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Andrés Cervantes Cáncer de Colon: Resultados de los estudios CRYSTAL, FIRE3 y CALGB-80405.

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Presentation on theme: "Andrés Cervantes Cáncer de Colon: Resultados de los estudios CRYSTAL, FIRE3 y CALGB-80405."— Presentation transcript:

1 Andrés Cervantes Cáncer de Colon: Resultados de los estudios CRYSTAL, FIRE3 y CALGB-80405

2 R CRYSTAL study design Presented by: Eric Van Cutsem FOLFIRI + cetuximab n=599 ( KRAS codon 12/13 WT, n=316) Stratification factors: ECOG performance status Region Treatment until disease progression, unacceptable toxicity, withdrawal of consent Irinotecan 5-FU LV FOLFIRI (q2w) 400 mg/m 2 initial dose then 250 mg/m 2 weekly 180 mg/m 2, day mg/m 2 bolus, then 2400 mg/m 2 infusion over 46 h 200 mg/m 2 *, day 1 Cetuximab n=1198 ( KRAS codon 12/13 WT, n=666: PCR clamping and melting curve analysis) R FOLFIRI n=599 (KRAS codon 12/13 WT, n=350) EGFR-expressing, previously untreated, mCRC *L-form; 400 mg/m 2, racemic. 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; LV, leucovorin; PCR, polymerase chain reaction; R, randomization; WT, wild-type Van Cutsem E, et al. N Engl J Med 2009;360: Van Cutsem E, et al. J Clin Oncol 2011;29:2011-9

3 RAS mutation analysis: BEAMing Presented by: Eric Van Cutsem KRAS and NRAS codons screened for particular missense* mutations: –KRASexon 3; codons 59, 61 exon 4; codons 117, 146 –NRAS exon 2; codons 12, 13 exon 3; codons 59, 61 exon 4; codons 117, 146 In line with other techniques which may be used clinically to determine RAS mutation status, a cutoff of ≥5% mutant to wild-type alleles was selected –Tumors were scored as RAS mutant if mutant alleles were detected at a prevalence of ≥5% of total amplified sequences, regardless of whether all loci were evaluable –Tumors were scored as RAS wild-type only if all 26 mutation assays were evaluable and prevalence of mutations was <5% *Resulting in a change in the specified amino acid

4 Study profile Presented by: Eric Van Cutsem Tumors evaluable for KRAS codon 12/13 status n=530 FOLFIRI alone n=599 Randomized and treated; full analysis population n=1198 FOLFIRI + cetuximab n=599 KRAS codon 12/13 wild-type n=316 KRAS codon 12/13 mutant n=214 Tumors evaluable for KRAS codon 12/13 status n=533 KRAS codon 12/13 mutant n=183 KRAS codon 12/13 wild-type n=350 RAS wild-type n=189 Other RAS mutant n=31 Evaluable for RAS status n=220 RAS wild-type n=178 Other RAS mutant n=32 Evaluable for RAS status n=210 Any RAS mutant n=214 Any RAS mutant n=246

5 Other RAS mutations: CRYSTAL Presented by: Eric Van Cutsem KRAS NRAS 3.3%5.6% EXON 3EXON 4EXON %0.9% EXON 2EXON 3EXON WT 3.5% 146 In 5 tumors with KRAS mutations, an NRAS mutation also detected (low prevalence, 0.1%–<5%, in 4/5 samples) In 1 tumor, 2 NRAS mutations detected (1 with low prevalence) Percentages relate to fraction of RAS evaluable patients with mutations in particular exons 430/666 patients with KRAS codon 12/13 wild-type tumors evaluable for tumor RAS status Other RAS mutations: 63/430 (14.7%) patients

6 RAS mutation rates: first-line studies StudyEvaluable patients* MethodOther RAS mutations, % CALGB/SWOG BEAMing †† 15.3 OPUS118BEAMing † 26.3 CRYSTAL430BEAMing † 14.7 FIRE-3 ‡ 407Pyrosequencing16.0 PRIME § 620Dideoxy sequencing/WAVE17.4 PEAK221Dideoxy sequencing/WAVE23.1 *For other tumor RAS mutations † 5% mutant/wild-type alleles diagnostic cutoff † † 1% mutant/wild-type alleles diagnostic cutoff ‡ KRAS codons 59 and 117 not considered § KRAS and NRAS codon 59 not considered Patients with KRAS codon 12/13 wild-type tumors

