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Novel Targets and Therapies for GI Malignancies: What does the future hold?. David H. Ilson, M.D., Ph.D. GI Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY. GI Cancers: US Incidence in 2013. 292,200 new cases and 144,570 deaths (49%) Case Fatality Rate: - PowerPoint PPT Presentation
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Novel Targets and Therapies for GI Malignancies: What does the future hold?
David H. Ilson, M.D., Ph.D.GI Oncology ServiceMemorial Sloan-Kettering Cancer CenterNew York, NY
GI Cancers: US Incidence in 2013
292,200 new cases and 144,570 deaths (49%)
Case Fatality Rate:
– Colorectal: 48%
– Esophagogastric: 66%
– Pancreatic: 85%
– HCC: 70%
Male > Female
Ongoing rise in Esophageal and GEJ Adenocarcinoma, HCC
Siegel et al, CA 63: 11-30; 2013
Gene Amplification more Common in Esophagogastric Cancer
296 Esophageal / Gastric Cancers, 190 CRC
Amplified genes in 37% Gas / Eso tumors
– FGFR1-2
– HER2
– EGFR
– MET
Targetable Receptors and Receptor Tyrosine Kinases
KRAS also amplified
Similar data for a Chinese series
Dulak AM et al Can Res 72: 4383; 2012
Molecular Targets: Esophageal and Gastric Cancer
Molecular Targets: Esophageal and Gastric Cancer
• KRAS mutation: <5%
• BRAF mutation: <5%
• EGFr mutation: <5%
• HER2 over expression / amplification: 10% to 25%– Trastuzumab + chemo improves OS in HER2+ disease
• CMET amplification: 10%– IHC over expression 40%
Dulak AM, et al. Cancer Res. 2012;72(17):4383-4393. Dulak AM, et al. Nat Genet. 2013;45(5):478-486. Lordick F, et al. Lancet Oncol. 2013;14(6):490-499. Bang YJ, et al. Lancet. 2010;376(9742):687-697.
ToGA Trial Design
HER2-positiveadvanced GC
(n = 584)
5FU or capecitabine + cisplatin(n = 290)
R
5FU or capecitabine + cisplatin
+ trastuzumab(n = 294)
Phase III, randomized, open-label, international, multicenter study
3807 patients screened 810 HER2-positive (22.1%)
• Stratification factors─ Advanced vs metastatic ─ GC vs GEJ─ Measurable vs nonmeasurable─ ECOG PS 0-1 vs 2─ Capecitabine vs 5-FU
Bang Y, et al. Lancet. 2010;376(9742):687-697
ToGA: Efficacy OutcomeToGA: Efficacy Outcome
• Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC
• Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4-month increase in OS with trastuzumab
− HR: 0.65 (95% CI: 0.51-0.83)
Chemotherapy + Trastuzumab
(n = 294)
Chemotherapy Alone
(n = 290) HR (95% CI) P Value
Primary endpoint
Median OS, months 13.8 11.1 0.74 (0.60-0.91) .0046
Secondary endpoints
Median PFS, months 6.7 5.5 0.71 (0.59-0.85) .0002
ORR, % 47.3 34.6 - .0017
• CR 5.4 2.4 - .0599
• PR 41.8 32.1 - .0145
ORR, overall response rateBang Y, et al. Lancet. 2010;376(9742):687-697.
Targeted Agents Phase III: HER2: Met Disease
LOGIC: Cape-Ox + / - Lapatinib (HER2+)
– First line
– Negative trial for OS
– Benefit in Asian pts
TYTAN: Paclitaxel + / - Lapatinib (HER2+)
– Second Line: Negative Trial
– PFS and Survival Benefit in subset of patients IHC 3+ for lapatinib
Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001 Bang et al GI Cancers Symposium 2013 Abstract 11
RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for
Esophageal Adenocarcinoma (Siewert I, II)
RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for
Esophageal Adenocarcinoma (Siewert I, II)
‘
CHEMORADIATIONCHEMORADIATION
HER-2 (+)(FISH)
HER-2 (+)(FISH)
TRASTUZUMAB+
CHEMORADIATION
TRASTUZUMAB+
CHEMORADIATION
SURGERYSURGERY
SURGERY+
TRASTUZUMAB (1 YR)
SURGERY+
TRASTUZUMAB (1 YR)
HER-2 (-)(FISH)
HER-2 (-)(FISH)
ALTERNATIVE STUDIES
ALTERNATIVE STUDIES
Chemoradiation: Carboplatin, Paclitaxel + RT 5040 cGy SurgeryMaintenance trastuzumab post opOS Primary Endpoint
HER2-Directed Therapy TrialsHER2-Directed Therapy Trials
• Ongoing HER2 Trials– First-line
- JACOB: Cape-Cis-Trastuzumab + / - Pertuzumab, 780 patients
- HELOISE: Cape-Cis + 2 dose levels of Trastuzumab, 400 patients
– Second-line:- GATSBY: Paclitaxel vs TDM-1
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGFVEGF-B
VEGF-C, VEGF-D
Fu
nct
ion
s
Large molecule VEGF inhibitors
Bevacizumab
Ramucirumab
Aflibercept (VEGF Trap)
Targeted Agents Phase III: Negative Trials for VEGF, mTOR, and EGFr
AVAGAST: Cape-Cisplatin + / - Bevacizumab
– Negative trial for OS
mTOR GRANITE: BSC vs Everolimus – Negative trial for OS
REAL 3: ECX + / - Panitumumab (U.K.)
