GI Highlights from ASCO 2014 - Hope Health Centerhopehealthreseda.com › Articles › Friday Fisher... · Microsatellite Instability (MSI) by PCR is a way to assess MMR status

GI Highlights from ASCO 2014

George Fisher, MD PhD

Professor of Medicine (Oncology)

2 Stanford Cancer Center 2 Stanford Cancer Center 2 Stanford Cancer Center

Disclosures

Research Funding

Genentech

Bristol-Meyers Squibb

Novartis

Polaris

Ipsen

NewLink Genetics

*XBiotech

*RadioRX

*Merck

*Trials opening in Fall 2014


Abstracts to present

Prognostic impact of defective mismatch repair

Dan Sargent et al. Analysis of Adjuvant Trials in ACCENT Database

“Maintenance” therapy for metastatic colon cancer

Miriam Koopman et al. Dutch Colorectal Cancer Group

Dirk Arnold et al. AIO Colorectal Study Group

5-FU +/- oxaliplatin with pre-op radiation and as adjuvant

Rodel et al. AIO-04 Trial: The German Rectal Cancer Study Group

First line metastatic colorectal cancer: EGFR vs VEGF

Alan Venook et al. CALGB and other NCI Cooperative Groups


Prognostic Impact of Defective Mismatch Repair in Stage II/III Colon Cancer: A Pooled

Individual Patient Data Analysis of 17 Adjuvant Trials from the ACCENT Database

D Sargent, Q Shi, G Yothers, S Tejpar, M Bertagnolli, S Thibodeau, T Andre, R Labianca, S Gallinger, SR Hamilton, G Monges, K Pogue-Geile, S Paik, D Klingbiel, A Roth, E Pavey, G Kim, F

Sinicrope for the ACCENT Collaborative Group


Defective DNA repair pathway

DESTABILIZATION OF GENOME

Defective Mismatch Repair (dMMR)

frequent mutations,

repeats = MSI

instability of short tandem

~15% of all Colon cancer


Defective Mismatch Repair (dMMR) results in Microsatellite Instability (MSI)

Microsatellite Instability (MSI) by PCR is a way to assess MMR status

IHC (MLH1, MSH2, MSH6, PMS2) allows testing for the key proteins in MMR and identifies affected gene

1dMMR (tested by IHC) 97% concordant with MSI-H by PCR

Odds of Lynch Syndrome (inheritable mutation in MMR gene) approximately 20% if MSI or dMMR

Remainder of MSI/dMMR accounted for by silencing of MMR genes by methylation

1Lindor et al, JCO 2002


dMMR Phenotype: Correlations

The dMMR phenotype has been associated in single study or observational series with:

Lower stage

Better prognosis

Higher histologic grade

Right-sided location

Mucinous histology

Possibly worse response to 5-FU1

1Sargent, JCO 2010


Methods

Collection of individual patient data from 26 randomized adjuvant colon cancer trials, presently > 37,800 patients

Initial goal: Clinical trial endpoints

MMR data available on 7803 pts from 17 trials

Ability to examine relationships between MMR status and outcomes based on detailed individual patient data with clinical trial quality follow-up


Stage II, Surgery Alone (N=307)

Time to Recurrence Overall Survival


TTR & OS Stage III, Surgery Alone (N=264)



TTR & OS Stage II, 5-FU Based Rx (N=1155)



TTR & OS Stage III, 5-FU Based Rx (N=2723)



Time from recurrence to death (dMMR vs. pMMR)

Stage 2 Stage 3


Conclusions

MMR status associated with multiple clinical/pathologic characteristics

Younger, Female, N0, T3/4, right sided

MMR did not impact post-recurrence survival

MMR is a prognostic marker in untreated stage II and III patients

Trend toward stronger effect in stage II


Clinical Implications

MMR is also prognostic in 5-FU treated patients, but with reduced impact (HR ~ 0.80)

Favorable prognosis of treated dMMR stage III patients indicates MMR should not guide treatment decisions in stage III

