1、1 Individualized Treatments for Advanced Colorectal Cancer: The KRAS Story David Z. Chang, MD, PhD UT MD Anderson Cancer Center 张 宗 圣 CSCO Annual Meeting 2019 2 SUMMARY Targeted therapies have improved clinical outcome of mCRC Need judicious use of these agents: when, how Many questions remaining Ho
2、w to overcome the high cost Treatments need to be individualized: biomarkers and genetic signatures 3 Story for GI at ASCO 2019 1st biomarker for individualized therapy for colorectal cancer: KRAS status predicts responsiveness (or lack of responsiveness) to EGFR targeted therapies 4 Advances in the
3、 Treatment of Colorectal Cancer 1980 1985 1990 2019 2000 2019 Capecitabine Oxaliplatin Cetuximab Bevacizumab Irinotecan 5-FU Panitumumab Median Survival BSC: 4-6 months 5FU: 10-14 months 5FU/OX/Iri: 20 months + targeted therapy: 30 months? 5 Some Historical Data EGFR Targeted Therapies in CRC Cetuxi
4、mab 351:337-345. 7 0 5 10 15 20 25 0 1 2 3 4 5 6 22.9% 5.7 mo 4.2 mo10.8% Objective Response Rate Median Duration of Response Cetuximab with irinotecan (n=218) Cetuximab as a single agent (n=111) Cetuximab Randomized Pivotal Trial: Response Rates P=0.007 Cunningham D, et al. N Engl J Med. 2019;351:3
5、37-345. 8 R A N D O M I Z E N=1298 Patients with CRC who progressed on 5FU, Oxaliplatin, GFR + Irinotecan Cetuximab + Irinotecan Jonker et al. AACR 2019. Abstract 3556. EPIC: Cetuximab + Irinotecan vs Irinotecan as 2nd-line Therapy 9 EPIC Study Efficacy Data Cetuximab is active in 2nd line, irinotec
6、an nave pts Lack of overall survival: cross-over effect? 10 CRYSTAL: Phase III Trial of FOLFIRI +/- Cetuximab in First-line mCRC R A N D O M I Z E FOLFIRI + cetuximab (608) First-line mCRC FOLFIRI (609) Cutsem et aI, et al. ASCO 2019. 4000. 11 CRYSTAL Efficacy Data Cetuximab +FOLFIRI (N=608) Irinote
7、can (N=609) P Value PFS 8.9 8 0.036 Response Rate (%) 46.9% 38.7% 0.005 Cetuximab improves RR, PFS in 1st line, in combination with FOLFIRI 12 Phase III Study: Panitumumab vs Best Supportive Care Peeters M, et al. AACR 2019. Abstract CP-1. R A N D O M I Z E Panitumumab (6 mg/kg q2 wk) + BSC (n=231)
8、N=463 Patients third -line mCRC EGFR expression required Optional panitumumab crossover study (n=174) Best supportive care (n=232) PD PD Stratification based on ECOG score, geographic region 13 Panitumumab Improves PFS over Best Supportive Care PFS longer with panitumumab vs BSC - HR, 0.54 (95% CI,
9、0.44-0.66; P0.000000001) *P0.0001. Peeters M, et al. AACR 2019. Abstract CP-1. Panitumumab (n=231) BSC (n=232) PR, n (%) 19 (8)* 0 (0) SD, n (%) 64 (28) 24 (10) Median duration response, wk (range) 17 (4+-40+) n/a 14 Only a small portion of patients responded to EGFR targeted therapies Majority of p
10、atients suffered the side effects and high cost without benefits Dilemma What may help select these patients? 15 EGF/EGFR Pathway ProliferationApoptosis Resistance Transcription Shc PI3K RafMEKK-1 MEKMKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 EGFR 16 17 Phase III Study: Panitumumab vs Best Supportive Car
