Evidence For SIRT In Metastatic Colorectal Cancer – First Line

Peter Gibbs

MBBS, FRACP, MD

Royal Melbourne Hospital

Walter and Eliza Hall Institute

Background

• SIRT ≈ HCC

• The multidisciplinary team

– Medical Oncologist – standard 1st, 2nd, 3rd, ?4th line Rx

– Liver surgeon

– Interventional radiologist

– Nuclear medicine physician

• Liver function still relevant – advanced CRC

• Many patients have an intact primary tumour

• Extra-hepatic disease more common

– At presentation

– As a site of failure

Overview

1. First line data

– Clinical trials and other

2. Personal experience of first line SIRT

– Case presentations

• Assessing response to SIRT

• Further patient management

3. Where to next?

First Line Therapy – Medical Oncologists Are Already A Little Confused

• Multiple cytotoxic and biologic treatment options

• Optimal sequencing?

• Optimal combinations?

EGFR antibodies – 1st line KRAS wt only

1st Line mCRC

Trial Therapy ORR PFS (mo) OS (mo)

CRYSTAL

(n=666) *

FOLFIRI

+/- Cetux*

40% vs. 57%

8,4 vs. 9,9

HR = 0,696

20.0 vs.23,5

HR = 0,796

PRIME

(n=656) *

FOLFOX

+/- Pani*

48% vs. 57%

10,0 vs.8,6

HR = 0,80

()

19,7 vs. 23,9

HR = 0.88

OPUS

(n=197) *

FOLFOX

+/- Cetux*

34% vs. 57%

7,2 vs.8,3

HR = 0,567

()

18,5 vs.22,8

HR = 0,855

COIN

(n=729) *

XELOX/

FOLFOX

+/- Cetux*

57% vs. 64%

–

8,6 vs.8,6

HR = 0,959

–

17,9 vs.17,0

HR = 1,038

NORDIC

(n=194)

FLOX

+/- Cetux

–

47 vs. 46%

–

8,7 vs. 7,9

HR = 1.07

–

22,0 vs. 21,0

HR = 1.14

SIRT First Line Data

• The data looks consistently very good (great)

• BUT

• Small series

• No randomised data with modern chemotherapy

• SIRT is not a drug – multiple implications

The Medical Oncologist and SIRT

• Multiple steps involved

– Discussing SIRT with patients

• Already a long talk

• Many oncologists not familiar with the data

– Organising SIRT (easier if locally available)

• Reviewing films with the radiologist

• Booking SIRT work-up

• Reviewing SIRT work-up

• Booking SIRT treatment

• Co-ordinating with chemotherapy

• Consequences

– Time and effort

• On top of organising chemotherapy

– Delays in starting – patient may be very anxious

Standard Drug Development Process

Level of

knowledge

100%

2-4 years 2-6 months 3-6 years 1-3 years Time

Pre-clinical studies Clinical trials

CHEMISTRY

Search for

active

substance

PHARMA-

COLOGY

Toxicology,

studies of

effects on

various

species of

animals

IND*

Processing

by the

authorities

PHASE II

Clinical

studies

on limited

number of

patients

100-200

persons

PHASE I

Studies of

effects on

healthy

human

subjects

50-100

persons

PHASE III

Comparative

studies on

large number

of patients

500-5,000

persons

NDA**

Processing

by the

authorities

PHASE IV

Post-

Marketing

Studies etc.

Level of

knowledge

* Investigational New Drug Application for permission to

administer a new drug to a human

Registration

introduction

in market

** New Drug Application Application for permission to

market a new drug

Liver-only or liver-predominant mCRC

1st-line 5-FU

BSC

Two Positive Randomised Studies In mCRC – 1990’sTreatment Paradigm

298-M-PPP EU rev. 0 1011

+/- Radioembolization

Radioembolization

Two Randomised Studies Combining SIRT With Fluoropyrimidine

Study Arms N = 70 patients Time To Liver Progression (p=0.001)

Survival

IH FUDR vs

SIRT + IH FUDR

34 FUDR alone

36 SIRT + FUDR

9.7 months

15.9 months

1 yr 2yr 3yr

68% 29% 6%

72% 39% 17%

Reference: Gray B, et al. Annals Oncology 2001, 12:1711-1720

Study Response Time To Progression

(P < 0.005)

Survival

(P = 0.02)

5-FU/LV vs

SIRT + 5-FU/LV

0 / 10

8 / 11 = 73%

3.6 months

18.6 months

12.8 months

29.4 months

Reference: Van Hazel G, et al. Journal of Surgical Oncology, 2004, 88: pp 78 – 85.