– Negative: Panitumumab had inferior outcomes
EXPAND: Cape-Cis + / Cetuximab (E.U.)
– Negative: Cetuximab trended inferior
COG: BSC vs Gefitinib (U.K.): Negative
Ohtsu A, et al. J Clin Oncol. 2011;29(30):3968-3976 Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943 Waddell T Lance Oncol 14: 481; 2013 Lordick F et al Lancet 14:490; 2013 Sutton JCO 30: 2012 (suppl 34 abstr 6)
EGFr: Definitive Cetuximab + Chemo RT SCOPE-1
Cape-Cis Cape-Cis-RT + / - RT
258 pts (65 AC,188 SCC)
RTOG 0436
Pac-Cis-RT + / - Cetuximab
328 pts (203 AC,125 SCC)
Crosby Lancet 14: 627; 2013 Suntha JCO 32: 2014 (suppl 3; abstr LBA6
VEGF Revisited?VEGF Revisited?
• Apatinib– Small-molecule multitargeted TKI with activity against VEGFR– China– 144 patients, placebo vs 850 mg/d or 425 mg BID– OS 2.5 months 4.0 months, 4.5 months– RR 10%
• Phase III Trial Planned
• Ramucirumab: Humanized moAb Targeting VEGr2 receptor
TKI, tyrosine kinase inhibitor; VEGFR, VEGF receptorLi J, et al. J Clin Oncol. 2013;31(26):3219-3225. Fuchs CS, et al. Lancet. 2014;383(9911):31-39.
VEGFr: Ramucirumab in Gastric Cancer: REGARD Trial
RANDOMIZATION, 355 patients
BSC + Placebo
Fuchs CS, et al. Lancet. 2014;383(9911):31-39
Gastric/GEJ Cancer with POD on FU or Platinum Based Chemo
BSC + Ramucirumab 8 mg/kg q 2 weeks
VEGF Revisited? Ramucirumab: REGARD Trial
VEGF Revisited? Ramucirumab: REGARD Trial
• PFS improved 2.1 months 3.8 months (HR 0.483, P<.0001)
• OS improved 3.8 months 5.2 months (HR 0.776, P = .047)
• Disease control improved from 23% to 49% (P<.0001)
• Essentially no toxicity (rare grade ≥3 hypertension 8%)
Fuchs CS, et al. Lancet. 2014;383(9911):31-39.
REGARD Trial: ResultsREGARD Trial: Results
27
HR (95% CI) = 0.776 (0.603-0.998)Log-rank P value (stratified) =.047
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 28
0
20
40
60
80
100
238 117
Number at riskRamucirumab
Placebo
15466
9234
4920
177
74
32
00
01
Ramucirumab (n = 238)Placebo (n = 117)Censored
Time Since Randomization, Months
Fuchs CS, et al. Lancet. 2014;383(9911):31-39.
