothers G, et al. J Clin Oncol 2011;29:3768-3774

(35)

Cross trial comparison vs 5FU/LV : Age

NSABP C-07 MOSAIC NO16968

FLOX FOLFOX XELOX

Age, years <70 ≥70 <70 ≥70 <70 ≥70

DFS HR

(95% CI)

0.76 (0.66-0.88)

1.03 (0.77-1.36) Na 0.91

(0.62-1.34)

0.80 (0.67-0.94)

0.86 (0.64-1.16) OS

HR

(95% CI)

0.80 (0.68-0.95)

1.18 (0.86-1.62) Na 1.10

(0.73-1.65)

0.82 (0.67-1.01)

0.91 (0.66-1.26)

Schmol H.J. ASCO GI 2012

(36)

Sanoff HK, et al. J Clin Oncol 2012;30:2624-2634

Effect of adjuvant chemotherapy,

stage III CC ≥ 75 years

(37)

Sanoff HK, et al. J Clin Oncol 2012;30:2624-2634

Effect of adjuvant chemotherapy,

stage III CC ≥ 75 years

(38)

Case 3.

• M/75

• ECOG 1

• Sigmoid colon cancer, pT3N1M0

• Adenocarcinoma, MD

 Capecitabine/FL

(39)

Metastatic CRC

(40)

Case 4.

• M/50

• ECOG 0

• Sigmoid colon cancer, cT3N1M1

• Initially unresectable Liver only metastasis

• Bx : Adenocarcinoma, MD, wKRAS

(41)

• 다음 중 어떤 치료를 먼저 선택하시겠습니 까 ?

① Cytoreductive surgery followed by CTx

② FOLFOXIRI

③ FOLFOX /FOLFIRI + Cetuximab

④ FOLFOX /FOLFIRI + Bevacizumab

⑤ FOLFOX or FOLFIRI

(42)

Case 5.

• M/60

• ECOG 2

• Sigmoid colon cancer, cT3N1M1

• Adenocarcinoma, MD, wKRAS

• First line chemotherpy : FOLFOX q 2wks

• Response evaluation after 8cycles (4 months) : SD

• Phr. Neuropathy Gr1->2

(43)

• 다음 중 어떤 치료를 선택하시겠습니까?

① Stop and Go

② FOLFIRI 로 변경

③ FOLFOX 지속 + Gabapentin add

④ FOLFOX 용량 감량 후 지속

⑤ FL maintnance without oxaliplatin

(44)

Case 6.

• M/50

• ECOG 1

• Sigmoid colon cancer, cT3N1M1

• Adenocarcinoma, MD, mKRAS

• First line chemotherpy : FOLFOX +

bevacizumab, (PD after 4 months)

(45)

• 다음 중 어떤 2 ^nd line 치료를 선택하시겠습 니까 ?

① Irinotecan ± Cetuximab

② FOLFIRI ± aflibercept

③ FOLFIRI ± Bevacizumab

④ Regorafenib

⑤ Perifosine + capecitabine

⑥ Clinical trial

(46)

Metastatic CRC:Practical Issues

1. Conversion therapy

2. Chemotherapy free interval vs. Maintenance vs. continous therapy

3. Treatment after progression on previous treatment

4. NEW agents: Aflibercept, Regorafenib

(47)

Metastatic CRC:Practical Issues

First

treatment for inoperable Colorectal Metastases

Re- assess

Curative track

Disease controlled but not curable

Disease progressed 3-4 months

(48)

Metastatic CRC:Practical Issues

1. Conversion therapy

2. Chemotherapy free interval vs. Maintenance vs. continous therapy

3. Treatment after progression on previous treatment

4. NEW agents: Aflibercept, Regorafenib

(49)

Conversion therapy

• Liver limited mCRC

~ 30% synchronous metastases

Additional ~ 50% will develop metastases 30% to 35% “liver only” metastases^[2]

75% to 90%

not candidates for surgery PALLIATIVE THERAPY R0 resection not possible 10% to 25%

candidates for SURGERY^[3]

Aim: R0 resection

Cure rate: ~ 25%

5-yr survival: ~ 30% to 70%^[4]

~ 75% of patients relapse^[5]

400,000 CRC cases/yr (US/Europe)^[1]

1. Galimi F, et al. Clin Cancer Res. 2011;17:3146-3156.

2. Clavien PA. Malignant liver tumors: current and emerging therapies. 2010.

3. Kemeny N. Oncologist. 2007;12:825-839.

4. Kanas GP, et al. Clin Epidemiol. 2012;4:283-301.

5. Koch M, et al. Ann Surg. 2005;241:199-205.

(50)

Response Correlates With Resection in Initially Unresectable mCRC

Folprecht G, et al. Ann Oncol. 2005;16:1311-1319.

