KRAS G13D mutation testing and anti-egfr therapy

KRAS G13D mutation testing and anti-egfr therapy

KRAS G13D mutation and anti-egfr therapy Current data do not support a need to specifically identify this mutation for assessing anti-egfr eligibility in mcrc Anti-EGFR treatment should not be used in patients with the KRAS G13D mutation Clinical data on the response of patients with G13D mutations to anti-egfr treatment are insufficient to change treatment practice Preclinical data should not be used to draw clinical conclusions Product labeling and guidelines continue to recommend anti- EGFR treatment only in patients with wild-type KRAS Data are limited, retrospective and conflicting Largest dataset: no consistent association of G13D and treatment benefit of panitumumab No statistically significant benefit in adding cetuximab in patients with G13D mcrc Other data refute the suggestion that G13D does respond to cetuximab mcrc, metastatic colorectal cancer Activating EGFR mutation (G719S) present in SW48 cell line used in De Roock et al (2010) paper Unknown how this affects sensitivity to cetuximab February 27, 2013 page 2 2012 Roche Taking recent data into account, latest NCCN guidelines support current labeling for use of panitumumab or cetuximab only in wild-type KRAS mcrc No changes have been made to the labeling of cetuximab or panitumumab: use only in wild-type KRAS mcrc

Should it affect eligibility for treatment with cetuximab or panitumumab in mcrc? 35 45% KRAS mutation 1 Codon Distribution (%) 12 79 13 19 61 1 Other 1 According to COSMIC (v54) 2 Wild-type KRAS KRAS mutation in codons 12, 13 or 61 No mutation identified Mutation identified Eligible for cetuximab or panitumumab Ineligible for cetuximab or panitumumab G13D: most frequent codon 13 mutation 2 Limited recent evidence that patients with G13D mutation do respond to anti-egfr agents in mcrc 3 4 should they be used in these patients? February 27, 2013 page 3 2012 Roche 1 Cunningham, D., et al. Lancet 2010;375:1030 1047; 2 COSMIC database (v54), http://sanger.ac.uk; 3 Tejpar, S., et al. J Clin Oncol 2012; epub; 4 De Roock, W., et al. JAMA 2010;304:1812 1820.

Data comparing outcomes of anti-egfr treatment in G13D vs other KRAS mutations are retrospective, limited and conflicting Study Peeters, M., et al. ASCO 2012, Abstract 383. Tejpar, S., et al. J Clin Oncol 2012; epub. De Roock, W., et al. JAMA 2010; 304:1812 1820. Gajate, P., et al. Clin Colorectal Cancer 2012; epub. Modest, D.P., et al. Int J Cancer 2012;131:980 986. Ulivi, P., et al. J Transl Med 2012;10:87. Retrospective analysis? Pooled data? WT KRAS (n) Other KRAS mutations (n) (3 trials of panitumumab) (CRYSTAL and OPUS trials; cetuximab) (7 trials or off-study treatment; cetuximab) (Case series; cetuximab) (AOI KRK-0104 trial; cetuximab) (Case series; cetuximab) *KRAS codon 12 mutations; () apparent benefit but not statistically significant vs no cetuximab February 27, 2013 page 4 2012 Roche KRAS G13D (n) 1496 898 213 845 450 83 () 464 265 45 () 58 40 12 79 41* 9 67 14 4 Consistent benefit of anti-egfr in G13D?

Largest dataset: no consistent association of G13D mutation and treatment benefit with panitumumab in mcrc 5 Panitumumab + FOLFOX: 1st-line mcrc Panitumumab + FOLFIRI: 2nd-line mcrc Panitumumab monotherapy: chemorefractory mcrc G13D significantly OS G12V significantly OS Similar response rates in patients with G13D and G12V KRAS mutation Pooled analysis of all 3 studies: Only G12A was a significant negative predictive factor for OS No single mutant KRAS allele was a consistent positive or negative predictive factor for PFS or OS in panitumumab-treated patients OS, overall survival; PFS, progression-free survival 5 Peeters, M., et al. ASCO 2012, Abstract 383. February 27, 2013 page 5 2012 Roche

