Clinical Spotlight in Metastatic Colorectal Cancer

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1 2015 European Oncology Congress Clinical Spotlight in Metastatic Colorectal Cancer Featured Research: ESMO Consensus on Metastatic CRC 2015 TRIBE: Cremolini C, et al. Lancet Oncol Aug 28. [Epub ahead of print]. CALGB 80405: Abstract 2007 PEAK: Abstract 2014 CAIRO3: Simkens LH, et al. Lancet. 2015;385(9980): AIO 0207: Hegewisch-Becker S, et al. Lancet Oncol Sept 9. [Epub ahead of print].

2 ESMO Guidelines on Treatment of Metastatic Colorectal Cancer (mcrc) Based on the presentation at the 2015 World Congress on Gastrointestinal Cancer in Barcelona Presented by Dirk Arnold

3 Key Factors to Improve Overall Survival (OS) in mcrc Improving first-line therapy efficacy and selecting the best treatment for the individual patient Using the "chance for cure" by resection of metastases (and other local ablative treatments) Using the "continuum of care" with optimizing treatment at different lines Van Cutsem E, et al. Ann Oncol (suppl 3): iii1-iii9.

4 The Most Important Questions for First-Line Treatment Selection Is the patient fit enough to receive "standard" treatment? Which treatment goals exist? All treatment decisions involving patients categorized as clinically fit must be made at a tumor board meeting by a multidisciplinary team (MDT) Which treatment intensity is the most appropriate? Chemo monotherapy +/- bevacizumab Chemo doublet +/- any monoclonal antibody Chemo triplet +/- bevacizumab The decision on the best systemic treatment should be informed by the appropriate molecular analyses Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

5 Molecular Pathology and Biomarkers RAS is a predictive biomarker for therapeutic choices involving EGFR antibody therapies in the metastatic disease setting [I, A] RAS testing is mandatory prior to treatment with EGFRtargeted monoclonal antibodies cetuximab and panitumumab [I, A] Primary or metastatic colorectal tumor tissue can be used for RAS testing RAS analysis should include (at least) KRAS exons 2, 3, and 4 (codons 12, 13, 59, 61, 117, and 146) and NRAS exons 2, 3, and 4 (codons 12, 13, 59, 61, and 117) Turnaround time for RAS testing (expanded RAS analysis) should be 7 working days from the time of receipt of the specimen by the testing laboratory, to the time of issuing of the final report, for >90% of specimens. Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

6 Molecular Pathology and Biomarkers Recommendation: BRAF testing Tumor BRAF mutation status should be assessed alongside the assessment of tumor RAS mutational status for prognostic assessment and/or potential selection for clinical trials [I, B] Recommendation: microsatellite instability (MSI) testing Except in the setting of genetic counseling, MSI testing is not yet recommended routinely in the metastatic disease setting Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

7 Fit Patients: Treatment Goals Fit patients with "disease control" as goal Long overall survival (OS), "chronic disease" in palliative care No disease-related symptoms Few treatment-related symptoms Fit patients with "cytoreduction" as goal Cure (potentially) Long OS, "chronic disease" in palliative care No disease-related symptoms Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

8 Factors for Decisions in First Line Chemotherapy with targeted agents is indicated in first-line treatment of patients unless contraindicated Drivers for First-Line Treatment Tumor Characteristics Patient Characteristics Treatment Characteristics Clinical presentation Tumor burden Tumor localization Age Toxicity profile Tumor biology Performance status Flexibility RAS mutation status Organ function Socioeconomic factors BRAF mutation status Comorbidities Quality of life, patient expectations and preferences Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

9 Treatment of Metastatic Disease Clinical condition of the patient Fit Unfit (but may be suitable) Unfit Goal FP ± bevacizumab; reduced-dosed doublet; anti-egfr BSC NED Patients with clearly resectable metastases Surgery alone Surgery with perioperative/ postoperative CT Doublet + anti-egfr Cytoreduction (Shrinkage) Molecular profile RAS wt RAS mt BRAF mt Combination + bevacizumab Triplet + bevacizumab Re-evaluation assessment of response every 2 months CT + biological agent Disease control (control progression) Molecular profile RAS wt RAS mt BRAF mt CT + bevacizumab Unusual Re-evaluation assessment of response every 2 months Goal Progressive disease Secondline Secondline Progressive disease Surgery Cytoreduction (Shrinkage) Disease control Continue Continue maintenance; or pause Continue maintenance; or pause Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

