2013 ASCO CRC Poster Discussion(Old Dog, New Tricks)

Weijing Sun, MD, FACPUniversity of Pittsburgh

• Bevacizumab in CRC Therapy: Doses, efficacy, maintenance, and impact of ages

- 3515, 3516, 3517, 3521 • S-1 in CRC: the un-replaceable role of fluoropyrimidines

in CRC therapy, and equivalence of different analogs : -3518, 3519• Early response is critical and an indicator for the overall

outcome: 3520

• What can we learn from these studies?• What is the potential impact of these studies

on clinic practice?

3516: FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer who have failed first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study Hiroshi Tamagawa, et al

Evaluated the optimal dose of Bevacizumab (2nd-line):A long-time question since the first day of bevacizumab in clinical practice: 5mg/kg vs. 10 mg/kg vs. 7.5 mg/kg (commonly used in q3wks regimen with XELOX)

Oxaliplatin based CTx + bevacizumab 5mg/kg R

Arm A: FOLFIRI + bevacizumab 5mg/kg

Arm B: FOLFIRI + bevacizumab 10mg/kg

Primary End Point: PFSSecondary end points: Toxicity, RR, TTF, OS, OS from the first-line, duration from the start of the first-line

N=367

PFS100

80

60

40

20

0 6 12 18 24 30 36

Hazard ratio: 0.95 (95% CI: 0.75-1.21)p= 0.676 (log-rank test)Median PFS: A = 6.1 month (95% CI: 5.3-7.0); B = 6.4 month (95% CI: 5.6-7.4)

AB

Months

PFS

Prob

abili

ty (%

)

Subgroup Analysis of PFS

LY metastasis no

yesPeritoneal metastasis no

yes

Age <65 years

≥65 years

Pretreatment <180 days

≥180 days

CEA <20 ng/mL

≥20 ng/mL

CA 19-9 <35 ng/mL

≥35 ng/mL

Sum of <50 mm

target lesions ≥50 mm

Arm B better

0.99(0.75-1.29)

1.08(0.71-1.66)

0.93(0.72-1.20)

1.31(0.78-2.20)

1.02(0.73-1.41)

1.00 (0.73-1.38)

0.75(0.46-1.24)

1.14(0.88-1.48)

1.25(0.88-1.77)

0.82(0.60-1.13)

1.09(0.77-1.55)

0.96(0.70-1.33)

1.22(0.87-1.71)

0.81(0.59-1.12)

Arm A better

Hazard Ratio (95% CI)

No differences: - dose intense of chemotherapy- subgroup analysis: sex, age, PS, primary site (rectal vs. colon)

metastatic characteristics (location, numbers, peritoneal mets), CEA, CA19-9…

Arm A(n=180)

Arm B(n=187)

PR, No. (%) 20 (11.1) 20 (10.7) p=1.00

SD, No. (%) 127 (70.6) 132 (70.6)

PD, No. (%) 25 (13.9) 22 (11.8)

NE, No. (%) 8 ( 4.4) 13 ( 7.0)

PFS RR

IFL + Placebo 6.2 months 35 %

IFL + Bev. 5 mg/kg 10.6 months 45%

PFS RR

FOLFOX 4.8 months 9.2%

FOLFOX + Bev. 10 mg/kg 7.2 months 21.8%

(Bev. 10 mg/kg) (2.8 months) (3.0%)

The Potential Impact of Bevacizumab Dose on the CRC Chemotherapy Efficacy

First line: AVF 2107g

Second line: E3200

PFS RR

5FU/LV 5.2 months 17 %

5-FU/LV + Bev. 5mg /Kg 9.0 months 40 %

5-FU/LV + Bev 10 mg /Kg 7.2 months 24 %

Initial Phase II: Kabbinavar

Conclusion• No significant difference was found in PFS between Arm A and Arm B. • No Surprise - dose of Bevacizumab was based on neither the Tumor

mass (size or numbers) nor the biologics (VEGF, or VEGFR levels) of Cancer.

