Optimizing Sequencing for Colorectal Cancer‐ What is Best and When?
Bassel F. El‐Rayes, MD Associate Professor of Medical Oncology Associate Director for Clinical Research and Director of GI Oncology Program Winship Cancer Institute Emory University
Disclosures • Research support: Bayer, Genentech‐Roche
1 Stage IV CRC: 2014
1980 1985 1990 1995 2000 2005 2010
Best supportive care 5-FU Irinotecan 30 Capecitabine Oxaliplatin Cetuximab 20 Bevacizumab Panitumumab 10
OS (Mos) Ziv-aflibercept Regorafenib Median OS 0 1980 1985 1990 1995 2000 2005 2010 Yr
Primary Management (Frontline) of Colorectal Cancer
2 Colorectal Cancer
Stage IV Colorectal Cancer
Clinical Presentation Mutational Status
Resectable : Y Borderline No Ras : Mutant No
Survival After Primary or Secondary Resection of Liver Metastases
Resectable (n = 425) Initially non resectable (n = 95) 54%
34% 50% 27%
34% 29%
0 1 2 3 4 5 6 7 8 9 10 Survival Time (years)
Bismuth et al, 1996
3 EORTC: Resectable Liver Metastases
100
80 HR: 0.77 (95.66% CI: 0.60-1.00; P = .041) 60 +8.1% at 3 yrs (%)
PFS 36.2% 40 Periop CT
20 28.1% Surgery only 0 0123456 Yrs • 5‐yr OS rate was not significantly different between FOLFOX or surgery alone (51.2% vs 47.8%; P = .34) Nordlinger B, et al. Lancet. 2008;371:1007-1016. Nordlinger B, et al. Lancet Oncol. 2013;14:1208-1215.
FOLFOX / FOLFIRI
Tournigand, C. et al. J Clin Oncol; 22:229-237 2004 Colucci, G. et al. J Clin Oncol; 23:4866-4875 2005
4 Key First‐line Chemotherapy Trials in mCRC: Efficacy
Comparative Regimens Median PFS, Mos Median OS, Mos
IFL vs FOLFOX vs IROX[1] 6.9 vs 8.7 vs 6.5 15.0 vs 19.5 vs 17.4
FOLFIRI vs FOLFOX4[2] 7.0 vs 7.0 14.0 vs 15.0
XELOX (CapeOx) vs FOLFOX4[3,4] 7.3 vs 7.7 19.0 vs 18.9
FOLFIRI vs mIFL vs CapeIRI[5] 7.6 vs 5.9 vs 5.8 23.1 vs 17.6 vs 18.9
1. Goldberg RM, et al. J Clin Oncol. 2004;22:23-30. 2. Colucci G, et al. J Clin Oncol. 2005;23:4866-4875. 3. Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012. 4. Cassidy J, et al. Br J Cancer. 2011;105:58-64. 5. Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786.
AVEX: PFS
The Lancet Oncology null 2013 null http://dx.doi.org/10.1016/S1470‐2045(13)70154‐2
5 FOLFOXIRI as First‐line Therapy
Trial RR, %Median TTP/PFS, Mos Median OS, Mos Souglakos 43.0 vs 33.6 8.4 vs 6.9 21.5 vs 19.5 (n = 283) Falcone 60 vs 34* 9.8 vs 6.9* 22.6 vs 16.7* (n = 244) *Statistically significant difference.
Souglakos J, et al. Br J Cancer. 2006;94:798-805. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.
Ongoing Trial
FOLFOX +Bev
CRC Stage IV Previously m‐FOLFIRINOX +Bev untreated
FOLFIRINOX+ Bev
6 Targeting VEGF
Phase III Trial of Bevacizumab + IFL
Second-line Placebo + IFL chemotherapy, (n=411) PD no Bev Previously Bevacizumab untreated mCRC Second-line (5 mg/kg, q2w) PD chemotherapy N=923 + IFL (n=402) ± Bev
Bevacizumab Second-line (5 mg/kg, q2w) PD chemotherapy + 5-FU/LV (n=110) ± Bev • Primary endpoint: overall survival • Secondary endpoints: PFS, RR, safety, response duration
* PD = progressive disease. Hurwitz et al. N Engl J Med. 2004;350:2335.
