Dr. Iain Tan. Senior Consultant GI Medical Oncologist National Cancer Centre Singapore

Transcription

1 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents Dr. Iain Tan Senior Consultant GI Medical Oncologist National Cancer Centre Singapore

2 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents 1. The case for aggressive therapy in borderline resectable / unresectable liver limited metastases 2. Components Multidisciplinary / Multi-modality management 3. Chemotherapy & Targeted Therapy prior to surgery 4. Chemotherapy & Targeted Therapy after surgery 5. The left and right issue OUTLINE 6. How I choose systemic therapy in borderline resectable/unresectable

3 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 Time (months) Over the past decade, OS has improved substantially in patients with mcrc Kopetz S, et al. J Clin Oncol 2009;27:

4 Multiple active systemic agents in mcrc Treatment Approaches to First-Line mcrc 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; Abstract Heinemann. ASCO Abstract LBA Falcone. ASCO Abstract 3505.

5 Landmark 1 st line CRC studies ORR PFS PFS HR OS AVF2107g IFL 35% OS HR + Bevacizumab 45% PRIME FOLFOX panitumumab CRYSTAL FOLFIRI Cetuximab TRIBE FOLFIRI/Bev 53% FOLFOXIRI/Bev 65% FIRE3 FOLFIRI/Bev 56% FOLFIRI/Cet 71% CALGB Chemo + Bev 57% Chemo + Cet 69%

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

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

8 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

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

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

11 Liver resection improves long-term survival Overall survival (%) Landmark 12-month landmark analysis evaluated the impact of liver resection on OS Error bars represent 95% CIs Liver resection No liver resection Patient status Resected Non resected Median OS (mo) HR year OS rate % % immonds PC, et al. Br J Cancer. 2006;94: 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:

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13 Kanas GP, et al. Clin Epidemiol 2012;4: ;

14 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

15 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

16 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents 1. The case for aggressive therapy in borderline resectable / unresectable liver limited metastases 2. Components Multidisciplinary / Multi-modality management 3. Chemotherapy & Targeted Therapy prior to surgery 4. Chemotherapy & Targeted Therapy after surgery 5. The left and right issue OUTLINE 6. How to choose systemic therapy

17 Components of Multidisciplinary / Multi-modality management Neoadjuvant systemic therapy Staged hepatectomy Portal vein embolization (PVE) Portal vein ligation (PVL) Radioembolization Locoregional ablative therapies Advanced imaging

18 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

19 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents 1. The case for aggressive therapy in borderline resectable / unresectable liver limited metastases 2. Components Multidisciplinary / Multi-modality management 3. Chemotherapy & Targeted Therapy prior to surgery 4. Chemotherapy & Targeted Therapy after surgery 5. The left and right issue OUTLINE 6. How I choose systemic therapy in borderline resectable/unresectable

20 General principles of systemic chemotherapy in borderline / unresectable liver-limited mcrc Give the most active regimen Goal of treatment Achieve R0 resection; maximum tumor shrinkage Early management of unseen micrometastases Consider surgery once it is resectable Achieve resectability rather than a CR If convertible to surgery, Sequencing of the different procedures Management of the primary role of post-operative chemotherapy

21 Resection rate 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) Response rate 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: Jones R et al. Eur J Cancer, 2014

22 Achieve resectability rather than a CR 83% of lesions that disappear whilst on chemotherapy are still active Need to resect before metastases completely disappear When to send for surgery?

23 Chemotherapy: The use of triplets + Greek Study (R0 resectn) PFS 10 m vs 7 m OS 23 m vs 17 m

24 Chemotherapy: The use of triplets

25 Targeted Therapy: The use of anti-vegf ORR PFS PFS HR AVF2107g IFL 35% OS OS HR + Bevacizumab 45% Modest, if any impact on ORR Issues of surgical safety/timing

26 Liver limited All patients Targeted Therapy: The use of anti-egfr Response and R0 resection rates: CRYSTAL and OPUS (KRAS exon2 wt) n RR (%) R0 resections (%) CRYSTAL FOLFIRI + Cetuximab FOLFIRI p< p=0.03 OPUS FOLFOX + Cetuximab FOLFOX p< p=0.22 FOLFIRI + Cetuximab FOLFIRI p= p=0.15 Left vs Right & extended Ras not considered FOLFOX + Cetuximab FOLFOX p= p=0.35

27 Mean change from baseline (%) PRIME study post-hoc analysis Mean (95% CI) percentage change in tumour load (sum of all target lesions) (WT RAS) FOLFOX4 (n = 224) Panitumumab + FOLFOX4 (n = 236) Median DpR*, % (Q1, Q3) 46 (23, 66) 54 (31, 72) P = Patients at risk: Panitumumab + FOLFOX4 FOLFOX Week number of measurement Douillard JY, et al. Eur J Cancer 2015;51: *Tumour shrinkage at nadir versus baseline tumour load (sum of the longest diameters of all target lesions).