20
HR (95% CI) = 0.483 (0.376-0.620)Log-rank P value (stratified) <.0001
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
0
40
60
80
100
238 117
Number at riskRamucirumab
Placebo21392
52
00
11327
6511
617
454
302
182
182
112
41
21
10
10
10
10
Time Since Randomization, Months
Ramucirumab (n = 238)Placebo (n = 117)Censored
OS PFS
Treat until disease
progression or
intolerable toxicity
• Important inclusion criteria:
- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma
- Progression after 1st line platinum/fluoropyrimidine based chemotherapy
•Stratification factors:
- Geographic region,
- Measurable vs non-measurable disease,
- Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
Ramucirumab 8 mg/kg day 1&15+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycleN = 330
Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
SCREEN
RANDOMIZE
Survival and safety
follow-up
VEGFr: RAINBOW: Study Design
1:1
Wilke GI Symposium 2014 LBA 7
RAINBOW: Ramucirumab + Paclitaxel for Metastatic Gastric Cancer
RAINBOW: Ramucirumab + Paclitaxel for Metastatic Gastric Cancer
• 665 pts with POD on fluorinated pyrimidine + platinum
• Weekly paclitaxel 80 mg/m2 + /- Ram 8 mg/kg
• PFS improved 2.9 months 4.4 months (HR 0.635, P<.0001)
• OS improved 7.4 months 9.6 months (HR 0.807, P = .0169)
• RR improved from 16% to 28% (p = 0.0010 (P<.0001)
• Increased toxicity neutropenia and hypertension
Wilke GI Symposium 2014 LBA 7
RamucirumabRamucirumab
• First-line: FOLFOX + / - Ramucirumab
– Randomized phase II
• Other VEGF agents
– FOLFOX + / - Pazopanib (TKI)
VEGF Adjuvant Trials Gastric Cancer
VEGF Adjuvant Trials Gastric Cancer
• MAGIC 2 Trial: EOX + / - Bevacizumab– Amended for HER2 + patients– Randomized to + / - Lapatinib (HER1-2 TKI)
CMET Pathway
Goyal L, et al. Clin Cancer Res. 2013;19(9):2310-2318.
CMET: Rilotumumab: Gastric Cancer First Line
Phase II
RANDOMIZE
ARM ARilotumumab (15 mg/kg) + ECX
Q3W (n = 40)
ARM BRilotumumab (7.5 mg/kg) + ECX
Q3W (n = 40)
ARM CPlacebo + ECXQ3W (n = 40)
Stratification factors:ECOG PS 0 vs 1LA vs Metastatic
E: Epirubicin: 50 mg/m2 IV, day 1C: Cisplatin: 60 mg/m2 IV, day 1
X: Capecitabine: 625 mg/m2 BID orally, days 1-2
Rilotumumab: IV over 60 ± 10 minutes prior to chemotherapyClinicalTrials.gov identifier: NCT00719550Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.
PFS and OS in c-MetHigh PatientsMedian Months
(80% CI) HR (80% CI)
6.9 (5.1, 7.5) 0.53 (0.25, 1.13)
4.6 (3.7, 5.2)
Median Months (80% CI) HR (80% CI)
11.1 (9.2, 13.3) 0.29 (0.11, 0.76)
5.7 (4.5, 10.4)
Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.
Ongoing Trials: Met Inhibitors
Targeting CMET, + IHC
RILOMET-1
– ECX + / - Rilotumumab (targeting ligand HGF)
MetGastric
– FOLFOX + / - MetMab (targeting receptor)
Tyrosine Kinase Inhibitors
– Promising phase I activity in CMET amplified
Fibroblast growth factor receptor
Ligand activated trans membrane growth factor receptor
Signals via RAS Map kinase and PI3K-AKT but also via Hedgehog and Notch pathways, and WNT
Phase II Trials
– Dovitinib (TKI) in FGFR gene amplified gastric cancer
– Dovitinib + Docetaxel in gastric cancer
PARP Inhibitors: Olaparib in Gastric Cancer
RANDOMIZATION:
Paclitaxel
Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013
Gastric/GEJ Cancer with POD on FP
Paclitaxel + Olaparinib
