State of the Art: Colorectal Cancer Liver Metastasis Dr. Iain Tan

State of the Art: Colorectal Cancer Liver Metastasis Dr. Iain Tan Consultant GI Medical Oncologist National Cancer Centre Singapore Clinician Scientist, Genome Institute of Singapore

OS (%) Overall survival for patients with mcrc treated at MD Anderson and Mayo clinics, by year of diagnosis 2470 patients from two highly specialized centers were included 100 80 60 1990 1991 1992 1994 1995 1997 1998 2000 2001 2003 2004 2006 40 20 0 0 12 24 36 48 60 Time (months) Over the past decade, OS has improved substantially in patients with mcrc Kopetz S, et al. J Clin Oncol 2009;27:3677 3683

List of chemotherapy drugs Chemotherapy 5 Fluorouracil / TS-One / Xeloda TAS-102 Oxaliplatin Irinotecan Targeting Blood Vessels Bevacizumab (Avastin) Aflibicept (Zaltrap) Targeting tumor molecular characterisitcs Cetuximab (Erbitux) Panitumumab (Vectibix) Targeting both molecular characteristics & blood vessels Regorafenib (Stivarga)

ESMO Guidelines for mcrc Oxaliplatin- Based First-line Irinotecan- Based First-Line Chemo- Triplet First line FOLFOX + pan or cet a 5-FU/OX 5-FU/OX + bev FU/IRI + cet a 5-FU/IRI 5-FU/IRI + bev 5-FU/ OX/IRI Second line 5-FU/IRI + bev FOLFIRI + aflib 5-FU/IRI (FOLF)IRI + pan/cet a 5-FU/OX + bev 5-FU/OX FOLFOX + cet/(pan) a Pan/cet a ± IRI or FU/bev Third line Regorafenib Pan/cet a ± IRI 5-FU + bev Regorafenib Pan/cet a ± IRI 5-FU + bev Regorafenib Fourth line Regorafenib Regorafenib a KRAS wildtype only. 5-FU, 5-fluorouracil; aflib, aflibercept; bev, bevacizumab; cet, cetuximab; FOLFIRI, 5-FU + leucovorin + irinotecan; FOLFOX, 5-FU + leucovorin + oxaliplatin; IRI, irinotecan; OX, oxaliplatin; pan, panitumumab; ESMO, European Soceity for Medical Oncology. Schmoll HJ, et al. Ann Oncol. 2012;23:2479-2516.

Landmark 1 st line CRC studies ORR PFS PFS HR OS AVF2107g IFL 35% 6.4 15.6 OS HR + Bevacizumab 45% 10.6 0.54 20.3 0.66 PRIME FOLFOX 7.9 20.2 + panitumumab 10.1 0.72 26 0.72 CRYSTAL FOLFIRI 8.4 20.2 + Cetuximab 11.4 0.56 28.4 0.69 TRIBE FOLFIRI/Bev 53% 9.7 25.8 FOLFOXIRI/Bev 65% 12.1 0.75 31 0.79 FIRE3 FOLFIRI/Bev 56% 10.2 25 FOLFIRI/Cet 71% 10.4 0.93 33.1 0.7 CALGB Chemo + Bev 57% 11.3 31.2 Chemo + Cet 69% 11.4 1.1 32 0.9

VELOUR (2 nd line) Placebo + FOLFIRI (n = 614) Aflibercept + FOLFIRI (n = 612) Hazard ratio p-value Median OS 12.1 mo 13.5 mo 0.82 0.0032 Median PFS 4.7 mo 6.9 mo 0.76 0.00007 Overall response 11.1% 19.8% 0.0001 CORRECT (3 rd line) Regorafenib Placebo HR [n=760] p-value Median PFS 1.9 mo 1.7 mo 0.49 <0.000001 Median OS 6.4 mo 5.0 mo 0.77 0.0052 RECOURSE (3 rd line) TAS-102 (n=534) Placebo (n=266) HR p-value Median PFS 2.0 mo 1.7 0.48 <0.0001 Median OS 7.1 mo 5.3 mo 0.68 <0.0001

