Download CRC - inoncology

State of the Art
Colorectal Cancer (CRC)
Marc Peeters, MD, PhD
Antwerp University Hospital
Edegem, Belgium
Objectives
02
 Review current approaches for the management of CRC
 Discuss current challenges/unmet needs in the treatment of
mCRC
CRC Is A Global Health Burden
03
Global: 1.4 million new CRC cases and 0.7 million deaths in 2012
Source: GLOBOCAN 2012.
Global Cancer Facts & Figures 3rd Edition.
http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-044738.pdf.
Incidence of CRC in the Americas
04
Male (M)
Female (F)
Combined (M+F)
Top 10
countries with
highest
incidence
(Est. no. x1000):
U.S. 134.3
Brazil 33.9
Canada 23.8
Argentina 13.5
*
Mexico 8.7
Columbia 5.7
Cuba 3.9
Chile 3.6
Peru 3.1
Venezuela 2.9
* Per 100,000, age standardized to the World Standard Population; Source:
GLOBOCAN 2012 Global Cancer Facts & Figures 3rd Edition.
http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-044738.pdf
CRC: Stages at Diagnosis and 5-Year Survival
05
SEER, Surveillance, Epidemiology, and End Results Program, NIH/NCI.
http://seer.cancer.gov/statfacts/html/colorect.html. Accessed August 26, 2015.
Treatments of Early Stage Colon and
Rectal Cancer
Treatment for Stage 0, I, II and III Colon and
Rectal Cancer (NCCN & EMSO Treatment Guidelines)
Colon1,2
Stage 0
Stage I
Local excision, simple
polypectomy, or segmentary
en-bloc resection
Wide surgical resection and
anastomosis
Surgery without adjuvant
chemotherapy
Stage II
Rectal3,4
07
Local excision by
Total Mesorectal Excision
(TME)
Tri-modal Therapy:
Chemo-radiation
High risk
features
Stage III
Surgery with Adjuvant
FOLFOX or CapeOX,
FLOX,
Capecitabine
Or 5-FU/Leucovorin
Rectal surgery
Adjuvant chemotherapy
1. Labianca et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24;Suppl 6:vi64-vi72; 2. NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015; 3. Glimelius et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. Ann Oncol. 2013;24;Suppl 6:vi81-vi88; 4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.3.2015.
Adjuvant Chemotherapy in Stage II Colon Cancer
Meta-analysis of 3732 patients from 12 trials
Benson et al. J Clin Oncol. 2004;22:3408.
Adjuvant Chemotherapy in Stage III Colon Cancer
MOSAIC trial1
•
Similar results were seen in other randomised adjuvant trials with other regimens2,3
1. André et al. J Clin Oncol 2009; 27:3109; 2. Yothers et al. J Clin Oncol. 2011; 29:3768;
3. Haller et al. J Clin Oncol. 2011;29:1465.
Trimodality Therapy in the Treatment of
Stage II/III Rectal Cancer
010
• It is effective, but is quite intensive and difficult to complete1
– EORTC 229212
• 27% did not initiate post-operative chemotherapy
• Only 43% received the planned dose
• Significant delay (≈18 weeks) from diagnosis until first dose of
systemic adjuvant chemotherapy, which may increase systemic
recurrence risk due to3:
– Delay in starting chemotherapy (FOLFOX)
– Omission of chemotherapy (FOLFOX)
– Intolerance or dose reduction
• Are all 3 modalities needed?3
1. Waiser. ASCO 2015.
2. Bosset et al. N Engl J Med 2006;355:1114.
3. Schrag. ASCO 2015.
Current Approaches to Improve the Management of
Patients With Stage II/III Rectal Cancer
011
• Total neoadjuvant treatment (both radiation and chemotherapy
before surgery) may help address the undertreatment issue1
• Multiple phase 2 trials show favourable results1
– High rates of clinical response and downstaging; pCR of 15-33%; no excess
surgical complication rates
• Ongoing Phase 3 trial (RAPIDO, NCT01558921)2
– CAPOX and XRT (5.5 weeks)→TME→Optional chemo vs
XRT (1 week)→XELOX (x6)→TME
• Trials testing selective use of one modality (radiation, surgery,
chemotherapy)
1. Schrag. ASCO 2015.
2. Available at: https://www.clinicaltrials.gov/ct2/show/
NCT01558921?term=RAPIDO&rank=1. Accessed September 1, 2015.