11、e 18 KRAS Mutation Predicts No Benefit from Panitumumab 19 CRYSTAL: Phase III Trial of FOLFIRI +/- Cetuximab in First-line mCRC R A N D O M I Z E FOLFIRI + cetuximab (608) First-line mCRC FOLFIRI (609) Cutsem et aI, et al. ASCO 2019. 4000. 20 CRYSTAL: PFS in Patients With the KRAS Mutation 0 0.2 0.4
12、 0.6 0.8 1.0 0 4 8 12 Mos PFS Estimate 16 Cetuximab + FOLFIRI FOLFIRI KRAS mutation (n = 192) HR: 1.07; P = .47 2 6 10 14 Median PFS cetuximab + FOLIFIRI: 7.6 mos Median PFS FOLIFIRI: 8.1 mos 0.1 0.3 0.5 0.7 0.9 Van Cutsem E, et al. ASCO 2019. Abstract 2. Reproduced with permission. 21 CRYSTAL: PFS
13、in Patients With WT KRAS 0 0.2 0.4 0.6 0.8 1.0 0 4 8 12 Mos 18 Cetuximab + FOLFIRI FOLFIRI WT KRAS (n = 348): HR: 0.68; P = .017 2 6 10 14 Median PFS cetuximab + FOLIFIRI: 9.9 mos Median PFS FOLIFIRI: 8.7 mos 0.1 0.3 0.5 0.7 0.9 16 1-yr PFS rate: 43% Van Cutsem E, et al. ASCO 2019. Abstract 2. Repro
14、duced with permission. 1-yr PFS rate: 25%PFS Estimate 22 CRYSTAL: Initial and Retrospective Results ITT Population K-ras Wild Type K-ras Mutation FOLFIRI FOLFIRI FOLFIRI With ERBITUX No ERBITUX With ERBITUX No ERBITUX With ERBITUX No ERBITUX # of Patients 599 599 172 176 105 87 Overall Response Rate
15、 47% 39% p=0.004 59% 43% p=0.003 36% 40% p=0.46 Median PFS 8.9 mos 8.0 mos Hazard Ratio: 0.85 p=0.05 9.9 mos 8.7 mos Hazard Ratio: 0.68 p=0.02 7.6 mos 8.1 mos Hazard Ratio: 1.07 p=0.75 23 24 25 KRAS Status and Efficacy of First-Line FOLFOX Cetuximab: OPUS Genomic DNA was isolated from archived tumor
16、 material KRAS mutation status of codons 12/13 was determined using a sensitive, quantitative PCR-based assay Population with tissue available for KRAS analysis (n = 233) was representative of overall ITT population (n = 337) in terms of demographics and efficacy parameters KRAS mutations detected i
17、n 42% (99/233) of evaluable samples Bokemeyer C, et al. ASCO 2019. Abstract 4000. 26 27 OPUS: Initial and Retrospective Results ITT Population K-ras Wild Type K-ras Mutation FOLFOX FOLFOX FOLFOX With ERBITUX No ERBITUX With ERBITUX No ERBITUX With ERBITUX No ERBITUX # of Patients 169 168 61 73 52 47
18、 Overall Response Rate 46% 36% p=0.006 61% 37% p=0.01 33% 49% p=0.11 Median PFS 7.2 mos 7.2 mos Hazard Ratio: 0.93 p=NSS 7.7 mos 7.2 mos Hazard Ratio: 0.57 p=0.02 5.5 mos 8.6 mos Hazard Ratio: 1.83 p=0.02 28 29 30 31 32 33 CAIRO2 Summary Cetuximab + bevacizumab/capecitabine/oxaliplatin decreased PFS
19、 without affecting OS Although manageable, cetuximab + bevacizumab/ chemotherapy increases skin toxicity and diarrhea adverse events Treatment discontinuation due to toxicity did not differ between arms -Negative interaction between anti-VEGF and anti- EGFR cannot be discounted Punt CJ, et al. J Cli
20、n Oncol. 2019;26(May 20 suppl):abstr LBA4011. 34 Is KRAS independent from skin rash as a predictor for response? Can dose escalation overcome KRAS mutant-type? 35 KRAS and Efficacy of Irinotecan and Cetuximab in mCRC: EVEREST Patients with irinotecan- refractory metastatic cancer Cetuximab 400 mg/m2
21、 initial dose then 250 mg/m2/wk + Irinotecan 180 mg/m2 Q2W Control Standard Cetuximab regimen (250 mg/m2/wk) (n = 23) Dose Escalation Cetuximab dose increases of 50 mg/m2 Q2W up to maximum 500 mg/m2/wk (n = 31) Nonrandomized Standard Cetuximab regimen (250 mg/m2/wk) S C R E E N I N G Day 22 Randomiz
