Role of SIRT Beyond First Line Therapy in Colorectal Cancer

Dr Toh Han Chong

Division of Medical Oncology

National Cancer Centre Singapore

MILESTONES IN THE TREATMENT OF COLON CANCER

SIR-Spheres microspheres in 2nd-line Treatment of Colorectal Cancer Liver Metastases

Investigator n Treatment ORR TTP/§PFS Survival

Lim 30 SIR-Spheres† (+ 5FU/LV)70% 33% 5.3 mo nr

van Hazel 25 SIR-Spheres† + irinotecan 48% 6.0 mo§ 12.2 mo

9.2 mo§L

Cove-Smith 8/33‡ SIR-Spheres† + (FOLFIRI- or 38% 9.5 mo§ 17.0 mo FOLFOX-based chemo)

phase II/III studies

2nd-line irinotecan 4–13% 2.6–4.3 mo§ 6.4–10 mo

irinotecan + cetuximab 16–27% 3.2–4.0 mo§ 8.6–10.7 mo

3rd-line panitumumab 9–14% 1.9–3.2 mo§ 6.3–9.3 mo

† SIR-Spheres microspheres; nr: not reported; §PFS; §L PFS in the liver

Lim et al. BMC Cancer 2005;5:132. van Hazel et al. J Clin Oncol 2009;27:4089–95. Cove-Smith, Wilson. WCGIC 2011; Abs P-0150. Schoemaker et al. Brit J Cancer 2004;91:1434–41. Van Cutsem et al. Brit J Cancer 2005;92:1055–62. Seymour et al. Lancet 2007;370: 143–52. Fuchs et al. JCO 2007;21:807–14. Sobrero et al. J Clin Oncol 2008;26:2311–9. de Cerqueira Mathias et al. ECCO 2007;5: Abs P3055. Wilke et al. ECCO 2007;5: Abs P3025. Cunningham et al. N Engl J Med 2004;351:337–45. Hecht et al. Cancer 2007;110:980–8. Van Cutsem et al. J Clin Oncol 2007;25:1658–64. Van Cutsem et al. Ann Oncol 2008;19:92–8. Muro et al. Jpn J Clin Oncol 2009;39:321–6.

419-EA-1011

SIR-Spheres microspheres in Salvage Therapy of Chemorefractory Colorectal Cancer Liver Metastases

Hendlisz et al. J Clin Oncol 2010;28:3687–94. Seidensticker et al. Cardiovasc Interv Radiol 2011; ePub. Cosimelli et al. Br J Cancer 2010; 103:324–31. Jakobs et al. J Vasc Interv Radiol 2008;19:1187–95. Cianni et al. Cardiovasc Interv Radiol 2009;32:1179–86. Nace et al. Int J Surg Oncol 2011; ePub. Cove-Smith, Wilson. WCGIC 2011; Abs. P-0150. Kennedy et al. Int J Radiat Oncol Biol Phys 2006;65:412–25.

Investigator n Treatment ORR SD TTP/§PFS Survival

Hendlisz 44 SIR-Spheres† + 5FU 10% 76% 5.5◊/4.5 mo 10.0 mo

5FU > salvage with 0% 35% 2.1 mo 7.3 mo SIR-Spheres† at PD

Seidensticker 29 SIR-Spheres† 41% 17% 5.5 mo§ 8.3 mo

29 best supportive care nr nr 2.1 mo§ 3.5 mo (matched-pairs)

Cosimelli 50 SIR-Spheres† 24% 24% 4 mo§ 12.6 mo

Jakobs 41‡ SIR-Spheres† 17% 61% 5.9 mo 10.5 mo

Cianni 41‡ SIR-Spheres† 46% 36% 9.3 mo§ 11.8 mo

Nace 51‡ SIR-Spheres† 13% 64% nr 10.2 mo

Cove-Smith 25/33‡ SIR-Spheres† + chemo 20% 36% 3.5–4.6 mo§ 13.2 mo

Kennedy 208‡ SIR-Spheres† 36% 55% responders 7.2 mo 10.5 mo non-responders/controls na na na 4.5 mo

P=0.0001 statistically significant data † SIR-Spheres microspheres; ◊ TTP liver; nr: not reported; ‡ retrospective data

HR 0.38◊/0.51; P=0.003◊/0.03 ns P=0.001

nr HR 0.26; P<0.001

419-EA-1011

In patients with chemorefractory colorectal liver mets, SIR-Spheres microspheres significantly improves survival

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Bester et al. J Vasc Inter Rad, 2011;23: 96-105

Comparative Retrospective Study: Overall Survival (Bester et al)

