MANAGEMENT OF ADVANCED COLORECTAL CANCER

Transcription

1 MANAGEMENT OF ADVANCED COLORECTAL CANCER Alberto Sobrero IRCCS San Martino IST Genoa Italy Disclosures : Pfizer, Roche, Merck, Amgen, Celgene, Bayer, Sanofi, Nordic, Takeda,BMS, Syrtex, Servier

2 outline 1 Advanced: where we are: > 30 mo mst implications 2 How did we get there? 3 The first line 4 players A doublet plus antivegf or antiegfr? B an update on R vs L side C 2 alternatives ways of thinking 1st line 4 How to continue: the issue of maintenance 5 True second lines and salvage ( rego and TAS102 ) 6 Innovative ( precision ): Pembro-Nivo, Her-2, napabucasin 7 Do not forget locoregional approaches

3 Simplification of the incremental overall benefit of the antineoplastic agents in advanced CRC ( 34 trials ) Agent gain in median OS FU 6 mo + Oxali irino 6 mo Anti VEGF 6 mo Anti EGFR 6 mo +

4 What we knew in the K-RAS era, up to 2 yrs ago, before the RAS era BEV 1 good efficacy in first and second line 2 no single agent activity 3 easy to use, little toxicity, however.. antiegfr 1 good efficacy in first and third line 2 single agent activity 3 K-RAS test needed, skin tox a major problem conclusion 1 efficacy in first line probably similar in K-RAS wt 2 bev better for first line when shrinkage not essential 3 anti EGFR better in third line if K-RAS wt

5 PRIME study (FOLFOX +/- panitumumab): survival according to KRAS and RAS mutation status Douillard et al. NEJM 2013

6 The RAS story OS HR (RAS wt) Difference in median OS between treatment arms (months) PRIME vs chemo CRYSTAL vs chemo FIRE vs chemo bev PEAK vs chemo bev 1. Douillard J-Y, et al. N Engl J Med 2013;369: Ciardiello F, et al. J Clin Oncol 2014;32:5s (suppl) (Abstract No. 3506) 3. Stintzing S, et al. Ann Oncol 2014;25(suppl 4):v1 v41 (Abstract No. LBA11) 4. Karthaus M, et al. EJC 2013;49 (suppl 3) (Abstract No. 2262) 5. Erbitux SmPC June/2014

7 To summarize: RAS wt, 1 st line 2 large studies of anti EGFR vs CT (Prime and Crystal) showing large benefit: 5 and 8 mo 2 large studies of anti EGFR vs CT BEV (Fire3 and PEAK) showing large benefit: 8 and 12 mo 1 large study of anti EGFR vs CT BEV (CALGB40805) showing no difference

8 CALGB/SWOG Overall Survival By Arm (All RAS Wild Type Patients) Arm Chemo + Bev Chemo + Cetux N (Events) 256 (178) 270 (177) Median (95% CI) 31.2 ( ) 32.0 ( ) HR (95% CI) 0.9 ( ) p 0.40 LENZ, ESMO, 2014

9 80405: Details STILL Pending Disparities Response Rate Duration of therapy / dose intensity Analysis special subsets: Patients rendered NED Details 2 nd and later treatments Maintenance Sequence

10 Summary: anti VEGF vs anti EGFR in first line US position: anti VEGF no matter RAS a) toxicity b) CALGB Others position: anti EGFR for most RAS wt

11 Right- and left-sided primary colon tumours have distinct biology 1 Right-sided Lower Increasing Female Higher TNM stage Larger tumours More mucinous type MUTYH-associated polyposis More active immune cells promoting immunogenicity CIMP/MSI/BRAF positive tumours predominate Incidence Presentation Genetics Immunology Molecular pathway Left-sided Higher Decreasing Male Lower TNM stage Smaller tumours Familial adenomatous polyposis Immunologically less active, promoting tolerogenesis Chromosomal instability tumours predominate Worse Survival Better Review included six meta-analyses, 12 reviews, 62 observational studies and seven additional supporting articles BRAF, v-raf murine sarcoma viral oncogene homolog B1; CIMP, cytosine-guanosine (CpG) island methylation phenotype; MSI, microsatellite instability; TNM, American Joint Committee on Cancer tumour node metastasis stage; 1. Lee GH, et al. Eur J Surg Oncol 2015;41:

12 The L and R story as an aid to uniformity R L CALGB CET vs BEV - 8 (-19) + 5 FIRE III CET vs BEV PEAK PANI vs BEV R bev better than anti EGFR by 4 to 8 (19) mo L anti EGFR better than BEV by 5 to 11 mo

13 NCIC CO.17 KRAS wt Right-sided colon cancer HR 0.66 (95% CI: ), p=0.18 Left-sided colon cancer HR 0.49 (95% CI: ), p=0.002 (n=78) (n=72) (n=122) (n=127) HR 0.73 (95% CI: ), p=0.26 HR 0.28 (95% CI: ), p< (n=78) (n=72) (n=122) (n=127) Non-significant trend towards longer OS and PFS with Erbitux vs BSC Right-sided: cecum, ascending colon, hepatic flexure or transverse colon Left-sided: splenic flexure, descending colon, sigmoid colon or rectosigmoid junction. Patients were excluded from the main analysis if they had primary rectal tumors (n=161) or if their primary tumor location was unknown (n=12) *RAS status was not assessed Longer OS and PFS with Erbitux than BSC 1. Brulé SY, et al. Eur J Cancer 2015;51:

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15 Summary - Left vs right sided tumours Is L better than R YES Does CT work better on L than on R? Does BEV work better on L than on R? May be NO Do anti-egfr work better on L than on R YES Do anti-egfr work on R YES Is BEV better than anti-egfr on R YES Are anti-egfr better than BEV on L YES

16 Onco Update Europe 2015 Loupakis NEJM 2014; 371(17):

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18 OS estimate AVEX - Overall survival Cape + BEV (n=140) Cape (n=140) HR=0.79 (95% CI: ) P= Δ 3.9 mos 16.8 mo 20.7 mo Time (months) Number at risk Cape + BEV Cape Cunningham et al, Lancet Oncol 2013 Oct;14(11):1031-2

19 Metastatic CRC treatment strategy: initial management CLINICAL CONDITION Fit GOAL unfit BSC; FP+/-bev ; red.dose doubl;anti-egfr Cure Cytoreduction MOLEC. TESTING Disease control MOLEC. TESTING Surgery periop RAS wt RAS mt braf mt Doublet + anti-egfr combo + bev triplet + bev RAS wt RAS mt braf mt Chemo + bio Assessment of response every 2-3 months GOAL chemo + bev Unusual, see text Cure Cytoreduction Continue Disease control Continue; Mainetnance or pause

20 NEED for CYTOREDUCTION 1. Conversion to resectable 2. Symptomatic 3. Impending catastrophe 4. Rapid progression clin course 5. Pt s attitude

21 outline 1 Advanced: where we are: > 30 mo mst implications 2 How did we get there? 3 Basis for ESMO GL: How to start treatment: the 4 players A doublet plus antivegf or antiegfr? B an update on R vs L side C 2 alternatives ways of thinking 1st line 4 How to continue: the issue of maintenance 5 True second lines and salvage ( rego and TAS102 ) 6 Innovative ( precision ): Pembro-Nivo, Her-2, napabucasin 7 Do not forget locoregional approaches

22 Maintenance STUDY AGENTS OUTCOME MACRO bevacizumab slightly inferior to contin CT + bev MACRO II cetuximab gain in PFS CAIRO-3 bev + cape PFS1 and 2 gain vs nothing SAKK bevacizumab minor PFS and OS gain vs nothing AIO 207 cape+bev / bev minor gains in os Hard to run trials: actually trials mirror practice Substantial gain in PFS1 Minimal gain in OS usually non significant

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24 Considerations for 1 st line therapy in mcrc - Not all mcrc patients receive treatment beyond 1 st line 1 - Response rates are typically highest with 1 st line therapy 2 1 st line 2 nd line 3 rd line 4 th line N = Abrams TA, et al. J Natl Cancer Inst 2014;106:djt371; 2. Tournigand C, et al. J Clin Oncol 2004;22: Data from a US-wide cohort of 4877 mcrc patients who received chemotherapy between January 2004 and March 2011.

