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Riccardo Giampieri Scuola di Specializzazione Oncologia Università Politecnica delle Marche Ancona How to manage patients with mutated KRAS tumors.

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Presentation on theme: "Riccardo Giampieri Scuola di Specializzazione Oncologia Università Politecnica delle Marche Ancona How to manage patients with mutated KRAS tumors."— Presentation transcript:

1 Riccardo Giampieri Scuola di Specializzazione Oncologia Università Politecnica delle Marche Ancona How to manage patients with mutated KRAS tumors

2 Hot-spot point mutations within codons 12 or 13 of the KRAS gene  constitutively active KRAS protein Constitutively active KRAS protein  cancer cell growth and survival through the RAF-MEK-ERK and PI3K-AKT pathways independently from EGFR signaling K-ras mutation

3 A controversial starting point… Patient harbouring K-ras mutated tumors: Easy patient! Difficult patient! ?

4 Why easy patient? -We know what DO NOT give to this patient -We know what CAN be given to this patient -Treatment sequence is almost always set without difficulties

5 What DO NOT give: preclinical data -Anti-EGFR monoclonal antibodies + DiFi colon cancer cell lines + k-ras mutation or not Benvenuti et al. Cancer Res 2007

6 Moroni Lancet Oncol 2005 n=31 Lièvre Clin Cancer Res 2006 n=30 Di Fiore Br J Cancer 2007 n=59 Frattini Br J Cancer 2007 n=27 Benvenuti Cancer Res 2007 n=48 Khambata-Ford J Clin Oncol 2007 n=80 De Roock ASCO Proc 2007 n=37 Finocchiaro ASCO Proc 2007 n=81 Response rate: analysis of 8 studies available in PubMed or from ASCO Proceedings: Responders (n=82) wt (93.0%) RAS mutated (7.0%) wt (56.1%) RAS mutated (43.9%) Non-Responders (n=312) p = 0.000000635 (Fisher’s exact test) Pre-treated patients and response rate differencies

7 FOLFOX FOLFOX+Cetuximab 168 pts 169 pts RR (%) 36 46 p=0.06 Kras status PFS (mo.) RR (%) C+Ffox Ffox C+Ffox Ffox Wt 7.7 7.1 61 37 Mutated 5.5 8.6 33 49 Bokemeyer C, ASCO 2008 First line: OPUS trial (randomized phase II) Bokemeyer C. ASCO 2008, J Clin Oncol 2009; 27(5)

8 OPUS trial k-ras mutant population: response rates FOLFOX N=47 ERBITUX + FOLFOX N=52 CR4.3%0% PR44.7%32.7% SD36.2%51.9% PD10.6%13.5% NE4.3%1.9% RR48.9%32.7% 95% CI (exact) [34.1%, 63.9%] [20.3%, 47.1%] ERBITUX + FOLFOX FOLFOX 49 33 p=0.106 Odds Ratio = 0.507 (95% CI: 0.223 –1.150) 0 10 20 30 40 50 60 Response rate (%) No benefit for Erbitux p = 0.106

9 Stratification by: –Region –ECOG PS FOLFIRI Irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus + 2400 mg/m 2 as 46-h continuous infusion) + LV (every 2 weeks) Cetuximab + FOLFIRI Cetuximab (IV 400 mg/m 2 on day 1, then 250 mg/m 2 weekly) + irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus + 2400 mg/m 2 as 46-h continuous infusion) + LV (every 2 weeks) R EGFR-detectable mCRC Primary endpoint –Progression-free survival time (as assessed by blinded independent review) Secondary endpoints –ORR (independent review) –OS –Quality of life (EORTC QLQ-C30) –Safety First line: CRYSTAL trial (phase III)

10 17.7 17.5 [14.4–20.6] [15.6–20.2] 1.03 [0.74–1.44] 0.85 KRAS wild-type FOLFIRI (n=176) Cetuximab + FOLFIRI (n=172) FOLFIRI (n=87) Cetuximab + FOLFIRI (n=105) KRAS mutant Parameter Median OS [95% CI] Hazard ratio [95% CI] P-value ITT FOLFIRI (n=599) Cetuximab + FOLFIRI (n=599) 18.6 19.9 [16.6–19.8] [18.5–21.3] 0.93 [0.81–1.07] 0.30 Median follow up time: 30 months 21.0 24.9 [19.2–25.7] [22.2–27.8] 0.84 [0.64–1.11] 0.22 Overall survival analysis based on K-ras status