22、ed: skin toxicity grade 0/1 Not eligible for randomization: skin toxicity grade 2/3 All patients continued to receive irinotecan Treatment until progression, unacceptable toxicity or withdrawal of consent Skin and tumor biopsy at baseline, Week 3, and at maximum cetuximab dose in dose-escalation arm
23、 Tejpar S, et al. ASCO 2019. Abstract 4001. 36 EVEREST: PFS (ITT Population) 0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 Days PFS Estimate 800 P .0001 KRAS mutant WT KRAS KRAS mutation present 83 days (95% CI: 75.9-90.2) 173 days (95% CI: 141.3-204.7) Tejpar S, et al. ASCO 2019. Abstract 4001. Reproduced wi
24、th permission. 37 EVEREST: PFS by Treatment Group and KRAS Status 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 Days Days Days KRAS mutant WT KRAS Control KRAS mutation present P = .014 KRAS mutant WT KRAS Dose Escalatio
25、n KRAS mutation present KRAS mutant WT KRAS Nonrandomized KRAS mutation present P .001 P = .020 Tejpar S, et al. ASCO 2019. Abstract 4001. Reproduced with permission. PFS Estimate PFS Estimate PFS Estimate 38 EVEREST SUMMARY Dose escalation of cetuximab did increase response rate Among patients with
26、out rash receiving, KRAS status still predicted response to cetuximab Among patients receiving escalated dose of cetuximab (to rash), KRAS MT still did not respond - Higher dose did not overcome KRAS status - Skin rash and KRAS are independent predictors 39 SUMMARY of Kras Data Kras status is a pred
27、ictive marker for EGFR targeted therapy - Patients with wild-type Kras may benefit from EGFR targeted therapy - Patients with mutant Kras may NOT benefit from EGFR targeted therapy Cetuximab may have detrimental effects in patients with mutant Kras Whenever considering to use EGFR targeted therapy,
28、Kras status should be tested. 40 Questions Raised by KRAS Data What to do with current trials involving EGFR targeted-agents? What to do for patients with mutated KRAS? Any other predictive markers? Develop more reliable, affordable assays to test KRAS status 41 Ongoing Studies: CALGB/SWOG 80405 Cet
29、uximab, Bevacizumab, and FOLFOX/FOLFIRI Investigator/Patient Chemotherapy Choice FOLFIRI or FOLFOX + Bevacizumab + Cetuximab + Bevacizumab + Cetuximab + Bevacizumab + Cetuximab + Bevacizumab + Cetuximab Randomization Randomization Available at: ctep.cancer.gov/resources/quarterly_news.pdf 42 Ongoing
30、 Study: iBET Study FOLFIRI + Cetuximab FOLFIRI +Cetuximab +Bevacizumab (5 mg/Kg) mCRC S/P FOLFOX/Avastin FOLFIRI +Cetuximab +Bevacizumab (10 mg/Kg) R A N D O M I Z E 43 What to Do for Patients with KRAS MT Tumor? Need novel agents Need trials specifically targeting this patient population 44 Other M
31、arkers? 45 EGFR Ligands (Epiregulin and Amphiregulin) Levels Correlate With Response to Cetuximab 46 Genetic Signatures to Predict Response? Gene expression profiles reflecting clinical response to neoadjuvant treatment in breast cancer Using genetic signatures to choose treatments for individual CRC patients? 47 Now the “future” is here: Individualized therapy for mCRC 48 Individualized Therapy in TCM 四 诊 八 纲 病情 诊 察 : 望、 问 、 闻 、切 病情分析 : 阴、阳、表、里、寒、 热 、虚、 实 49 THANK YOU!