In a stage II pt where treatment is considered, MMR should be tested, and dMMR pts should not be recommended for treatment due to their excellent prognosis (90% 5 yr OS)


Clinical Implications

MMR is also prognostic in 5-FU treated patients, but with reduced impact (HR ~ 0.80)

Favorable prognosis of treated dMMR stage III patients indicates MMR should not guide treatment decisions in stage III

In a stage II pt where treatment is considered, MMR should be tested, and dMMR pts should not be recommended for treatment due to their excellent prognosis (90% 5 yr OS)

?perforation, ?obstruction ?angiolymphatic invasion, ?low node count

?T4, poorly differentiated


Miriam Koopman, L Simkens, A May, A ten Tije, G Creemers, O Loosveld, F de Jongh, F Erdkamp, Z Erjavec, A van der Torren, J van der Hoeven, P Nieboer, J Braun, R Jansen, J Haasjes, A Cats, J Wals, V Derleyn, A Honkoop, L Mol,

H van Tinteren, C Punt

Maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer Final results and subgroup analyses of the phase 3 CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG)


Study Schema

SD or better after 6 cycles

CAPOX- B

observation

R

capecitabine + bevacizumab

PD

PFS2

any treatment incl. CAPOX-B

PFS1

PD

PFS2 = time from randomization to progression upon re-introduction of CAPOX- B

PFS2 is considered to be equal to PFS1 for patients in whom CAPOX- B is not reintroduced after PFS1 for any reason


0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

Mean

Qo

L s

co

re

Weeks

observation

maintenance

CAIRO3 Quality of life during maintenance/observation

Between-group difference: 3.9 (95%CI 1.2; 6.5) p=0.004 (not clinically relevant, < 10)

QoL was maintained during maintenance treatment, and was clinically not inferior compared to QoL in observation arm

248 186 112 57 40 14 10 O

243 164 114 92 76 50 36 M


Authors’ Conclusions

Maintenance treatment with capecitabine and bevacizumab after 6 cycles of CAPOX-B in metastatic CRC achieves:

• significant benefit in median PFS2 (primary endpoint), PFS1 and TT2PD

• non-significant benefit in median OS

• Patients with synchronous disease with resected primary tumor, and patients with a CR/PR as best response to induction treatment appear to benefit most from maintenance treatment in terms of OS

• QoL is maintained and clinically not inferior compared to observation


Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no treatment,

following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with

metastatic colorectal cancer (mCRC): A non-inferiority phase III trial: AIO 0207

D. Arnold, U. Graeven, C. Lerchenmueller, B. Killing,

R. Depenbusch, C.-C. Steffens, S. Al-Batran, T. Lange,

G. Dietrich, J. Stoehlmacher, A. Tannapfel,

H.-J. Schmoll, A. Reinacher-Schick, S. Hegewisch-Becker

on behalf of the AIO CRC Study Group


AIO 0207: Treatment schema

FP* + Bev

any FP* +/- Bev

+/- Ox

Bev

no treatment

Induction: 24 wks Maintenance:

non-PD Re-Induction

*FP= any fluoropyrimidine in a standard protocol (e.g. mFOLFOX6, FOLFOX4, Cape/Ox, LV5FU2; Cape 2x1000)

Bev used in standard doses (5mg/kg q 2 wks or 7.5mg/kg q 3wks arm A; 7.5 mg/kg 3q 3 wks arm B)

R

1st p

rogre

ssio

n

2nd

pro

gre

ssio

n

PFS1

TFS

Stratification Adjuvant tx.

CR/PR vs. SD ECOG PS

CEA @ baseline

FP* + Bev +

Oxaliplatin

with CR/PR/SD

Presented by: Dirk Arnold, on behalf of the AIO CRC study group

Induction:

24 wks

Maintenance: non-PD Re-Induction

Stratification Adjuvant tx.

