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Fight Colorectal Cancer

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Dr. Leonard SaltzMemorial Sloan Kettering Cancer Center

Chief, Gastrointestinal Oncology

Understanding Colorectal Cancer Treatment Options

Leonard B. Saltz, MD

Chief, Gastrointestinal Oncology

Memorial Sloan Kettering Cancer Center, New York, NY

Disclosures• I have consulted for and/or have research

supported by:

• Roche/Genentech• Bristol Myers Squibb• Imclone• Bayer• Merck• Biothera• Novartis• Sanofi• Immunomedex• Lorus• Morphotek

Overview

• Understanding the language

• Standard chemotherapy options

• Toxicities and quality of life

• New agents

• Life after standard chemo

Terms Requiring Definitions

• Cure• Overall Survival• Median Overall Survival• Progression-free Survival• Response• Stable Disease• Antitumor activity, Benefit• Progression of Disease

Other terms

• “significantly better” – does not necessarily equal:

“substantially better”

• “statistically significantly better”– Does not necessarily equal:

“clinically significantly better”

Anatomy of the Large Intestine

Staging of Colorectal Cancer (CRC)

• Stage I: Not full thickness

• Stage II: Full thickness

• Stage III: Positive nodes

• Stage IV: Distant mets

Colorectal Cancer Cure Rate

• Stage I 95%

• Stage II 80%

• Stage III 65% +

• Stage IV <10%

Intent of Therapy

• Curative

• Adjuvant

• Neo-Adjuvant

• Palliative

Chemotherapy for Metastatic

Disease

1996: Drugs Available for CRC

• 5-FU (5-Fluorouracil)

2012: Drugs Available for CRC

• 5FU (5-Fluorouracil)• Camptosar (Irinotecan)• Eloxatin (Oxaliplatin)• Xeloda (Capecitabine)• Erbitux (Cetuximab)• Avastin (Bevacizumab)• Vectibix (Panitumumab)

– Aflibercept (anticipated late 2012)– Regorafenib (anticipated late 2012)

Combination Chemotherapy for CRC

Anatomy of the “FOLFs”• FOL = folinic acid (a.k.a. leucovorin)• F = 5FU (5-fluorouracil)• OX = oxaliplatin (Eloxatin)

= FOLFOX

• FOL = folinic acid (a.k.a. leucovorin)• F = 5FU (5-fluorouracil)• IRI = irinotecan (Camptosar)

= FOLFIRI

FOLFIRI vs. FOLFOX

Efficacy of First Line Regimen

Tournigand et al, JCO 2004

p=0.9 21.5 m 20.4 mOS

p=0.65 8.1 m 8.5 mPFS

p=0.68 54% 56%RR

FOLFOXFOLFIRI

Oral Chemotherapy

Cautionary Notes

• Just as likely to have side effects as i.v. chemo

• No convenience benefit unless all drugs taken are oral

• Requires a highly motivated patient capable of assuming substantial responsibility

• Difficult if nausea, vomiting, or diarrhea are present or expected

Anti-AngiogenesisThe Angiogenic Switch

1-2 mm

Angiogenic

Switch

Small tumor• Nonvascular• “Dormant”

Larger tumor• Vascular• Metastatic potential

........................

.... ..... .... .....

........................

.... .....

........................

........................

........................

Maturation factors present

Normal and Tumor Blood Vessels

Normal Blood Vessels Tumor Blood Vessels

Reduced integrin expression

Less dependent on cell survival factors

.... ..... Less permeable

Leaky

Preferential expression of v3 v5 & 51

integrins

Fewer pericytes

Growth and survival factors (eg, VEGF)

present

.... .....

