Post on 02-Aug-2020
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