CR/PR vs. SD ECOG PS

CEA @ baseline


TFS (Time to Failure of Strategy): All arms

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

Rate

without event

FP/Bev: n=141, 115 events, median = 6.8 months

Bev: n=153, 129 events, median = 6.5 months

No therapy: n=153, 138 events, median = 6.1 months

0 4 8 12 16 20 24 28 32 36 38 2 6 10 14 18 22 26 30 34

Log rank test: p=0.099

Median TFS all patients: 6.5 months (from randomization)



FP/bev: n=157, 70 events, median = 23.8 months

Bev: n=156, 67 events, median = 26.2 months

No therapy: n=156, 66 events, median = 23.1 months

0 5 10 15 20 25 30 35 40 45

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

Median OS all patients: 23.7 months (from randomization)

N=473 Interim analysis: 203 events

Log rank p=0.70

Rate

without event

OS from start of maintenance



My Conclusions regarding “Maintenance”

If PFS is desired, fluoropyrimidine + bev favored over bev alone

But what of fluoropyrimidine alone?

Modest, at best, overall survival advantage for maintenance

Perhaps better in those with good response to induction therapy

Perhaps better in those with synchronous metastases with primaries removed

But when should primary be removed?

“No impact on QOL” (Really???)


Rectal Cancer


Efforts to improve cure rates for rectal cancer

Infusional 5-FU over bolus (phase III)

5-FU + irinotecan (Phase II)

Capecitabine over 5-FU (Phase III)

Addition of EGFR inhibitors (randomized Phase II)

Addition of VEGF inhibitors (Phase II)

Addition of oxaliplatin


Preoperative chemoradiotherapy and postoperative chemotherapy with 5-FU and oxaliplatin versus 5-FU alone in locally advanced rectal cancer Results of the CAO/ARO/AIO-04 randomized phase III trial

C. Rödel, T. Liersch, R. Fietkau, W. Hohenberger, U. Graeven, T. Hothorn, D. Arnold, H. Raab, C. Wittekind, C. F. Hess, L. Staib, H. Becker, R. Sauer

German Rectal Cancer Study Group


Pre-op vs Post-op Chemoradiation

5-FU: 1 g/m2/d x 5

RT: 50.4 Gy

5-FU: 500 mg/m²/d TME

R

TME

RT: 50.4 Gy

5-FU: 1 g/m2/d x 5 5-FU: 500 mg/m²/d

Sauer R. et al., N Engl J Med 2004


10 year Update

Sauer R. et al., J Clin Oncol 2012


10 year Update

Sauer R. et al., J Clin Oncol 2012

More effective systemic therapy needed!


RT 50.4 Gy + 5-FU

1000 mg/m² days 1-5 + 29-33

RT 50.4 Gy + 5-FU/OX Oxaliplatin: 50 mg/m² d 1, 8, 22, 29

5-FU: 250 mg/m² d 1-14 + 22-35

T ME

mFOLFOX6 Oxaliplatin: 100 mg/m² d1,q15

Folinic acid: 400 mg/m² d1 5-FU: 2400 mg/m² d1-2

8 cycles (4 months)

5-FU 500 mg/m² d 1-5, q29

4 cycles (4 months)

Phase III: CAO/ARO/AIO-04

Best arm of CAO/ARO/AIO-94:

Based on phase I/II trials:

Note: Chemo gap during 3rd week of RT

Rödel, C et al. ASCO 2014


Disease-free Survival: Intent to Treat



Overall Survival: Intent to Treat



Pathologic Responses

Pathology Preop

CRT 5-FU

n=615

Preop

CRT 5-FU/OX

n=596

Lymph nodes examined (median, range)

15 (0-81) 14 (0-79)

Completeness local resection (%) R0 R1 R2

95 1 2

95 3 1

TNM stage (%) ypT0N0 (pCR) I II III IV (cM1 + pM1)

13* 28 24 27 6

17* 25 26 26 3

*p= 0.038 (unplanned, exploratory))


Neoadjuvant ChemoRT with oxaliplatin

Study #Pts ChemoRT Regimen ypCR Rate (%)