Supporting pericytes present

Phase III IFL +/- Avastin in Metastatic

Colorectal Cancer

IFL + Placebo (n = 412)

IFL + Avastin(n=403) P Value

Median overall survival 15.6 m 20.3 m 0.00003

Median Progression-Free Survival

6.2 m 10.6 m <0.00001

Response Rate 35% 45% 0.003

Hurwitz et al.. NEJM 2004

Bevacizumab: Safety concerns

• Gastrointestinal perforation

• Arterial thrombotic events

EGF Receptor Signaling Transduction

MAPK

MEK

Gene TranscriptionCell Cycle Progression

M

G1S

G2

PI3-K

RAS RAF

SOS

GRB2

PTEN AKTSTAT

R

KpY

R

pY

pY

K

Proliferation / Maturation

Survival / Apoptosis

Angiogenesis Metastasis

Cetuximab + Irinotecan)Independent Radiology Review

Irinotecan-Refractory Patients, n=120 (Saltz et al: ASCO 2001)

PR 27 (22.5%) (95% C.I. 15%-31%)SD 9 ( 7%) (minimum 12 weeks)

• Median Dur. of response (n=27): 186 days• Investigator-reported PR= 23 (19%)

Single Agent Cetuximab: Investigator-Reported Response Rate (n=57)

(Saltz et al, JCO 2004)

• PR = 6 (10.5%, 95% CI 4%-22%)• SD = 21 (37%)

– Minimum 12 weeks required for stable disease.

• Independent review confirmed 5 PR’s, for response rate of 8.8%.

“BOND” Trial

• Randomized Phase II trial in Irinotecan-refractory CRC

• Cetux + Irinotecan versus Cetux• 2:1 randomization, 300 pts• 1o endpoint: response rate

Bond Trial: Results(Cunningham et al, NEJM 2004)

Cetux + Irino Cetux

RR 22.9% 10.8%

PFS 4 m 1.6 m

Cetux Trials in Refractory CRC

Response Rate

Cetux + CPT-11 (Saltz, ASCO 2001)

22.5%

Cetux + CPT-11 (Cunningham, NEJM 2004)

22.9%

Cetux (Saltz, JCO 2004)

10.5%

Cetux (Cunningham, NEJM 2004)

10.8 %

CRYSTAL Trialvan Cutsem et al: NEJM 2009

• Randomized phase III trial of first line FOLFIRI +/- weekly cetuximab.

• Measurable metastatic colorectal cancer

• 1217 patients randomized

CRYSTAL TRIAL: EfficacyVan Cutsem: ASCO 2007

FOLFIRI-Cetux

(n=599)

FOLFIRI(n=599)

P value

PFS 8.9 m 8.0 m 0.048

1 yr PFS 34% 23%

RR 47% 39% 0.0038

SD 37% 47%

DCR 84% 86%

Understanding KRAS

• Protein in the cell involved in transmitting signal from receptor on cell surface to the nucleus

• If the gene for KRAS is mutated, then the KRAS protein sends a signal regardless of whether there is a signal from the surface receptor or not

EGF Receptor Signaling Transduction

MAPK

MEK

Gene TranscriptionCell Cycle Progression

M

G1S

G2

PI3-K

RAS RAF

SOS

GRB2

PTEN AKTSTAT

R

KpY

R

pY

pY

K

Proliferation / Maturation

Survival / Apoptosis

Angiogenesis Metastasis

Understanding KRAS

• If KRAS is mutated, Erbitux and Vectibix won’t work, and therefore are not used

• If KRAS is wild-type (non-mutated) then Erbitux or Vectibix might work

• Median overall survival benefit in trials with KRAS wild-type tumors is in range of 3-4 months

CRYSTAL Trial:PFS time by

skin reactions: cetuximab + FOLFIRI

Grade of Skin Rash

0-1 (none or mild)

2 (moderate)

3 (severe)

Progression-free survival 5.4 m 9.4 m 11.3 m

Some Other Toxicities

• Nausea / Vomiting

• Diarrhea

• Fatigue

• Neurotoxicity

MOSAIC: FOLFOX for Stage II – III Colon Cancer: Peripheral Sensory Neuropathy

Andre et al: JCO 2009%

of

trea

ted

pat

ien

ts

48.1

30.9

22.2

1412

8.8

31.4

7.24.2 2.9 1.7 2.1

12.5

1.4 1.2 0.5 0.5 0.50

10

20

30

40

50

60

During Tx 6 months 1 year 2 years 3 years 4 years

Grade 1

Grade 2

Grade 3

27.6 17.4 14.2 11.4

Neurotoxicity from Oxaliplatin• Cold sensitivity

• Numbness and tingling

• Loss of position sense

• Loss of fine motor skill

• Pain

What’s new?