PARP Inhibition in Gastric Cancer: Olaparib
Patients randomized to Paclitaxel + / OlaparibTissue testing for ATM protein
Negative in13% = In vitro sensitivity to olaparib 124 patients randomized, ATM + / -OS benefit in ATM + / -, Greater in ATM –Phase III Trial planned
Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013
Trials of Targeted Agents1st Line
Target Agent Trial Regimen Number Status
HER2 Pertuzumab JACOB XP + T +/- Pertuzumab
780 Ongoing
HER2 Trastuzumab HELOISE XP + T (2 doses) 400 Ongoing
CMET Rilotumumab Rilomet-1 ECX + / - Rilo 650 Ongoing
CMET Onartuzumab MetGastric FOLFOX + /- O 800 Ongoing
EGFr Panitumumab NCT01627379 5-FU-Cis + / - Pan
300 Ongoing
VEGFr Pazopanib PaFLO FLO + / - Pazop 75 Ongoing
2nd Line
mTOR Everolimus AIOST00111 Pac + / - Evero 665 Ongoing
HER2 TDM-1 GATSBY Pac vs TDM-1 412 Ongoing
EGFr Nimotuzumab NCT01813253 Irino + / - Nimo 400 Ongoing
PARP Olaparib Pac + / - Olap Planned
Esophagogastric Cancer: ImmunotherapiesEsophagogastric Cancer: Immunotherapies• Agents that deregulate immune suppression
• Anti PD-1 phase I:
– PD-1: T cell programmed cell death receptor, blockade may enhance immune responses
– Active in NSCLC, RCC
– 7 gastric cancers, no activity
• Anti PDL-1 phase I– MPDL3280A: Blocks ligand
– PR in 1/1 Gastric Cancer, 26/29 responses ongoing
– Enhanced activity in PDL-1 + patients
• Ipilimumab
– Anti CTLA-4 antibody
– Phase II
– FOLFOX capecitabine maintenance vs ipilumimab
Ribas A, et al. N Eng J Med. 2012;366:2443 Herbst R et al. JCO 31 (supp): Abstract 3000
HCC: Sorafenib is the Standard for Advanced Disease
SHARP TRIAL ASIA PACIFIC TRIAL
Llovet NEJM 359: 378; 2008 Chang Lancet Oncol 10:25; 2009
OS 4.5 6.2 months, HR 0.68OS 7.9 10.7 months, HR 0.69
Sorafenib in HCC
Modest single agent activity in Child’s A pts with HCC
Toxicity monitoring and dose reduction are key
Outcomes vary depending on geographic region, etiology and severity of cirrhosis
No biomarker has been identified
Failed Phase III TrialsAgent Target Number Overall Survival
First Line
Sunitinib vs Sorafenib
VEGFr, PDGFr, C-KIT, FLT3
1074 8.1 vs 10 months, HR 1.31
Brivanib vs Sorafenib
VEGFr, FGFr 1155 9.5 vs 9.9 months, HR 1.07
Erlotinib/Placebo vs E/Sorafenib
EGFR 720 9.5 vs 8.5 months, HR 0.929
Linifanib vs Sorafenib
VEGFr, PDGFr 1035 9.1 vs 9.8 months, HR 1.046
Second Line
Brivanib vs BSC VEGFr, FGFr 395 9.4 vs 8.2 months, HR 0.89
Sorafenib OS consistently 8.5-10 months
Ongoing Single Agent Studies
Angiogenesis:
– Ramucirumab, TSU-68, Cedirinab, Pazopanib, lenvatinib, Axitinib
CMET:
– Tivantinib, cabozantinib, foretinib, METmab, IMC-280, LY2875358
EGFR:
– Lapatinib, cetuximab
mTOR:
– Everolimus, temsirolimus, sirolimus, CC-23
Ongoing Single Agent Studies
MEK
– Selumetinib, rafametinib
HDAC
– Belinostat, resminostat
HSP-90
– Genetespib
Oncolytic viruses
– JX-594
Immunotherapy
– Tremelimumab, PD-1, PD-L1
CMET Targeted Therapy in HCC Tivantinib vs Placebo in HCC
– CMET TKI
107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib
– 160 mg tivantinib vs placebo
– Cross over permitted at POD
TTP HR 0.64, p = 0.04
– OS not different, given cross over (6.2-6.6 months)
CMET IHC low, better prognosis, no benefit from tivantinib
CMET IHC high, OS 3.8 to 7.2 months (HR 0.38, p = 0.01) with tivantinib
Phase III Trial planned in CMET high pts