ACCORD 12 291 Cape + RT 14

293 Cape + Oxali 50mg/m2 wkly+RT 19(p=0.09) NS

STAR-01 379 FU CI+RT 16

368 FU CI+ Oxali 60mg/m2 wkly+RT 16 (p=NS) NS

NSABP R-04 636 FU/Cape + RT 18

640 FU/Cape + Oxali 50mg/m2 wkly+RT 20(p=0.42) NS

PETACC-6 547 Cape+RT 12

547 Cape + Oxali 50mg/m2 wkly+RT 14(p=0.27) NS

CAO/ARO/AIO-

04

623 FU CI+RT 13

613

FU CI + Oxali 50mg/m2 wkly+RT 17(p=0.04)

unplanned, exploratory

Slide courtesy of Gyorgy Bodoky


My Conclusions

Oxaliplatin has no role in pre-operative therapy of resectable localized rectal cancer

Improvement in ypCR in this study not supported by other trials

Perhaps helpful in selected cases of metastatic rectal cancer??

Adjuvant (post-op) oxaliplatin remains a reasonable option and likely a standard of care for those with higher risk and well enough to receive it

Possible exceptions: elderly? ypCRs? Clinical stage T3N0 with ypT1,2N0 ???


?’s in the Management of Rectal Cancer

Among T3 or N1 upper rectal cancers, who does not need radiation?

Among T1-3 low lying rectal cancers receiving chemoradiation, who does not need an APR?

Among T3 or N1 rectal cancers who undergo neoadjuvant chemoradiation, who does not need post-operative chemotherapy?


PROSPECT Trial: Attempt to define a subset of patients who do not need radiation

*Clinical Stage

T3 or N1 Upper Rectal

R

FOLFOX x 3 months

Standard chemoradiation

If response

surgery

If no response

*MRI staged; > 5 cm from anal verge

Post-op Chemo


In Pursuit of “Best” 1st Line Therapy

Prevailing wisdom in 2004

FOLFIRI and FOLFOX: similar efficacy

Bevacizumab (VEGF): effective with 1st line chemotherapy

Cetuximab (EGFR): effective as 2nd or 3rd line treatment

Bevacizumab + Cetuximab: active combination in 2nd line

Venook et al. ASCO 2014








Now 10 years smarter

KRAS mutations predict resistance to EGFR antibodies

Combining VEGF and EGFR antibodies can be harmful

Drop oxaliplatin in favor of “maintenance” option









Now 10 years smarter

KRAS mutations predict resistance to EGFR antibodies

Combining VEGF and EGFR antibodies can be harmful

Drop oxaliplatin in favor of “maintenance” option

Median Survival 20-22 months Venook et al. ASCO 2014


Irreconcilable differences…

Is there a “preferred” chemo for biologics?

Is FOLFIRI + bev > FOLFOX / CAPOX + bev??

Is FOLFIRI + EGFR Ab > FOLFOX / CAPOX + EGFR Ab??



Irreconcilable differences…

Is there a “preferred” chemo for biologics?

Is FOLFIRI + bev > FOLFOX / CAPOX + bev??

Is FOLFIRI + EGFR Ab > FOLFOX / CAPOX + EGFR Ab??

Is EGFR Ab better than VEGF Ab?

FIRE-3: FOLFIRI + Cetuximab > FOLFIRI + Bevacizumab

Primary endpoint: response rate (no difference)

Secondary endpoints: PFS (no difference)

Overall Survival (favored cetuximab)



FIRE-3 Study Design

Primary endpoint: response rate Key inclusion criteria - Patients ≥18 years with histologically confirmed diagnosis of mCRC - ECOG PS 0-2 - prior adjuvant chemotherapy allowed if completed >6 month efore inclusion Amendment in October 2008 to include only KRAS wildtype patients 150 active centers in Germany and Austria

mCRC 1st-line therapy KRAS wild-type

N=592

Randomize 1:1

FOLFIRI + Cetuximab

Cetuximab: 400 mg/m2 i.v 120 min initial dose 250 mg/m2 i.v. 60 min ; q 1 w

FOLFIRI + Bevacizumab

Bevacizumab: 5 mg/ kg i.v.30-90 min ; q 2w

Heinemann et al ASCO 2013


FIRE-3 Overall Survival Results

297 295

numbers at risk

218 214

111 111

60 47

29 18

9 2

Pro

bab

ilit

y o

f su

rviv

al

12 24 36 48 60 72

Events

n/N (%)