5-Year Survival Rate for Stage IV CRC Remains Only 6% Treatment Approaches to First-Line mcrc 2000 2000 2000 2000 2004 2004 2007 2008 2011 2011 2011 2013 2013 2013 5-FU/LV bolus 5-FU/LV infusion IFL LVFU2/irinotecan FOLFOX IFL + bevacizumab FOLFOX/FOLFIRI XELOX/FOLFOX + bevacizumab FOLFOX + cetuximab FOLFIRI + cetuximab FOLFOX + panitumumab FOLFIRI + bevacizumab FOLFIRI + cetuximab FOLFOXIRI + bevacizumab Overall Survival (months) *KRAS wildtype tumors. Note: Informal comparison as these are not head-to-head clinical trials. 1. Saltz. N Engl J Med. 2000; 2. Douilliard. Lancet. 2000; 3. Goldberg. J Clin Oncol. 2004; 4. Hurwitz. N Engl J Med. 2004; 5. Saltz. J Clin Oncol. 2008; 6. Falcone. J Clin Oncol. 2007; 7. Bokemeyer. Ann Oncol. 2011; 8. Van Cutsem. J Clin Oncol. 2011; 9. Douilliard. ASCO; 2011. Abstract 3510. 10. Heinemann. ASCO 2013. Abstract LBA3506. 11. Falcone. ASCO 2013. Abstract 3505.

Metastases 8

Overall survival (%) Landmark Liver resection improves long-term survival 12-month landmark analysis evaluated the impact of liver resection on OS Error bars represent 95% CIs 100 80 60 40 20 Liver resection No liver resection Patient status Resected Non resected Median OS (mo) HR 0.35 5-year OS rate 65.3 55% 26.7 19.5% 0 0 12 24 36 48 60 72 Time (months) 70% of population included Liver resection dramatically improves long-term survival and offers a real chance for cure Kopetz S, et al. J Clin Oncol 2009;27:3677 3683

Stage 4 Colorectal Cancer is a Continuum of disease Low disease burden, generally with a single solitary site of spread Less extensive More extensive

Less extensive More extensive Chemotherapy & Surgical removal of the site of metastasis with the intention of achieving cure Low disease burden, generally with a single solitary site of spread

Meta-analysis: (Resected CLM ): Post-op 5FU vs. Surgery alone Meta-analysis of RCT of adjuvant therapy with after curative resection of CLM recurrence free survival (HR.84 P =.003) and overall survival (HR.81 P =.04) % absolute difference in 3-year PFS Hazard Ratio P-value EPOC: (Resectable CLM ) Perioperative FOLFOX vs. Surgery alone All patients (n=182 per arm) All eligible Patients (n=171 per arm) +7.2% (28.1% to 35.4%) +8.1% (28.1% to 36.2%) 0.79 P=0.058 0.77 P=0.041 All resected Patients (n=151 per arm) +9.2% (33.2% to 42.4%) 0.73 P=0.025 New-EPOC: (Resectable CLM ) Perioperative Chemo vs Perioperative Cetuximab/Chemo ORR PFS PFS HR OS OS HR Chemo 42% 20.5 NR + Cetuximab 50% 14.1 1.49 39.1 1.48

Less extensive More extensive Chemotherapy to reduce size of metastases with the intention of to convert to a situation where surgery becomes feasible intermedaite disease burden, generally not operable upfront but with limited disease spread

Survival (%) Survival after chemotherapy plus surgery for metastases 100 80 60 40 20 48% 33% Resectable liver metastases Resectable after chemotherapy FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI 5-FU BSC 30% 23% 0 1 2 3 4 5 6 7 8 9 10 BSC = best supportive care Time (years) Colon Cancer Collaborative Group. Br Med J 2000;321:521 522 Tournigand C, et al. J Clin Oncol 2004;22:229 237; Adam R, et al. Ann Surg 2004;240:644 658

Less extensive More extensive Chemotherapy to control tumor, improve symptoms, maintain quality of life and prolong life