• However, patients with first-line treatment <180 days, CEA ≥20 ng/mL, sum of target lesions ≥50 mm seem to benefit from bev 10 mg/kg.

• May make sense as larger tumor burden may be benefit with more Bev.

• The results from study suggest that the optimal dose of continuous bev as second-line treatment is 5 mg/kg.

• With the efficacy from this and other studies and cost-effective ration—Agree!

No need to have any further debate regarding the appropriate dose of Bevacizumab in CRC therapy (in the 2nd line setting)

3517: Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the ITACa randomized clinical trialAlessandro Passardi, et al

Alessandro Passardi et al

Baseline CharacteristicsPatient Characteristics CT+bevacizumab N=176 CT N=194Age: median years (range) 66 (34-83) 66 (33-82)Male % 61 59Performance Status (ECOG) % 0 82 79 1-2 18 21Tumor localization % rectum 23 26 colon 77 74Stage at diagnosis % I-III 17 17 IV 83 83CT regimen % folfox 59 61 folfiri 41 39KRAS % wild type 59 55 mutant 41 45Prior cancer therapy % surgery 76 75 radiotherapy 10 10 Adjuvant chemotherapy 19 13

0.00

0.20

0.40

0.60

0.80

1.00P

FS

0 6 12 18 24 30 36months

Events / n (%) Median PFS(95% CI)

-------- CT + B 159 / 176 (90.3) 9.6 (8.2-10.3)

-------- CT 178 / 194 (91.8) 8.4 (7.2-9.0)

= 1.2 months

HR = 0.87, 95% CI (0.70-1.08), p = 0.212

OS: 20.6 months in both arms [p=0.278, HR 1.18 (0.88-1.58)]

RR: 48.9 (CT +B) vs. 47.9 % (p=0.371)

CT + B CT

Treatment cycles (N) 2083 1945Treatment cycles per patient median (range)

8 (1-43) 6 (1-28)

Cycles with reduction of CT: N (%)

291 (14.0)

404 (20.8)

CT Cumulative dose: median (range)

90 (44-100)

87 (48-100)

- A relative small study with diverse CT regimens (60% FOLFOX)

- Appeared as ‘NO16966’ Data

- No data in 2nd and 3rd line therapy

- Will not change current practice

PFS

3515: Maintenance therapy with bevacizumab with or without erlotinib in metastatic CRC according to KRAS: Results of the GERCOR DREAM phase III trial. C. Tournigand, et al

mFOLFOX7 bevacizumab

XELOX2 bevacizumab

FOLFIRI bevacizumab

Bevacizumab (7.5 mg/kg q3w)

+ erlotinib (150 mg/d)

until PD

RANDOMIZATION

NoProg

N=222

N=224

INDUCTION, N=700 MAINTENANCE, N=446

Bevacizumab (7.5 mg/kg q3w)

until PD

REGISTRATION

Primary end point: PFS on maintenance therapySecondary endpoints : OS, OS from maintenance, Duration without chemotherapy, RR, Survival according to KRAS mutational status

OPTIMOX 1

FOLFOX4(n=312)

FOLFOX7(n=313)

6 cycles

FOLFOX7

6 cycles

LV5FU2

12 cycles

Clinic Chemptherapy Goal: Increasing the efficacy, minimize/delay the toxicity- Optimox 1: maintain the efficacy and decreasing the toxicity with ‘stop

and go’ strategy- Biological agents benefit in combination with chemotherapy - VEGF inhibitors vs. EGFR inhibitor(s) and combination? Maintenance?

The impacts of Kras status?