(51)

Similar Survival After Primary or

Secondary Resection of Liver Metastases

Adam R. Ann Oncol. 2003;14(suppl 2):ii13-ii16.

(52)

Regimen, % Response Rate Resection Rate

FOLFOX 40-50 25-35

FOLFIRI 40-50 25-30

FOLFOXIRI 50-60 30-50

Conversion therapy:

Efficacy of cytotoxic regimens

Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.

Barone C, et al. Br J Cancer. 2007;97:1035-1039.

Ho WM, et al. Med Oncol. 2005;22:303-312.

Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.

De La Cámara R, et al. ASCO 2004. Abstract 3593.

Abad A, et al. Acta Oncol. 2008;47:286-292.

(53)

Conversion therapy:

Efficacy of Cetuximab, CRYSTAL trial

Van Cutsem E, et al. ASCO 2007. Abstract 4000.

(54)

wKRAS unresectable

CLM (N = 138)

Arm A:

FOLFIRI or mFOLFOX6 + Cetuximab (n=70)

Ye L, et al. J Clin Oncol. 2013;31:1931-1938.

Primary endpoint: rate of patients converted to resection Secondary endpoint: RR, survival

Arm B:

FOLFIRI or mFOLFOX6 (n=68)

Conversion therapy:

Efficacy of Cetuximab, Randomized

controlled trial

(55)

• R0 resection rates for liver meta – 25.7% vs 7.4% (P<0.01)

• RR : 57.1% vs 29.4% (P<0.01)

Conversion therapy:

Efficacy of Cetuximab, Randomized controlled trial

Ye L, et al. J Clin Oncol. 2013;31:1931-1938.

(56)

• Nonrandomized phase II trial: XELOX + bevacizumab

• 56 patients with mCRC and potentially resectable liver metastases

• Objective response rate: 73.2%

• pCR: 8.9%

• No increased bleeding

• Postoperative liver function and regeneration normal in 98%

of patients

Conversion therapy:

Efficacy of Bevacizumab

Gruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.

(57)

Conversion therapy : Issues

• Role of FOLFOX better established than FOLFIRI – Better toxicity profile, more clinical data

• FOLFOXIRI attractive but at expense of increased toxicity

• Duration of preoperative therapy

– Treat to resectability and not to best response – Minimizes hepatotoxicity

• Role of biologics is evolving

– Data with cetuximab appears to be most mature in wild-type KRAS CRC

– Bevacizumab is an appropriate option in setting of mutant KRAS

– If bevacizumab is used, discontinue 6-8 wks before planned surgery

(58)

Case 4.

• M/50

• ECOG 0

• Sigmoid colon cancer, cT3N1M1

• Initially unresectable Liver only metastasis

• Bx : Adenocarcinoma, MD, wKRAS

 FOLFOX/FOLFIRI + Cetuximab

 FOLFOX/FOLFIRI + Bevacizumab

 FOLFOXIRI

 FOLFOX/FOLFIRI

(59)

Metastatic CRC:Practical Issues

1. Conversion therapy

2. Chemotherapy free interval vs. Maintenance vs. continous therapy

3. Treatment after progression on previous treatment

4. NEW agents: Aflibercept, Regorafenib

(60)

OPTIMOX1: Stop-and-Go Strategy in mCRC

Previously untreated

patients (N = 620)

Arm A: FOLFOX4 every 2 wks until progression

Arm B: FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles,

then reintroduction of FOLFOX7

Tournigand C, et al. J Clin Oncol. 2006;24:394-400.