10 Choice of First-Line Treatment Fit patients with "disease control" as goal The recommendation is chemotherapy (doublet > single agent) plus bevacizumab first line, with EGFR antibody therapy as an option for patients with RAS wild-type disease Should be re-evaluated every 2-3 months. Where there is evidence of good disease control, patients should continue on therapy, and after two positive re-evaluations, active maintenance should be considered. Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

11 Choice of First-Line Treatment Fit patients with cytoreduction or shrinkage as a goal For (curable) patients with RAS wild-type tumors, a cytotoxic doublet plus an EGFR antibody should be the treatment of choice, and those with RAS mutant tumors should receive a cytotoxic triplet ± bevacizumab, or cytotoxic doublet plus bevacizumab If after the first re-evaluation at 2 months there is evidence of tumor shrinkage, patients should be recommended for potentially curative surgery, with a view to eliminating all evidence of disease (R0 resection and/or ablative strategy) Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

12 Maintenance Treatment Patients receiving FOLFOX or CAPOX as induction therapy should be allocated to maintenance therapy after 6-8 cycles Patients receiving FOLFIRI as induction should continue for (at least) as long as tumor shrinkage continues / disease stabilization is maintained Patients receiving induction therapy with singleagent FP (5-FU or capecitabine) plus bevacizumab should be maintained on this until progression Optimal maintenance treatment after a bevacizumab-containing induction is a combination of fluoropyrimidine plus bevacizumab. Bevacizumab monotherapy as maintenance is not recommended. Van Cutsem E, et al. ESMO Consensus on metastatic CRC 2015: in preparation.

13 Continuum of Care in mcrc Strategic scenarios in the continuum of care of mcrc A. Scenario 1 B. Scenario 2 C. Scenario 3 First line Cytotoxic doublet 1 + bevacizumab Cytotoxic doublet 1 + bevacizumab Cytotoxic doublet 1 + anti-egfr antibody 2 Second line Cytotoxic doublet 1 + bevacizumab or aflibercept 3 Cytotoxic doublet 1 + anti-egfr antibody 2 Cytotoxic doublet 1 + bevacizumab or aflibercept 3 Third line Irinotecan or FOLFIRI anti-egfr antibody 2 Regorafenib Regorafenib Fourth line Regorafenib 1 Cytotoxic doublets: Fluoropyrimidines + oxaliplatin or irinotecan; 2 RAS wild-type; 3 Aflibercept: Only in combination with FOLFIRI Van Cutsem E, et al. Ann Oncol (suppl 3): iii1-iii9.

14 Key Factors to Improve Overall Survival in mcrc Improving first-line therapy efficacy and selecting the best treatment for the individual patient Using the "chance for cure" by resection of metastases (and other local ablative treatments) Using the "continuum of care" with optimizing treatment at different lines Van Cutsem E, et al. Ann Oncol (suppl 3): iii1-iii9.

15 FOLFOXIRI Plus Bevacizumab Versus FOLFIRI Plus Bevacizumab As First-Line Treatment of Patients With Metastatic Colorectal Cancer: Updated Overall Survival and Molecular Subgroup Analyses of the Open-Label, Phase 3 TRIBE Study Cremolini C, Loupakis F, Antoniotti C, Lonardi S, Ronzoni M, Zaniboni A, Tonini G, Salvatore L, Chiara S, Carlomagno C, Banzi C, Allegrini G, Negri F, Barone C, Fontanini G, Borrelli N, Giordano M, Macerola E, Boni L, Falcone A