Median

(months)

95% CI

― FOLFIRI + Cetuximab

158/297

(53.2%)

28.7 24.0 – 36.6

― FOLFIRI + Bevacizumab 185/295

(62.7%)

25.0 22.7 – 27.6

HR 0.77 (95% CI: 0.62 – 0.96)

Log-rank p= 0.017


FIRE-3 Overall Survival Results

297 295

numbers at risk

218 214

111 111

60 47

29 18

9 2

Pro

bab

ilit

y o

f su

rviv

al

1. Secondary endpoint 2. No difference in ITT Response or PFS 3. Median duration of treatment ~ 5 months 4. Median PFS ~ 10 months 5. Curves diverge at 24 months: during expected time of third line therapies

12 24 36 48 60 72

Cetux

Bev


Original Design of CALGB 80405

Chemo + Cetuximab

Chemo + Bevacizumab

mCRC 1st-line

STRATA:

FOLFOX/FOLFIRI Prior adjuvant

Prior XRT

FOLFIRI

or FOLFOX

MD

choice Chemo + Cetuximab + Bevacizumab

New findings altered design: KRAS matters Bev + Cetux inferior to either alone


CALGB/SWOG 80405: Final Design

N = 1140

1° Endpoint: Overall Survival

Chemo + Cetuximab

Chemo + Bevacizumab

mCRC 1st-line

KRAS wild type (codons 12,13)

STRATA:

FOLFOX/FOLFIRI Prior adjuvant

Prior XRT

FOLFIRI

or FOLFOX

MD

choice



Eligibility Criteria

Untreated metastatic CRC

Adjuvant chemo okay if > 12 months since last dose

ECOG 0-1

KRAS wild type at codons 12 &13

At enrollment, investigators:

Choose: FOLFOX or FOLFIRI

Document intent: Palliative or plan to resect all metastases



Patient Characteristics

ARM A

CHEMO +

BEV

N=55N=559 (%)

ARM B

CHEMO +

CETUX

N=578 (%)

TOTAL

N=1137 (%)

Age median (range) 59 (21-85) 59 (20-89) 59 (20-89)

Male 348 (62.3) 349 (60.4) 697 (61.3)

Primary in place 157 (28) 154 (27) 311 (28)

Palliative Intent 465 (86.4) 458 (82.5) 923 (84.4)

FOLFOX / FOLFIRI (%) 73 /27 74 / 26 73 / 27



Adverse events…

Just what you’d expect…


CALGB 80405: Overall Survival

Arm N (Events) OS (m)

Median 95% CI

Chemo + Cetux 578 (375) 29.9 27.0-32.9

Chemo + Bev 559 (371) 29.0 25.7-31.2

P=0.34 HR 0.925 (0.78-1.09)



CALGB 80405: Progression Free Survival

Arm N (Events) PFS (m)

Median 95% CI

Chemo + Bev 559 (498) 10.8 9.7-11.4

Chemo + Cetux 578 (499) 10.4 9.6-11.3

P=0.55 HR 1.04 (0.91 -1.17)



Overall Survival for FOLFOX Treated

Arm N (Events) OS (m) Median

95% CI

FOLFOX + Cetux 426 (277) 30.1 26.6-34.8

FOLFOX + Bev 409 (290) 26.9 24.7–30.0

P=0.09 HR 0.9 (0.7-1.0)



Overall Survival for FOLFIRI Treated

Arm N(Events) OS (m) Median

95% CI

FOLFIRI + Bev 150 (81) 33.4 27.3-41.3

FOLFIRI + Cetux 152 (98) 28.9 25.6-34.2

P=0.28 HR 1.2 (0.9-1.6)



Cetuximab + [FOLFOX vs. FOLFIRI]


