Anti-EGFR Antibodies in Metastatic Colorectal Cancer: Which Patients, When, and How? J. Randolph Hecht, MD David Geffen School of Medicine at UCLA
Jan 12, 2016
Anti-EGFR Antibodies in Metastatic Colorectal Cancer:
Which Patients, When, and How?
J. Randolph Hecht, MD
David Geffen School of Medicine at UCLA
Disclosures
• Research Funding
Amgen
Novartis
GSK
Pfizer
ImClone
Genvec
Roche
Anti-EGFR Ab: Clinical Development
• Single Agent Phase II, Salvage– Saltz, JCO, 2004– Hecht, Cancer, 2007
• Single Agent Randomized Trials, Salvage– 408 Van Cutsem, JCO 2007 – CO.17 Jonker, NEJM, 2008
• Modest RR ~10%
• Modest improvement in PFS, OS
CO.17
Jonker, NEJM, 2007
Combination Trials• Cetuximab
– Saltz (Salvage) Cetuximab+ Irinotecan– Cunningham (2nd line, Salvage) Cetuximab+Irinotecan– EPIC (2nd line) Sobrero PhIII Irinotecan +/- cetuximab– 80203 (1st line) Venook rPhII FOLFOX/FOLFIRI +/- cetuximab– OPUS (1st line) Bokemeyer rPhII FOLFOX +/- cetuximab– CRYSTAL (1st line) Van Cutsem PhIII FOLFIRI +/- cetuximab– COIN (1st line) Maughan PhIII FOLFOX/XELOX +/- cetuximab– CAIRO2 (1st line) Tol CapeOx/bev +/- cetuximab
• Panitumumab– Berlin (1st line) PhII 5-FU/Irinotecan + panitumumab– PRECEPT (2nd line) PhII Cohn FOLFIRI + panitumumab– STEPP (2nd line) PhII Mitchell FOLFIRI + panitumumab– PACCE (1st line with bev) Hecht PhIII FOLFOX/IRI + bev +/- panitumumab
Progression-free survival time (months)
PF
S e
stim
ate
1.0
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 2 4 6 8 10 12 14 16 18 20
HR = 0.851; 95% CI = [0.726-0.998]
Stratified log-rank p-value = 0.0479
8.9 mo
8.0 mo
FOLFIRI, n=599
Cetuximab + FOLFIRI, n=599
1-year PFS rate23% vs 34%
Subjects at risk
FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI
599 499 392 298 196 103 58 29 12 5 1
CRYSTAL Trial: PFS
Van Cutsem ASCO 2007
Bokemeyer, JCO, 2009
OPUS
Standard Therapy of Metastatic CRC: US 2007
1st Line: FP/oxaliplatin (usually) + bevacizumab
2nd Line: – FOLFIRI + bevacizumab– Irinotecan + cetuximab
3rd Line: – Irinotecan + cetuximab– Single agent cetuximab or panitumumab
Questions Regarding EGFR Abs:
• Clearly only a subset of patients benefit from EGFR antibody therapy, yet almost all patients get some toxicity
• How do we determine which patients will benefit from such therapy?
• Should anti-EGFR Mabs be used earlier in treatment?
EGFR Signaling Pathway
Extracellular
Intracellular
Ligand
EGFR
PI3K
Akt
Ras
Raf
MEK
MAPK
Cell motility
MetastasisAngiogenesis
Proliferation
Cell survivalDNA
PTEN
KRAS
GTPase downstream from numerous receptors
Mutations (codons 12, 13, 61) activating and found in ~40% of CRC regardless of stage
Smaller retrospective trials indicated lack of response with EGFR antibodies (Lievre, De Roock, Khambata-Ford, etc.)
KRAS as a Biomarker for Panitumumab Response in
Metastatic CRC
Patients With Mutant KRAS
Meanin Wks
Stratified log rank test: P < .0001
115/124 (93)
Patients With Wild-Type KRAS
1.0
0.9
Pro
po
rtio
n W
ith
PF
S
0.8
0.70.60.50.4
0.3
0.20.1
00 2 4 6 8 10
Events/N (%)Medianin Wks
Pmab + BSCBSC alone
114/119 (96)
12.37.3
19.09.3
HR: 0.45 (95% CI: 0.34–0.59)
12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52
Weeks
Pro
po
rtio
n W
ith
PF
S
1.0
0.90.8
0.70.60.50.4
0.30.20.1
00 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50
Weeks
Pmab + BSCBSC alone Mean
in Wks
76/84 (90)
Events/N (%)Medianin Wks
95/100 (95)
7.47.3
9.910.2
HR: 0.99 (95% CI: 0.73–1.36)
52
Amado et al., JCO 2008.