16 TRIBE Study Profile 508 patients randomly assigned FOLFIRI + Bevacizumab (N = 256) 195 included in molecular subanalysis KRAS and BRAF wildtype (N = 45) KRAS/NRAS mutation positive (N = 119) BRAF mutation positive (N = 12) FOLFOXIRI + Bevacizumab (N = 252) 196 included in molecular subanalysis KRAS and BRAF wildtype (N=48) KRAS/NRAS mutation positive (N = 117) BRAF mutation positive (N = 16) FOLFIRI, 5-fluorouracil, leucovorin, irinotecan FOLFOXIRI, 5-fluorouracil, leucovorin, oxaliplatin, irinotecan Cremolini C, et al. Lancet Oncol Aug 28. [Epub ahead of print]

17 OS Probability TRIBE Results: Overall Survival FOLFIRI + Bev: N = 256 / Died = 200 FOLFOXIRI + Bev: N = 252 / Died = FOLFIRI + Bev, median OS : 25.8 months FOLFOXIRI + Bev, median OS : 29.8 months HR 0.80 [ ] P = FOLFIRI + BEV FOLFOXIRI + BEV Follow-Up Time, Months FOLFIRI + Bev FOLFOXIRI + Bev Cremolini C, et al. Lancet Oncol Aug 28. [Epub ahead of print]

18 OS Probability RAS and BRAF Mutational Status: Prognostic Impact RAS and BRAF wildtype median OS: 37.1 months RAS mutated, median OS: 25.6 months BRAF mutated, median OS: 13.4 months Likelihood test: P< Follow-Up Time, Months Cremolini C, et al. Lancet Oncol Aug 28. [Epub ahead of print]

19 Treatment Effect in Molecular Subgroups N FOLFIRI + Bev Median OS FOLFOXIRI + Bev Median OS HR [95% CI] P ITT population [ ].030 RAS and BRAF evaluable [ ].159 RAS and BRAF wild-type [ ] RAS mutated [ ] BRAF mutated [ ] RAS wild-type [ ] RAS mutated [ ] Median PFS of BRAF mutation-positive group: FOLFIRI vs FOLFOXIRI, 5.5 mo vs 7.5 mo.522*.658* Cremolini C, et al. Lancet Oncol Aug 28. [Epub ahead of print]

20 A Genome-Wide Association Study (GWAS) of Overall Survival (OS) in 609 Metastatic Colorectal Cancer (mcrc) Patients Treated With Chemotherapy And Biologics in CALGB Abstract 2007 Innocenti F, Owzar K, Chen J, Sibley A, Niedzwiecki D, Bertagnolli M, Friedman P, Furukawa Y, Kubo M, Ratain M, Blanke C, Heinz-Josef L, Venook A, McLeod H

21 CALGB Study Design mcrc 1 st -line KRAS wild-type (codons 12,13) FOLFIRI or FOLFOX Chemo + Cetuximab STRATA: FOLFOX/FOLFIRI Prior adjuvant Prior XRT MD Choice Chemo + Bevacizumab Primary cohort: N = Endpoint: Overall Survival Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

Genome-Wide Association Studies (GWAS) in CALGB 80405 Rationale CALGB 80405: One of the very few large studies conducted so far in mcrc No GWAS in mcrc with these regimens Constitutional systems

22 Genome-Wide Association Studies (GWAS) in CALGB Rationale CALGB 80405: One of the very few large studies conducted so far in mcrc No GWAS in mcrc with these regimens Constitutional systems (angiogenesis, inflammation, immunity) and cancer progression Germline variation in the host DNA and new genes associated with survival Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

23 Patient Characteristics All Patients (N = 1137) ARM A ARM B Chemo+BEV Chemo+CETUX GWAS Patients (N = 609) ARM A ARM B Chemo+BEV Chemo+CETUX Sex Age Male Female Median Range Non-Caucasian Primary in place FOLFOX/FOLFIRI 245/79 256/90 157/45 155/47 Palliative Intent Prior Radiation Prior Adjuvant Chemo Median OS in genotyped patients 29.6 months [95% CI: (26.9, 32.6), range: ] Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

24 Genome-Wide Genotyping Primary cohort N = 609 genetic europeans OmniExpressExome chip 719,461 common single nucleotide polymorphisms (SNPs) Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