95% CI

FOLFIRI + Bev 150 (81) 33.4 27.3-41.3

FOLFIRI + Cetux 152 (98) 28.9 25.6-34.2


95% CI

FOLFOX + Cetux 426 (277) 30.1 26.6-34.8

FOLFOX + Bev 409 (290) 26.9 24.7–30.0



Bevacizumab + [FOLFOX vs. FOLFIRI]


95% CI

FOLFIRI + Bev 150 (81) 33.4 27.3-41.3

FOLFIRI + Cetux 152 (98) 28.9 25.6-34.2


95% CI

FOLFOX + Cetux 426 (277) 30.1 26.6-34.8

FOLFOX + Bev 409 (290) 26.9 24.7–30.0


?


Patients Rendered Disease Free

N (Events) Median (95% CI)

124 (34) 66.3 (59.8-NA)


11% of all patients rendered disease free


CALGB 80405: Data Pending

Response Rate

Duration of therapy / Dose intensity

Subset analysis:

Patients rendered disease free

Impact of adjuvant therapy

Second line therapy analysis

Extended RAS

Quality of Life Analysis



Slide courtesy of Dueck, Schrag, Naughton

------- Bevacizumab ------- Cetuximab



Molecular Correlatives Planned

Concordance of local vs central KRAS results

Extended KRAS analysis

Tumor transcriptome

DNA Sequencing (circulating cell free, tumor, germ-line)

Proteomic analysis of plasma

Other planned analyses:

Right vs Left sided primary / Intact vs Resected primary

Gender / Disparities / Pharmacoeconomics

Vitamin D / Lifestyle / Diet


Could Extended RAS Change Result?

EXON 2 EXON 3 EXON 4 EXON 1 NRAS

12 13 61 117 /146

3.8%

EXON 15 EXON 11 BRAF

600

EXON 2 EXON 3 EXON 4 EXON 1 KRAS

61 146

4.9% 4.3%

59

12 13

wt

2% 0%

0% 10%

Among KRAS ex wt patients, an additional 14-20% of tumors with other RAS mutation was found in PRIME, PEAK and FIRE-3 studies

Schwartzberg L. et al. JCO 2013 (abstr 3631)


Could Extended RAS Change Outcome?

Study WT KRAS ex 2 WT AII RAS

Prime (+/- Panitumumab)1

N 656 512

PFS HR / p 0.8 / 0.02 0.72 / 0.04

OS HR / p 0.83 / 0.072 0.78 / 0.043

FIRE-3 (Cetuximab vs Bevacizumab)2

N 592 342

PFS HR / p 1.06 / 0.54 0.93 / 0.54

OS HR / p 0.77 / 0.017 0.70 / 0.011

PEAK (Panitumumab vs Bevacizumab)3

N 285 170

PFS HR / p 0.84 / 0.22 0.66 / 0.03

OS HR / p 0.62 / 0.009 0.63 / 0.058

1Douillard JY, NEJM 2013; 2Schwartzberg L, JCO 2013 (A3631); 3Stintzing S, EJC 2013 (Proc ECCO)


J Clin Oncol, 1992

Overall Survival: CALGB 80405 compared with

meta-analysis from 1992


CALGB 80405: My Conclusions

Patients and oncologists have choices…

Irinotecan or Oxaliplatin; VEGF or EGFR antibody

Extended RAS likely to shift hazard ratio; unlikely to make enough difference to be clinically significant

[OS Hazard Ratio 0.925 – *(0.05 or 0.07) = 0.85 or 0.87]

New bar for median overall survival of 29 months

Subset rendered disease free with median of 66 months

Provocative subsets: e.g. FOLFIRI + Bev vs FOLFOX + Bev

Important correlations to come…

Genomic / Proteomic / Site dependence / prior adjuvant *Magnitude of difference between codon 1,2 KRAS and extended KRAS


Impact on Practice?


Documents

GI Highlights from ASCO 2014 - Hope Health Centerhopehealthreseda.com › Articles › Friday Fisher... · Microsatellite Instability (MSI) by PCR is a way to assess MMR status