Charles D. Blanke, M.D., F.A.C.P.

OHSU Cancer Institute

Metastatic Colorectal Cancer: What to Use (or not), How to Prevent Toxicity (or not) and Whom to Treat

(or not)

Abstract 279: Interim results from PACCEAbstract 279: Interim results from PACCEJ. Randolph Hecht and associatesJ. Randolph Hecht and associates

Panitumumab 6 mg/kg Q2W

Ox-CTBevacizumab

Ox-based CT(eg, FOLFOX)

N = 800Inv choice

Iri-based CT(eg, FOLFIRI)

N = 200Inv choice

Ox-CTBevacizumab

Panitumumab Panitumumab 6 mg/kg Q2W6 mg/kg Q2W

Iri-CTIri-CTBevacizumabBevacizumab

Iri-CTIri-CTBevacizumabBevacizumab

RANDOMIZE

1:1

1:1

SCREENING

PACCE Summary

• Primary endpoint: PFS on oxali-arms– Results descriptive only for CPT-11-arms

• Patients on p-mab arm slightly higher risk

• Toxicity: a lot more grade 3/4 events on p-mab arm– Five grade 5 events versus 1 for chemo-bevacizumab

• Efficacy: ORR same on central review; 9% p-mab local

• PFS descriptively worse for p-mab on central review (10.1 vs. 11.7 mo); PFS same on local (11 vs. 10.7 mo)

PACCE and KRAS

P-MAB No P-MAB

Analyzed for ras (%) 90 84

% wild-type/mutant 55/45 60/40

Local ORR wild-type 70 59

ORR mutant 41 44

Author Conclusions

• Locally-assessed ORR better for p-mab– Differences central/local based on censoring, clinical PD

• Since most came off for non-PD, PFS endpoint invalidated

• Increased ORR with p-mab seen only with wild-type ras – ras may be prognostic and predictive

General Comments about Hecht Study

• Well-conducted trial

• Poor results not entirely unexpected, given previous report of panitumumab with oxaliplatin/bevacizumab

• ORR were modestly better with p-mab, PFS the same or worse– Need to seriously explore toxicities with double antibodies

Major Questions from PACCE

• Should we close C80405?

• What about ras?

• What is the future of panitumumab?

Should we close C80405?: NO• Cetuximab and panitumumab are different agents, with different binding

affinities, and possibly different cellular effects

• Cetuximab has a goodly amount of phase II data in combination with chemo- and biotherapy, as well as proof of efficacy in a wide-variety of tumor types– It has shown an overall survival benefit in colorectal cancer

• Similarly, phase III data in combination very strong

• Early analysis showed no danger signals for cetuximab-bevacizumab combination

What about ras?: I don’t know• Wild-type patients versus mutants had a higher ORR on arms with or

without p-mab

• Can ras exclude/predict p-mab benefit?– Previous trials showed 0% ORR to anti-EGFR MoAbs in mutant ras patients– There is not a 100% ORR in wild-type patients– Some suggest excluding mutant ras patients from MoAb studies

• Need prospective trials to absolutely validate findings– In the meantime, perhaps we need to stratify by mutational status– We definitely need to collect tissue from any large-scale trials, for correlative analysis

The Future of Panitumumab:

• Wide-variety of 1st- and 2nd-line studies in CRC– Multiple combinations with other biologics, including

anti-IGFR-1 mAb– Some include bevacizumab– No early signs of disproportionate toxicities

Ra

mFOLFOX7+bev+ Ca2+/Mg2+

mFOLFOX7+bev+ Ca2+/Mg2+

mFOLFOX7+bev+ placebo

mFOLFOX7+bev+ placebo

OXBEV LV CI 5FU

BEV LV CI 5FU

OX

BEV LV CI 5FU

OXBEV LV CI 5FU

X 8 cycles

X 8 cycles

X 8 cycles

Intermittentoxaliplatin

Continuousoxaliplatin

‘treat to failure’

Abstract #280: Effect of intravenous calcium and magnesium versus placebo on response to FOLFOX+bevacizumabin the CONcePT trial: Hochster et al.

