Analysis of KRAS/NRAS and BRAF mutations in FIRE-3

Transcription

1 Analysis of KRAS/NRAS and BRAF mutations in FIRE-3 A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type KRAS (exon 2) metastatic colorectal cancer patients S. Stintzing, A. Jung, L. Rossius, D.P. Modest, L. Fischer von Weikersthal, T. Decker, M. Möhler, W. Scheithauer, T. Kirchner, V. Heinemann

2 Disclosures Research funding / advisory boards Merck KGaA Roche Amgen Sanofi-Aventis

3 FIRE-3 study design mcrc 1st-line therapy KRAS wild-type Randomize 1:1 FOLFIRI + Cetuximab Cetuximab: 400 mg/m 2 i.v. 120min initial dose 250 mg/m 2 i.v. 60min q 1w FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v min q 2w FOLFIRI q2w: 5-FU: 400 mg/m 2 (i.v. bolus); folinic acid: 400mg/m 2 irinotecan: 180 mg/m 2 5-FU: 2,400 mg/m 2 (i.v. 46h) Primary endpoint: Overall response rate (RECIST 1.0) Amendment in October 2008 to include only KRAS wild-type patients 150 active centers in Germany and Austria

4 FIRE-3 study results Overall survival months 25.0 months Cetuximab + CT (FOLFIRI) (n=297) Bevacizumab + CT (FOLFIRI) (n=295) OS estimate 0.50 Δ = 3.7 months 0.25 HR=0.77 p= Months since start of treatment Cetuximab + CT Bevacizumab + CT p value Overall response rate (primary endpoint not met) 62% 58% Progression-free survival 10.0 months 10.3 months Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)

5 Distribution of mutations in mcrc Rare KRAS Mutations NRAS Mutations New RAS mt ~10% KRAS mt ~40% RAS wt ~50%

6 KRAS WT exon 2 subset KRAS EXON 1 EXON 2 EXON 3 EXON wt ?? NRAS EXON 1 EXON 2 EXON 3 EXON ??? BRAF EXON 11 EXON ??

7 Tumor samples N= 637 tumor samples KRAS exon 2 WT n=592 (100%) N= 488 (82.4%) tumor material available of KRAS wild-type ITT not KRAS wild-type ITT: 115 redundant tumor samples: 14 no tumor on block: 20 successful mutational analysis: KRAS 61: 431 KRAS 146: 458 NRAS exon 2: 464 NRAS exon 3: 468 N= 407 (69%) RAS mutational analyses successful in all RAS locations

8 Tested Mutations KRAS exon 2 wild-type subset KRAS EXON 1 EXON 2 EXON 3 EXON wt % 4.9% NRAS EXON 1 EXON 2 EXON 3 EXON % 2% 0% BRAF EXON 11 EXON % 10%

9 Consort Diagram N=752 mcrc 1st-line unselected patients KRAS unknown= 30 No treatment= 13 No treatment KRAS mt = 4 N=592 KRAS exon 2 wild-type ITT population N=113 KRAS exon 2 mutant population* N=407 (69%) RAS evaluable population N=342 RAS wild-type N=65 (16%) New RAS mutant N=58 FOLFIRI + Cetuximab N=55 FOLFIRI + Bevacizumab N= 171 FOLFIRI + Cetuximab N= 171 FOLFIRI + Bevacizumab N= 34 FOLFIRI Cetuximab N= 31 FOLFIRI + Bevacizumab *Updated analysis from Stintzing S, et al. Ann Oncol 2012;23:

10 Comparability of Evaluated Groups Baseline Parameters of Patients Characteristic ITT, KRAS wt exon 2 population N=592 RAS evaluable population N= 407 Sex, male, % Age, median, years Age < 65, % Age 65, % Age > 70, % ECOG Performance Status, % , Leukocyte count 8,000/µl, % Alkaline Phosphatase 300 U/L, %

11 Comparability of Evaluated Groups Tumor-Related Characteristics Characteristic Site of primary tumor Colon Rectum Colon + Rectum ITT, KRAS wt exon 2 population N= RAS evaluable population N= Liver metastasis only Yes Prior treatment Surgery Adjuvant chemotherapy Radiotherapy pretreatment Number of metastatic sites 1 site 2 sites

12 Comparability of Evaluated Groups Response Parameters ITT, KRAS wt exon 2 population N=592 RAS evaluable population N= 407 FOLFIRI Cetuximab N= 297 FOLFIRI Bevacizumab N= 295 FOLFIRI Cetuximab N= 205 FOLFIRI Bevacizumab N= 202 ORR 62% 58% 61% 59.4% Progression-free survival (median, months) Overall survival (median, months)

13 2nd-line treatment: RAS evaluable population (N=407) Alive after 1st-line therapy Any 2nd-line therapy FOLFIRI + Cetuximab N= % (174/205) 78.7% (137/174) FOLFIRI + Bevacizumab N= % (169/202) 76.9% (130/169) 2nd-line substances, % n=137 (100) n=130 (100) Fluoropyrimidine % Oxaliplatin % Irinotecan % Bevacizumab % Anti-EGFR mab % Treatment with a substance not being part of 1st-line therapy