Santoro Lancet Oncol 14: 55; 2013
OS CMET High
CMET Targeted Therapy in HCC Cabozantinib vs Placebo in HCC (4007)
– CMET and VEGR2 TKI, most patients failed sorafenib
107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib
– 100 mg cabozantinib, stable disease randomized to placebo or continuation
– Cross over permitted at POD
41 treated
PFS 4.4 mos, OS 15 mos in all pts
RR 5%, Stable disease 78%
Larger phase II trial planned
Verslype et alJ Clin Oncol 30: 2012 (suppl Abst 4007)
Promising Signals
Ramucirumab
– Anti VEGFr2
– RR 10%, PFS 4 months, OS 12 months
Lenvatinib
– VEGFr1-3, FGFr1-4, RET, KIT, PDGFrβ TKI
– 37% modified RECIST response rate
– TTP 12.8 months, OS 18.7 months
Immunotherapy
– Anti CTLA-4
– RR 17%, PFS 6 months
Ongoing Trials First Line
– Sorafenib vs Sorafenib + Doxorubicin (CALGB 80802)
– Lenvantinib vs Sorafenib
Sorafenib + Local Regional Therapy
– Sorafenib + / - SBRT (RTOG 1112)
– Sorafenib + / - TACE (ECOG)
– Sorafenib vs Y90
Second Line
– Ramucirumab vs BSC
– ADI-PEG 20 vs BSC
– Tivantinib and Cabozantinib vs BSC
– Regorafenib vs BSC
Pancreatic Cancer
Improvements in Chemotherapy
Gemcitabine G + Nab-Paclitaxel FOLFIRINOX
OS 6 months 8.5 months 11.1 months
Response: 6% 23% 32%
Targeted Agents
– Only approved agent is EGFr TKI Erlotinib
Moore, et al. J Clin Oncol, 2007
NCI PA.3 Phase III TrialUntreated Advanced Pancreas Ca
Stratify N= 569
•LA vs M1•Center•PS 0-1 vs 2
Primary Enpoint OS80% power, 33% increase
Gemcitabine +
Placebo
RANDOMIZE
Gemcitabine +
Erlotinib
Moore, et al. J Clin Oncol, 2007
Months
Su
rviv
al D
istr
ibu
tio
n F
un
cti
on 1.00
0.75
0.50
0.25
00 6 12 18 24
PA.3 Overall SurvivalG + Erlotinib
(N= 261)G + Placebo
(N= 260)
Med. Survival (mths) 6.24 mths 5.9 mths
1-Year Survival 23% 17%
CR + PR 8.6% 8%
CR + PR + SD 57% 49%
HR= 0.82 (0.69-0.99) p= 0.038
*Adjusted for PS and extent of disease at baseline† From Cox regression model‡ From 2-sided log-rank test
Molecular CorrelatesGemcitabine +/- Erlotinib PA.3
• N= 569 pts – 117 samples (21%)
– EGFR (+) or (–) no correlation with outcome– Post-hoc K-ras mutational status analysis
Trend to OS benefit in the pts with wild-type K-ras
Gem Gem + E HR P-value
K-ras mutant 7.4 mths 6.0 mths 1.07 0.78
K-ras WT 4.5 mths 6.1 mths 0.66 0.34
Moore, et al. ASCO, 2007 (Abst #4521)
Genetic Alterations in Pancreatic CaGene Mutation/ Deletion• p16 80% • K-ras (B-raf) 90%+• p53 70%• SMAD4/ TGFβR1+2 55%• BRCA 1, 2, PALB2 5-8%• Mismatch repair genes 4%• STK11 (Peutz-Jeghers) 5%• MKK4 5-13%• FANCC/ FANCG 5% Amplification/ Overexpression• PI3K/ Akt, c-myc, Shh/ Gli, Notch, etc (10-30%)
Infiltrating pancreatic ca
Other Genetic Changes• Telomere shortening• Widespread allelic loss
Courtesy, M. Goggins (JHCC)
NegativePhase III Anti-Vascular Trials in PC
Drug N RR Med OS Reference
Gemcitabine + Bevacizumab590
13% 5.8 mths KindlerCALGB 80303Gemcitabine + Placebo 10% 6.1 mths
Gemcitabine + Erlotinib + Bevaciz.607
13.5% 7.1 mths Van CutsemAViTAGemcitabine + Erlotinib 8.6% 6 mths
Gemcitabine + Axitinib593
NR 8.5 mthsKindler
Gemcitabine + Placebo NR 8.3 mths
Gemcitabine + Aflibercept594
NR 7.7 mthsRougier
Gemcitabine + Placebo NR 6.5 mths
Kindler, HJ. J Clin Oncol, 2010. Van Cutsem, E. J Clin Oncol, 2009. Kindler, HJ. Lancet Oncology, 2011. Rougier, P. ESMO, GI, 2010