R

PACCE: PFS and OSOx-CT + BEV

(n=410)Ox-CT + BEV + Pmab

(n=413)HR

(95% CI)

PFS (mos) 11.1 months 9.6 months 1.27 (1.05-1.53)

OS ( mos) >24 months 19.4 months 1.43 (1.11-1.83)

ORR 46% 45%

Iri-CT + BEV(n=115)

Iri-CT + BEV + Pmab(n=115)

HR(95% CI)

PFS (mos) 11.7 10.1 1.21 (0.80-1.82)

OS (mos) 20.5 20.7 NR

ORR 39% 43% 1.15 (OR)

CAPOX/ Bev CAPOX/BEV/Cet p value

n = 368 n = 368

Median PFS (months)

(HR; 95% CI)

10.7

(9.7-12.5)

9.6

(8.5-10.7)

0.018

(1.21;1.03-1.45)

Median OS (months)

(HR; 95% CI)

20.4

(18.1-26.1)

20.3

(17.9-21.6)

0.21

(1.15;0.93-1.43)

Response rate

(CR + PR)44% 44% 0.88

Disease control rate

(CR + PR + SD)83% 81% 0.39

CAIRO2

  Bev alone(N=228)

Bev + erlotinib(N=224)

HR[95% CI]

P value

Maintenance PFS(from randomization)

4.6 [4.1-5.7]

5.9[4.5-6.4]

HR 0.76[0.61-0.94]

0.0096

PFS(from registration)

9.3 [8.7-10.1]

10.2 [9.5-11.5]

HR 0.75[0.61-0.93]

0.0088

OS(from registration)

27.9 [24.1-31.1]

28.4 [25.1-33.9]

HR 0.89[0.70-1.12]

0.8857

Survivals

BevacizumabN=228

Bevacizumab + ErlotinibN=224

Diarrhea 2 (1) 20 (9)Skin toxicity 0 (0) 46 (20)

Grade 3/4 Toxicity (%)

Maintenance PFS(randomized population, from randomization)

B B + E

No. of patients 228 224

Events 183 159

Censored 45 65

Median maint. PFS

4.6 5.9

HR [95% CI] 0.76 [0.61-0.94]

P value 0.0096

CAIRO2: KRAS genotyping (n=501)Kras WT (n=305) 61%

Kras Mutated (N=196) 39%

p

PFS (months)

CAPOX +B 10.7 12.5 0.92CAPOX +B+C 10.5 8.6 0.47

p 0.10 0.043OS (months)

CAPOX +B 23.0 24.9 0.90CAPOX +B +C 22.2 19.1 0.52

p 0.49 0.35

SurvivalsKras WT  Bev alone

(N=111)Bev + erlotinib

(N=129)HR

[95% CI]P value

m PFS(from randomization)

5.9[4.0-6.5]

6.0[4.5-7.8]

HR 0.86[0.64-1.15]

0.3153

PFS(from registration)

9.7 [8.7-11.0]

10.9 [9.7-12.6]

HR 0.82[0.61-1.11]

0.1974

OS(from registration)

31.5 [27.5-38.1]

31.8 [26.6-37.9]

HR 0.92[0.66-1.30]

0.6443

 Kras Mut Bev alone(N=89)

Bev + erlotinib(N=91)

HR[95% CI]

P value

Maintenance PFS(from randomization)

4.4 [3.8-5.3]

4.7[3.6-7.1]

HR 0.77[0.54-1.08]

0.124

PFS(from registration)

9.9 [8.6-10.8]

9.8 [8.4-12.2]

HR 0.80[0.57-1.13]

0.212

OS(from registration)

26.9 [22.4-33.2]

26.3 [21.0-34.4]

HR 1.06[0.72-1.55]

0.767

Maintenance PFSWT KRAS Mut KRAS

- The addition of erlotinib to bevacizumab following induction therapy with bevacizumab-based chemotherapy significantly increases the maintenance PFS.

- In contrast to anti-EGFR Mabs, KRAS tumor status does not select patients with mCRC benefiting from erlotinib

However: Will the results change the practice?• Bevacizumab alone is not standard, and without clear benefit

(SAKK 41/06, abs 3503); and after OPTIMOX 1, 5-FU (or Capecitabine)+ bevacizumab is already the maintenance therapy in many practices (which is supported by CAIRO3, abs 3502).