No statistically significant benefit in favour of adding cetuximab vs chemotherapy alone in first-line treatment of KRAS G13D mcrc 3 Impact of KRAS mutation on overall survival Study Pooled analysis CRYSTAL OPUS KRAS mutation status WT (n=83) G13D (n=83) G12V (n=125) Other (n=325) WT (n=666) G13D (n=60) G12V (n=91) Other (n=246) WT (n=179) G13D (n=23) G12V (n=34) Other (n=79) Favors chemotherapy + cetuximab 0,1 1 5 Adjusted HR (95% CI) Favors chemotherapy Data from preplanned prospective randomized clinical trials are required before such findings should be considered in clinical decision making HR, hazard ratio; CI, confidence interval 3 Tejpar, S., et al. J Clin Oncol 2012;June 25, epub ahead of print. February 27, 2013 page 6 2012 Roche

No statistically significant benefit in favour of cetuximab vs no cetuximab in patients with CT-refractory KRAS G13D mcrc 4 Any cetuximab vs no cetuximab Cetuximab monotherapy vs no cetuximab Impact of KRAS mutation on overall and progression-free survival KRAS subset Overall survival Progression-free survival Overall survival Progression-free survival KRAS mutation status WT G13D Other WT G13D Other WT G13D Other WT G13D Other Favors cetuximab 0,1 1 Adjusted HR (95% CI) G13D vs WT KRAS p=0.06 p=0.79 p=0.15 p=0.36 Prospective randomized trials are needed before conclusions about potential beneficial effects of cetuximab in G13D-mutated chemotherapy-refractory mcrc should be inferred 5 G13D vs other KRAS mutations p=0.003 p=0.05 p=0.13 p=0.07 Favors no cetuximab CT, chemotherapy February 27, 2013 page 7 2012 Roche 4 De Roock, W., et al, JAMA 2010;304:1812 1820.

Other data refute the suggestion that G13D does respond to cetuximab Gajate et al 5 Misale et al 6 Summary Results Evaluated the influence of G13D mutant in patients treated with cetuximab before the role of KRAS was established After treatment with cetuximab, patients with G13D mutated tumors did not experience significantly better outcomes vs other KRAS mutations: PFS HR 0.88 (95% CI 0.44 1.75), p=0.72 OS HR 0.50 (95% CI 0.23 1.09), p=0.084 Treatment with cetuximab was associated with a longer PFS and OS in patients with wild-type KRAS compared with G13D Looked at acquired resistance to cetuximab and panitumumab in cell line models and some CRC patients Analyses of metastases from 11 patients who developed resistance to cetuximab or panitumumab identified development of G13D as the most frequently acquired mutation: G13D in 4 patients G12D/G13D in 1 patient Q61H in 1 patient Remaining 4 patients had wild-type KRAS Conclusion These results support the current clinical practice These results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in CRC February 27, 2013 page 8 2012 Roche 5 Gajate, P., et al. Clin Colorectal Cancer 2012; epub; 6 Misale, S., et al. Nature 2012;486:532 536.

Preclinical data should not be used to draw clinical conclusions Human colorectal SW48 cells 4 KRAS G12V mutated KRAS G13D mutated Growth unaffected by cetuximab Growth inhibited by cetuximab BUT: Activating EGFR mutation (G719S) present in SW48 cell line Unknown how this combination affects sensitivity to cetuximab No conclusions should be drawn regarding potential clinical consequences 4 De Roock, W., et al, JAMA 2010;304:1812 1820. February 27, 2013 page 9 2012 Roche

Latest NCCN guidelines support current labeling for use of panitumumab or cetuximab only in wild type KRAS mcrc 7 February 27, 2013 page 10 2012 Roche 7 National Comprehensive Cancer Network Guidelines Version 3.2012 Colon Cancer. Available at www.nccn.org, accessed August 2012..

Updated guidelines from the Spanish Society of Pathology also recommend anti-egfr therapy in patients with wild type KRAS only 8 February 27, 2013 page 11 2012 Roche 8 García-Alfonso, P., et al. Clin Transl Oncol; Epub ahead of print June 27, 2012.

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