New Targets, New DrugsTarget Class of Drug Example of Drug
IGF-1R Antibody to IGF-1RTyrosine kinase inhibitor
AMG 479, MK-0646, IMC-A12OSI-906
RAS Farnesyl transf. inhibitorOncolytic viral agents
Tipifarnib, SalarasibReovirus
mTOR/ P13K/ AKT/MEK
mTOR inhibitorAKT, P13K
Everolimus, temsirolimusMK-2206, XL-765, BKM-120, Selumetinib
Hedgehog (Hh)Notch
Small molecule Hh inhibitorGamma-secretase inhibitor
GDC-0449, IPI-926, LDE-225R04929097
PMSCA Antibody to PSCA AGS-1C4D4
SRC SRC, bcr-abl inhibitor Dasatinib, AZD 0530
TRAIL Antibody to DR4, DR5 MapatumumabAMG 655
Integrin Antibody to α5β1 integrin Volociximab
PARP PARP inhibitor AZD 2281, ABT-888, BSI-201
Vaccines/ Immunotherapy Checkpoint inhibitors, vaccines Ipilumimab, nivolumab,
GVAX/CRS207
Phase II: GVAX + / - CRS-207 GVAX: Irradiated, GM-CSF secreting allogeneic
pancreatic cancer cell lines given intradermally, preceded by Cytoxan to reduce T regs
CRS-207: Live-attenuated Listeria monocytogenes which expresses mesothelin immune stimulant
90 pts previous treated randomized 2: 1 to
C/GVAX + CRS-207 or C/GVAX alone
OS 6.1 vs 3.9 months (HR 0.54, p = 0.011)
More CA 19-9 stabilization with combination
Le J Clin Oncol 32: 2014 (suppl 3; abstr 177)
Recent Negative Phase II-III Targeted TherapyDrug Trial Med PFS or OS Reference
Gem + AMG-479 (IGF-1R) Phase III GAMMA No ChangePress Release
Gem + Placebo
Gem + Sorafenib Phase III BAYPAN PFS 5.7 mosGoncalves Ann Oncol 2012Gem + Placebo 3.8 mos
Gem Phase II LEAP OS 6.0 mos Poplin ASCO 2013CO-1.01 (hENT1) 6.0 mos
Gem + Masitinib (CKIT, PDGF, FGF)
Phase III 7.7 mos Deplanqa GI
Symposium 2013Gem + Placebo 6.0 mos
Gem + IPI-926 (Shh) Phase II6.0 mos
Press Release
Gem 5.9 mos
Gem + Vismodegib Phase II6.3 mos
Catenacci ASCO 2012
Gem (Shh) 5.4 mos
Novel Targets Stroma and Microenvironment
– PEGPH20: degrades hyaluronic acic, may increase drug delivery
– Onoing phase II:
Nab-P + / - PEGPH20
FOLFIRINOX + / - PEGPH20
BRCA mutant pancreatic cancers (5%)
– Deficient homologous DS DNA repair
– Results in genomic instability, chromosomal deletion and exchange
– PARP inhibition
Cis-Gem + / Veliparib, randomized phase II
Ongoing Randomized Phase II-III Trials
Number Target
Phase III
Gem + / - TH302 (alkylating agent)
660 Hypoxic Environment
Phase II
Gem-Nab-P + / - PEGPH20
M402OMP59R5OGX-427
132148140132
Hyaluronic acidStromaNotchHSP27
Gem + / -MSC193698
AfatinibTL-118
17411780
MEKEGFR, HER2Angiogenesis
Gem-Cis + / - Veliparib 70 PARP
Approved Targeted Agents in CRC Growth factor receptor inhibitors:
– VEGFr/ VEGF
Anti VEGF A ligand antibody: Bevacizumab
Soluble VEGF receptor: Aflibercept
VEGFr TKI: Regorafenib
– EGFr:
Anti EGFr antibodies:
Cetuximab
Panitumumab
Integration of VEGF Targeted Agents into Chemotherapy
Bevacizumab can be used with first line FOLFIRI, 5-FU/capecitabine, FOLFOX
Bevacizumab can be continued into second line chemotherapy, with FOLFOX or FOLFIRI
Alfibercept can be used second line with FOLFIRI after POD on FOLFOX/Bev
Regorafenib: Late line therapy after POD on all conventional lines of therapy
Intracellular
Extracellular
Src PLC GAP Grb2 Shc Nck Vav Grb7 Crk
Ras
PKC
Survival, Growth, Proliferation, Adhesion, Migration, Angiogenesis, Metastasis
PI3K MAPK JNK
Abl
HER1/EGFR Signaling Pathways
P P
Data from Sedlacek. Drugs. 2000;59:435.