7 Van Cutsem E, et al. J Clin Oncol 2015; 33: ahead of print. PFS OS EFFICACCY ACCORDING TO RAS SUBGROUPS

8 Progression-free survival Presented by: Eric Van Cutsem KRAS codon 12/13 wild-type*RAS wild-type Probability of PFS FOLFIRI + cetuximab FOLFIRI Number of patients at risk Months HR (95% CI) 0.56 (0.41–0.76) No. of events Median, months 95% CI – – Probability of PFS Months Number of patients at risk 1 0 HR (95% CI) 0.70 (0.56–0.87) No. of events Median, months 95% CI – –9.2 FOLFIRI + cetuximab FOLFIRI *Van Cutsem E, et al. J Clin Oncol 2011;29:2011-9

9 Overall survival Presented by: Eric Van Cutsem RAS wild-type Probability of OS Number of patients at risk Months FOLFIRI + cetuximab FOLFIRI HR (95% CI) 0.69 (0.54–0.88) No. of events Median, months 95% CI – –24.5 KRAS codon 12/13 wild-type* Probability of OS Months HR (95% CI) 0.80 (0.67–0.95) No. of events Median, months 95% CI – – Number of patients at risk FOLFIRI + cetuximab FOLFIRI *Van Cutsem E, et al. J Clin Oncol 2011;29:2011-9

10 Conclusions Presented by: Eric Van Cutsem This retrospective subgroup analysis supports the use of FOLFIRI + cetuximab as first-line treatment in patients with RAS wild-type mCRC –Significant improvements in PFS (HR 0.56), OS (HR 0.69) and ORR (odds ratio 3.11) associated with addition of cetuximab to FOLFIRI –No benefit nor deleterious effect seen in patients with RAS mutations The safety profile in the RAS wild-type and RAS mutant subgroups is similar and in line with expectations Exclusion of patients with other RAS mutations from the KRAS codon 12/13 wild-type treatment population improves the benefit-risk ratio associated with the addition of cetuximab to FOLFIRI Molecular testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment for patients with mCRC

11 FIRE-3 study design FOLFIRI + Cetuximab Cetuximab: 400 mg/m 2 i.v. 120min initial dose 250 mg/m 2 i.v. 60min q 1w 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 + Bevacizumab Bevacizumab:5 mg/kg i.v min q 2w mCRC 1st-line therapy KRAS wild-type mCRC 1st-line therapy KRAS wild-type Randomize 1:1 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 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)

12 Heinemann V, et al. Lancet Oncol Lancet Oncol Sep;15(10): Cetuximab + CTBevacizumab + CTp value Overall response rate (primary endpoint not met) 62%58%0.183 Progression-free survival10.0 months10.3 months0.547 Cetuximab + CT (FOLFIRI) (n=297) Bevacizumab + CT (FOLFIRI) (n=295) OS estimate HR=0.77 p= months 25.0 months Overall survival Months since start of treatment FIRE-3 study results ITT KRAS exon 2 wild-type population

13 Tumor samples N= 488 (82.4%) tumor material available of KRAS wild-type ITT DNA of insufficient quality: 13 N= 475 (80.2%) RAS mutational analyses successful in all RAS locations not KRAS wild-type ITT: 115 redundant tumor samples:14 no tumor on block:20 not KRAS wild-type ITT: 115 redundant tumor samples:14 no tumor on block:20 N= 637 tumor samples KRAS exon 2 WT n=592 (100%) Final RAS wild-type population N=400 Final RAS wild-type population N=400 New RAS mutant N= 75 (15.8%) New RAS mutant N= 75 (15.8%)

14 ORR and PFS Final RAS* wild-type population Events n/N (%) Median (months) 95% CI ― FOLFIRI + Cetuximab 164/199 (82.4%) – 11.8 ― FOLFIRI + Bevacizumab 169/201 (84.1%) – 11.7 HR 0.97 (95% CI: 0.78 – 1.20) p (log-rank)= 0.77 * KRAS and NRAS exon 2, 3 and 4 wild-type months since start of treatment No. at risk Probability of survival N=400 Cetuximab + FOLFIRI (N=199) Bevacizumab + FOLFIRI (N=201) OR/ (95% CI) p-value ORR, % (95% CI) 65.3 (58.3–51.6) 58.7 (51.6–65.6) 1.33 (0.88–1.99) 0.18