Treatment of Metastatic CRC
Management of Resectable
Metastatic CRC
Treatment of Resectable Synchronous Metastatic
Colon Cancer (NCCN)
014
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015.
Treatment of Resectable Synchronous Metastatic
Rectal Cancer (NCCN)
015
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.3.2015.
Treatment for Resectable Metachronous Metastatic
Colon or Rectal Cancer: NCCN Guidelines
016
Neoadjuvant
Chemotherapy:
FOLFOX or CapeOx
(preferred)
FLOX
Capecitabine
Or 5-FU/Leucovorin
Surgery
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.3.2015.
Adjuvant
Chemotherapy
Treatment of Unresectable
Metastatic CRC
Approved Targeted Agents for the Treatment of
Unresectable Metastatic CRC
018
Bevacizumab
ziv-Aflibercept
VEGFA VEFGA
VEGFB VEGFC
PIGF
VEGFD
FGF
PDGF
Cetuximab
VEGFC
VEGFD
Panitumumab
*Ramucirumab
PDGFR-α
PDGFR-β
FGFR-1
VEGFR-1
VEGFR-3
VEGFR-2
FGFR-3
FGFR-2
Regorafenib
Migration
Proliferation
Survival
Angiogenesis
*Approval by FDA was granted in April 2015; approval by EMA is pending.
Modified from Clarke & Hurwitz. J Gastrointest Oncol. 2013;4:253.
Permeability
EGFR
First-line Treatment of mCRC
NCCN Guidelines: Recommendations for the
First-line Treatment of Metastatic CRC
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015.
ESMO Guidelines for the First-line Treatment of
Metastatic CRC
*
*
*
*2nd-line treatment of patients refractory to an irinotecan-based chemotherapy regimen must consist of an oxaliplatin-containing combination (FOLFOX or CAPOX); and
for patients refractory to FOLFOX or CAPOX, an irinotecan-based regimen is proposed as 2nd-line treatment.
Van Cutsem et al. Ann Oncol. 2014;25(suppl 3):iii1-iii9.
Summary of Pivotal Trials of Anti-VEGF and Anti-EGFR
Agents in the 1st-line Treatment of mCRC
022
Trial
Agent
Treatment
Control
AVF2017/A1
Bevaciz.
Bevaciz. +
IFL
CRYSTAL2,3
Cetux.
Panitum.
PRIME4,5
OS
PFS
(mos)
HR
P
(mos)
HR
P
IFL
20.3 vs 15.6
0.66
<0.001
10.6 vs 6.2
0.54
<0.001
Cetux.
+ FOLFIRI
FOLFIRI
28.4 vs 20.2*
(RAS WT)
0.69
0.0024
11.4 vs 8.4
0.56
<0.001
Panitum.
+ FOLFOX4
FOLFOX4
25.8 vs 20.2*
(RAS WT)
0.77
0.009
10.8 vs 9.2
0.72
<0.004
Bold indicates primary endpoint of the clinical trial
Bevaciz, Bevacizumab; Cetux., Cetuximab, Panitum., Panitumumab; IFL, fluorouracil, irinotecan, leucovorin; CT; chemotherapy; WT, Wild type;
OS, overall survival; mos, months; HR, hazard ratio; P, P-value.
1. Hurwitz et al. N Engl J Med. 2004;350:2335; 2. Van Cutsem et al. N Engl J Med. 2009;360:1408; 3. Van Cutsem et al. J Clin Oncol. 2015;33:692; 4. Douillard et al. J Clin
Oncol. 2010;28:4697; 5. Douillard et al. N Engl J Med. 2013;369:1023.
Second-line Treatment of mCRC
NCCN Guidelines: Recommendations for the
Second-line Treatment of Metastatic CRC
024
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015.
