The left versus right colon cancer story What is the truth?

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Mervin Barker
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1 The left versus right colon cancer story What is the truth? Prof. V. Heinemann CCC LMU, Klinikum Grosshadern Ludwig-Maximilian-University of Munich, Germany Three stages of truth (Schopenhauer) Ridicule Violent opposition Acceptance for granted

2 Conflicts of Interest Advisory Boards: Merck, Amgen, Roche, Servier, Sanofi, Bayer, Novartis, Boehringer-Ingelheim, SIRTEX, MSD, BMS Honorary fees: Merck, Amgen, Roche, Servier, SIRTEX, MSD, BMS, Servier Scientific grants: Merck, Amgen, Roche, Servier, Boehringer-Ingelheim, SIRTEX, MSD, BMS, Pfizer, Shire

3 Sidedness affects treatment decisions 20-40% most of the evidence Molecular Profile 60-80% RAS wt CT doublet + moab RAS mt Combination CT + bevacizumab BRAF mt CT triplet + bevacizumab Right-sided Left-sided

4 Prognostic Relevance of Primary Tumour Sidedness in Clinical Studies Clearly better outcome in LPT: HR 1.5 favors RC favors LC Holch et al. Eur J Cancer 2017

5 Prevalence of right-sided tumors in clinical studies Study Regimen Right-sided location CRYSTAL PRIME FIRE-3 PEAK CALGB FOLFIRI + Cetuximab FOLFIRI FOLFOX + Panitumumab FOLFOX FOLFIRI + Cetuximab FOLFIRI + Bev FOLFOX + Panitumumab FOLFOX + Bev Chemo + Cetuximab Chemo + Bev 19% 27% 19% 24% 19% 25% 29% 21% 30% 34% Range: 19-34%

6 Bevacizumab Effect of sidedness on survival

7 Pooled Analysis: NO16966 and AVF2107 Right side Sidedness was determined in 1590 (72%) of 2214 pts 27% right 73% left Left side Conclusions: Incomplete analysis Bevacizumab comparably improves OS in LSP and RSP Effect not significant in RSP Loupakis BJC 2018

8 TRIBE: Impact of Sidedness on OS FOLFOXIRI + Bev FOLFIRI + Bev Unselected pts LSP: HR 0.99 RSP: HR 0.56 RAS/BRAF-wt LSP: HR 0.88 RSP: HR 0.50 Unselected pts Right-sided Left-sided FOLFOXIRI + Bev FOLFIRI + Bev FOLFOXIRI + Bev FOLFIRI + Bev ORR 63.9% 54.6% 64.6% 56.6% Cremolini C, et al. Ann Oncol 2018

9 TRIBE: Impact of Sidedness on OS FOLFOXIRI + Bev FOLFIRI + Bev Unselected pts LSP: HR 0.99 RSP: HR 0.56 RAS/BRAF-wt LSP: HR 0.88 RSP: HR 0.50 Unselected RSP: FOLFOXIRI pts plus Right-sided bevacizumab may be regarded Left-sided as a preferred option in pts fit for combination and independent of their molecular status FOLFOXIRI + Bev FOLFIRI + Bev FOLFOXIRI + Bev FOLFIRI + Bev LSP: Doublet plus bevacizumab remains the preferred option ORR 63.9% 54.6% 64.6% 56.6% Cremolini C, et al. Ann Oncol 2018

10 Anti-EGFR agents Effect of sidedness on survival Meta-analysis: Meta-analysis: chemo doublet +/- EGFR-i (PRIME, CRYSTAL) head-to-head comparisons: EGFR-i versus bevacizumab (CALGB, FIRE-3, PEAK)

11 PRIME (FOLFOX +/- Panitumumab): Effect of Sidedness Clear benefit from Pmab No benefit from Pmab Boeckx N, et al. Ann Oncol 2017

12 Holch J, Eur J Cancer Meta-analysis: addition of an anti-egfr agent to chemo Overall Survival Left-sided mcrc PRIME CRYSTAL Left-sided primary Clear benefit from anti-egfr therapy right-sided mcrc PRIME CRYSTAL Right-sided primary No benefit from anti-egfr therapy

13 Head to head comparisons anti-egfr agents versus bevacizumab

14 FIRE-3 (FOLFIRI + Cetuximab versus FOLFIRI + Bevacizumab) Effect of Sidedness No significant difference Cetuximab superior: Δ=10mo Tejpar S, et al. JAMA Oncopl 2016

15 Meta-Analysis of Head to Head Comparisons Overall survival Left-sided mcrc CALGB/SWOG FIRE-3 PEAK Left-sided primary Clear benefit from anti-egfr agents compared to bevacizumab right-sided mcrc CALGB/SWOG FIRE-3 PEAK Right-sided primary Strong trend in favor of bevacizumab Holch J, Eur J Cancer. 2017

16 Meta-Analysis of Head to Head Comparisons Progression-free survival Left-sided mcrc right-sided mcrc Comment Comparable effects of sidedness on PFS and OS

0 mo 1.3 0.28 38.3 mo 28.0 mo 0.63 0.002 CALGB (n=474) 13.7 mo 29.2 mo 1.36 0.10 39.2 mo 32.6 mo 0.77 0.04 PEAK (n=234) 17.