Continuing Avastin

• TML trial shows that continuation of Avastin with 2nd line therapy improves median overall survival by 1.4 months

Aflibercept

• Adding aflibercept to second line FOLFIRI improves median overal survival by 1.5 months.

• Not clear that this offers any advantage over second line Avastin

• No evidence that Aflibercept by itself, or with chemo that has failed, has any benefit

Regorafenib vs Placebo

RegorafenibN=505

PlaceboN=255

Median Overall Survival 6.4 months 5.0 months

Partial Response 1% 0.4%

Stable Disease 43% 15%

DCR* 41.0 15%

*DCR = PR+SD (≥6 weeks after randomization)

Van Cutsem et al: Proc ASCO 2012

What can we do when we’ve used up the standard drugs?

Treatment options after standard care

• Clinical trials

• Supportive care / hospice care

Clinical Trials

• Phase I What is the highest tolerable dose and what are the side effects?

• Phase II Is it safe and active in a defined population?

• Phase III Is it better that standard care?

• Phase IV Post-marketing studies; variations on a theme.

Clinical Trials: Important Concepts:

• Informed consent

• Right to refuse/withdraw

• No hidden agendas

• No hidden placebos

Supportive care

• Important in ALL aspects of cancer care– Pain control– Emotional Support– Nutrition– Exercise– Discussions of end of life care preferences

Seductive Traps• The internet

• Alternative care

• Unproven drugs and procedures– (Beware the rhetorical “what harm could it do?”

A. Venook (Discussant) ASCO 2012

COST of

CARE

The Elephant in the Room

Average Selling Price (ASP) + 6% (about 5 yr old data)

(Patient assumption: 75 kg, 1.8 m2 patient, two weeks Rx)

• 5FU 500 mg/m2 $ 7• Leucovorin 500 mg/m2 $ 47• Xeloda 2000 mg/m2/d $ 1065• Camptosar 180 mg/m2 $ 2135• Eloxatin 85 mg/m2 $ 3296

• Avastin 5 mg/kg $ 2283• Erbitux 250 mg/m2 $ 4964

Impact on Cost of Care: back of the envelope

• Bevacizumab – $2864 per 400 mg vial*– Average weekly dose = 175 mg

• Regorafenib – Sorafenib $8377 / month

• Aflibercept– $$$ unknown

– A Venook, Discussant ASCO 2012

$$ per UCSF pharmacy

$$$ unknown

Cost of Bev beyond progression(Cost of only the bev; no MD, nursing, or pharmacy fees, no other meds)

• $2864 per 400 mg vial -> $7.16 per mg– 175 mg/week x 4.33 weeks/month = 758 mg/month – If vials are shared:

758 mg/month x $7.16/mg = $5427.28 per month,

x 5.7 months = $30,935.50 per patient treated

for 1.4 months OS benefit ->

$30,935.50 x 8.57 = $265,117 per year of life saved

– If vials not shared, then $2864 every 2 weeks for 24.7 weeks (5.7 months) -> $35,370.40 per patient treated

$35,935.40 x 8.57 = $303,124 per year of life saved

– (note: these are not Quality-adjusted)

Colorectal cancer in 2012: my reality check

• These are modest advances• A minority of patients appear to benefit• And the costs are unsustainable

THE CHALLENGE • Actually deliver on promise of personalized

medicine• To do so, we need better tools to predict

outcomes• And it must be affordable

A. Venook, ASCO Discussant 2012

Challenges

• Maintain optimism tempered by, and grounded in, reality

• Select therapies rationally

• Assure availability of appropriate therapies to all patients

Conclusions

• Treatment options for colon cancer patients are better than they were, but not as good as they need to be.

• Please consider participation in clinical trials when they are appropriate. Without your help, we can’t make the progress that we all so desperately need.

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Fight Colorectal Cancer

Funding Research DirectlyLisa Dubow Fund

http://fightcolorectalcancer.org/research/lisa-fund

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