Survival Distribution Function0.000.250.500.751.00 Years0.00.5 1.01.5 2.02.5 3.0STRATA:extrahep=No Censored extrahep=No

0

25

50

75

100

Overa

ll Surv

ival (%

)

0 6 12 18 24 30 36

Time from receiving or potentially eligible for SIR-Spheres microspheres (months)

Hazard Ratio 0.8 0.3 0.4 0.5 0.6 0.7

N Median Survival (95% CI) SIR-Spheres microspheres : 224 11.9 months (10.1 – 14.9) Standard Care: 29 6.6 months Hazard Ratio: 0.50 (0.30 – 0.77)

P=0.001

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Matched Pair Analysis: Study Design (Seidensticker et al)

• 1° end point: OS

• 2° end points: PFS, ORR, safety and tolerability

Matched mCRC

pairs by prior

treatment history

and

tumor burden +

liver involvement;

metastases;

ALP; CEA level

(N=29 per arm)

Seidensticker et al CVIR 2012; 35; 1066‒1073

ALP=alkaline phosphatase; BSC=best supportive care; CEA= carcinoembryonic antigen.

Patients who received

SIR-Spheres*

compared to those on

BSC alone

* SIR-Spheres microspheres

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Seidensticker et al CVIR 2012; 35; 1066‒1073].

0 2.5 5 7.5 10 12.5 15 17.5

Survival Distribution Function0.000.250.500.751.00 Years0.0 0.51.01.52.0 2.53.0STRATA: extrahep=NoCensored extrahep=No

0

25

50

75

100

Overa

ll Surv

ival (%

)

Time (months)

Best Supportive Care 29 3.5 mo (1.9–5.7)

SIR-Spheres microspheres 29 8.3 mo (6.6 –10.2)

n Median Survival, months

P<0.001

Hazard Ratio 0.26 (95% CI 0.15–0.48)

Matched Pair Analysis: Overall Survival (Seidensticker et al)

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Matched Pair Analysis: Safety (Seidensticker et al)

• Adverse events following SIRT were predominately transient and self-limiting, including:

– grade 1–2 fatigue (69%)

– grade 1 abdominal pain/nausea (48%)

– 3 patients developed grade 2 gastrointestinal ulcer, which were managed medically

– 3 cases of grade 3 radiation-induced liver disease (RILD) were medically managed and not life-threatening

Seidensticker et al CVIR 2012; 35; 1066‒1073 9

Stratification

•Institution

•Interval to progression on chemotherapy

Random Assignment

5FU protracted IV infusion (300

mg/m2 D1–14 q3w) 5FU protracted IV infusion (225

mg/m2 D1–14 C1

and 300 mg/m2 D1–14

q3w thereafter)

until progression

SIR-Spheres microspheres

on Day 1 (D1) Cycle 1 (C1)

until progression

Eligible Patients

Liver-only mCRC,

PS 0–2, refractory to

chemotherapy

Arm A: Arm B:

Eligible Patients Crossover

Liver-dominant mCRC,

PS 0–2 SIR-Spheres microspheres

Randomized Controlled Trial in Refractory

Patients: Study Design

(Hendlisz et al)

+

Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694. 10

In patients with chemorefractory colorectal liver mets, SIR-Spheres microspheres significantly prolongs time to liver

progression

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Randomized Controlled Trial in Refractory Patients: Adverse Events (Hendlisz et al)

Parameter 5FU Alone 5FU + SIR-Spheres microspheres

n = 23 n = 21

Grades 1–2 Grades 3–4 Grades 1–2 Grade 3–4

Gastrointestinal

Stomatitis 1 1 2 -

Nausea - - 5 -

Constipation 3 - - -

Anorexia 6 1 5 -

Pain

Abdominal pain 3 - 4 -

Myalgia 1 - 2 -

Constitutional Fatigue 6 5 8 - Dermatological/Skin 2 - - - Hand-foot syndrome 2 - - 1 Pulmonary 1 2 - - Other Toxicity 1† - 2‡ -

Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694.

† ascites; ‡ 1 with thrombocytopenia, 1 with stomach ulcer, ascites 12

Safety of SIR-Spheres microspheres in mCRC patients

Side Effect Incidence

Grade Clinical Presentation Prevention/Treatment 2 3

Constitutional Total

43% 1%

Weight loss 3% 0% Days 0-7 post treatment *Antiemetics, † low-dose steroids for 7

days

Fatigue 37% 1% Days 0-14 post treatment †Low-dose steroids for 7 days

Fever 2% 0% Days 0-3 post treatment Pan-cultures not necessary.