7 Overall Survival
100 Median survival Placebo + IFL: 15.6 months 80 Bev + IFL: 20.3 months HR=0.66, P<0.001
Placebo + IFL (n=411) 60 Bev + IFL (n=402)
1-year survival OS (%) 40 74% vs 63%
20 2-year survival 45% vs 30% 0 0 612182430 Months
Error bars represent 95% CIs. Hurwitz et al. N EnglJ Med. 2004;350:2335.
Bev/Irinotecan‐Based Regimens
Trial AVF2107 BICC-C PACE (N=411 vs 402) (N=57 vs 60) (N=115)
Treatment IFL +/‐ Bev Bev+ IFL or FOLFIRI Iri/Bev OS 15.6 vs 20.3 28.0 vs 19.2 20.5 <0.001 0.037 PFS 6.2 vs 10.6 11.2 vs 8.3 11.7 <0.001 0.28 RR 34.8 vs 44.8 57.9 vs 53.3 40%
1.Hurwitz, H N Engl J Med. 2004;350:2335. 2. Fuchs , CJ CO2007 3. Hect, JR JCO 2009
8 Bev/Oxaliplatin‐Based Regimens
Trial NO16966 PACE CARIO 2 (N=701 vs 699) (410) (N=375)
Treatment FOLFOX/XELOX +/‐ FOLFOX+ Bev XELOX/Bev Bev OS 19.9 vs 21.2 24.5 20.4 0.077 PFS 8.0 vs 9.4 11.4 10.7 0.0023 On-treatment : 7.9 vs 10.4 <0.0001 RR 38 vs 38 48 40
1.Cassidy, J JCO 2008 2. Hecht, JR JCO 2009 3. Tol, J New Eng JM 2009
Targeting EGFR
9 The Ras Mutation
Khambata-Ford, S. et al. J Clin Oncol; 25:3230-3237 2007
Retrospective Studies: KRAS Interaction With EGFR Inhibitors
RR N (% Study Regimen Mutan mKRAS) WT t Lievre, 2008 Cetuximab 114 (32) 44 0 De Roock, 2008 CT + Cetuximab 113 (41) 41 0 Tejpar, 2008 Irinotecan + Cetuximab 89 (36%) 37 0 Tabernero, 2008 Cetuximab 48 (41) 28 0 Di Fiore, 2007 CT + Cetuximab 59 (37) 12 0 Finocchiaro, 2007 Cetuximab ± CT 81 (40) 27 6 Khambata-Ford, Cetuximab 80 (38) 10 0 2007 Amado, 2008 Panitumumab 208 (40) 17 0
Lievre. J Clin Oncol. 2008;26:374; De Roock. Ann Oncol. 2008;19:508; Tejpar. ASCO. 2008 (abstr 4001); Tabernero. ASCO GI. 2008 (abstr 435); Di Fiore. Br J Cancer. 2007;96:1166; Finocchiaro. ASCO. 2007 (abstr 4021); Khambata-Ford. J Clin Oncol. 2007;25:3230; Amado. J Clin Oncol. 2008;26:1626.
10 First Line EGFR‐Targeted Agents
Trial Comparative Regimens Median PFS, Mos Median OS, Mos CRYSTAL[1] FOLFIRI/Cetux vs FOLFIRI 9.9 vs 8.4 23.5 vs 20.0 FOLFOX4/Pmab vs FOLFOX4 9.6 vs 8.0 23.8 vs 19.4 PRIME[2‐4] FOLFOX4/Pmab vs FOLFOX4 10.1 vs 7.9 26.0 vs 20.2 (KRAS/NRAS WT) FOLFOX/XELOX/Cetux vs COIN[5] 8.6 vs 8.6 17.0 vs 17.9 FOLFOX/XELOX
• Worse PFS outcome with panitumumab + FOLFOX4 in mutant KRAS disease[3]
1. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 2. Douillard JY, et al. J Clin Oncol. 2010;28:4697- 4705. 3. Douillard JY, et al. ASCO 2013. Abstract 3620. 4. Douillard JY, et al. N Engl J Med. 2013;369:1023- 1034. 5. Maughan TS, et al. Lancet. 2011;377:2103-2114.