Summary of Pivotal Trials of Antiangiogenic and Anti-EGFR
Agents in the 2nd-line Treatment of mCRC
025
Trial
Agent
Treatment
Control
ML18147/A1
Bevaciz.
Bevaciz.
+ Switch
CT
VELOUR2
ziv-Aflib.
RAISE3
Ramucir.
200501814,5
Panitum.
OS
PFS
(mos)
HR
P
(mos)
HR
P
Switch
CT
11.2 vs 9.8
0.81
0.006
2
5.7 vs 4.1
0.68
<0.0001
Ziv-Aflib.
+ FOLFIRI
FOLFIRI
13.5 vs
12.1
0.817
0.003
2
6.9 vs 4.7
0.758
0.001
Ramucir.
+ FOLFIRI
FOLFIRI
13.3 vs
11.7
0.844
0.021
9
5.7 vs 4.5
0.793
0.0005
FOLFIRI
14.5 vs
12.5
0.92
0.37
6.4 vs
3.7
0.58
0.014
Panitum.
+ FOLFIRI
Bold, indicates primary endpoint of the clinical trial
Bevaciz, Bevacizumab; Panitum., Panitumumab; ziv-Aflib., ziv-Aflibercept; Ramucir., Ramucirumab, Regoraf., Regorafenib; IFL, fluorouracil,
irinotecan, leucovorin; CT; chemotherapy; BSC, best supportive care; OS, overall survival; mos, months; HR, hazard ratio; P, P-value.
1. Bennouna et al. Lancet Oncol. 2013;14:29; 2. Van Cutsem et al. J Clin Oncol. 2012;30:3499-506;
3. Tabernero et al. Lancet Oncol. 2015;16:499; 4. Peeters et al. J Clin Oncol. 2010;28:4706;
5. Peeters et al. Ann Oncol. 2014;25:107.
Current Management of 3rd-line mCRC
NCCN Guidelines: Recommendations for the
3rd-line Treatment of Metastatic CRC
027
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015.
Summary of Pivotal Trials of Targeted Agent in the 3rd-line
Treatment of mCRC
OS
Trial
PFS
Agent
Treatment
Control
CORRECT1
Regoraf.*
Regorafenib
+ BSC
BSC
6.4 vs 5.0
0.77
0.0052
1.9 vs 1.7
0.49
<0.001
NCIC CO.172*
Cetux.
Cetux.
BSC
9.5 vs 4.8
(RAS WT)
0.55
<0.001
3.7 vs 1.9
0.40
<0.001
Amado et al.3
Panitum.
Panitum.
+ BSC
BSC
8.1 vs 7.6
(RAS WT)
0.67
0.004
2.8 vs 1.7
0.45
<0.001
*In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy.
1. Grothey et al. Lancet Oncol. 2013;381:303; 2. Karapetis et al. N Engl J Med. 2008;359:1757;
3. Amado et al. J Clin Oncol. 2008;26:1626.
Key Issues in the Treatment of mCRC
Anti-EGFR vs Anti-VEGF in the
First-line Treatment of mCRC
Anti-EGFR vs Anti-VEGF in the First-line Treatment
of mCRC
Phase 3 trials
Trial
PEAK trial1
KRAS-wt: N=285
Regimen
Primary endpoint
Secondary
endpoints
Post-PD
treatment
FOLFOX +
panitum
vs
FOLFOX + bev
KRAS-wt:
PFS: 10.9 (panitum)
vs 10.1 mos (bev)
(HR, 087; P=0.353)
KRAS-wt:
OS: 34.2 (panitum) vs
24.3 mos (bev)
(HR, 0.62, P=0.009)
Anti-EGFR :
Bev arm: 38%
Panitum arm: 21%
RAS-wt:
PFS: 13 (panitum) vs
9.5 mos (bev)
(HR, 0.65; P=0.029)
RAS-wt:
OS: 41.3 (panitum) vs
28.9 mos (bev)
(HR, 0.63; P=0.058)
KRAS-wt:
ORR (independent):
66.5% (cetux) vs
55.6%
(OR, 1.18; P=0.18)
KRAS-wt:*
OS:
28.7 (cetux) vs 25 mos
(bev)
(HR, 0.77; P=0.017)
RAS-wt:
ORR (independent):
72% (cetux) vs 56%
(OR, 2; P=0.003)
RAS-wt:*
OS:
33.1 (cetux) vs 25 mos
(bev)
(HR, 0.7; P=0.0059)
RAS-wt: N=170
FIRE-3 trial2,3
KRAS-wt: N=592
RAS-wt: N=400
FOLFIRI + cetux
vs
FOLFIRI + bev
*No significant difference in median PFS between the arms.