17 H-to-H Comparisons: FIRE-3, PEAK, CALGB Overall Survival according to sidedness Right-Sided Primary Tumours Left-Sided Primary Tumours Study Chemo + anti-egfr Chemo + Bevacizumab HR P Chemo + anti-egfr Chemo + Bevacizumab HR P FIRE-3 (n=394) 18.3 mo 23.0 mo mo 28.0 mo CALGB (n=474) 13.7 mo 29.2 mo mo 32.6 mo PEAK (n=234) 17.5 mo 21.0 mo 43.4 mo 32.0 mo 0.84 na Very poor survival in EGFR-i treated RPT EGFR-i work even better in LSP Bevacizumab works in LSP

18 Anti-EGFR agents Effect of sidedness on ORR

19 Meta-analysis: addition of an anti-egfr agent to chemo ORR: Left- and right-sided mcrc Left-sided mcrc PRIME CRYSTAL Left-sided primary Clearly favors anti-egfr treatment right-sided mcrc PRIME CRYSTAL Right-sided primary Trend in favor of anti-egfr treatment Holch J...Heinemann V, Eur J Cancer Jan;70:87-98.

20 Meta-analysis: Head to head comparisons ORR: Left- and right-sided mcrc Left-sided mcrc CALGB/SWOG FIRE-3 PEAK Left-sided primary Clearly favors anti-egfr treatment right-sided mcrc CALGB/SWOG FIRE-3 PEAK Right-sided primary Trend in favor of anti-egfr treatment Holch J...Heinemann V, Eur J Cancer Jan;70:87-98.

21 VOLFI (FOLFOXIRI + Panitumumab versus FOLFOXIRI) Effect of intensified treatment in RPT vs LPT ORR (primary objective) N FOLFOXIRI + Pmab FOLFOXIRI P Full analysis set % 60.6% Left % 68.0% 0.02 Right % 37.5% 0.34 Conclusion In RPT there is a discordant effect of Pmab on ORR and PFS Geissler M, et al. ASCO #3509, 2018

22 Later treatment lines Effect of sidedness on OS

NCIC CO.17: Relevance of sidedness in pretreated patients* *KRAS wild-type HR = 0.66 p=0.18 HR = 0.49 p=0.002 Conclusions Highly selected patient population BRAF V600 mutation RC 4.7% LC 0.8% HR = 0.

23 NCIC CO.17: Relevance of sidedness in pretreated patients* *KRAS wild-type HR = 0.66 p=0.18 HR = 0.49 p=0.002 Conclusions Highly selected patient population BRAF V600 mutation RC 4.7% LC 0.8% HR = 0.73 p=0.26 HR = 0.28 p < Cetuximab is effective compared to BSC Effects smaller in right-sided than left-sided mcrc *Patients who had previously been treated with a fluoropyrimidine, irinotecan, and oxaliplatin or had contraindications to treatment with these drugs Brulé SY, et al. Eur J Cancer 2015

24 What is the truth?

25 Continuum of DNA Alterations 50 CIMP-high MSI-high BRAF Mutation Anteil positive Fälle (%) Caecum (n = 243) Colon ascendens (n = 295) Hepatic flexur (n = 46) Colon transversum (n = 91) Splenic flexur (n = 33) Colon descendens (n = 83) Colon sigmoideum (n = 314) Rectosigmoid (n = 106) Rectum (n = 232) right-sided *CIMP: CPG-island methylation phenotype; MSI, microsatellite instability left-sided According to Yamauchi M. et al., Gut 2012;61:847-54

26 Prevalence of CMS According to Sidedness 608 patients with stage I-IV CRC FIRE-3 FIRE-3 Loree JM, et al. Clin Cancer Res 2018;

27 HR for OS According to Primary Tumor Location Loree JM,... Kopetz S; Clin Cancer Res 2018

1 months Depth of response correlated significantly with OS

28 FIRE-3: Greater DpR correlates with longer OS R N = 400 FOLFIRI + Cetuximab Prim. Endpoint = ORR FOLFIRI + Bevacizumab Δ = 8.1 months Depth of response correlated significantly with OS (two-sided Bravais Pearson test) Stintzing S, et al. Lancet Oncology 2016

29 Sidedness differentially affects the relation between EGFR-i induced ORR and OS Discordance of ORR and OS in right-sided mcrc DpR is predictor of OS in left-sided mcrc?

Left versus right colon cancer story: My Take RAS

not accepted/tolerated D: chemo doublet T: chemo

30 Left versus right colon cancer story: My Take RAS wt Right-sided Left-sided T + EGFR-i D/T + Bev D + EGFR-i D + Bev if ORR is a primary goal if OS is a primary goal if OS is a primary goal if EGFR-i are not accepted/tolerated D: chemo doublet T: chemo triplet default recommendation default recommendation

31 Clinical Practice Recommendation: LPT RAS-wt mcrc: Define RAS- and BRAF mutation status upfront Prefer an anti-egfr agent in 1st-line treatment if prolongation of OS is a primary goal (most patients) If anti-egfr agents are not accepted or tolerated switch to a doublet plus bevacizumab

32 Clinical Practice Recommendation: RPT RAS-wt mcrc: Focus on exploration of family history Define BRAF mutation and MSI status upfront Prefered 1st-line treatment option: triplet plus bevacizumab Alternative option: triplet plus anti-egfr agent if tumor reduction or conversion therapy is a primary goal if you are willing to evaluate early tumor response (e.g. after 6-8 weeks) in case of insufficient response: immediately switch to bev-based therapy

MANAGEMENT OF ADVANCED COLORECTAL CANCER

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 outline