Are all KRAS mutations the same?
11 Analysis of KRAS/NRAS Mutations
PFS Subgroup n HR for Progression or Death (95% CI) Primary analysis Nonmutated KRAS exon 2 656 0.80 (0.66‐0.97) Mutated KRAS exon 2 440 1.29 (1.04‐1.62) Prospective‐retrospective analysis Nonmutated RAS 512 0.72 (0.58‐0.90) Mutated RAS 548 1.31 (1.07‐1.60) Nonmutated KRAS exon 2, mutated other RAS 108 1.28 (0.79‐2.07)
0.40 0.63 1.00 1.58 2.51 Panitumumab-FOLFOX4 Better FOLFOX4 Alone Better OS Subgroup n HR for Progression or Death (95% CI) Primary analysis Nonmutated KRAS exon 2 656 0.83 (0.67‐1.02) Mutated KRAS exon 2 440 1.24 (0.98‐1.57) Prospective‐retrospective analysis Nonmutated RAS 512 0.78 (0.62‐0.99) Mutated RAS 548 1.25 (1.02‐1.55) Nonmutated KRAS exon 2, mutated other RAS 108 1.29 (0.79‐2.10)
0.40 0.63 1.00 1.58 2.51 Panitumumab-FOLFOX4 Better FOLFOX4 Alone Better
Douillard JY, et al. N Engl J Med. 2013;369:1023-1034.
BRAF Mutation Status
KRAS WT/BRAF WT KRAS WT/BRAF MT (n = 566) (n = 59) CRYSTAL Trial FOLFIRI Cetuximab + FOLFIRI Cetuximab + FOLFIRI FOLFIRI (n = 289) (n = 277) (n = 33) (n = 26) Median OS, mos 21.6 25.1 10.3 14.1 (95% CI) (20.0-24.9) (22.5-28.7) (8.4-14.9) (8.5-18.5) HR (95% CI) 0.830Median (0.687-1.004) OS: 23 0.908Median (0.507-1.624) OS: P value* .0547mos 12.7440 mos Median PFS, mos 8.8 10.9 5.6 8.0 (95% CI) (7.6-9.4) (9.4-11.8) (3.5-8.1) (3.6-9.1) HR (95% CI) 0.673 (0.528-0.858) 0.934 (0.425-2.056) P value* .0013 0.8656 OR rate, % 42.6 61.0 15.2 19.2 (95% CI) (36.8-48.5) (55.0-66.8) (5.1-31.9) (6.6-39.4) P value† < .0001 .9136
*Stratified log-rank test. †Cochran-Mantel-Haenszel test. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011‐2019.
12 KRAS status does not impact antiangiogenic therapy outcome
No Impact for KRAS status
13 Bevacizumab Shows PFS Benefit Regardless of KRAS Status
Mutant KRAS Wild‐Type KRAS (n=78) (n=152)
Median PFS Median PFS 1.0 1.0 IFL + Placebo 5.5 mo IFL + Placebo 7.4 mo IFL + Bev 9.3 mo IFL + Bev 13.5 mo 0.8 0.8 Free Free
0.6 HR=0.41; P=0.0008 0.6 HR=0.44; P<0.0001 Progression 0.4 0.4
0.2 0.2 Proportion Progression Proportion
0.0 0.0 0 5 10 15 20 25 0Duration 5 10 of PFS (Months) 15 20 25 Duration of PFS (Months)
Rosen. Ann Oncol. 2008;19:vi19 (abstr O‐035).
VEGFI or EGFRI in Frontline Setting?
14 FIRE‐3 Trial: FOLFIRI + Either Cetux or Bev in KRAS WT
FOLFIRI + Cetuximab
Cetuximab: 400 mg/m2 IV 120 min initial dose mCRC first‐line 250 mg/m2 IV 60 min q1w therapy Randomize KRAS wild‐type 1:1 (N = 592) FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg IV 30‐90 min q2w
• Primary endpoint: ORR (mRECIST 1.0) • Amendment in October 2008 to include only KRAS WT (ex 12/13) pts • 150 active centers in Germany and Austria Heinemann V, et al. ASCO 2013. Abstract LBA3506.