• Erlotinib is not indicated in CRC

May help future investigation of anti-VEGF mAb + Anti-EGFR TKI in mCRC

Conclusions

3521: Results according to age in AVEX, a randomized phase 3 trial of bevacizumab with capecitabine for elderly patients with mCRCMark P. Saunders, et al

Previously untreated mCRC, age 70 years

N=280

Capecitabine 1000 mg/m2 b.i.d. days 1–14, q21d

Bevacizumab 7.5 mg/kg day 1, q21d

+Capecitabine 1000 mg/m2 b.i.d.

days 1–14, q21d

Stratification factors:• ECOG PS (0–1 vs 2)• Geographic region

Randomize 1:1

Are elderly patients at increased risk for toxicity secondary to Bevacizumab, and how old is old?

Progression-free and overall survival*

*Overall population. 113 PFS events in the BEV + cape arm; 127 PFS events in the cape arm; 75 OS events in each treatment arm. BEV = bevacizumab; cape = capecitabine; CI = confidence interval; OS = overall survival; PFS = progression-free survival

140 99 68 41 23 13 8 2 2 1 0

140 82 38 13 6 4 1 1 1 1 0

Number at riskBEV + cape

Cape

Time (months)

PFS

estim

ate

1.0

0.8

0.6

0.4

0.2

0.0

0 4 8 12 16 20 24 28 32 36 40

5.1 mo

9.1 mo

HR=0.53 (95% CI: 0.41–0.69)P<0.001

Time (months)

1.0

0.8

0.6

0.4

0.2

0.0

0 4 8 12 16 20 24 28 32 36 40 44O

S es

timat

e

16.8 mo 20.7 mo

HR=0.79 (95% CI: 0.57–1.09), P=0.182

Number at riskBEV + cape

Cape

2

1

140 120 95 81 60 44 34 16 12 8 5

140 108 85 62 49 33 19 11 9 6 5

Bevacizumab + Capecitabine (n=140) Capecitabine (n=140)

A. Progression-free survival B. Overall survival

Progression-free and overall survival

Outcome

70 – 74 years 75 – 79 years ≥80 years

Bev + Capen=55

Capen=46

Bev + capen=57

Capen=66

Bev + capen=28

Capen=28

Median PFS, mos(95% CI)

7.6(6.0–11.8)

5.0 (4.0–6.5)

9.8(7.1–11.4)

5.1(4.1–7.4)

10.5(5.0–14.5)

5.1(2.2–7.1)

Hazard ratio (95% CI)Log-rank P

0.52 (0.32–0.83)<.001

0.60 (0.40–0.89).016

0.36 (0.19–0.71).003

Median OS, months(95% CI)

20.7 (13.7–26.1)

22.2(9.7–42.7)

19.8(13.8–27.3)

17.4(11.9–23.0)

19.7(7.5–26.9)

12.6(6.6–17.0)

Hazard ratio (95% CI)Log-rank P

0.91 (0.50–1.66) .55

0.79 (0.48–1.30).37

0.62 (0.31–1.24).24

AE, %

70 – 74 years 75 – 79 years ≥80 years

Bev + Capen=54

Capen=46

Bev + capen=53

Capen=64

Bev + capen=27

Capen=26

Any AE 96 94 96 95 93 100Grade ≥3 AE 63 41 55 41 59 58SAE 35 28 26 30 30 46Grade 5 AE* 7 11 8 9 11 19AE leading to dose interruption/modification 61 33 49 47 52 54

Any AE leading to discontinuation 22 7 30 17 22 19AE, %

70 – 74 years 75 – 79 years ≥80 years

Bev + Capen=54

Capen=46

Bev + capen=53

Capen=64

Bev + capen=27

Capen=26

Bleeding/hemorrhage 20 11 30 6 26 –Hypertension 15 2 26 6 15 8VTE 11 7 13 6 11 –Proteinuria 13 – 4 2 4 –ATE 4 – 2 2 11 12

No major difference of AEs comparing with other Bevacizumab studies

Conclusions• A statistically significant improvement in PFS with the addition of

bevacizumab to capecitabine (HR, 0.53; P<.001)

– Patients grouped according to age (70–74 years, 75–79 years, ≥80 years) had a similar PFS benefit

• The safety profile was consistent with previously reported data and consistent across age subgroups

• Suggests that the combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for elderly with good PS

- Age is ‘relative’, even with anti-angiogenic agent, (however, data here is only for Bev… ).