1.Schwartzberg et al. J Clin Oncol.2014;32:2240; 2.Heinemann V et al. Lancet.
Oncol. 2014;15:1065; 3. Stintzing S et al. Ann Oncol.2014;25:abstr LBA11.
Cetuximab-arm:
78% received
nd
2 -line treatment
Bev-arm:
76% received
nd
2 -line treatment
Anti-EGFR vs Anti-VEGF in the First-line Treatment
of mCRC (cont’d)
Phase 3 trial
Trial
CALGB 80405)1-3
KRAS-wt:
N=1,137
RAS-wt: N=526
Regimen
Primary endpoint
Secondary endpoints
Post-PD
treatment
FOLFOX or
FOLFIRI + cetux
vs
FOLFOX or
FOLFIRI + bev
KRAS-wt:
OS: 29.9 (cetux)
vs 29 mos (bev)
(HR, 92; P=0.30)
KRAS-wt:
PFS: 10.4 (cetux) vs 10.8
mos (bev)
(HR, 1.04, P=0.55)
Details not
provided
RAS-wt:
OS: 30.8 (cetux) vs
30.3 mos (bev)
(HR, 0.9; P=0.40)
RAS-wt:
PFS: 10.9 (cetux) vs 11.4
mos (bev)
(HR, 1.1; P=0.31)
1.Venook et al. J Clin Oncol. 2014;32(suppl 5s; abstr LBA3).
2. Lenz et al. Ann Oncol. 2014;25(abstr 5010).
3. Venook et al. Ann Oncol. 2014;25:(abstr LBA10).
Issues Associated With Anti-EGFR
Therapies in the Treatment of mCRC
The Majority of mCRC Patients Are Not Suitable
for EGFR-targeted Therapies
034
• RAS (KRASNRAS)- and
BRAF-mutations predict lack of
response to anti-EGFR therapy1-3
• The majority of mCRC patients
(≈56%) harbour mutant KRAS/NRAS
or BRAF1-3
– Only 44% of these patients are RAS
and BRAF wild type and suitable for
anti-EGFR-containing therapy
• However, even RAS- and BRAF-wt
status in CRC does not ensure
responsiveness to anti-EGFR agents,
suggesting additional determinants of
sensitivity3
1. NCCN Clinical Guidelines. V3.2015; 2. Cancer Genome Atlas Network. Nature.
2012;487:330; 3. Fakih. J Clin Oncol. 2015;33;1809-24; 4. Bettegowda et al. Sci Transl
Med. 2014;6:224ra24
Frequency of KRAS, RAS and BRAF
mutations in mCRC
Development of Treatment-related Resistance Is a Major
Issue in Patients With KRAS- and or BRAF- WT mCRC
035
• Emergence of RAS and BRAF mutations
during anti-EGFR treatment as mechanism of
resistance1-4
– Majority of patients with RAS and BRAF WT
disease will test positive for one or more
KRAS, NRAS, or BRAF mutations in the cDNA
or on repeat tumour biopsy before or at the
time of anti-EGFR resistance2
– RAS mutations seen in up to 60% of tumour
samples biopsied at the time of resistance to
anti-EGFR therapy3,4
– In a study of 24 objective responders to
anti-EGFR therapy who subsequently
progressed, 23 developed a detectable
mutation involving the MAPK pathway. The
majority of these were RAS- or BRAFactivating mutations2
1. Fakih. J Clin Oncol. 2015;33;1809-24; 2. Bettegowda et al. Sci Transl Med.
2014;6:224ra24; 3. Misale et al. Nature. 2012;486:532; 4. Diaz et al. Nature.