15 Overall survival Final RAS* wild-type population Events n/N (%) Median (months) 95% CI ― FOLFIRI + Cetuximab 107/199 (53.8%) – 39.4 ― FOLFIRI + Bevacizumab 133/201 (66.2%) – 28.1 HR (95% CI: 0.54 – 0.90) p (log-rank)= months since start of treatment No. at risk Probability of survival * KRAS and NRAS exon 2, 3 and 4 wild-type Δ = 8.1 months

16 Independent radiological review An independent, centralized radiological review (blinded to treatment arms) was performed to evaluate: Tumor response according to RECIST 1.1 Early tumor shrinkage (ETS) (-20% diameter change) measured at 1st CT after baseline (6 weeks) Depth of response defined as the percentage of maximal tumor shrinkage observed at the nadir compared with baseline

17 p = Fisher´s exact test (two-sided) CT evaluable population FOLFIRI + Cetuximab FOLFIRI + Bevacizumab ORR%95%-CI% Odds ratio p KRAS exon 2 wt n= – – ( ) Final RAS wt n= – – ( ) Independent evaluation of response

18 Evaluation of ETS Rate (Early Tumor Shrinkage) p = Fisher´s exact test (two-sided) Rate of Early Tumor Shrinkage* CT evaluable population FOLFIRI + Cetuximab FOLFIRI + Bevacizumab Odds ratio p %95%-CI% KRAS exon 2 wt n= – – ( ) Final RAS wt n= – – ( ) *ETS: early tumor shrinkage ≥20% at 6 weeks

19 Evaluation of Depth of Response (DpR*) SE = standard error; p = two-sided Wilcoxon test p FOLFIRI + CetuximabFOLFIRI + Bevacizumab p median DpR % SE% KRAS exon 2 wt n= (±54.6%)- 32.9(± 44.3%) Final RAS wt n= (±54.8%)- 32.3%(± 42.3%)< *DpR: percentage of maximal tumor shrinkage observed at the nadir compared with baseline Depth of response correlated significantly with OS and PFS (two-sided Bravais Pearson test)

20 Depth of response correlates with overall survival CRYSTAL study Cetuximab + FOLFIRI (n=315) FOLFIRI (n=348) p Median DpR (95% CI) p< Median OS (95% CI) 23.5 ( )20.0 ( ) P< adopted from Mansmann et al, ASCO GI 2013 abstract #427 ETS predicts sensitivity to treatment ETS predicts the potential DpR DpR predicts OS Time under treatment  OS ETS DpR (smallest tumor size) Model

21 Depth of response correlates with overall survival FIRE-3 Study (AIO KRK-0306) Cetuximab + FOLFIRI (n=157) Bevacizumab + FOLFIRI (n=173) p Median DpR (95% CI) p< Median OS (95% CI)33.1 (24.5 – 39.4)25.0 (23.0 – 28.1) P= Time since start of treatment  OS ETS Tumor nadir Fire-3 data ETS predicts sensitivity to treatment DpR predicts OS PFS Tumor load at Baseline Lethal tumor load

22 Summary of RAS analyses Extended RAS testing was possible in >80% of FIRE-3 ITT. 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 Median OS was markedly superior (Δ = 8.1 months, HR 0.70) in all-RAS wild-type patients receiving 1 st -line therapy with cetuximab

23 CALGB/SWOG 80405: PHASE III trial of irinotecan/5- FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): Expanded ras analyses Heinz-Josef Lenz, Donna Niedzwiecki, Federico Innocenti, Charles David Blanke, Michelle R. Mahoney, Bert H. O'Neil, James Edward Shaw, Blase N. Polite, Wilbur Franklin, Wendy Frankel, Howard Hochster, James Norman Atkins, Richard M. Goldberg, Robert J. Mayer, Richard L. Schilsky, Monica M. Bertagnolli, Alan Venook for the ALLIANCE and SWOG