Acetaminophen in low doses safe for 3-7 days

GI Total

25% 5%

Nausea 9% 1% Days 0-3 post treatment *Antiemetics, †low-dose steroids for 7

days

Emesis 6% 1% Days 0-3 post treatment *Antiemetics, † low-dose steroids for 7

days

Pain 11% 2% Days 0-14 post treatment Analgesics prn

Ulceration 5%

(median) (0-20%)

Nausea, pain beyond day #14 post treatment

Prophylactic embolisation of GDA, Gastric arteries

1. Kennedy AS, McNeillie P, Dezarn WA et al. International Journal of Radiation Oncology, Biology and Physics 2009; 74: 1494-1500. 2. Sangro B, Carpanese L, Cianni R et al. Hepatology 2011; 54: 868-878.

Most common acute (0-30 days) and delayed (31+ days) CTCAE 3.0 grade 2-3 toxicities1,2

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Safety of SIR-Spheres microspheres in mCRC patients

Side Effect Incidence

Grade Clinical Presentation Prevention/ Treatment

2 3 GI

Total (cont.) 25% 5%

Radiation Cholecystitis <1% Persistent abdominal pain Avoid cystic artery

Hepatic Abscess <1% Abdominal pain, septic symptoms Prophylactic antibiotics in patients

with violated ampulla or prior Whipple

Biochemical 16% 2% Steady rise first 6 weeks post

treatment, return to baseline by 12 weeks post treatment

Appropriate radiation dose selection

Radiation Pancreatitis

<1% Abdominal pain, elevated

enzymes typical for pancreatitis Supportive care

Radiation Induced Liver Disease (RILD)

<1% (median) (0-4%)

Progressive ascites and elevation of Alkaline Phosphatase, AST, ALT and +/- total bilirubin, ammonia

levels

Steroids, supportive care

Radiation Pneumonitis

<1%

Can be asymptomatic, but serious cases present with pleural

effusion and can progress to ARDS

Steroids, supportive care

1. Kennedy AS, McNeillie P, Dezarn WA et al. International Journal of Radiation Oncology, Biology and Physics 2009; 74: 1494-1500. 2. Sangro B, Carpanese L, Cianni R et al. Hepatology 2011; 54: 868-878.

Most common acute (0-30 days) and delayed (31+ days) CTCAE 3.0 grade 2-3 toxicities1,2

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• Median survival after Yttrium90 Radioembolization was 10.5 months with 21% survival at 24 months.

• ORR: 72%

• Four factors were associated with poor prognosis:

1. Extensive tumour volume

2. Number of previous lines of chemotherapy

3. Poor radiological response to treatment

4. Low pre-op Haemoglobin.

• Clinical toxicity after treatment were minor (grade I/II) and resolved without active intervention.

• Conclusion: Yttrium90 Radioembolization is a safe and effective treatment for unresectable, chemorefractory m-CRC.

• Treatment at an earlier stage before chemoresistance develop and before extensive infiltration is present should be considered.

Saxena, Bester et al Annals of Surgical Oncology. 2014

• Review 20 papers ( 979 Patients) between 2004 – 2012.

• All patients failed 3 lines of chemotherapy.

• Median survival 12 months.

• Most cases of acute toxicity were mild (Grade I or II) resolved without intervention.

• Grade 4 less than 3%.

• The most common acute toxicities were fatigue (38.5 %), abdominal pain (16 %) and nausea/vomiting (19 %).

• Prognostic factors identified with a poor outcome:

– The presence of extra-hepatic disease

– Extensive pre-treatment chemotherapy (≥ 3 lines) -

– Extensive liver disease (≥ 26 %).

J Cancer Res Clin Oncol 2013

European Society Medical Oncology: m-CRC guidelines September 2014.

Van Cutsem E et al on behalf of the ESMO Guidelines Working Group for m-CRC.

ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Ann Oncol 2014; 25 (Suppl 3): iii1-iii9.

Statement: “In patients with liver-limited metastases failing

the available chemotherapeutic options, radioembolisation

with Yttrium90 resin microspheres can also prolong the time to

progression.” ( Level II - small randomised trials).

Integrating SIRT into the mCRC treatment paradigm

SIRT Clinical Trials

Radioembolisation K-ras and Raf Mutants

Radioembolisation

Radioembolisation

> Radioembolisation

> Radioembolisation

Liver-only or liver-

predominant mCRC

Resectable Potentially curative

surgery or ablation

1st-line chemotherapy

2nd-line chemotherapy

nth-line chemotherapy

Chemorefractory?

10–20%

<20%

Decre

ase R

R

+/- Biologics

+/- Biologics VEGF

+/- Biologics EGFR

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