2012;486:537.
Current Approaches to Overcome Resistance
to EGFR-targeted Agents in mCRC
036
• Inhibition of RAS signalling pathway in
patients with BRAF V600 mutations
Anti-EGFR
– Dabrafenib + trametinib1
• ORR: 7%
• mPFS: 3.5 months
– Panitumumab + dabrafenib2
• ORR: 10%
• mPFS: 10.1 months
EGFR
Dabrafenib
RAS
BRAF
Trametinib
– Panitumumab + dabrafenib + trametinib2
• ORR: 26%
• mPFS: 9.0 months
• Remains an active area of research and clinical
development
MEK
ERK
Proliferation, Survival, etc.
1. Corcoran et al. J Clin Oncol. 2014;32(suppl;abstr 3517).
2. Atreya et al. J Clin Oncol. 2015;33(suppl; abstr 103).
Limited Therapeutic Options in the
Treatment of Patients Who Failed All
Standard Therapies
Current Unmet Needs in the Treatment of
Patients Who Failed All Standard Therapies
038
• Many patients with mCRC who progress on all approved standard
therapies maintain good performance status and thus remain eligible for
further therapy1
• However, treatment of these patients remains challenging as viable
therapeutic options are limited1,2
• Regorafenib is the only targeted agent currently approved for treatment of
patients progressing on all standard therapies2
• Regorafenib provides a modest improvement in efficacy (an improvement
of 1.4 months and 0.2 months in median OS and PFS, respectively) and is
associated with a number of treatment-related toxicities1,2
– Most common grade ≥3 AEs: hand-foot skin reaction (17%), fatigue (10%),
rash/desquamation (6%)
– In a subset analysis of 500 patients with mCRC, high-foot skin reaction (all
grades): 46.6%
1. Grothey et al. Lancet Oncol. 2013;381:303.
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015.
Emerging Data in the Treatment of Patients
With mCRC Who Failed ≥3 Lines of Prior
Therapies
Phase 3 Trial of Regorafenib Monotherapy for
Previously Treated mCRC (CORRECT Trial)
Regorafenib
• Confirmed adenocarcinoma
CRC
• Failure during or within 3
months following last
administration of approved
standard therapies
• ECOG PS 0-1
N=760
R
A
N
D
O
M
I
S
E
(160 mg once daily for 3 weeks of
each 4-week cycle) + BSC until PD,
death, unacceptable toxicity,
withdrawal, or discontinuation
n=505
2:1
Placebo
+ BSC
Until PD, death, unacceptable toxicity,
withdrawal, or discontinuation
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, DCR, and safety
Grothey et al. Lancet. 2013;381:303.
n=255
Efficacy of Regorafenib in
Relapsed/Refractory CRC: OS and PFS
042
Median Overall Survival:
6.4 vs 5.0 mos.
Median Progression-Free Survival:
1.9 vs 1.7 mos.
Grothey et al. Lancet. 2013;381:303.
Safety Regorafenib in Relapsed/Refractory CRC: AEs
Regorafenib
n=500 (%)
Placebo
n=253 (%)
42 (8)
7 (3)
333 (67)
57 (23)
Dose reductions
188 (38)
8 (3)
Dose interruptions
304 (61)
55 (22%)
253 (51)
31 (12)
Hand-foot skin reaction
83 (17)
1 (<1)
Fatigue
46 (9)
12 (5)
Hypertension
36 (7)
2 (1)
Diarrhoea
35 (7)
2 (1)
Rash or desquamation
29 (6)
0
Hypophosphataemia
19 (4)
1 (<1)
Oral mucositis
15 (3)
0
Thrombocytopaenia
13 (3)
1 (<1)
Anaemia
12 (2)
0
Hyperbilirubinaemia
10 (2)
2 (1)
Proteinuria
7 (<1)
1 (<1)
Voice change
1 (<1)
0
Nausea
2 (<1)
0
Vomiting
3 (1)
0
Fever
4 (1)
0
Discontinued study due to AEs
Dose modification
Treatment-related AEs (grade ≤3)
Overall
AEs of higher incidence (Regorafenib vs placebo)
Grothey et al. Lancet. 2013;381:303.