CONCEPT: Summary

• Primary objective: TTF for continuous oxali vs. intermittent• Randomization to Ca/Mg stopped because it hindered

accrual• Study closed early when interim data was used to conduct an

unplanned interim analysis – Confirmed ORR on arms without Ca/Mg versus ORR with 32.9% /17.3%

• After closure an Independent Radiology Review Committee was formed to review images blindly and retrospectively – ORR non-significantly higher on Ca/Mg arms– Schedule (intermittent versus continuous) did not affect ORR

CONCEPT: Summary

• Primary objective: TTF for continuous oxali vs. intermittent• Randomization to Ca/Mg stopped because it hindered

accrual• Study closed early when interim data was used to conduct an

unplanned interim analysis – Confirmed ORR on arms without Ca/Mg versus ORR with 32.9% /17.3%

• After closure an Independent Radiology Review Committee was formed to review images blindly and retrospectively – ORR non-significantly higher on Ca/Mg arms– Schedule (intermittent versus continuous) did not affect ORR

CONCEPT Author Conclusions

• Ca/Mg did not affect ORR based on an independent radiologic review

• Analysis had innumerable limitations -Trial not intended to evaluate effects of Ca2+Mg2+ on ORR-Sample size was small -Significant amounts of missing data

• Additional outcomes from study pending- Especially info on whether Ca/Mg actually mitigated neurotoxicity

Chemo- and Neuroprotectants: Nothing New in Concept

• Chemoprotectants in general have been used for decades– Leucovorin, CSF, amifostine

• We have strategized against peripheral neuropathy caused by a variety of agents– Using amifostine, glutamine, venlafaxine

• We have fought against oxali-induced neuropathy– Gabapentin, carbamazepine, xaliproden

Questions Raised by CONCEPT Study

• Do we have to stop using Ca/Mg?

• What other strategies do we have to minimize or treat oxaliplatin neuropathy?

Questions Raised by CONCEPT Study

• Do we have to stop using Ca/Mg?

• What other strategies do we have to minimize or treat oxaliplatin neuropathy?

Do we have to stop using Ca/Mg? Sort of

• I’m not yet convinced there is a deleterious effect

• Trials in metastatic colorectal cancer cannot allow use

• Not acceptable for adjuvant use

• Would help to know if it works

What other strategies do we have to minimize or treat oxaliplatin neuropathy?

• Drug protectants

• Modulate and lessen exposure to the platin– Use irinotecan instead– Intermittent schedules

Phase III trial of chemotherapy with or without Phase III trial of chemotherapy with or without irinotecan in the front-line treatment of irinotecan in the front-line treatment of metastatic colorectal cancer in elderly metastatic colorectal cancer in elderly

patients.patients.

FFCD 2001-02 trial. FFCD 2001-02 trial. Results of a planned interim analysis.Results of a planned interim analysis.

E Mitry, JM Phelip, F Bonnetain, S Lavau Denes, X Adhoute, M Gasmi, JL Jouve, F Khemissa, T Lecomte, T

Aparicio

Study designStudy design

R1 mCRC

≥ 75 years

Stratification criteria

• Center• Charlson index (0 vs 1-2 vs 3+)• Karnofsky index (100 vs 90-80 vs 70-60)• Previous adjuvant CT• Sex• Age (< 80 vs. 80 yrs)• Alkaline phosphatases (≤ 2N vs. > 2N)

LV5FU2

R2

0

IRINOTECANLV5FU2s

Study designStudy design

R1 mCRC

≥ 75 years

Stratification criteria

• Center• Charlson index (0 vs 1-2 vs 3+)• Karnofsky index (100 vs 90-80 vs 70-60)• Previous adjuvant CT• Sex• Age (< 80 vs. 80 yrs)• Alkaline phosphatases (≤ 2N vs. > 2N)