FIRE‐3 Trial: FOLFIRI + Either Cetux or Bev in KRAS WT
1.00 28.7 mos Cetuximab + CT (FOLFIRI) Bevacizumab + CT (FOLFIRI) 0.75 ∆ = 3.7 mos 0.50 25.0
OS Estimate mos 0.25 HR: 0.77 P = .017 0 0 12 24 36 48 60 72 Mos Since Start of Treatment Cetuximab + CT Bevacizumab + CT P Value ORR, % 62 58 .183 (primary endpoint not met) PFS, mos 10.0 10.3 .547 Heinemann V, et al. ASCO 2013. Abstract LBA3506.
15 FIRE‐3: OS in RAS* Wild Type
1.0 Events, Median, 95% CI n/N (%) Mos ― FOLFIRI + cetuximab 91/171 33.1 24.5- (53.2) 39.4 0.75 ― FOLFIRI + bevacizumab 110/171 25.6 22.7- (64.3) 28.6 HR: 0.70 (95% CI: 0.53-0.92; log-rank P = .011) 0.50
∆ = 7.5 mos
Probability of Survival of Probability 0.25
0 0 12 24 36 48 60 72 Mos Since Start of Treatment Pts at 171 128 71 39 20 6 Risk, n 171 127 68 26 9 1 Stintzing S, et al. ECC 2013. Abstract LBA17. *KRAS and NRAS exon 2, 3, and 4 wild type.
First‐Line Therapy SWOG/CALGB Intergroup Trial: C80405
Bevacizumab mFOLFOX6 Cetuximab Or Randomize FOLFIRI
Bevacizumab + Cetuximab
16 CALGB/SWOG 80405: OS in the ITT Population
100 mOS (95% CI), mos CT + Cetux 29.9 (27.0‐32.9) CT + Bev 29.0 (25.7‐31.2) 80 HR 0.925 (0.78-1.09) 60 P = 0.34
OS (%) 40
20
0 0 12 24 36 48 60 72 84 Mos Venook AP, et al. ASCO 2014. Abstract LBA3.
80405: OS in Systemic Therapy + Surgery
100
80
60
OS (%) 40
N (Events) mOS, Mos (95% CI) 20 124 (34) 66.3 (59.8‐NA)
0 0 12 24 36 48 60 72 84 Mos Venook AP, et al. ASCO 2014. Abstract LBA3.
17 CALGB vrs. FIRE‐3
FIRE‐3 CALGB 80405 • Superior OS in EGFRI‐ arm • Same OS • • Same PFS and RR • Same PFS and RR
• 100% received FOFIRI • 70% received FOLFOX
• Extended Ras mutation • Extended Ras mutations shows increased benefit in pending favor of EGFRI
Frontline Options
• Oxaliplatin‐based regimen: – Bevacizumab plus XELOX or FOLFOX – EGFRI plus FOLFOX (in Extended Ras mutation wild type)
• Irinotecan‐based regimen: – Bevacizumab plus FOLFIRI – EFGR I plus FOLFIRI(in Extended Ras mutation wild type)
18 Management of Colorectal Cancer Beyond Progression
Aflibercept
19 VELOUR Study Design
R Aflibercept 4 mg/kg IV, day 1 A + FOLFIRI N 600 q2 weeks Metastatic D Disease Colorectal Cancer O 1:1 Death M Progression Stratification factors: I •ECOG PS (0 vs 1 vs 2) 600 Placebo IV, day 1 Z •Prior bevacizumab (Y/N) + FOLFIRI E q2 weeks
Primary endpoint: overall survival
Van Cutsem, E JCO 2012
VELOUR : Overall Survival (OS) in ITT Population
1.0 Overall Survival
0.8 Aflibercept + FOLFIRI (n=612) Placebo + FOLFIRI (n=614) 0.6 HRa=0.82 (95.34% CI, 0.71‐0.94) P=0.0032 0.4 OS Estimate
0.2 12.1 13.5 mos mos 0 06123 9 1518 21 24 27 3033 36 39 Time, Months