043
Phase 3 Trial of TAS-102 in Relapsed/Refractory
mCRC (RECOURSE Trial)
TAS-102
• Confirmed adenocarcinoma
CRC
• Failure of ≥2 prior regimens
of standard chemotherapies
for mCRC
• Known KRAS mutation
status
• ECOG PS 0-1
R
A
N
D
O
M
I
S
E
(35 mg/m2/dose)
2x daily days 1-5 and 8-12 of each
28-day cycle,
until discontinuation
n=534
2:1
N=800
Placebo
Placebo tablets
2x daily days 1-5 and 8-12 of each
28-day cycle,
until discontinuation
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, DCR, and safety
TAS-102, an oral, nucleoside anti-cancer agent
Mayer et al. N Engl J Med. 2015;372:1909.
n=266
Efficacy TAS-102 in Relapsed/Refractory CRC:
OS and PFS
046
Overall Survival:
7.1 vs 5.3 mos.
Mayer et al. N Engl J Med. 2015;372:1909.
Progression Free Survival:
2.0 vs 1.7 mos.
Safety of TAS-102 in Relapsed/Refractory CRC: AEs
TAS-102
n=533 (%)
Discontinued study due to AEs
Dose reduction
19 (4)
Placebo047
n=265 (%)
4 (2)
73 (14%)
Treatment-related AEs (grade ≤3)
Overall
370 (69)
137 (52)
Neutropaenia
200/528 (38)
0
Leukopaenia
113/528 (21)
0
Anaemia
96/528 (18)
8/263 (3)
Thrombocytopaenia
27/528 (5)
1/263 (<1)
Febrile neutropaenia
20 (4)
0
Nausea
10 (2)
3 (1)
Vomiting
11 (2)
1 (<1)
Diarrhoea
16 (3)
1 (<1)
AEs of higher incidence (TAS-102 vs placebo)
Mayer et al. N Engl J Med. 2015;372:1909.
Ongoing Phase 3 Trial in Patients With
mCRC Who Failed All Standard Therapies
Mechanism of Resistance to Antiangiogenic Agents
049
 Currently available antiangiogenic therapies
mainly target VEGF/VEGFR and PDGFR
signalling and thus do not neutralize all relevant
mechanisms involved in angiogenesis1,2
 Acquired resistance to VEGF-targeted therapy
is a major challenge for treatment of advanced
or metastatic tumours2,3
 Activation or upregulation of FGF/FGFR and
PDGF/PDGFR signaling serves as a
mechanism of resistance to VEGF/VEGFRtargeted therapy4-6
 The PDGF/PDGFR and FGF/FGFR pathways
have been implicated in the development of
resistance to antiangiogenesis through induction
of epithelial mesenchymal transition (EMT)7-9
Image obtained from http://newscentre.boehringeringelheim.com/content/dam/internet/opu/newshome/com_EN/images/events/oncology_and_respiratory/angiokinase_info.pdf
1. Rogosin et al. Clin Lung Cancer 2012;13:326-33; 2. Clarke and Hurwitz. J Gastrointest Oncol. 2013;4:253-63; 3. Ellis and Hicklin. Clin Cancer Res.
2008;14:6371; 4. Batchelor et al. Cancer Cell. 2007;11:83-95; 5. Casanovas et al. Cancer Cell. 2005;8:299-309; 6. Erber et al. FASEB J. 2004;18:338; 7.
Eckert et al. Cancer Cell. 2011;19:372-86; 8. Jechlinger et al. J Clin Invest. 206;116;1561-70; 9. Wu et al. Cancer Treat Rev. 2013;39:640.