11 Overall survival analysis based on K-ras status

12 Continuous* XELOX or FOLFOX Arm A R First-line mCRC (n= 2,445) Arm B Continuous XELOX or FOLFOX + cetuximab Arm C Intermittent ‡ XELOX or FOLFOX *Treatment until disease progression or unacceptable toxicity ‡ Stop and Go treatment (12 weeks then restart at progression) MRC Sponsored study supported by Merck 109 UK and Irish Hospitals 65% XELOX; 35% FOLFOX (patient/physician choice) Maughan, et al. ESMO 2009 First line: COIN trial (phase III)

13 Maughan, et al. ESMO 2009 COIN trial: response rates based on K-ras status All patientsKRAS wild-typeKRAS mutant FOLFOX /XELOX (n=815) Cetuximab + FOLFOX /XELOX (n=815) FOLFOX /XELOX (n=367) Cetuximab + FOLFOX /XELOX (n=362) FOLFOX /XELOX (n=268) Cetuximab + FOLFOX /XELOX (n=297) ORR at 12 weeks (%)454950594140 Odds ratio1.17 (p=0.124)1.44 (p=0.015)0.97 (p=0.877) Best overall response (%) 515357644643 Odds ratio1.08 (p=0.428)OR=1.35 (p=0.049)OR=0.88 (p=0.449)

14 The 045 Phase I: Study Design FOLFIRI: irinotecan 180 mg/m 2 over 30–90 min; FA 400 mg/m 2 over 2 hours; 5-fluorouracil 200 mg/m 2 as bolus and 2400 mg/m 2 over 46 hours given every 2 weeks CONTROL ARM (GROUP A) 10-patient cohort ERBITUX (400 mg/m 2 on day 1, then 250 mg/m 2 weekly) EXPERIMENTAL ARM (GROUP B) 10-patient cohorts ERBITUX at escalating doses for successive cohorts: 400, 500, 600, 700 mg/m 2 once every second week 6 weeks’ treatment Complete PK profile obtained during this period FOLFIRI added to patients’ current ERBITUX regimen Evaluate best overall response Progression-free survival PART I PART II 1º endpoint DLT assessment 2º endpoints Tabernero et al. ASCO GI 2008 (Abstract No. 435) Study AIO 045 Maybe it is dose related…

15 KRAS status MonotherapyCombination therapy Wild-type n=29 Mutation n=19 Wild-type n=29 Mutation n=19 RR, n (%) [95% CI] 8 (27.6) [12.7–47.2] 0 (0) [0–17.7] 16 (55.2) [35.7–73.6] 6 (31.6) [12.6–56.6] p=0.015p=0.144 Median PFS, months [95% CI] —— 9.4 [7.0–11.3] 5.6 [3.3–12.2] HR: 0.47, p=0.0475 KRAS mutations were detected in 19 samples (40%) of KRAS evaluable population Tabernero J, et al. ASCO GI 2008 (Abstract No. 435) … Of course not

16 Panitumumab anyone?

17 KRAS wild-type Amado et al. J Clin Oncol 2008;26 Panitumumab single agent Amado RG, et al. J Clin Oncol 2008;26:1626-34

18 181 Trial (PFS) (2°line FOLFIRI+/-panitumumab) Peeters et al. J Clin Oncol 2010

19 181 Trial (OS) Peeters et al. J Clin Oncol 2010

20 PRIME trial (PFS) (1°line FOLFOX+/-Panitumumab) Douillard et al. J Clin Oncol 2010

21 PRIME trial (OS) Douillard et al. J Clin Oncol 2010

22 So, we can’t give THAT… But WHAT can we give?

23 Bevacizumab: IFL+/- Bevacizumab and K-ras status (PFS) Hurwitz et al. The Oncologist 2009 0.0 0.2 0.4 0.6 0.8 1.0 0510152025 Duration of PFS (Months) Proportion Progression-Free 0.0 0.2 0.4 0.6 0.8 1.0 0510152025 Duration of PFS (Months) Proportion Progression-Free Group: Mutant (n = 78)Group: Wild-type (n = 152) Median PFS (mo) IFL + placebo 5.5 IFL + BV 9.3 Median PFS (mo) IFL + placebo 7.4 IFL + BV 13.5 HR :0.44; P <.0001HR: 0.41; P =.0008

24 Bevacizumab: IFL+/- Bevacizumab and K-ras status (OS) Hurwitz et al. The Oncologist 2009 0.0 0.2 0.4 0.6 0.8 1.0 051015202530 Duration of Survival (Months) Proportion Surviving Group: Mutant (n = 78)Group: Wild-type (n = 152) 0.0 0.2 0.4 0.6 0.8 1.0 051015202530 Duration of Survival (Months) Proportion Surviving Median OS (mo) IFL + placebo 13.6 IFL + BV 19.9 Median OS (mo) IFL + placebo 17.6 IFL + BV 27.7 HR: 0.58; P =.04HR: 0.69; P =.26