25 Scope and Statistical Methods Discover genetic associations with survival Primary endpoint: overall survival (OS) Cox proportional hazard model Both arms combined Test for effects of arm (cetuximab vs bevacizuamb) and chemotherapy (irinotecan vs oxaliplatin) Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

26 Results Top 3 Significant SNPs Select Three Genes RDH14 (HR 1.63, p,1.12x10-6 ) Retinol dehydrogenase 14 Oxidoreductive catalytic activity towards retinoids TMEM16J (HR 1.52, p<2.03x10 ) Transmembrane protein 16J Intracellular calcium-activated chloride channel activity AXIN1 (HR 1.40, p<4.26x10-6 ) Axin 1 (Axin) A cytoplasmic protein interacting with APC, beta-catenin, glycogen synthase kinase 3 beta, protein phosphate 2, and itself Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

AXIN1 and Colorectal Cancer The Wnt signaling is central to the biology of colorectal cancer AXIN1 and APC function in the assembly of a β-catenin destruction complex.

27 AXIN1 and Colorectal Cancer The Wnt signaling is central to the biology of colorectal cancer AXIN1 and APC function in the assembly of a β-catenin destruction complex. Degradation of β-catenin is a key regulated step of the Wnt pathway AXIN1 acts as a tumor suppressor Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract Rosenbluh J, et al. Trends Pharmacol Sci. 2014;35(2):

28 rs (G to A) in AXIN1 Common (30% allele frequency) Intronic Unknown function A allele associated with worse overall survival Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

29 Probability rs (G>A) in AXIN1 Overall Survival rs A/A G/A G/G AA 18.4 ( ) months GA 25.6 ( ) months GG 36.6 ( ) months Overall Survival Time HR 1.40, P< 4.26x10-6 Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

30 Probability Probability rs (G>A) in AXIN1 Overall Survival by Chemo FOLFOX A/A G/A G/G FOLFIRI A/A G/A G/G Overall Survival Time P = 3.89x10-6 HR = 1.48 ( ) Overall Survival Time P =.26 HR = 1.19 ( ) Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

31 TCGA Data for Stage IV CRC 89 stage IV 1M SNP array for germline DNA variation Tumor mrna expression by RNAseq Overall survival data Use of another SNP in AXIN1 Very high linkage disequilibrium (r ) with rs TCGA, The Cancer Genome Atlas Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

32 Probability TCGA - AXIN1 SNP vs OS A/A G/A N = 89 P =.09 HR = 1.75 ( ) Overall Survival Time, Months Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

33 Conclusions A SNP in AXIN1 confers worse survival in mcrc TCGA data confirm a trend for OS AXIN1 is a tumor suppressor in mcrc Germline variation in AXIN1 might have a prognostic role Replication in larger datasets and functional studies are ongoing Innocenti F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2007.

34 Final Analysis of the PEAK Trial: Overall Survival and Tumour Responses During First-Line Treatment With mfolfox6 + Either Panitumumab or Bevacizumab in Patients With Metastatic Colorectal Carcinoma Abstract 2014 Rivera F, Karthaus M, Randolph Hecht J, Fasola G, Canon J-L, Guan X, Demonty G, Schwartzberg L

mfolfox6 (n = 82) 13 m vs 10.1 m HR 0.66, P =.03 100 90 80 70 60 50 40 30 20 10 OS Treatment Group +12.

35 Proportion Alive, % Randomized, Phase II PEAK Trial 285 p KRAS Ex2 wt mcrc 1 st line K-NRAS wt: 170 pts FOLFOX- Panitumumab FOLFOX-Bevacizumab RR: Pani 64% vs Beva 60%, P = NS Primary Endpoint PFS Treatment Group Panitumumab + FOLFOX6 (n = 88) Bevacizumab + mfolfox6 (n = 82) 13 m vs 10.1 m HR 0.66, P = OS Treatment Group m Panitumumab + FOLFOX6 (n = 34) Bevacizumab + mfolfox6 (n = 49) 41.3 m vs 28.9 m HR 0.63, P =.05 Schwartzberg LS, et al. J Clin Oncol. 2014;32(21): Months