Primary endpoint:

duration of disease control

FOLFOX 4 until TF

FOLFOX7 FOLFOX7

sLV5FU2

(61)

• FOLFOX7 for 6 cycles followed by maintenance

therapy and reintroduction was as active and better tolerated than FOLFOX4 until progression

• No difference in median duration of disease control

– HR: 0.99 (95% CI: 0.81-1.15; P = .89)

• Less grade 3/4 toxicity reported in patients receiving maintenance vs standard therapy (48.2% vs 54.4%;

P = NS)

• Less grade 3 sensory neurotoxicity reported in

patients receiving maintenance vs standard therapy (13.3% vs 17.9%; P = .12)

Tournigand C, et al. J Clin Oncol. 2006;24:394-400.

OPTIMOX1: Stop-and-Go Strategy in mCRC

(62)

OPTIMOX2: Maintenance Therapy or

Chemotherapy-Free Intervals in mCRC

Patients with previously untreated

mCRC

(N = 202; enrolled between Feb 2004

and April 2006)

Arm B: 6 cycles of mFOLFOX7, complete stop of chemotherapy, then reintroduction of mFOLFOX7 at progression or before tumor

progression reaches baseline measures Arm A: mFOLFOX7 for 6 cycles, maintenance

without oxaliplatin for 12 cycles, then reintroduction of FOLFOX7

Chibaudel B, et al. J Clin Oncol. 2009;27:5727-5733.

mFOLFOX7 mFOLFOX7

sLV5FU2

mFOLFOX7 mFOLFOX7

CFI

(63)

OPTIMOX2: Maintenance Therapy or

Chemotherapy-Free Intervals in mCRC

Chibaudel B, et al. J Clin Oncol. 2009;27:5727-5733.

(64)

GISCAD: Intermittent or Continous chemotherapy in mCRC

Patients with previously untreated

mCRC (N = 337)

Arm B: FOLFIRI administered every 2 weeks Until PD

(n=170)

Arm A: FOLFIRI administered every 2 weeks 2 months on and 2 months off

Until PD (n=167)

Labianca R, et al. Ann Oncol. 2011;22:1236-1242.

RR evaluation, every 4 months

Primary endpoint: OS

^FOLFIRI

FOLFIRI FOLFIRI FOLFIRI

(65)

GISCAD: Intermittent or Continous chemotherapy in mCRC

Labianca R, et al. Ann Oncol. 2011;22:1236-1242.

Grades 3-4 toxicity (mainly myelosuppression, fever, diarrhea) was similar.

(66)

MACRO: Maintnance Strategy in mCRC

Previously untreated

patients (N = 480)

Arm A: XELOX + Bevacizumab 6 cycles, every 3 wks

(n=239)

Eduardo DR, et al. Oncologist. 2012;17:15-25.

Primary endpoint: PFS

Arm B: XELOX + Bevacizumab 6 cycles, every 3 wks

(n=241)

XELOX

+ Bevacizumab

Bevacizumab

Until PD

(67)

MACRO: Maintnance Strategy in mCRC

Eduardo DR, et al. Oncologist. 2012;17:15-25.

(68)

Case 5.

• M/60

• ECOG 2

• Sigmoid colon cancer, cT3N1M1

• Adenocarcinoma, MD, wKRAS

• First line chemotherpy : FOLFOX q 2wks

• Response evaluation after 8cycles (4 months) : SD

• Phr. Neuropathy Gr1->2

 FOLFOX (용량감량 or GABA add) 지속

 FL maintnance without oxaliplatin

(69)

Metastatic CRC:Practical Issues

1. Conversion therapy

2. Chemotherapy free interval vs. Maintenance vs. continous therapy

3. Treatment after progression on previous treatment

4. NEW agents: Aflibercept, Regorafenib

(70)

E3200: Bevacizumab in Second-line Therapy for mCRC

Arm C Bevacizumab

(n = 243) Arm A

FOLFOX4 + Bevacizumab (n = 286)

Arm B FOLFOX4

(n = 291) Patients with

previously treated mCRC; no previous

bevacizumab (N = 820)

FOLFOX4

Oxaliplatin 85 mg/m² on Day 1 q2w

5-FU 400 bolus/600 mg/m² IV on Days 1 and 2 q2w LV 200 mg/m² on Days 1 and 2 q2w

Bevacizumab

10 mg/kg on Day 1 q2w

Giantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544.

(71)

E3200: OS

Giantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544.