• FOLFOX is the most active systemic therapy • Radiosensitising properties of oxaliplatin

Rationale

Sharma et al 2007

• 18 patients with response (90%), 2 patients SD • 2 patients underwent liver resection

Results

• Phase I study, 20 patients • FOLFOX 4 plus SIRT

Trial Design

SIR-Spheres microspheres + FOLFOX4 in mCRC: CT Response

Patient 2: Baseline CT scan pre-SIRT

Patient 2: CT scan 6 months post-SIRT

Sharma Study Patient 5

Baseline: Functional liver: 1215 ml. Tumour: 370 ml 6 month: Functional liver: 1034 ml. Tumour: 45 ml

Outcome: Patient resected

Baseline CT scan slices

6 Month CT scan slices

Summary Of First Line Trial Data

• Two positive studies with 5-FU alone – Option for patients not fit for combination chemotherapy

/biologics

• Encouraging phase I data combined with FOLFOX – No safety concerns

– High response rates

– Down-staging to resection

Observations From This Series

• 62 y.o. University Professor • Five liver lesions, treated June 2002 => Complete response, remains alive and well

- Responses are slow - Prolonged control of liver disease is possible when SIRT

is used with first line chemotherapy - Most patients fail outside the liver

Personal Experience and Observations

• 1st line setting is where the major benefit is seen

– QUALITY of response

• “Depth of response”

• Duration of response

– Potential for long term control (durable CRs)

• Potential for down-staging to surgery

– Increasing confidence re safety of surgery after SIRT

– Minimise chemotherapy pre surgery

• With increasing lines of therapy

– Lower response rates

– Shorter duration of response

57 y.o. male, renal transplant with renal impairment,

immunosuppression and steroids - diagnosed October 2009

57 y.o. male, renal transplant with renal impairment,

immunosuppression and steroids - diagnosed October 2009

December 2010

December 2010, liver

resection

Liver and lung metastases developed 12 months later

June 2012

5268

1541

256

62

21

11

10

100

1000

10000

June

July

August

September

October

November

December

January

CEA

June 2012

December 2012

October 2014

October 2012

September 2013

December 2009

August 2014

December 2009

August 2014

No uptake on PET => Observe

May 2012

….numerous metastatic deposits spread throughout the liver……

January 2014

=> Liver resection, remains disease free

October 2014 March 2014

October 2014 March 2014

October 2014 March 2014

Substantial uptake on PET => Planned for resection

CEA 1159 => 8

Evaluating Response After SIRT

• Particularly a challenge with first line Rx?

• Responses can be slow

– Often no CT change at 2 months (change in CEA within weeks)

– Ongoing response over 6-8 months

• Challenging to evaluate residual changes post Rx

– Resect if uptake on PET

– Watch closely if no uptake on PET

• “Pseudoprogression” is not uncommon

Baseline 2 months

Baseline 2 months

4 months 6 months

CEA 34.5 CEA 2.9

CEA 1.9 CEA 2.3

November 2010 September 2010

November 2010

November 2010 September 2010

November 2010

CT scan abdomen and pelvis …there has been disease progression with a moderate amount of ascites evident and with thickening of the greater omentum. .. diffuse low density throughout the liver, likely to represent increased metastatic disease..

Impression: disease progression with increased ascites, peritoneal and hepatic disease.

November 2010 September 2010

November 2010

CT scan abdomen and pelvis …there has been disease progression with a moderate amount of ascites evident and with thickening of the greater omentum. .. diffuse low density throughout the liver, likely to represent increased metastatic disease..

Impression: disease progression with increased ascites, peritoneal and hepatic disease.