Integration of EGFR Agents in Colorectal Cancer: KRAS WT tumors
First Line:
– Cetuximab, Panitumumab approved to combine with FOLFIRI or FOLFOX
– Capecitabine based trials with Cetuximab failed toxicity
Second, Third Line
– Cetuximab, Panitumumab approved as monotherapy
– Suggested added benefit when combined with irinotecan or FOLFIRI second line
BRAF mutant patients are eligible for EGFR therapy
All KRAS Mutant Patients Should Not Get Cetuximab
Current testing looks at KRAS exon 2 mutations
Trial of FOLFOX + / - Cetuximab
An additional 17% had KRAS exon 3/4, NRAS exon 2/3/4
Douillard NEJM 369:11;2013
Primary endpointPrimary endpoint: OS: OS Secondary endpointsSecondary endpoints: ORR, PFS, TTF, DOR, and safety: ORR, PFS, TTF, DOR, and safety
CALGB 80405: Bevacizumab vs Cetuximab in First-line KRAS WT mCRC
Untreated Untreated KRAS WT KRAS WT mCRCmCRC(n=1500)(n=1500)
BevacizumabBevacizumab+ FOLFOX+ FOLFOXor FOLFIRIor FOLFIRI
CetuximabCetuximab+ FOLFOX+ FOLFOXor FOLFIRIor FOLFIRI
PDPD
PDPD
RR
NCT identifier: NCT00265850. 5757
• Key inclusion criteria– Patients ≥18 years with histologically confirmed diagnosis of mCRC– ECOG PS 0-2– prior adjuvant chemotherapy allowed if completed >6 month before inclusion
• Amendment in October 2008 to include only KRAS wildtype patients
• 150 active centers in Germany and Austria
Phase III study design
FOLFIRI + CetuximabCetuximab: 400 mg/m2 i.v. 120min initial dose
250 mg/m2 i.v. 60min q 1w
FOLFIRI + CetuximabCetuximab: 400 mg/m2 i.v. 120min initial dose
250 mg/m2 i.v. 60min q 1w
FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w
FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w
mCRC1st-line therapyKRAS wild-type
N= 592
Randomize 1:1
FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2 irinotecan: 180 mg/m2
5-FU: 2,400 mg/m2 (i.v. 46h)
Evaluation of ORR
p = Fisher´s exact test (one-sided) p = Fisher´s exact test (one-sided)
FOLFIRI + Cetuximab FOLFIRI + BevacizumabOdds ratio
pORR % 95%-CI % 95%-CI
ITT population
(N= 592)62.0 56.2 – 67.5 58.0 52.1 – 63.7
1.180.85-1.64 0.183
Assessable for response
(N= 526)72.2 66.2 – 77.6 63.1 57.1 – 68.9
1.521.05-2.19 0.017
Progression-free survival
0.75
1.0
0.50
0.25
12 24 36 48 60 72
months since start of treatment
297295
numbers at risk
10099
1915
106
54
3
0.0
Pro
ba
bil
ity
of
su
rviv
al
Eventsn/N (%)
Median(months)
95% CI
― FOLFIRI + Cetuximab 250/297(84.2%)
10.0 8.8 – 10.8
― FOLFIRI + Bevacizumab 242/295(82.0%)
10.3 9.8 – 11.3
HR 1.06 (95% CI 0.88 – 1.26)Log-rank p= 0.547
Overall survival
Eventsn/N (%)
Median(months)
95% CI
― FOLFIRI + Cetuximab 158/297(53.2%)
28.7 24.0 – 36.6
― FOLFIRI + Bevacizumab 185/295(62.7%)
25.0 22.7 – 27.6
HR 0.77 (95% CI: 0.62 – 0.96)Log-rank p= 0.017
0.012 24 36 48 60 72
months since start of treatment
297295
numbers at risk
218214
111111
6047
2918
92
0.75
1.0
0.50
0.25
0.0
Pro
ba
bil
ity
of
su
rviv
al
I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab (RAISE)I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab (RAISE)
Stratification factors:•Region•KRAS status•First-line TTP (<>6 mos)
1:1
mCRC afterfailure
FP/oxaliplatin+ BEV regimen
R
525 pts Ramucirumab IV+ FOLFIRI q 2 weeks
525 pts Placebo + FOLFIRIq 2 weeks
62
Primary EP: OSAccrual completedPIs: Tabernero
Anti-CTLA4 in CRCAnti-CTLA4 in CRC
1/45 crc: PR
(response duration 15m)
Median PFS 2.3m
45% alive >6months
Chung et al. JCO 2010
0/18 crc0/18 crc