(72)

ML18147(TML): Bevacizumab Beyond Progression

Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

Standard second-line CT (oxaliplatin or irinotecan based) until PD

(n = 411)

BEV 2.5 mg/kg/wk +

standard second-line CT (oxaliplatin or irinotecan-based) until PD

(n = 409) Progressive mCRC after

BEV + standard first-line CT (either oxaliplatin or

irinotecan based) (n = 820)

Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS (≤ 9 or > 9 mos),

time from last BEV dose (≤ 42 or > 42 days),

ECOG PS at baseline (0/1 or 2)

(73)

ML18147(TML): OS

Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

(74)

FOLFIRI q 2w until PD (n = 595)

Panitumumab 6.0 mg/kg/wk + FOLFIRI q 2w

until PD (n = 591) Progressive mCRC after only

one prior CT (5FU based,

no irinotecan, no anti-EGFR) (n = 1186)

Panitumumab+FOLFIRI vs. FOLFIRI in Second-line Therapy for mCRC

Peeters M, et al. J Clin Oncol. 2010;28:4706-4713.

(75)

Panitumumab+FOLFIRI vs. FOLFIRI in Second-line Therapy for mCRC

Peeters M, et al. J Clin Oncol. 2010;28:4706-4713.

wKRAS mKRAS

HR=0.73

(95% CI, 0.59 to 0.99) P=0.004

HR=0.85

(95% CI, 0.70 to 1.04) P=0.12

(76)

Aflibercept (VEGF-Trap)

Ciombor K K et al. Clin Cancer Res 2013;19:1920-1925

(77)

Phase III VELOUR study:

FOLFIRI ± Aflibercept as Second-Line

Patients with mCRC progressing on 1^st-line Ox-

based CT (N = 1226)

Arm A: FOLFIRI + aflibercept 4 mg/kg q2w (n = 600)

Arm B: FOLFIRI + placebo q 2w (n = 600)

Primary endpoint: OS

Secondary endpoints: PFS, ORR, safety, immunogenicity

*30% had previous bevacizumab.

Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.

(78)

Phase III VELOUR study: OS, PFS

Aflibercept/FOLFIRI Median: 6.90 mos Aflibercept/FOLFIRI

Median: 13.50 mos Placebo/FOLFIRI

Median: 12.06 mos

Placebo/FOLFIRI Median: 4.67 mos

(79)

Increased Grade 3/4 AEs in Aflibercept Arm, % FOLFIRI + Aflibercept (n = 611)

FOLFIRI + Placebo (n = 605)

Any 83.5 62.5

Diarrhea 19.3 7.8

Asthenia 16.9 10.6

Stomatitis/ulceration 13.7 5.0

Infection 12.3 6.9

Palmar-plantar erythrodysesthesia 2.8 0.5

Anti-VEGF–associated events

Hypertension 19.3 1.5

Hemorrhage 2.9 1.7

Arterial thromboembolic events 1.8 0.5

Venous thromboembolic events 7.9 6.3

Neutropenia 36.7 29.5

Complicated neutropenia 5.7 2.8

Thrombocytopenia 3.3 1.7

Phase III VELOUR study: Adverse events

(80)

Median Survival, mos Previous Bevacizumab No Previous Bevacizumab FOLFIRI +

aflibercept (n = 186)

FOLFIRI + placebo (n = 187)

FOLFIRI + aflibercept

(n = 426)

FOLFIRI + placebo (n = 427)

PFS 6.7 3.9 6.9 5.4

HR (95% CI) 0.661 (0.512-0.852) 0.797 (0.679-0.936)

OS 12.5 11.7 13.9 12.4

HR (95.34% CI) 0.862 (0.673-1.104) 0.788 (0.699-0.927)

Phase III VELOUR study: Stratified by Previous Bevacizumab

Allegra CJ, et al. ASCO 2012. Abstract 3505.

(81)

Regorafenib

• Regorafenib orally active, diphenylurea multikinase inhibitor

Regorafenib

RET

VEGFR -1, -2, -3

FGFR-1, -2 c-Kit, PDGFR a/b

Raf-1, BRAF, BRAFV600E FDA-approved in mCRC previously treated with

fluoropyrimidine-, oxaliplatin-, and irinotecan-based CT; an anti-VEGF therapy; and an anti-EGFR therapy (if KRAS wild type)

Strumberg D, et al. Expert Opin Investig Drugs. 2012;21:879-889.