Nintedanib: An Oral Triple Angiokinase Inhibitor
• Simultaneously inhibits multiple angiokinases
at low nanomolar concentrations (IC50)1-3
–
–
–
VEGFR-1, -2, and -3
PDGFR-a/b
FGFR-1, -2, and -3
• Demonstrated high antiangiogenic and antitumour activity as monotherapy or in
combined regimens in multiple preclinical
models including bevacizumab-resistant CRC
xenograft3
• Long-term treatment with nintedanib does not
induce EMT in multiple preclinical models2
1. Hilberg et al. Cancer Res. 2008;68-4774; 2. Kutluk Cenik et al. Mol Cancer Ther.
2013;12:992; 3. Mésange et al. Oncotarget. 2014;5:4709.
Nintedanib is approved in the European union (EU) under the brand name
VARGATEF® for use in combination with docetaxel in adult patients with locally
advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology
after first-line chemotherapy. Registration conditions differ internationally, please refer to
locally approved prescribing information. Nintedanib is not approved in other indications.
BIBF 1120
Antitumour Activity of Nintedanib in mCRC
051
Study design
Activity
Nint + mFOLFOX
n=85
Bev + mFOLFOX
80
•
•
•
•
Confirmed mCRC
(adenocarcinoma)
Previously
untreated patients
ECOG PS ≤2
Adequate organ
functions
N=126
R
A
N
D
O
M
I
S
E
Nintedanib
(150 or 200 mg bid)
+
mFOLFOX6
70
70.2
62.1
63.5
56.1
60
50
40
2:1
Bevacizumab
(5 mg/kg q2wks)
+
mFOLFOX6
30
20
10
0
n=41
•
PFS (9 mos)
Primary endpoint: PFS rate at 9 months
mFOLFOX6= oxaliplatin 85 mg/m2, I-leucovorin 200 mg/m2 or d,I-leucovorin 400 mg/m2,
5-FU bolus 400 mg/m2 followed by 2400 mg/m2, every 2 weeks
Van Cutsem E et al. Ann Oncol. 2015 Aug 12. pii:mdv286. [Epub ahead of print]
ORR*
*Confirmed ORs
Phase 3 Trial of Nintedanib in Relapsed/Refractory
CRC (LUME-COLON 1)
Currently recruiting patients
Double-blind, randomised study of Nintedanib vs Placebo in Refractory CRC
• Confirmed adenocarcinoma CRC
• Progression on standard therapies or
withdrawn from standard treatment
due to unacceptable toxicities.
Previous standard treatment must
include:
•
•
•
•
•
•
Fluoropyrimidine
Oxaliplatin
Irinotecan
Bevacizumab or Aflibercept
Cetuximab or Panitumumab for pts. with RAS
WT tumours
Prior treatment with Regorafenib allowed
R
A
N
D
O
M
I
S
E
• ECOG PS = 0-1
N=764 (estimated)
Nintedanib
(200 mg bid)
+
BSC in 21-day courses
until PD or undue toxicity
1:1
Placebo
+
BSC
• Co-primary endpoints: OS, PFS
• Secondary endpoints: ORR, DCR, safety (frequency and severity of AEs,
lab parameters).
Lenz et al. J Clin Oncol. 2015;33(suppl 3) GI Cancers Symposium. Abstract TPS794.
https://clinicaltrials.gov/show/NCT02149108. Accessed August 18, 2015.
Where Do We Go from Here?
How Do We Further Improve Patient Outcomes?
Identification of Potentially Novel Targetable Driver
Mutations in mCRC
Analysis of 224 tumour and normal pair tissue samples
Cancer Genome Atlas Network. Nature. 2012;487:330-337.
Novel Therapeutic Approaches:
Anti-PD-1/PD-L1 Agents in mCRC
• Nivolumab (anti-PD-1)1,2
– No activity in a Phase 1 trial with advanced tumours included 17 patients with
mCRC
– Subsequent case report that 1/17 patients achieved CR with evidence of PD
after 3 years
• BMS936559 (anti-PD-L1)3
– No activity in a Phase I trial with advanced tumours included 18 patients with
mCRC
• Atezolizumab (MPDL3280A)4,5
– 1/4 patients with mCRC responded; responses seen in both PD-L1+ and PD-Ltumours
– MPDL3280A + bev (refractory mCRC): 8% ORR*
– MPLD3280A + bev + FOLFOX (oxal-naïve): 36% ORR*
*Unconfirmed ORR.