New definition of resectability Practical rather than dogmatic All liver metastases that can be completely removed while leaving at least 30% of remnant liver... Even in cases with extrahepatic tumors, if these are also resectable In practice: 3 categories of patients Easily resectable: Marginally resectable: Definitely non-resectable: Complete resection with good margins No margins, small liver remnant Concomitant extrahepatic (resectable) Widespread hepatic disease Non-resectable extrahepatic Multiple metastatic sites Adam R. 2009

Strategies Liver metastases resectable non optimal resectable > 4 Metastases synchronous CRCLM Primary LN-positive bilobar CRCLM technically problematic: Close to 3 hepatic veins Close to portal bifurcation Primary unresectable neo CT + Liver resection Neoadjuvant Chemotherapy Operation possible Palliative Chemotherapy

The multidisciplinary team The impact of a multidiscplinary team approach in the treatment of colorectal cancer with liver metastases: Liver-limited metastatic colorectal cancer as a curable disease

Resection rate 0.6 0.5 0.4 0.3 0.2 Resection rate of metastases and tumor response Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96; p=0.002) Studies including non-selected patients with mcrc (solid line) (r=0.74; p<0.001) 0.1 0 0.3 0.4 0.5 0.6 0.7 Response rate 0.8 0.9 Phase III studies including non-selected patients with mcrc (dashed line) (r=0.67; p=0.024) Folprecht G, et al. Ann Oncol 2005;16:1311 1319

Liver limited All patients Response and R0 resection rates: CRYSTAL and OPUS (KRAS wt) n RR (%) R0 resections (%) CRYSTAL FOLFIRI + ERBITUX FOLFIRI 316 350 57 40 p<0.001 5.1 2.0 p=0.03 OPUS FOLFOX + ERBITUX FOLFOX 82 97 57 34 p<0.003 7.3 3.1 p=0.22 FOLFIRI + ERBITUX FOLFIRI 68 72 71 44 p=0.002 13.2 5.6 p=0.15 FOLFOX + ERBITUX FOLFOX 25 23 76 39 p=0.018 16.0 4.3 p=0.35 Van Cutsem ASCO-GI 2011

CELIM: Study design Patients with technically unresectable/ 5 liver metastases of CRC without extrahepatic metastases Biopsy EGFR screening Randomization Primary endpoint: Response rate FOLFOX6 + cetuximab FOLFIRI + cetuximab Blinded surgical review Therapy: 8 cycles (~4 months) Evaluation of resectability Technically unresectable Technically resectable 4 further treatment cycles Resection Therapy continuation for 6 cycles (~3 months) Folprecht G, et al. Lancet Oncol 2010;11:38 47

Folprecht G, et al. Lancet Oncol 2010;11:38 47 ; Van Cutsem ASCO-GI 2011 CELIM :Objective Response and Resection Rates Objective Response Rate KRAS wild-type (n=67) CR/PR, % 70 95% CI, % 58 81 Responses confirmed by 2 nd CT scan according to RECIST or by resection FOLFOX6 + cetuximab (n=53) (%) FOLFIRI +cetuximab (n=53) (%) All patients (n=106) (%) R0 resections 38 30 34 R1-resect / Resect + RFA 2 8 5 RFA 9 6 8 R0/R1 resect / RFA 49 43 46

Probability, % CELIM: Time to intervention 60 Time to intervention 50 40 30 20 10 Time of chemotherapy 1 month shorter than with FOLFOX alone *(cross trial comparisons) 0 0 2 4 6 8 10 12 14 16 Time (months) 44 patients were resected, 5 patients had exploratory laparotomy Median time to intervention (resection/laparotomy): 5.1 months Median number of cycles prior to intervention: 8 Folprecht. Lancet Oncol 2010; Alberts. JCO 2005

CELIM: Prolonged survival after R0 resection PFS R0 resected Not R0 resected HR=2.07 (1.35-3.16) p=0.001 OS R0 resected Not R0 resected HR=2.34 (1.37-4.01) p=0.002 Folprecht G, et al. EMCC 2011 (Abstract No 6009)

Colorectal Liver Metastasis : A Continuum of disease Less extensive More extensive Low disease burden, generally with a single solitary site of spread intermediate disease burden, generally not operable upfront but potentially convertible to an operable state Chemotherapy to control tumor, improve symptoms, maintain quality of life and prolong life