28 Patients (%) PRIME study post-hoc analysis Resection rates (WT RAS and LLD) Updated analysis Panitumumab + FOLFOX4 (n = 48) FOLFOX4 (n = 41) 35 33% = 6.5% P = 0.644* 31% = 14.2% P = 0.145* 30 27% % Any resection Complete resection Douillard JY, et al. Eur J Cancer 2015;51: *Descriptive P-value (Fisher exact test).

29 PRIME study post-hoc analysis OS in patients with any resection (WT RAS, LLD and non-lld) Kaplan Meier estimate 100 Panitumumab + FOLFOX4 (n = 35) Events, n Median OS, months FOLFOX4 (n = 29) HR = 0.66 (95% CI, ) P = Douillard JY, et al. Eur J Cancer 2015;51: Months Median RFS after resection (n = 38) was 22.0 vs 12.4 months with panitumumab + FOLFOX4 vs FOLFOX4, respectively (HR = 0.66; P = ) Censor indicated by vertical bar. WT RAS = WT KRAS and NRAS exons 2/3/4. RFS, relapse-free survival.

30 Targeted Therapy: The use of anti-egfr Four RCTs involving 484 WT KRAS patients were included: PRIME (Douillard et al. 2010) COIN (Maughan et al. 2011) CRYSTAL (Van Cutsem et al. 2011) OPUS (Bokemeyer et al. 2011) WT KRAS = WT KRAS exon 2 (codons 12 and 13) for PRIME, CRYSTAL and OPUS plus WT KRAS exon 3 (codon 61) for COIN Left vs Right & extended Ras not considered

31 Targeted Therapy: The use of anti-egfr liver-confined metastases deemed nonresectable by a local multidisciplinary team, which included > three liver surgeons and one radiologist. Left vs Right & extended Ras not considered Ye et al. JCO 2013

32 liver-confined metastases deemed nonresectable 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

33 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, % 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 R1-resect / Resect + RFA RFA R0/R1 resect / RFA

34 Probability, % CELIM: Time to intervention 60 Time to intervention Time of chemotherapy 1 month shorter than with FOLFOX alone 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

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

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38 Depth of Response and Early Tumour Shrinkage Chemo + / - Anti-EGFR Median DpR % w ETS > 20% (>20% vs <20%) :PFS HR OS HR % w ETS > 30% (>30% vs <30%): PFS HR OS HR Study n +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo +EGFR-ab chemo PRIME (updated RAS analysis) % 46% 72% 57% % 38% CRYSTAL WT KRAS % 39% OPUS WT KRAS % 54% : 1 arm Pan/FOLFIRI 65 59% 74% Chemo + / - Biologic Median DpR % ETS > 20% 13.3 vs % 14.3 vs 7.8 PFS HR (ETS >20% vs< 20%) OS HR (ETS >20% vs< 20%) % ETS > 30% PFS HR (ETS >30% vs<30%) OS HR (ETS >30% vs<30%) Study n +EGFR-ab +VEGF-ab +EGFR-ab +VEGF-ab +EGFR-ab +VEGF-ab +EGFR-ab +VEGF-ab 13.1 vs 11.3 vs 43.4 vs 32.5 vs PEAK WT-RAS (final analysis) % 46% 75% 62% FIRE3 WT-RAS (wk 6) % 32% 68% 49% CALGB 1137 ORR: 69% ORR: 54% Triplet chemo: (combined analysis TRIP/MACBETH/TRIBE (wt RAS/RAF) % 38% 70% 62% % 45% +EGFR-ab 13.0 vs EGFRab +VEGFab +VEGFab 11.1 vs 9.7 +EGFR-ab +VEGF-ab 43.8 vs 35.1 vs VEGF + 2 vs 3 chemo n + Ox Bev/5FU-iri + Ox Bev/5FU-iri TRIBE (no RAS analysis) % 38% 63% 52%