36 Summary of PFS, OS, and ORR Results RAS WT and RAS WT/BRAF WT Populations PFS Panitumumab + mfolfox6 (n = 88) RAS WT Bevacizumab + mfolfox6 (n = 82) Panitumumab + mfolfox6 (n = 77) RAS WT / BRAF WT Bevacizumab + mfolfox6 (n = 79) Patients with event, n (%) 64 (73) 70 (85) 55 (71) 67 (85) Median, months (95% CI) 12.8 (10.7, 15.1) 10.1 (9.0, 12.7) 13.1 (11.6, 16.2) HR (95% CI); P value 0.68 (0.48, 0.96); (0.42, 0.88);.0075 OS 10.1 (9.0, 12.7) Patients with event, n (%) 57 (65) 58 (71) 48 (62) 55 (70) Median, months (95% CI) 36.9 (27.9, 46.1) 28.9 (23.3, 32.0) 41.3 (31.6, 46.7) 28.9 (23.9, 33.1) HR (95% CI); P value 0.76 (0.53, 1.11); (0.48, 1.04);.08 ORR Responders, n (%) [95% CI] 57 (65) [54, 75] 49 (60) [49, 71] 49 (64) [52, 74] Odds ratio (95% CI); P value 1.12 (0.56, 2.22); (0.58, 2.38); (59) [47, 70] CI, confidence intervals; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression- free survival; WT, wild type Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014.

37 Proportion Event Free, % Proportion Event Free, % PFS RAS WT / BRAF WT Populations Median PFS, (95% CI), months HR (95% CI) P value RAS WT Panitumumab + mfolfox6 (n = 88) 12.8 (10.7, 15.1) 0.68 (0.48, 0.96).029 Bevacizumab + mfolfox6 (n = 82) 10.1 (9.0, 12.7) Median PFS, (95% CI), months 13.1 (11.6, 16.2) HR (95% CI) P value RAS WT / BRAF WT Panitumumab + mfolfox6 (n = 77) 0.61 (0.42, 0.88).0075 Bevacizumab + mfolfox6 (n = 79) 10.1 (9.0, 12.7) 100 Panitumumab + mfolfox6 (n = 88) Bevacizumab + mfolfox6 (n = 82) 100 Panitumumab + mfolfox6 (n = 77) Bevacizumab + mfolfox6 (n = 79) Pmab* Bmab* Months Months CI, confidence intervals; HR, hazard ratio; OS, overall survival; PFS, progression- free survival; WT, wild type. Censor indicated by vertical bar *+ mfolfox6 Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract Pmab* Bmab*

38 Proportion Alive, % Proportion Alive, % OS RAS WT / BRAF WT Populations RAS WT RAS WT / BRAF WT Median OS, (95% CI), months HR (95% CI) P value Panitumumab + mfolfox6 (n = 88) 36.9 (27.9, 46.1) 0.76 (0.53, 1.11).15 Bevacizumab + mfolfox6 (n = 82) 28.9 (23.3, 32.0) Median OS, (95% CI), months HR (95% CI) P value Panitumumab + mfolfox6 (n = 77) 41.3 (31.6, 46.7) 0.70 (0.48, 1.04).08 Bevacizumab + mfolfox6 (n = 79) 28.9 (23.9, 33.1) 100 Panitumumab + mfolfox6 (n = 88) Bevacizumab + mfolfox6 (n = 82) 100 Panitumumab + mfolfox6 (n = 77) Bevacizumab + mfolfox6 (n = 79) Months Months Pmab* Pmab* Bmab* Censor indicated by vertical bar. *+ mfolfox6 Bmab* CI, confidence intervals; HR, hazard ratio; OS, overall survival; PFS, progression- free survival; WT, wild type. Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract *+ mfolfox6