24 RAS mutation analysis: BEAMing KRAS and NRAS genes were screened for particular missense* mutations: –KRASexon 2; codons 12, 13 exon 3: codon 59, 61 exon 4; codons 117, 146 –NRAS exon 2; codons 12, 13 exon 3; codons 59, 61 exon 4; codons 117, 146 In line with other techniques which may be used clinically to determine RAS mutation status, a cutoff of ≥1% mutant to wild-type alleles was used to discriminate patients –Tumors were scored as RAS mutant if mutant alleles were detected at a prevalence of ≥1% of total amplified sequences, regardless of whether all loci were evaluable –Tumors were scored as RAS wild-type only if all 26 mutation assays were evaluable and prevalence of mutant alleles was <1% *Resulting in a change in the specified amino acid

25 Study profile KRAS WT codons 12/13 N=1137 Chemo + Bev N=559 Evaluable for RAS analysis N=324 (26 NA) RAS WT N=256 RAS mut N=42 Chemo + Cetux N=578 Evaluable for RAS analysis N=346 (23 NA) RAS WT N=270 RAS mut N=53

26 Efficacy: RAS Subgroups SubgroupChemo + BV N Chemo + CET N Response Rate (%)* BV vs CET p-value PFS time Hazard ratio 95% CI p-value OS time Hazard ratio 95% CI p-value RAS evaluable** vs 68.8 p< vs 10.9 ‡ p= vs 30.8 ‡ p=0.49 RAS wild-type vs 68.6 p< vs 11.4 ‡ –1.3 p= vs 32.0 ‡ –1.1 p=0.40 *406 RAS evaluable and 319 RAS WT patients evaluable for response **Patients with KRAS codon 12/13 wild-type tumors for which tumor DNA samples were evaluable for other RAS mutations ‡ Median, months

27 Progression Free Survival By Arm (All RAS Wild Type Patients) Arm N (Events) Median (95% CI) HR (95% CI) p Chemo + Bev 256 (221) 11.3 ( ) 1.1 ( ) 0.31 Chemo + Cetux 270 (241) 11.4 ( )

28 Overall Survival By Arm (All RAS Wild Type Patients) Arm N (Events) Median (95% CI) HR (95% CI) p Chemo + Bev 256 (178) 31.2 ( ) 0.9 ( ) 0.40 Chemo + Cetux 270 (177) 32.0 ( )

29 Overall Survival by Arm (All RAS Wild Type FOLFOX Patients) Arm N (Events) Median (95% CI) HR (95% CI) p Chemo + Bev 192 (137) 29.0 ( ) 0.86 ( ) 0.2 Chemo + Cetux 198 (129) 32.5 ( )

30 Overall Survival by Arm (All RAS Wild Type FOLFIRI Patients) Arm N (Events) Median (95% CI) HR (95% CI) p Chemo + Bev 64 (41) 35.2 ( ) 1.1 ( ) 0.7 Chemo + Cetux 72 (48) 32.0 ( )

31 Conclusions All patients with newly diagnosed mCRC should be tested for RAS Overall Survival > 30 months in both arms sets a new benchmark for patients with mCRC which was achieved across a broad clinical trials network and suggests that the results apply in a variety of practice settings. First line therapy should reflect treatment goal and concern for potential side effects. With additional data such as dose intensity, treatment duration, location, tumor shrinkage, second line therapies and additional biomarker for anti-EGFR and anti VEGF AB we might understand better the differences between FIRE3 and 80405

32 Venook AP and Tabernero J. J Clin Oncol 2015; 33:4-6

33

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35 Shi Q, et al. J Clin Oncol 2015; 33:22-28.

36 CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Resected Pts n=180 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Chemo + Cetux n=105 Age, years Median (range)59 (21–85)59 (20–89)55 (24–82)55 (21–79) Male, % Non-Caucasian, % FOLFOX, %* Prior Radiation, %* Prior Adjuvant Chemotherapy, %* Palliative intent, % Primary in place, % Liver metastases only, % *Stratification Factor Achieve NED: 132 /180

37 CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132) Arm N (Events) Median (95% CI) HR (95% CI) p Chemo + Bev 50(15) 67.4 (50.6-NA) 1.2 ( ) 0.56 Chemo + Cetux 82(30) 64.1 ( )

38 CALGB/SWOG 80405: Patients undergoing surgery and rendered NED Subset of patients survive > 5 years Patients likelier to have “curative” surgery on cetuximab-containing regimen Outcomes similar between arms Expanded RAS may distinguish prognosis in this already select group of patients Opportunity to interrogate clinical and tumor factors related to curability


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