39 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents 1. The case for aggressive therapy in borderline resectable / unresectable liver limited metastases 2. Components Multidisciplinary / Multi-modality management 3. Chemotherapy & Targeted Therapy prior to surgery 4. Chemotherapy & Targeted Therapy after surgery 5. The left and right issue OUTLINE 6. How I choose systemic therapy in borderline resectable/unresectable

40 Adjuvant Chemo post resection of colorectal liver mets

41 All patients (n=182 per arm) All eligible Patients (n=171 per arm) All resected Patients (n=151 per arm) % absolute difference in 3-year PFS +7.2% (28.1% to 35.4%) +8.1% (28.1% to 36.2%) +9.2% (33.2% to 42.4%) Hazard Ratio P-value 0.79 P= P= P=0.025

42 The NEW EPOC Study A randomised clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in KRAS wild-type patients with operable metastases from colorectal cancer

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44 Proportion event free Results Chemotherapy The NEW EPOC Study A randomised clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in KRAS wild-type patients with operable metastases from colorectal cancer HR %CI (1.04, 2.12); p= Time to progression or death (months) Number at risk Arm A Arm B Arm A Arm B HR %CI (0.85, 2.58); p= Time to death (months) Number at risk Arm A Arm B Arm A Arm B ORR PFS PFS HR OS OS HR Chemo 42% 20.5 NR + Cetuximab 50%

45 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents 1. The case for aggressive therapy in borderline resectable / unresectable liver limited metastases 2. Components Multidisciplinary / Multi-modality management 3. Chemotherapy & Targeted Therapy prior to surgery 4. Chemotherapy & Targeted Therapy after surgery 5. The left and right issue OUTLINE 6. How I choose systemic therapy in borderline resectable/unresectable

46 Primary CRC tumor localization (left vs right) Right colon (ascending) Transverse colon Small intestine Left colon (descending) Rectum Anus Sigmoid (colon) Right-sided tumors ~40% (increasing)* Associated with: Older, female patients Mucinous, signet-ring histology Microsatellite instability Poorly differentiated KRAS and BRAF mutations EGFR expression *High-incidence CRC populations Left-sided tumors ~60%* Associated with: Chromosomal instability p53 mutation COX2 expression Aneuploidy High EGFR ligand expression (COIN study) Iacopetti, B. Int J Cancer 2002;101: ; Brule SY, et al. ASCO 2013 (Abstract No. 3528); Adams R, et al. ASCO 2012 (Abstract No. 3516)

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48 Right versus left: RAS WT Data from retrospective analysis 1 st line PRIME CRYSTAL FIRE-3 CALGB PEAK 2 nd line 181? 3 rd line and beyond CO-17 Left sided primary mcrc, anti- EGFR leads to better clinical outcome compared to chemotherapy or chemotherapy plus bevacizumab Right sided primary results suggest little survival benefit for anti-egfr 1 st line +/- 2 nd line, but small numbers does impact on interpretation

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50 Holch et al, EJC 2017 (70) 87-98

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52 Arnold et al, Annals of Oncology 28: , 2017

53 Targeted Therapy: Head-to-head ORR (1 st line) FIRE3 PEAK

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55 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents 1. The case for aggressive therapy in borderline resectable / unresectable liver limited metastases 2. Components Multidisciplinary / Multi-modality management 3. Chemotherapy & Targeted Therapy prior to surgery 4. Chemotherapy & Targeted Therapy after surgery 5. The left and right issue OUTLINE 6. How I choose systemic therapy in borderline resectable/unresectable

56 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents How I choose systemic therapy in borderline resectable/unresectable RIGHT LEFT RAS wildtype FOLFOXIRI Anti-EGFR/FOLFOX or FOLFOXIRI RAS mutant FOLFOXIRI FOLFOXIRI All FOLFOXIRI (+/- Bev) 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

57 ESMO-ASIA 2017 Preceptorship (GI cancers) Session: Metastatic colorectal cancer, liver limited metastases Topic: Unresectable or borderline resectable : chemotherapy +/- targeted agents 1. The case for aggressive therapy in borderline resectable / unresectable liver limited metastases 2. Components Multidisciplinary / Multi-modality management 3. Chemotherapy & Targeted Therapy prior to surgery 4. Chemotherapy & Targeted Therapy after surgery 5. The left and right issue CONCLUSION 6. How I choose systemic therapy in borderline resectable/unresectable

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