25 Primary endpoint –6-month PFS Secondary endpoints –OS, PFS, toxicity, secondary resection of liver or lung metastases Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD) R = randomisation; WT = wild-type; MT = mutant Bevacizumab + CAPIRI (n=120) [KRAS WT=44; KRAS MT=21] Bevacizumab + CAPOX (n=127) [KRAS WT=56; KRAS MT=21] Previously untreated mCRC (n=247) R AIO 0604 study: design of the trial

26 Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD) AIO 0604 study: CAPIRI arm

27 Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD) AIO 0604 study: CAPOX arm

28 Masi, et al. Lancet Oncology 2010 Avastin 5 mg/kg Irinotecan 165 mg/m 2 Oxaliplatin 85 mg/m 2 L-LV 200 mg/m 2 5-FU continuous infusion 3200 mg/m 2 Day 1Days 2–3 Cycles repeated every 2 weeks for 12 cycles followed by maintenance Avastin until PD FOIB study: design

29 K-ras a B-raf b WT (n=34) MT (n=21) WT (n=45) MT (n=10) Responders, n (%)28 (82)15 (71)34 (75)9 (90) Non-responders, n (%) 6 (18)6 (29)11 (25)1 (10) a Responders vs non-responders: p=0.503 (Fischer’s exact test) b Responders vs non-responders: p=0.430(Fischer’s exact test) Masi et al. Lancet Oncology 2010 FOIB study: retrospective analysis on K-ras status, RR

30 Masi et al. Lancet Oncology 2010 Time (months) 100 75 50 25 0 Progression-free (%) 0102030 K-ras WT: median PFS: 13.4 months K-ras MT: median PFS: 12.6 months Log-rank test: p=0.433 HR=0.78 95% CI: 0.38–1.51 FOIB study: retrospective analysis on K-ras status, PFS

31 Possible 1°line therapeutic options –Bevacizumab+FOLFOX (XELOX) –Bevacizumab+FOLFIRI (XELIRI) –FOLFOXIRI To sum up…

32 So… Where is the “Difficult” part?

33 Starting in a “knee-deep in trouble” situation… K-ras is not only a PREDICTIVE factor… It is also a PROGNOSTIC factor Of a WORSE prognosis

34 K-ras prognostic: RASCAL

35 CRYSTAL study OS: K-ras also prognostic?

36 K-ras mutated: a name fits all? 7 more frequent mutations >98% Rare mutations 2% The only mutation with prognostic value? RASCAL II Br J Cancer 2001

37 The G13D case: someone begs to differ…

38 So… not every Kras mutated tumor doesn’t respond to anti-EGFR…?

39 NORDIC VII: trial design

40 NORDIC VII: PFS according to K-ras status

41 NORDIC VII: OS according K-ras status

42 Cetuximab + FOLFIRI Cetuximab + FOLFOX4 Cetuximab + FOLFIRI Cetuximab + OxFp Cetuximab + FOLFOX 6 or FOLFIRI Cetuximab + FOLFIRI Cetuximab + FOLFOX 6 Cetuximab + capecitabine Cetuximab (continuous) + FLOX Cetuximab + capecitabine + oxaliplatin + bevacizumab 2009 20082009 2008 200920102009 Difference (wt-mt) Response Rate NORDIC VII: Comparison with other studies (OS)

43 Cetuximab + FOLFIRI Cetuximab + FOLFOX4 Cetuximab + FOLFIRI Cetuximab + OxFp Cetuximab + FOLFIRI Cetuximab + FOLFOX 6 Cetuximab + capecitabine Cetuximab (continuous) + FLOX Cetuximab + capecitabine + oxaliplatin + bevacizumab 2009 200820092008 200920102009 Difference (wt-mt) PFS NORDIC VII: Comparison with other studies (PFS)

44 CAPIRI + cetuximab (n=93) CAPOX + cetuximab (n=92) Previously untreated mCRC (n=185) R Stintzing, et al. ESMO 2010 (Abstract 582PD) Primary endpoint –response rate Secondary endpoints –TTP, disease control rate, tolerability AIO KRK-0204: CAPIRI/CAPOX+Cetuximab

45 CAPOX + cetuximab and CAPIRI + cetuximab are feasible, with acceptable toxicity profiles Both regimens are effective, with comparable efficacy KRAS status did not influence ORR KRAS WT patients showed only a trend towards longer OS and PFS vs KRAS MT patients Stintzing, et al. ESMO 2010 (Abstract 582PD) AIO KRK-0204: Conclusions

46 What is then the MOST predictive factor for anti-EGFR efficacy?

47 Douillard, et al. ASCO 2010 PRIME trial: efficacy by SKIN TOXICITY

48 Thanks for the attention…


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