- Key issue is careful patient selection.

3518: Non-inferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer: A randomized phase III trial (ACTS-CC)

Yoshihiko Nakamoto, et al. ACTS-CC study group

S-1: 80, 100, 120 mg/day according to BSA in 2 divided doses daily Day 1-28, q6w x 4 cycles (24w)

S-1UFT: 300-600 mg/day according to BSALV: 75mg/dayin 3 divided doses dailyDay 1-28, q5w x 5 cycles (25w)

UFT/ LV

pStage IIIColon Cancer (C-RS) ・ Curatively resected ・ Age: 20 - 80 y.o. ・ PS: 0-1

Control armTest arm

Stratification factors　 ・ LN metastasis (N1/N2)　 ・ Institution

R

Primary End Point: 3-yr DFS, Non inferiority margin of HR in DFS: 1.29Target sample size ： 1,480 pts. with one-sided α=0.05, β=0.20

Biochemical action of S-1 and UFT/LVEffector Modulator ① Modulator ②

S-1 CDHPDPD inhibition（ strong ）

oteracilDecreasing GI toxicity

UFT/LV uracilDPD inhibition （ moderate ）

LVPotentiation of

TS inhibition

DPD ： Dihydropyrimidine dehydro- genase TS ： thymidylate synthetaseCDHP ： 5-chloro-2,4-dihydroxypyridine

tegafurProdrug of 5-FU

- Potent DPD inhibitory activity - Easy administration (Twice-daily p.o.)- Low price (1/2 of UFT/LV, 1/3 of mFOLFOX6 in Japan)

DFS and OSMedian follow-up: 41.3 months (1.8-52.2) EAS ： n=1,518

88.2%

80.1% 75.5%

71.8%

86.5%77.6% 72.5%

66.1%

S-1

UFT/LV

HR 0.85 [95%CI: 0.70-1.03], p=0.1003

One-sided p<0.0001 (non-inferiority)

No. at risk

0y 1y 2y 3y 4y 5y

S-1 758 658 594 533 167

UFT/LV

760 649 573 476 77

98.8% 96.8%

93.6% 88.3

%98.9% 96.6% 92.7%

86.1%

HR 0.86 [95%CI: 0.62-1.19]P=0.3600

No. at risk

0y 1y 2y 3y 4y 5y

S-1 758 743 723 666 144

UFT/LV

760 741 713 658 147

S-1

UFT/LV

Conclusions

- Adjuvant chemotherapy using S-1 will be a treatment option for stage III colon cancer in Japan

- S-1 for stage III CRC is non-inferior in DFS to that of UFT/LV. - AEs were acceptable, and the completion rate of the protocol Tx. was high.

NSABP C-06 3 yr. DFS 5 yr DFS 5 yr. OS

5-FU/LV 74.5 % 68.2 % 78.7 %UFT 74.5 % 67.2 % 78.5 %

- Might fit in US pts, based on NSABP C-06 data, however, not available in USA

3519: A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: the SOFT study. D. Takahari, et al SOFT Study Group

Stratification factors:• With vs. without adjuvant chemotherapy

•Institutions

n=512

mFOLFOX6+Bev (n=256)L-OHP: 85 mg/m2 d1

Bev: 5 mg/kg d1l-LV: 200mg/m2 d1

5-FU: 400mg/m2 bolus d15-FU: 2,400mg/m2 46 hr civ d1,2

repeated every 2 wks

SOX+Bev (n=256)L-OHP: 130 mg/m2 d1

Bev: 7.5 mg/kg d1S-1: 80, 100, 120 mg*/body d1-14

repeated every 3 wks

mCRC1st lineAge: 20 - 80

PS: 0-1

*According to body surface area, BSA < 1.25 m2, 1.25=<BSA <1.5, BSA >=1.5

Non-inferiority

Control arm Test arm

R

PFS and OS

0 6 12 18 24 30 36 420

0.25

0.5

0.75

1

mFOLFOX6+BevSOX+Bev

mFOLFOX6+Bev : 10.2 M (95% CI:9.5-11.3)SOX+Bev: 10.2 M (95% CI:9.4-11.1)