What About EGFR Ab/Chemotherapy Combinations 1st Line in KRAS WT Pts?
1st Line Chemotherapy/Ab Trials KRAS WT
Maughan ESMO 2009
CRYSTAL PFS 9.9 vs 8.7m HR 0.68 p=0.017
OPUS PFS 7.7 vs 7.2 HR 0.57 p=0.016
COIN PFS 8.6 vs 8.6 m HR 0.96 (0.84-1.09) p=0.60
What About Panitumumab/ Chemotherapy (without Bevacizumab) Combinations
First Line?
Randomized phase 3 study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as first-line
treatment in patients with metastatic colorectal cancer: the PRIME trial
S. Siena,1 J. Cassidy,2 J. Tabernero,3 R. Burkes,4 M.E. Barugel,5
Y. Humblet,6 D. Cunningham,7
F. Xu,8 J. Gansert,8 J.Y. Douillard9 1Ospedale Niguarda Ca’ Granda, Milan, Italy; 2The Beatson West Of Scotland Cancer
Centre, Glasgow, United Kingdom; 3Vall d'Hebron University Hospital, Barcelona, Spain; 4Mount Sinai Hospital, Toronto, Canada; 5Hospital de Gastroenterología,
Buenos Aires, Argentina; 6Centre du Cancer de l'Université Catholique de Louvain, Brussels, Belgium; 7The Royal Marsden NHS Foundation Trust, London, United Kingdom; 8Amgen Inc., Thousand Oaks, California, 9Centre René Gauducheau,
Nantes, France;
Study Schema and Stratification
Treatment Treatment Arm 1:Arm 1:
Panitumumab Panitumumab 6.0 mg/kg Q2W + 6.0 mg/kg Q2W + FOLFOX4 Q2WFOLFOX4 Q2W
EENNRROOLLLLMMEENNTT
EENND D OOF F
TTRREEAATTMMEENNTT
LLOONNGG
TTEERRMM
FFOOLLLLOOWW
UUPP
Disease assessment Disease assessment every 8 weeksevery 8 weeks
Treatment Arm 2:Treatment Arm 2:
FOLFOX4 Q2WFOLFOX4 Q2W
Enrollment Target:Enrollment Target:1150 patients 1150 patients
Randomization stratification:Randomization stratification:• ECOG score: 0-1 vs. 2ECOG score: 0-1 vs. 2• Geographic Region: Western Geographic Region: Western
Europe, Canada, and Australia Europe, Canada, and Australia vs. Rest of the Worldvs. Rest of the World
SSCCRREEEENNIINNGG
PRIME PRIME Study Study CountriesCountries
CanadaCanada
United KingdomUnited KingdomBelgiumBelgiumFranceFranceSpainSpainSwitzerlandSwitzerlandItalyItalyPolandPolandCzech RepublicCzech RepublicHungaryHungaryLatviaLatvia
SouthSouthAfricaAfrica
MexicoMexicoCostaCostaRicaRica
BrazilBrazilChileChileArgentinaArgentina
AustraliaAustralia
Siena Results
• Primary Endpoint (KRAS WT) – PFS: 9.5 vs 8.0m; HR 0.80 (0.66-0.97) p=.02
• Secondary Endpoints (KRAS WT)– OS: 23.9 vs 19.7m; HR 0.83 (0.67-1.02) p=.07– RR: 55 vs 48%
• Increased toxicity: skin, diarrhea, mucositis
• ECOG 2 HR 1.99 (0.96-4.15)
Conclusions• Large, well done randomized trial• KRAS WT data analyzed prospectively• Reached PFS endpoint• Improved OS, but p=0.07• Worse outcome has been seen in ECOG 2 pts in similar
trials• How does this compare to other EGFR Ab 1st line trials?