25 Options for Second-Line Therapy Start antiangio (bev, aflib, ramu) Change antiangio (aflib, ramu) Continue VEGF inhibition (bev, aflib) Switch antibodies (anti-egfr)

26 True second lines: options

27 New drugs in chemoresistant mcrc (third and further lines) Trial Therapy RR PFS (mo) OS (mo) Yoshino Lancet Onc 2012 phase II Yoshino, ESMO-GI 2014 Van Cutsem RECOURSE, ESMO 2014 Pl + BSC TAS-102+BSC n=169 Pl + BSC TAS-102+BSC n=800 0% vs 1% 1.0 vs 2.0 HR % vs 1.6% 1.7 vs 2.0 HR 0.48; 6.6 vs 9.0 HR vs 7.1 HR 0.68 Grothey, CORRECT Lancet 2013 BSC Regorafenib n=753 0% vs 1% 1.7 vs 1.9 HR vs 6.4 HR 0.77 Li, CONCUR ESMO- GI 2014 Kim, ESMO 2014 BSC Regorafenib n=204 0% vs 4.4% 1.7 vs 3.2 HR vs 8.8 HR 0.55

28 CONCLUSIONS: REGO vs TAS REGO TAS 1 One more theoretical chance Possibility of outlyers OS % prolonged PFS Everybody benefits Tolerability Tox-related determinant of efficay QOL + +(+) Lancet New Eng. J. Med.

29 Place in therapy Which toxicity so far? Myelo Symptomatic Rego Triflu-tipi Triflu-tipi Rego

30 outline 1 Advanced: where we are: > 30 mo mst implications 2 How did we get there? 3 Basis for ESMO GL: How to start treatment: the 4 players A doublet plus antivegf or antiegfr? B an update on R vs L side C 2 alternatives ways of thinking 1st line 4 How to continue: the issue of maintenance 5 True second lines and salvage ( rego and TAS102 ) 6 Innovative ( precision ): Pembro-Nivo, Her-2, napabucasin 7 Do not forget locoregional approaches

31 PD-1 Inhibitors Active in Pretreated dmmr/msi-h mcrc Pembrolizumab Nivolumab (CheckMate-142) MMR- Proficie nt CRC 0% RR 16% DCR MMR- Deficien t CRC 57% RR 89% DCR FU 13 months MMR- Deficient CRC 32% RR 70% DCR FU 21 months 34% RR 62% DCR P<.001 by logrank test Le DT, et al. J Clin Oncol. 2016;34(suppl): Abstract 103. Le DT, et al. N Engl J Med. 2015;372(26): Overman MJ, et al. Lancet Oncol. 2017;18(9): Overman MJ, et al. J Clin Oncol. 2018;36(suppl 4S): Abstract 554.

32 Nivolumab + Ipilimumab (CheckMate-142): PFS and OS No. at Risk OS, % Nivolumab + ipilimumab a,b Nivolumab 1,e,f Nivolumab + ipilimumab a,d Nivolumab 1,e,f 9-month rate (95% CI), % 76 (67.0, 82.7) 54 (41.5, 64.5) 12-month rate (95% CI), % 71 (61.4, 78.7) 50 (38.1, 61.4) PFS, % c Nivolumab + ipilimumab Nivolumab Months Nivolumab + ipilimumab Nivolumab month rate (95% CI), % 87 (80.0, 92.2) 78 (66.2, 85.7) 12-month rate (95% CI), % 85 (77.0, 90.2) 73 (61.5, 82.1) Nivolumab + ipilimumab Nivolumab Months André T, et al. J Clin Oncol. 2018;36(suppl 4S): Abstract 553. Overman MJ, et al. J Clin Oncol Jan 20. [Epub ahead of print]. 3 2

33 CLOCC STUDY, ASCO 2015 abstr 3501

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