PFS HR=1.021 (95% CI:0.847-1.232)

Best overall response mFOLFOX6+Bev (n=233) No. of pts*

SOX+Bev (n=234)No. of pts*

p value

NE 16 21

RR (%) 62.7 61.5 0.8026

DCR (%) 89.3 89.3 0.9872

R0 resection rate 22 24

R0-R (%) 22 (8.6%) 24 (9.4 %) 0.7678

0 6 12 18 24 30 36 420

0.25

0.5

0.75

1

mFOLFOX6+Bev : 30.9 M (95% CI:28.6-33.1)SOX+Bev : 29.6 M (95% CI:25.8- …)

Median follow-up duration: 23.4 M (0.3 to 37.8)

mFOLFOX6+BevSOX+Bev

OS

HR=1.052 (95% CI:0.805-1.376

Sex MaleFemale

Age <65

65≦Primary lesion Colon

RectosigmoidRectum

Histology tub1,2por1,2

　 OtherHistory of surgery for Nocolorectal cancer 　 YesHistory of adjuvant Notherapy for CRC Yes

Target lesions NoYes

Liver metastases NoYes

Lung metastases No

Yes

BSA(m2) < 1.25

1.25 < 1.50≦1.50 ≦

SOX+Bev better mFOLFOX6+Bev better

P value for interactionSub-group No. of pts329182

273

2382578516643721

53

119

39243378

44467

197

314395

116

14

175

322

0.1880

0.2592

0.5409

0.3367

0.3285

0.9947

0.8514

0.3837

0.0419

0.9150

Subgroup analysis of PFS(FAS)

0.25 2.5

D.Takahari, et al. ASCO 2013; Abstract #3519

Conclusions

SOX + Bev can replace with mFOLFOX6 + Bev as a first-line treatment for mCRC in Japan with a more convenient regimen

D.Takahari, et al. ASCO 2013; Abstract #3519

3520: Prognostic value of early objective tumor response (EOTR) to 1stline systemic therapy in mCRC: Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD (Aide et Recherche en Cancérologie Digestive) database

Dirkje W Sommeijer, et al, the ARCAD Group

Available Data 15 Studies 42 Arms

13,949 Patients

Response Data 15 Studies 42 Arms

11,987 Patients w/RR

1962 patients missing status or dates

EOTR8 5 Studies 10 Arms

3,037 Patients

EOTR6 5 Studies 16 Arms

4,632 Patients

EOTR12 10 Studies 32 Arms

6,688 Patients

Target 4 Studies 8 Arms

1,833 Patients

Non-Target 5 Studies 8 Arms

2,799 Patients

Target 3 Studies 6 Arms

1,828 Patients

Non-Target 4 Studies 4 Arms

1,209 Patients

Target 5 Studies 14 Arms

2,382 Patients

Non-Target 9 Studies 18 Arms

4,306 Patients

15 Studies: N9741, OPTIMOX 1, FOCUS, AVF2192g, AVF2107g, HORG,

HORIZON H, FOCUS 2, NO16966, OPTIMOX 2, PACCE, MAX,

Macco, PRIME, HORIZON IH

OS and PFSEOTR at 6 weeks EOTR at 12 weeks

EOTR at 8weeks

PFS PFS PFS

EOTR at 6, 8, 12 weeks, overall response rate and PFS and OS

(adjusting with age, gender, PS, Mets in liver and lung)

PFS OS

Discussion- Clinic investigation: EORT warrants further consideration

as a potential surrogate endpoint to detect early signals for future trials, particularly randomized studies .

- Clinic Practice: EORT as a ‘clinic surrogate prognostic factor’ in mCRC treatment

- Questions:a) Early response vs. Duration of responseb) Tumor biologyc) Early response brings more treatment options

(resection, local-regional therapy, more lines of therapy), improved quality of life.