Van Cutsem, E JCO 2012
20 VELOUR Most Frequent AEs
Placebo + FOLFIRI, % Aflibercept + FOLFIRI, % AE, Safety Population (n=605) (n=611) All Grades Grade 3/4 All Grades Grade 3/4 Diarrhea 56.5 7.8 69.2 19.3 Neutropeniaa 56.3 29.5 67.8 36.7 Complicated neutropenia – 2.8 – 5.7 Asthenic conditions (HLT) 50.2 10.6 60.4 16.9 Stomatitis and ulceration (HLT) 34.9 5.0 54.8 13.7 Thrombocytopeniaa 33.8 1.7 47.4 3.3 Infections (SOC) 32.7 6.9 46.2 12.3 Decreased appetite 23.8 1.8 31.9 3.4 Weight decreased 14.4 0.8 31.9 2.6 Palmar plantar erythrodysesthesia 4.3 0.5 11.0 2.8 Skin hyperpigmentation 2.8 0 8.2 0 Dehydration 3.0 1.3 9.0 4.3
Van Cutsem, E JCO 2012
Bevacizumab
21 TML‐1 Design
Standard second- BEV + line CT standard PD Randomise 1:1 first-line CT BEV + (n=820) CT switch: standard second- Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin line CT
Primary endpoint • Overall survival (OS) from randomisation Secondary endpoints • Progression-free survival (PFS) included • Best overall response rate • Safety •Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based) • First-line PFS (≤9 months, >9 months) • Time from last BEV dose (≤42 days, >42 days) • ECOG PS at baseline (0/1, 2)
Bennouna, J Lancet 2013
OS: ITT population
1.0 CT (n=410) BEV + CT (n=409)
0.8 Unstratifieda HR: 0.81 (95% CI: 0.69–0.94) 0.6 p=0.0062 (log-rank test) Stratifiedb HR: 0.83 (95% CI: 0.71–0.97) 0.4 p=0.0211 (log-rank test) OS estimate
0.2
9.8 mo 11.2 mo 0 0 6 12 18 24 30 36 42 48 Time (months)
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
Bennouna, J Lancet 2013
22 PFS: ITT population
1.0 CT (n=410) BEV + CT (n=409)
0.8 Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) 0.6 p<0.0001 (log-rank test) Stratifiedb HR: 0.67 (95% CI: 0.58–0.78) 0.4 p<0.0001 (log-rank test) PFS estimate 0.2
4.1 mo 5.7 mo 0 0 6 12 18 24 30 36 42 Time (months)
Bennouna, J Lancet 2013
Both VELOUR and TML suggest that continuing antiangiogenic therapy beyond progression is beneficial
23 EGFR‐I
Second‐line Therapy With EGFRI
Trial Comparative Regimens PFS, Mos OS, Mos EPIC[1] Irinotecan/Cetux vs Irinotecan 4.0 vs 2.6* 10.7 vs 10.0 181[2] FOLFIRI/Pmab vs FOLFIRI 5.9 vs 3.9* 14.5 vs 12.5 SPIRITT[3] FOLFIRI/Pmab vs FOLFIRI/Bev 7.7 vs 9.2 18.0 vs 21.4 PICCOLO[4] Irinotecan/Pmab vs Irinotecan HR: 0.78† 10.9 vs 10.4
*Statistically significant difference. Retrospective KRAS analysis (< 25% of pts enrolled). †P = .015
1. Sobrero AF, et al. J Clin Oncol. 2008;26:2311-2319. 2. Peeters M, et al. J Clin Oncol. 2010;28:4706-4713. 3. Hecht JR, et al. ASCO 2013. Abstract 335. 4. Seymour MT, et al. Lancet Oncol. 2013;14:749-759.