RESPONSE RATE
1/14 crc: CRRESPONSE RATE
BMS-936559 BMS-936558
RESPONSE RATE0/19 crc
MPDL3280A
1/4 crc
RESPONSE RATE
Anti-PDL1 Anti-PD1
Net N =55 CRC patients
Study Design (CA209-142 trial)to open January 2014: anti PD-1Study Design (CA209-142 trial)
to open January 2014: anti PD-1
BRAF V600E Inhibitor: PLX4032 (Vemurafenib)BRAF V600E Inhibitor: PLX4032 (Vemurafenib)
78% Response Rate
-100
-75
-50
-25
0
25
50
75
100
%C
han
ge
Fro
m B
asel
ine
(Su
m o
f L
esio
n S
ize)
-100
-75
-50
-25
0
25
50
75
100
%C
han
ge
Fro
m B
asel
ine
(Su
m o
f L
esio
n S
ize)
5% Response Rate
Refractory Melanoma Refractory Colorectal
Oncogene mutation does not imply oncogene dependence
Flaherty et al NEJM ‘10 Kopetz et al ASCO ‘10
Understand the biological context in which particular mutations occur
Low AKT activation
Minimal hypermethylation
High AKT activation
Extensive hypermethylation
Kopetz, CTPM Jan 2011
Randomized Phase II of Dual BRAF + EGFR Inhibition in BRAFmut mCRC
Primary endpoint: PFSArm B design pending outcomes from ongoing Phase 1 studies
N=42 ~800 screened
Eligibility:1) BRAF V600
mutation2) Prior treatment for
metastatic disease3) No more than 2
prior progression on chemotherapy
4) No prior cetuximab
Stratified:1) Prior treatment
with irinotecan
R
Cetuximab + Irinotecan
Vemurafenib + Cetuximab +Irinotecan
PFS
Arm A
Arm B
Courtesy: Scott Kopetz
Prominent cMET / HGF InhibitorsProminent cMET / HGF Inhibitors
Agent Structure Target
Rilotumumab Human monoclonal antibody
HGF
Onartuzumab (metMab)
Humanized monovalent antibody
c-MET
Tivantinib (ARQ 197)
Small molecule c-MET kinase
Cabozantinib (XL184)
Small molecule c-MET kinase
Phase 2 Study DesignPhase 2 Study Design
Eligibility• Age ≥ 18 years• Inoperable, locally
advanced or metastatic disease
• KRAS WT• 1 line of prior systemic
Tx• ECOG PS 0-1• No prior anti-EGFR
therapy
RANDOMIZE
N = 1501:1
DOUBLE
BLIND
Tivantinib(ARQ 197)360 mg PO BID
Cetuximab 500 mg/m2 IV q14 days
+
PlaceboPO BID
Irinotecan 180 mg/m2 IV q14 days
Cetuximab 500 mg/m2 IV q14 days
+ Irinotecan 180 mg/m2 IV q14 days
Primary Endpoint:PFSSecondary Endpoints:OS, ORR, safety
Stratification Factors:1) ECOG PS (0 vs 1)2) Best response to 1st-line therapy (CR/PR/SD vs PD) Eng et al., ASCO 2013
Progression-Free SurvivalFull Analysis Set (median follow-up: 15.9 mo)
Progression-Free SurvivalFull Analysis Set (median follow-up: 15.9 mo)
HR = 0.85 (95% CI, 0.55 - 1.33)Stratified log-rank P = 0.38
Pro
gre
ssio
n-F
ree S
urv
ival,
%
0 3 9 156 12 18 21
Time Since Randomization, mo
100
75
50
25
0Placebo (n = 57)Tivantinib (n = 60)
Events Median, mo 95% CI
T 44 8.3 5.6 - 10.8
P 37 7.3 5.3 - 9.0
Eng et al., ASCO 2013
PFS and OS by MET ExpressionPFS and OS by MET ExpressionMET-High MET-Low
Pro
gre
ssio
n-F
ree S
urv
ival,
%
0 3 6 9 12 15 18
100
50
75
25
0
Tivantinib(n = 24)Placebo(n = 20)
Overa
ll S
urv
ival,
%
0 4 8 12 16 20 24 28 32Time Since Randomization, mo
100
50
75
25
0
0 3 6 9 12 15 2118
100
50
75
25
0
Pro
gre
ssio
n-F
ree S
urv
ival,
%
Time Since Randomization, mo
100
50
75
25
0
Overa
ll S
urv
ival,
%
21
HR = 0.78 (95% CI, 0.24 - 2.47)Log-rank P = 0.67
HR = 0.22 (95% CI, 0.06 - 0.80)Log-rank P = 0.01
HR = 0.74 (95% CI, 0.36 - 1.52)Log-rank P = 0.41
HR = 0.58 (95% CI, 0.25 - 1.36)Log-rank P = 0.20
Tivantinib(n = 11)Placebo(n = 12)
PFS
OS
0 4 8 12 16 20 24 28 32
ORR: T = 54.2%; P = 30.0% ORR: T = 27.3%; P = 41.7%
Eng et al., ASCO 2013