39 Mean Change From Baseline, % Tumor Response-Related Efficacy RAS WT Population Panitumumab + mfolfox6 (n = 88) Bevacizumab + mfolfox6 (n = 82) Median DoR, months (95% CI) 11.4 (10.0, 16.3) 9.0 (7.6, 9.5) HR (95% CI); P value 0.59 (0.39, 0.88); Median TTR, months (95% CI) 2.3 (1.9, 3.7) 3.8 (2.1, 5.7) HR (95% CI); P value 1.19 (0.81, 1.74); 0.37 Median DpR, months (Q1, Q3) 65.0 (45.7, 89.5) 46.3 (29.5, 63.3) P value Mean (95% CI) Percentage Change From Baseline In Tumor Load Over Time Bmab + mfolfox6 Pmab + mfolfox Weeks Pmab + mfolfox Bmab + mfolfox CI, confidence interval; DoR, duration of response; Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract DpR, depth of response; ETS, early tumor shrinkage; HR, hazard ratio; TTR, time to response

Between-Treatment Comparisons of PFS and OS Outcomes by Tumor Shrinkage at Week 8 RAS WT Population Panitumumab + mfolfox6 Tumor Shrinkage at Week 8 <30 30 Bevacizumab + mfolfox6 Panitumumab +

40 Between-Treatment Comparisons of PFS and OS Outcomes by Tumor Shrinkage at Week 8 RAS WT Population Panitumumab + mfolfox6 Tumor Shrinkage at Week 8 <30 30 Bevacizumab + mfolfox6 Panitumumab + mfolfox6 Bevacizumab + mfolfox6 n (%) 29 (36) 41 (55) 51 (64) 33 (45) Odds ratio a, (95% CI) P value 1.99 (0.99, 4.10) Median PFS, months (95% CI) 11.6 (7.5, 15.4) 9.7 (7.5, 12.9) 13.0 (10.9, 18.1) 11.1 (9.0, 16.6) HR (95% CI) P value Median OS, months (95% CI) HR (95% CI) P value 0.79 (0.45, 1.38) (0.45, 1.23) (17.5, 42.3) 23.9 (20.1, 29.0) 43.8 (36.4, 63.0) 35.1 (29.9, NE) 0.75 (0.43, 1.31) (0.42, 1.42) 0.41 CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; WT, wild type a Odds ratio is defined as the odds of having 30% tumor shrinkage in the panitumumab + mfolfox6 arm relative to the odds in the bevacizumab + mfolfox6 arm Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014.

Intra-Treatment Comparisons of PFS and OS Outcomes by Tumor Shrinkage at Week 8 RAS WT Population Tumour Shrinkage at Week 8 <30 30 <30 30 Panitumumab + mfolfox6 Bevacizumab + mfolfox6 n (%) 29 (36)

41 Intra-Treatment Comparisons of PFS and OS Outcomes by Tumor Shrinkage at Week 8 RAS WT Population Tumour Shrinkage at Week 8 <30 30 <30 30 Panitumumab + mfolfox6 Bevacizumab + mfolfox6 n (%) 29 (36) 51 (64) 41 (55) 33 (45) Median PFS, months (95% CI) 11.6 (7.5, 15.4) 13.0 (10.9, 18.1) 9.7 (7.5, 12.9) 11.1 (9.0, 16.6) HR (95% CI) 0.62 (0.35, 1.10) 0.60 (0.36, 1.01) Median OS, months (95% CI) 34.2 (17.5, 42.3) 43.8 (36.4, 63.0) 23.9 (20.1, 29.0) 35.1 (29.9, NE) HR (95% CI) 0.40 (0.22, 0.72) 0.43 (0.24, 0.78) Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014.

42 Conclusions This final analysis of the PEAK trial found a significant improvement in PFS for patients with RAS WT mcrc receiving first-line treatment with panitumumab + mfolfox6 vs bevacizumab + mfolfox6 (HR: 0.68; P =.029) Median OS was numerically longer in the panitumumab vs bevacizumab arm 8.0 months longer in the RAS WT population (36.9 months vs 28.9 months) 12.4 months longer in the RAS WT/BRAF WT population (41.3 months vs 28.9 months) ORR was similar between treatments, but tumor responses with panitumumab occurred earlier, lasted longer, and were deeper vs bevacizumab Based on PEAK, panitumumab + mfolfox6 is an effective first-line treatment for patients with RAS WT mcrc HR, hazard ratio; mcrc, metastatic colorectal cancer; OS, overall survival; WT, wild type Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014.