But the liver lesions are getting smaller……

November 2010 September 2010

November 2010 January 2011

Adverse Events

• REILD

• Gastric ulceration

• Thrombocytopenia

The SIRFLOX Trial

Principal Investigators: Peter Gibbs, MD

Guy van Hazel, MD

Sponsored by Sirtex

SIRFLOX is an open-label, multi-centre RCT

532

SIRFLOX aims to compare standard-of-care

first-line chemotherapy + SIR-Spheres

against chemotherapy alone in patients with

inoperable CRC liver metastases

SIRFLOX Key Inclusion Criteria

• Histologically confirmed adenocarcinoma of the colon or rectum

• Unequivocal and measurable CT evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent

• Limited extra-hepatic metastases are allowed:

– Up to 5 lung metastases ≤1 cm or 1 metastasis of ≤1.7 cm

– Lymph nodes <2 cm in 1 anatomic region (chest, abdomen, pelvis)

• Adequate haematological, renal and hepatic function

• WHO Performance Status 0 – 1

• Life expectancy >3 months without any active treatment

SIRFLOX Patient Population: Liver-Only or Liver-Dominant Metastases

SIRFLOX Key Exclusion Criteria

• Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis

• Prior chemotherapy for any malignancy (adjuvant chemotherapy for colorectal cancer permitted provided that completed ≥6 months before study entry)

• Concurrent or previous malignancy other than adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix

• Previous radiotherapy delivered to the upper abdomen

• Peripheral neuropathy > grade 1 (NCI-CTCv3)

• Pregnant or breast feeding

SIRFLOX Endpoints

Primary endpoint: •Progression free survival Secondary endpoints: •Progression free survival in the liver •Tumour response rate (liver ± any site) •Hepatic and extra-hepatic recurrence rate •Health-Related Quality of Life •Toxicity and safety •Liver resection rate

•Overall survival – will be reported later as the primary endpoint of the a priori analysis of SIRFLOX + FOXFIRE + FOXFIRE-Global

SIRFLOX Statistical Considerations

• Primary endpoint of PFS by central independent imaging review

• 80% power and 95% confidence, corresponding to a relative risk reduction of 25% (hazard ratio of 0.75)

• Expected (pooled) event rate of 438 (86%) progressions in 510 patients

• 532 patients recruited to allow sufficient information for independent imaging review and adjudication

SIRFLOX Results

• No efficacy data available

• Independent Data Safety Management Committee

– 120 patient safety review

– 40 patient bevacizumab safety review

SIRFLOX

SIRFLOX completed patient recruitment in Q1 2013; Results will be available in Q1/Q2 2015

Me

tasta

tic c

olo

recta

l ca

nce

r (m

CR

C)

Completion of

patient

recruitment

(>500

patients)

Primary

Endpoint

(PFS)

available

Detailed

presentation

of results at

ASCO Annual

Scientific

Meeting?

Calendar Year

Cu

rre

nt

2013 2014 2015 2016 2017

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 H1 H2 H1 H2

Survival analysis of SIRFLOX-FOXFIRE trial patients

Overall survival analysis on > 1000 patients

SIRFLOX

-PFS ->500 patients

FOXFIRE & FOXFIRE Global

-Overall Survival ->500 patients

Key Differences Between FOXFIRE or FOXFIRE-Global vs. SIRFLOX

• FOXFIRE

– Limited extra-hepatic metastases in the lung (≤5 and amenable to future definitive local therapy) and/or permitted single site of other extra-hepatic disease after approval of the Trials Office vs. ≤5 lung metastases ≤1 cm or 1 metastasis of ≤1.7 cm and/or lymph nodes <2 cm in 1 anatomic region (chest, abdomen, pelvis)

– Chemotherapy backbone: OxMdG vs. mFOLFOX-6

– Biologic agent: bevacizumab or cetuximab vs. bevacizumab

– SIR-Spheres administered in Cycle 2 vs. Cycle 1

• FOXFIRE-Global

– Local imaging review vs. central independent imaging review

SIRFLOX +

FOXFIRE +

FOXFIRE-Global SIRFLOX

SIRFLOX completed patient recruitment in Q1 2013; Results will be available in Q1/Q2 2015

Me

tasta

tic c

olo

recta

l ca

nce

r (m

CR

C)

Completion of

patient

recruitment

(>500

patients)

Primary

Endpoint

(PFS)

available

Detailed

presentation

of results at

ASCO Annual

Scientific

Meeting?

Calendar Year

Cu

rre

nt

2013 2014 2015 2016 2017

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 H1 H2 H1 H2

Primary

Endpoint

(Overall Survival)

available

Thankyou for your attention