24 Cetuximab: Pivotal Trial
• ERBITUX initial dose: 400 mg/m2 (2-hr IV) • Maintenance dose: 250 mg/m2 weekly (1-hr IV) • Irinotecan: same dose and schedule as ERBITUX + irinotecan patients had previously failed (n = 218)
Patients with EGFR-expressing mCRC who progressed after 2:1 Randomization irinotecan-based chemotherapy Crossover after progression
Stratification • Performance status • Prior oxaliplatin • Treatment center ERBITUX single agent (n = 111)
Cunningham D, et al. N Engl J Med. 2004;351:337-345.
Cetuximab: Combination With Irinotecan
Time to Progression, All Patients (N = 329)
25 Subsequent lines RAS Wild type‐1
• Switch chemotherapy backbone – FOLFOX to FOLFIRI – FOLFIRI to FOLFOX AND
• Switch or continue Monoclonal antibody – EGFRI to Bevacizumab – Bevacizumab to EGFR I or Aflibercept – Bevacizumab continue Bev
Subsequent lines RAS Wild type‐2
• Keep same chemotherapy backbone – FOLFIRI AND
• Switch or continue Monoclonal antibody – Bevacizumab to EGFR I
26 Subsequent lines RAS Mutated
• Switch chemotherapy backbone – FOLFOX to FOLFIRI – FOLFIRI to FOLFOX AND
• Switch or continue Monoclonal antibody – Bevacizumab to Aflibercept – Bevacizumab continue Bev
When all else fails….Regorafenib
27 Regorafenib: an oral multikinase inhibitor1‐3
Regorafenib IC Biochemical 50 mean ± SD nmol/l activity (n)
Regorafenib VEGFR1 13 ± 0.4 (2)
Murine VEGFR2 4.2 ± 1.6 (10)
Murine VEGFR3 46 ± 10 (4)
TIE2 311 ± 46 (4)
PDGFR-β 22 ± 3 (2)
FGFR1 202 ± 18 (6)
KIT 7 ± 2 (4) Inhibition of tumor Inhibition of Inhibition of RET 1.5 ± 0.7 (2) microenvironment proliferation neoangiogenesis signaling RAF-1 2.5 ± 0.6 (4) KIT B-RAF 28 ± 10 (6) PDGFR-β VEGFR1-3 PDGFR B-RAFV600E 19 ± 6 (6) FGFR TIE2 RET 1. Wilhelm SM et al. Int J Cancer 2011. 2. Mross K et al. Clin Cancer Research 2012. 3. Strumberg D et al. Expert Opin Invest Drugs 2012.
CORRECT: Patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy
2:1
Evaluation with CT scan of abdomen and chest every 8 weeks
Grothey, A Lancet 2013
28 Overall survival (primary endpoint)
Grothey, A Lancet 2013
Progression‐free survival
Grothey, A Lancet 2013
29 Overall response and disease control rates
Regorafenib significantly improves DCR compared to placebo
Regorafenib Placebo Best response, % N=505 N=255 Complete response 0 0 PR 1.0 0.4 SD 42.8 14.5 Progressive disease 49.5 80.0
DCR* 41.0 14.9
*DCR = PR + SD (≥6 weeks after randomization); p<0.000001 Grothey, A Lancet 2013
Adverse Events
Regorafenib Placebo N=500 N=253 Adverse event, % All Grade Grade Grade All Grade Grade Grade grades 3 4 5* grades 3 4 5* Hand-foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0 Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0 Hypertension 27.8 7.2 0 0 5.9 0.8 0 0 Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0 Rash / desquamation26.05.8004.0000 Anorexia 30.4 3.2 0 0 15.4 2.8 0 0 Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0 Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0 Fever 10.4 0.8 0 0 2.8 0 0 0 Nausea 14.4 0.4 0 0 11.1 0 0 0 Bleeding 11.4 0.4 0 0.4 2.8 0 0 0 Voice changes 29.4 0.2 0 0 5.5 0 0 0 Weight loss 13.80002.4000
Grothey, A Lancet 2013
30 Colorectal Cancer‐Future Questions
• Need better biomarkers to decide on how to select the targeted agents.
• Where does the EGFR blocker fit in the KRAS wild type? – Frontline vs. refractory disease
• Potentially resectable stage IV disease –is there a role for targeted agents?
Thank You
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