43 Maintenance Therapy for mcrc

44 Maintenance Treatment With Capecitabine and Bevacizumab in Metastatic Colorectal Cancer (CAIRO3): A Phase 3 Randomised Controlled Trial of the Dutch Colorectal Cancer Group Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M

45 CAIRO3 Study Design PFS1 PFS2 Observation SD or better after 6 cycles CAPOX-B R PD Reintroduction CAPOX-B PD Stratification factors: Prior adjuvant therapy, serum LDH, response to induction treatment, WHO PS, institution Primary endpoint: PFS2 Capecitabine + bevacizumab PFS2 is considered to be equal to PFS1 for patients in whom CAPOX-B is not reintroduced after PFS1 for any reason LDH, lactate dehydrogenase; PD, progressive disease; PFS, progression-free survival; SD, stable disease; WHO PS, World Health Organization performance score Simkens LH, et al. Lancet. 2015;385(9980):

46 CAIRO3 Study Profile 558 patients enrolled 279 patients observation 279 patients maintenance Patients 168 (60%) Re-introduction of CAPOX-B Patients 111 (40%) - 7 ongoing obs no treatment - 73 other treatment Patients 132 (47%) Re-introduction CAPOX-B Patients 147 (53%) - 13 ongoing maint no treatment - 88 other treatment - (1 IC withdrawn) Simkens LH, et al. Lancet. 2015;385(9980):

47 PFS2 Probability Primary Endpoint PFS Median PFS2 Observation 8.5 m [95% CI: ] Maintenance (CAP-B) 11.7 m [95% CI: ] Stratified HR 0.67 [95% CI: ] P value <.0001 Adjusted HR 0.64 [95% CI: ] 0.4 Induction treatment of 6x cycles CAPOX-B prior to randomization not included (4-5 m) 0.2 CAP-B PFS2 = PFS1 for patients in whom CAPOX-B is not reintroduced after PFS 1 for any reason Observation Time, months Observation CAP-B Simkens LH, et al. Lancet. 2015;385(9980):

48 Mean QoL Score CAIRO3 Quality of Life During Maintenance/Observation Between-group difference: 3.9 (95% CI 1.2; 6.5) P =.004 (not clinically relevant, <10) Observation Maintenance Observation Maintenance Simkens LH, et al. Lancet. 2015;385(9980):

49 Grade 3/4 Adverse Events Observation (N = 279) Maintenance (N = 278) P value Grade 3 Grade 4 Grade 3/4 Grade 3 Grade Any grade 3/ (34%) Clinical adverse event 4 Grade Hypertension 49 (18%) (24%) 0 -- Hand-foot skin reaction 3/4 167 (60%) < (23%) 0 -- <.0001 Sensory neuropathy 13 (5%) 1 (<1%) (10%) Laboratory abnormalities Hyperbilirubinemia 0 1 (<1%) (5%) Simkens LH, et al. Lancet. 2015; 385(9980):

50 Maintenance Strategies After First-Line Oxaliplatin Plus Fluoropyrimidine Plus Bevacizumab for Patients With Metastatic Colorectal Cancer (AIO 0207): A Randomised, Non-Inferiority, Open-Label, Phase 3 Trial Hegewisch-Becker S, Graeven U, Lerchenmüller CA, Killing B, Depenbusch R, Steffens CC, Al-Batran SE, Lange T, Dietrich G, Stoehlmacher J, Tannapfel A, Reinacher-Schick A, Quidde J, Trarbach T, Hinke A, Schmoll HJ, Arnold D

51 AIO 0207: Study Design Induction: 24 wks Re-Induction FP* + Bev + Oxaliplatin With CR/PR/SD R FP* + Bev Bev No treatment 1 st progression Any FP* +/- Bev +/- Ox 2 nd progression Stratification Adjuvant tx CR/PR vs SD ECOG PS baseline PFS 1 *FP = any fluoropyrimidine in a standard protocol (eg, mfolfox6, FOLFOX4, Cape/Ox, LV5FU2, Cape 2 x 1000) Bev used in standard doses (5 mg/kg q 2 wks or 7.5 mg/kg q 3 wks arm A; 7.5 mg/kg 3q 3 wks arm B) Hegewisch-Becker S, et al. Lancet Oncol Sep 8. [Epub ahead of print]