14 Evaluation of ORR FOLFIRI + Cetuximab FOLFIRI + Bevacizumab ORR % 95%-CI % 95%-CI Odds ratio p KRAS exon 2 WT ITT population (N= 592) * RAS WT (N= 342) ** RAS MT (N= 65) ** KRAS exon 2 MT and RAS MT (N= 178) ** p = *one-sided Fisher s exact test ** two-sided Fisher s exact test

15 Evaluation of PFS FOLFIRI + Cetuximab FOLFIRI + Bevacizumab PFS months 95%-CI months 95%-CI Hazard ratio p KRAS exon 2 WT ITT population (N= 592) ( ) RAS WT (N= 342) ( ) 0.54 RAS MT (N= 65) ( ) KRAS exon 2 MT and RAS MT (N= 178) ( ) p = log-rank test

16 Progression-free survival RAS* wild-type Probability of survival Events n/n (%) FOLFIRI + Cetuximab 144/171 (84.2%) FOLFIRI + Bevacizumab 143/171 (83.6%) Median (months) 95% CI HR 0.93 (95% CI: ) p (log-rank)= 0.54 No. at risk months since start of treatment * KRAS and NRAS exon 2, 3 and 4 wild-type

17 Evaluation of OS FOLFIRI + Cetuximab FOLFIRI + Bevacizumab PFS months 95%-CI months 95%-CI Hazard ratio p KRAS exon 2 WT ITT population (N= 592) ( ) RAS WT (N= 342) ( ) RAS MT (N= 65) ( ) 0.57 KRAS exon 2 MT and RAS MT (N= 178) ( ) 0.60 p = log-rank test

18 Overall survival RAS* wild-type Probability of survival Events n/n (%) FOLFIRI + Cetuximab 91/171 (53.2%) FOLFIRI + Bevacizumab 110/171 (64.3%) Median (months) 95% CI HR 0.70 (95% CI: ) p (log-rank)= Δ = 7.5 months No. at risk months since start of treatment * KRAS and NRAS exon 2, 3 and 4 wild-type

19 Summary FIRE-3 is the first study to compare cetuximab plus FOLFIRI to bevacizumab plus FOLFIRI in 1 st -line treatment of mcrc The RAS evaluable population was in all respects comparable to the ITT population In patients with all-ras wild-type tumors ORR and PFS were not significantly different between treatment arms OS was markedly superior (Δ = 7.5 months, HR 0.70) in all- RAS wild-type patients receiving 1 st -line therapy with cetuximab No benefit was observed when patients with RAS-mutant tumors were treated with FOLFIRI plus cetuximab as compared to FOLFIRI plus bevacizumab

20 Conclusions Upfront determination of RAS (KRAS and NRAS) mutation status appears highly recommendable in patients with metastatic disease Patients with all-ras wild-type tumors have a clinically relevant survival benefit when first-line treatment with cetuximab is offered

21 Acknowledgement Patients and their families FIRE-3 study investigators Germany: Fischer von Weikersthal, Decker, Jäger, Al-Batran, Vehling-Kaiser, Heintges, Kiani, Lerchenmüller, Kahl, Kullmann, Seipelt, Stauch, Müller (Ansbach), Hielscher, Scholz, Niederle, Schäfer, Lindig, Möhler, Höffkes, Rost, Reeb, Geißler, Denzlinger, Kubin, Maschmeyer, Burckhard, Knorrenschild, Ketzler, Schmits, Siebler, Schepp, Schneider, Harich, Bohle, Mergenthaler, Eggers, Puchtler, Uhlig, Römmele, Schmidt (München), Raßmann, Engel, Zimber, Link, Gehbauer, Lerch, Hebart, Königsmann, Kiehl, Kempf, Wolff, Fleck, Meiler, Schwittay, Herrmann, Schlimock, Spes, Bair, Pihusch, Stötzer/Salat, Lambertz, Müller (Osnabrück), Schwella, Michl, Breunig, Schlag, Behringer, Demandt, Gassmann, Schneider-Kappus, Quitzsch, Weiß, Siveke, Respondek, Sölling, Prügl, Haberl, Schulze, Feder, Schmidt (Bochum), Peuser, Schulz-Abelius, Walther, Fauth, Dürk, Hagen, Truckenbrodt, Constantin, Slawik, Hitz, von Wichert, Koch, Abele, Horndasch, Schanz, Hoffmann (Ludwigshafen), Holtmann, Hoffmann (Weimar), Fries, Erhardt, Luhn, Pfeiffer, Porschen, Rummel, Perker, Mittermüller, Matzdorff, Kappauf, Greif, Pohl, Post, Pistorius, Buschmann, Holtkamp, Zöller, Hartnack, Kreibich, Winkelmann, Jakobs, Müller (Leer), Cordes, Weber, Fischinger, von Schilling, Losem, Kindler, Hegewisch-Becker, Abendhardt Austria: Scheithauer, Samonig, Dittrich, Ziebermayr, Andel, Thaler, Ludwig, Ulrich-Pur