– Overlapping CI with CRYSTAL and OPUS– Where does COIN fit in?
• Does the chemotherapy backbone matter?• Should panitumumab be approved 1st line?
Conclusions (cont.)• The question is not cetuximab vs panitumumab
but EGFR Ab vs bevacizumab in KRAS WT• Increased RR with EGFR Ab• Increased GI, skin toxicity vs rare ATE, perforation• PEAK (rPhII)
– mFOLFOX6 + panitumumab– mFOLFOX6 + bevacizumab
• CALGB 80405 (PhIII)– FOLFOX/FOLFIRI + cetuximab– FOLFOX/FOLFIRI + bevacizumab– FOLFOX/FOLFIRI + cetuximab + bevacizumab
What About EGFR Ab/Chemotherapy Combinations Second Line?
EPIC (Sobrero)PFS 4.0 vs 2.6m HR 0.78 p=<.0001RR 16.4 vs 4.2%No OS difference (? crossover)
KRASODAC HR 0.70 but <25%of pts
What about panitumumab/chemotherapy combinations second line in KRAS WT patients?
Randomized phase 3 study of panitumumab with Randomized phase 3 study of panitumumab with FOLFIRI vs FOLFIRI alone as 2nd-line treatment in FOLFIRI vs FOLFIRI alone as 2nd-line treatment in patients with metastatic colorectal cancer: Patient patients with metastatic colorectal cancer: Patient
reported outcomes (PRO)reported outcomes (PRO)
M. Peeters,M. Peeters,1 1 T. Price,T. Price,22 Y. Hotko, Y. Hotko,33 A. Cervantes, A. Cervantes,44 M. Ducreux,M. Ducreux,5 5 T. André,T. André,66 A. H. Strickland, A. H. Strickland,77 G. G.
Wilson,Wilson,88 Y. Tian, Y. Tian,99 J. Gansert J. Gansert99
11University Hospital Ghent, Ghent, Belgium; University Hospital Ghent, Ghent, Belgium; 22Queen Elizabeth Hospital, Woodville, Australia; Queen Elizabeth Hospital, Woodville, Australia; 33Uzhgorod National University, Uzhgorod Regional Oncology Dispensary, Uzhgorod, Uzhgorod National University, Uzhgorod Regional Oncology Dispensary, Uzhgorod,
Ukraine; Ukraine; 44Hospital Clínico Universitario de Valencia, Valencia, Spain; Hospital Clínico Universitario de Valencia, Valencia, Spain; 55Institut Gustave Institut Gustave Roussy, Villejuif, France; Roussy, Villejuif, France; 66Pitié-Salpétrière HospitalPitié-Salpétrière Hospital, Paris, France; , Paris, France; 77Monash Medical Center, Monash Medical Center,
East Bentleigh, AustraliaEast Bentleigh, Australia; ; 88Christie Hospital, Manchester, United KingdomChristie Hospital, Manchester, United Kingdom ; ; 99Amgen Inc., Amgen Inc., Thousand Oaks, CaliforniaThousand Oaks, California
Peeters Results
• Primary Endpoints (KRAS WT)– PFS: 5.9 vs 3.9m; HR 0.73 (0.59-0.90) p=.004– OS: 14.5 vs 12.5m; HR 0.85 (0.70-1.04) p=.12
• Secondary Endpoint– RR: 35 vs 10%
• Increased toxicity: skin, diarrhea, mucositis– Improved EQ-5D OHR (VAS) but not HSI (5 EQ-5D OHR (VAS) but not HSI (5
dimensions) in KRAS wtdimensions) in KRAS wt
Conclusions
• Large well done study• First prospective second line in KRAS WT• Expected toxicity, ? significance of PRO• Excellent PFS, OS in both arms• Statistical improvement in PFS, but not OS in a
“good” KRAS wt group but wide Cis• Should panitumumab be approved in 2nd line
combined with irinotecan based therapy?• Is this the new standard in second line KRAS
WT metastatic CRC?