LV5FU2

R2

0

IRINOTECANLV5FU2s

Study designStudy design

R1 mCRC

≥ 75 years

Stratification criteria

• Center• Charlson index (0 vs 1-2 vs 3+)• Karnofsky index (100 vs 90-80 vs 70-60)• Previous adjuvant CT• Sex• Age (< 80 vs. 80 yrs)• Alkaline phosphatases (≤ 2N vs. > 2N)

LV5FU2

R2

0

IRINOTECANLV5FU2s

Study designStudy design

R1 mCRC

≥ 75 years

Stratification criteria

• Center• Charlson index (0 vs 1-2 vs 3+)• Karnofsky index (100 vs 90-80 vs 70-60)• Previous adjuvant CT• Sex• Age (< 80 vs. 80 yrs)• Alkaline phosphatases (≤ 2N vs. > 2N)

LV5FU2

R2

0

IRINOTECANLV5FU2s

*150 mg/m2

FFCD Trial: Summary

• Objectives: Primary-PFS; secondary-usual efficacy, qol, geriatric assessment

• Patient characteristics: not balanced overall, but age stratification ok– ~ half patients were 80 years or older

• RECIST response rate: 18% without irinotecan versus 31% with

Mitry Conclusions

• These results are only descriptive at this point

• A phase III trial in the elderly is feasible

• Patients age 75 or greater can be given standard chemotherapy

Mitry: General Comment(s)

• Conduct: OK

• Conclusions: OK

• A lot more data will be forthcoming

-Lots of toxicity; lower than expected response rates

Why are Mitry Data Important?

• Half of all cancers occur in pts > 70 years of age

• Elderly otherwise live a long time– 80 y/o: 8 more years of life

• Elderly are under-represented in clinical trials– Frank exclusion– Enrollment always low even if allowed

Why are Mitry Data Important (cont.)?• The irinotecan package insert calls for an automatic

dose-reduction of irinotecan in those > 70 y/o

• > 2/3rds of pts 70-95 y/o are willing to undergo high-intensity chemotherapy, if offered1

– 90-100% would take “mild” chemotherapy

1Extermann J Clin Oncol 2003

Why are Mitry Data Unsurprising?• We have a gazillion (6) trials and meta-analyses

testing irinotecan in the elderly– Efficacy in the elderly is greater for combinations with

irinotecan – Median survival is similar for elderly and youngsters– Toxicity is not increased across the board in elderly

• Occasional trends toward neutropenia or diarrhea

• Ditto for oxaliplatin and limited data from targeted agents

EDITORIAL COMMENTS

3232

The Evolution of Therapy in mCRC

BSC

0

6 12 18 24Median OS (mo)

~4-6 mo

10-12 mo

~ 15-16 mo

20.3 mo

24 mo

19-20 mo

5-FU/LV

FOLFOX4 or CAPOX

IFL + bevacizumab

IFL or FOLFIRI

21.5 moFOLFOX6*

?FOLFOXIRI + bevaciz + cetuximab ?36 mo

FOLFOXIRI

3333

Leichman Year 2000 Conclusions:

“It is likely that in the near future, one or a combination of these aberrations will assist

in determining the most appropriate treatment for each individual patient”

3434

Conclusions: Today’s Abstracts

• Panitumumab does not add to PFS when given with irinotecan/bevacizumab to the general population with colorectal cancer

– Strong evidence from this and other trials suggests anti-EGFR antibodies benefit those with wild-type k-ras

• An intervention to minimize toxicity and applied to all comers getting FOLFOX may worsen efficacy

• Age alone is not a good eligibility criterion for deciding whether or not to use chemotherapy

3535

Metastatic Colorectal Cancer: What to Use (or not), How to Prevent Toxicity (or not) and

Whom to Treat (or not)

We have the genetic tools to potentially predict efficacy and toxicities for specific agents in unique recipients. Why aren’t we more rigorously studying this strategy?

3636

Unknown GI Symposium Discussant Year 20XX- Conclusions:

“Today we have learned targeting one or a combination of these (molecular) aberrations can lead to the selection of markedly effective

and minimally toxic therapy. We can now determine the most appropriate treatment

for each individual patient.”