(82)

CORRECT: Regorafenib After Failure of All Available Standard Therapy in mCRC

Patients with progression

after all available standard therapy (N = 760)

Arm A: Regorafenib 160 mg po qd + BSC 3 wks on, 1 wk off

(n = 505)

Arm B: Placebo + BSC 3 wks on, 1 wk off

(n = 255) 2:1

• Primary endpoint: overall survival

• Approximately 50% of patients with ≥ 4 systemic therapies

All patients had received bevacizumab

Eric Van Cutsem, et al. Lancet. 2013;21:879-889.

(83)

CORRECT: OS, PFS

Regorafenib vs placebo OS: 6.4 vs 5.0 mos HR: 0.77 (P = .0052)

Regorafenib vs placebo PFS: 1.9 vs 1.7 mos HR: 0.49 (P < .0001)

(84)

Regorafenib (n = 500)

Placebo (n = 253)

Grade 3 Grade 4 Grade 3 Grade 4

Any event 253 (51%) 17 (3%) 31 (12%) 4 (2%)

G3/4 AEs

affecting ≥5% of patients

Fatigue 46 (9%) 2 (<1%) 31 (12%) 4 (2%)

Hand-foot skin reaction 83 (17%) 0

Diarrhoea 35 (7%) 1 (<1%) 12 (5%) 1 (<1%)

Hypertension 36 (7%) 0 1 (<1%) 0

Rash or desquamation 29 (6%) 0 2 (1%) 0

• Most adverse events occurred early in the course (during cycles 1–2)

• Serious adverse events, 219/500 (44%) : 100/253 (40%)

• 100 Deaths, 69 (14%) : 41 (16%)

• 11 Aes not associated with PD

– Regorafenib group : pneumonia (n=2), gastrointestinal bleeding (n=2), intestinal obstruction (n=1), pulmonary haemorrhage (n=1), seizure (n=1), sudden death (n=1) – placebo group : pneumonia (n=2), sudden death (n=1)

CORRECT: Adverse events

(85)

CORRECT Trial Analysis: Biomarkers and Response to Regorafenib in mCRC

Jeffers M, et al. ASCO GI 2013. Abstract 381.

(86)

Perifosine

• Oral alkylphospholipid

• Inhibition of multiple signal transduction pathways

- AKT inhibition - NF-kB inhibition

- Activation of apoptotic pathway via JNK

• Perifosine and 5FU show profound synergistic

cytotoxicity in colon cancer cell

lines

(87)

Randomized placebo controlled Phase II trial of Perifosine

Patients with 2^nd or 3^rd line

mCRC (N = 38)

Perifosine 50 mg PO QD

Capecitabine 825 mg/m² BID d1-14 q 21days

(n = 20)

Placebo PO QD

(n = 18)

Primary endpoint: TTP

Secondary endpoints: ORR, OS, safety

Bendell JC, et al. J Clin Oncol. 2011;29:3494-4400.

(88)

Randomized placebo controlled Phase II trial of Perifosine

Bendell JC, et al. J Clin Oncol. 2011;29:3494-4400.

(89)

X-PECT study: Phase III trial of Perifosine

Patients with refractory

mCRC

Perifosine 50 mg PO QD

(n = 234)

Placebo PO QD

(n = 234)

Primary endpoint: OS

Secondary endpoints: RR, PFS, Toxicity, Biomarkers

ASCO 2012, Abstract No. LBA3501

(90)

X-PECT study: Phase III trial of Perifosine

ASCO 2012, Abstract No. LBA3501

(91)

Case 6.

• M/50

• ECOG 1

• Sigmoid colon cancer, cT3N1M1

• Adenocarcinoma, MD, mKRAS

• First line chemotherpy : FOLFOX + bevacizumab, (PD after 4 months)

 FOLFIRI ± Bevacizumab

 FOLFIRI ± aflibercept

(92)

What Is the Optimal Treatment of Second- line mCRC?

(93)

What Is the Optimal Treatment of Second- line mCRC?

(94)

What Is the Optimal Treatment of Second- line mCRC?

(95)

ASCO 2013

1. Phase III randomized, placebo (PL)-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity (sNT), N08CB: An alliance for clinical trials in oncology study.

2. Randomized comparison of FILFIRI plus cetuximab versus FOLFIRI plus

bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3).

3. FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group.

4. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG).

5. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study.

Colorectal cancer

Recent advances in treatment