Conclusions (cont)• How does this compare with bevacizumab
containing regimens?– ECOG 3200 (Giantonio, JCO 2007)– BRITE “study” (Grothey, JCO, 2008)
• Randomized Trials (KRAS WT)– ML18147/AIO0504 (PhIII)
• FP/Ox vs FP/Ox + bevacizumab• FP/Iri vs FP/Iri + bevacizumab
– SPIRITT (rPhII)• FOLFIRI + panitumumab• FOLFIRI + bevacizumab
– S0600 (PhIII)• FOLFIRI/Iri + cetuximab• FOLFIRI/Iri + bevacizumab
Does BRAF Mutation Identify Nonresponders?
Extracellular
Intracellular
Ligand
EGFR
PI3K
Akt
Ras
Raf
MEK
MAPK
Cell motility
MetastasisAngiogenesis
Proliferation
Cell survivalDNA
PTEN
BRAF Background
• BRAF is a serine/threonine kinase downstream of KRAS
• V600E mutation is found in 5-10% of CRCs• Mutation mutually exclusive with KRAS mut• Correlatated with poor prognosis
– Ogino, Gut, 2009– Tol, NEJM, 2009 (letter)
• Retrospective studies correlated with lack of response– Di Nicolantonio, JCO, 2008
Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer: the influence of KRAS and
BRAF biomarkers on outcome: updated data from the CRYSTAL trial
Eric Van Cutsem*, I Lang, G. Folprecht, M.P. Nowacki,
S. Cascinu, I. Shchepotin, J. Maurel,
D. Cunningham, Ph Rougier,
I. Celik, C.H. Köhne
*University Hospital Gasthuisberg,
Leuven, Belgium
Updated CRYSTAL Results KRAS WT (From Paper and ASCO)
• More pts analyzed, longer follow-up, retrospective analysis
• PFS– 9.9 vs 8.4m HR 0.70 p=.0012
• OS– 23.5 vs 20.0m HR 0.80 p=.0093
• PS 2 ? less benefit (small numbers)• Yes, OS is now statistically significant, but
does this change anything?
Clinical efficacy in KRAS wild-type tumors by BRAF mutation status
KRAS wt/BRAF wt (n=566)
KRAS wt/BRAF mt (n=59)
FOLFIRI
(n= 289)
Cetuximab +FOLFIRI (n= 277)
FOLFIRI
(n=33)
Cetuximab +FOLFIRI
(n=26)
Median OS mo[95% CI]
21.6[20.0–24.9]
25.1[22.5–28.7]
10.3[8.4–14.9]
14.1[8.5–18.5]
HR [95% CI]p-valuea
0.830 [0.687–1.004]0.0549
0.908 [0.507–1.624]0.7440
Median PFS mo[95% CI]
8.8[7.6–9.4]
10.9[9.4–11.8]
5.6[3.5–8.1]
8.0[3.6–9.1]
HR [95% CI]p-valuea
0.679 [0.533–0.864]0.0016
0.934 [0.425–2.056]0.8656
OR rate (%)[95% CI]
42.6[36.8–48.5]
61.0[55.0–66.8]
15.2[5.1–31.9]
19.2[6.6–39.4]
p-valueb <0.0001 0.9136
CI, confidence interval; OR, best overall response; OS, overall survival; PFS, progression-free survival; mo, months; mt, mutant; wt, wild-type
aStratified log-rank test; bCochran-Mantel-Haenszel test
Conclusions• BRAF confirmed as marker of poor prognosis
• Not so fast on excluding people from EGFR treatment (NCCN guidelines), but small numbers
• Need to look at randomized studies to validate predictive markers
• Possible target for therapy (PLX4032 in melanoma)
Standard Therapy of Metastatic CRC: US 2010
KRAS WT1st Line:
FP/oxaliplatin or Iri + bevacizumabFP/Ox or Iri + cetuximab*FP/Ox + panitumumab*
2nd Line: FP/oxaliplatin or Iri + bevacizumabIrinotecan + cetuximab (if EGFR Ab not used 1st line)FOLFIRI + panitumumab* (if EGFR Ab not used 1st line)
3rd Line: Irinotecan + cetuximab (if EGFR Ab not used earlier)Single agent cetuximab or panitumumab (if not used earlier)
Standard Therapy of Metastatic CRC: US 2010
KRAS Mut1st Line:
FP/oxaliplatin or Iri + bevacizumab
2nd Line: FOLFIRI or FP/ox + bevacizumab
3rd Line: Clinical trialBSC