52 Induction: 24 wks AIO 0207: Study Design Maintenance: non-pd Re-Induction FP* + Bev + Oxaliplatin With CR/PR/SD R FP* + Bev Bev No treatment Other drugs/2 nd line Or no further treatment Stratification Adjuvant tx CR/PR vs SD ECOG PS baseline PFS 1 TFS *FP = any fluoropyrimidine in a standard protocol (eg, mfolfox6, FOLFOX4, Cape/Ox, LV5FU2, Cape 2 x 1000) Bev used in standard doses (5 mg/kg q 2 wks or 7.5 mg/kg q 3 wks arm A; 7.5 mg/kg 3q 3 wks arm B) Hegewisch-Becker S, et al. Lancet Oncol Sep 8. [Epub ahead of print]

53 852 assessed for eligibility AIO 0207 Trial Profile 837 eligible 825 started induction 472 randomized and eligible 12 major protocol violations N = 353 (42%) not randomized Progression 128 (36%) Mets resection 44 (12%) Unacceptable toxicity 52 (15%) SAE 54 (15%) Patient s wish 51 (14%) Investigator decision 33 (9%) Death 29 (8%) 158 FP/Bev 156 Bev mono 158 no Tx * More than one reason could be registered Accrual: Sept 2009-Feb 2013 This data set: Median duration of follow-up: 17.0 months SAE, serious adverse event Hegewisch-Becker S, et al. Lancet Oncol Sep 8. [Epub ahead of print]

Time to Failure Of Strategy, % AIO 0207: Time to Treatment Failure 100 Events Median (95% CI) Fluoropyrimidine plus bevacizumab 129 6.9 mo (6.1-8.5) 80 Bevacizumab alone 145 6.1 mo (5.3-7.

54 Time to Failure Of Strategy, % AIO 0207: Time to Treatment Failure 100 Events Median (95% CI) Fluoropyrimidine plus bevacizumab mo ( ) 80 Bevacizumab alone mo ( ) No treatment mo ( ) 60 Log-rank P test: No. at Risk Follow-Up Time, Months FU plus Bev Bev alone No Treatment Hegewisch-Becker S, et al. Lancet Oncol Sep 8. [Epub ahead of print] 42 45

55 Time to Failure Of Strategy, % AIO 0207: Progression-Free Survival 100 Events Median (95% CI) Fluoropyrimidine plus bevacizumab mo ( ) 80 Bevacizumab alone mo ( ) No treatment mo ( ) No. at Risk Follow-Up Time, months FU plus Bev Bev alone No Treatment Hegewisch-Becker S, et al. Lancet Oncol Sep 8. [Epub ahead of print] 42 45

56 AIO 0207: Need for Reinduction 170 (36%) underwent reinduction after maintenance Fluoropyrimidine + Bev: 30 (19%) Bev alone: 67 (43%) No maintenance: 73 (46%) OS did not differ significantly between groups Hegewisch-Becker S, et al. Lancet Oncol Sep 8. [Epub ahead of print]

57 Conclusions First-line and maintenance options have expanded considerably, necessitating greater insight into treatment selection Selection of targeted therapy should be guided by molecular analysis and other disease characteristics Active targeted therapy-based maintenance can reduce risk of progression Consider other first-line options

Κίκα Πλοιαρχοπούλου. Παθολόγος Ογκολόγος Ευρωκλινική Αθηνών

Κίκα Πλοιαρχοπούλου. Παθολόγος Ογκολόγος Ευρωκλινική Αθηνών Κίκα Πλοιαρχοπούλου Παθολόγος Ογκολόγος Ευρωκλινική Αθηνών Time (months) Survival outcomes in mcrc have progressively improved over the past two decades Treatment options for many patients Multidisciplinary