1. Topalian et al. N Engl J Med. 2012;366:2443; 2.Lipson et al. Clin Cancer Res. 2013;19:462;
3. Brahmer et al. N Engl J Med. 2012;366:2455; 4. Herbst et al. J Clin Oncol. 2013;31(suppl; abstr 3000);
5. Bendell et al. J Clin Oncol. 2015;33(suppl 3; abstr 704).
Ongoing Trials With Anti-PD-1 Agents in mCRC
Trial
Study Title
Assess the Efficacy of Pembrolizumab
Phase 2
NCT02437071 Plus Radiotherapy or Ablation in
Metastatic Colorectal Cancer Patients
Study of Pembrolizumab in
Phase 2
Combination With Chemotherapy for
NCT02375672 Patients With Advanced Colorectal
Cancer
A Phase 2 Study of Pembrolizumab in
Combination With Azacitidine in
Phase 2
NCT02260440 Subjects With Chemo-refractory
Metastatic CRC
Phase 1/2
Pembrolizumab and Monoclonal
NCT02318901 Antibody Therapy in Advanced Cancer
Treatment
1° Endpoint
Status
Combination Radiation Therapy or
Ablation Plus Pembrolizumab
Response Rate
Recruiting
Combination FOLFOX6
Chemotherapy with Pembrolizumab
PFS
Recruiting
Combination Azacitidine with
Pembrolizumab
Response Rate
Recruiting
Combination of Pembrolizumab with
Trastuzumab, ado-Trastuzumab
emtansine, or Cetuximab
RP2D
Recruiting
Phase I/IIA Study MK-3475 With
Phase 1/2
Combination FOLFOX6
Safety
Recruiting
NCT02268825 Chemotherapy in Patients With
Chemotherapy with Pembrolizumab
Advanced GI Cancers (MK-3475 GI)
Phase 1:
A Study of the Safety, Tolerability, and
Safety
(DLT)
Efficacy of INCB24360 Administered in Combination with INCB24360 (IDO1
Phase 1/2
Phase
2:
Recruiting
NCT02327078 Combination With Nivolumab in Select Inhibitor) with Nivolumab
Response Rate &
Advanced Cancers
Overall Survival
Study of Nivolumab Plus Chemotherapy
Combination of Nivolumab with
Phase 1/2
RP2D
Recruiting
Temsirolimus or Irinotecan or
in
Patients
With
Advanced
Cancer
NCT02423954
Irinotecan
plus
Capecitabine
(NivoPlus)
PFS, Progression free survival; RP2D, Recommended phase 2 dose; DLT, dose limiting toxicities.
www.clinicaltrials.gov. Accessed Sept. 3, 2015.
Anti-PD-1/PD-L1 in mCRC:
The Need to Identify the Right Patient Population
Phase 2 trial of pembrolizumab in 41 patients with progressive metastatic carcinoma
with or without mismatch repair deficiency
OS
PFS
Not reached
2.2 months
Not reached
5.0 months
• ORR/SD
– Mismatch repair deficient (n=10): 40%/50%
– Mismatch repair proficient (n=18): 0/11%
Le et al. N Engl J Med. 2015;372:2509.
Ongoing Phase 2 trial in mismatch repair
deficient or microsatellite (MSI)-high mCRC
patients (NCT02460198)
Ongoing Trials With Anti-PD-1 Agents in MMR and
MSI-high mCRC
Trial
Study Title
Study of Pembrolizumab as
Monotherapy in Participants
Phase 2
NCT0246019 With Previously-Treated Locally
8
Advanced Unresectable or
Metastatic Colorectal Cancer
(KEYNOTE-164)
Phase 2
NCT0187651 Phase 2 Study of MK-3475 in
Patients With Microsatellite
1
Unstable (MSI) Tumors
A Study of Nivolumab and
Phase 1/2
Plus Ipilimumab in
NCT0206018 Nivolumab
Recurrent and Metastatic Colon
8
Cancer (CheckMate 142)
IR-PFS, immune-related progression free survival
www.clinicaltrials.gov. Accessed September 3, 2015.
Treatment
1°
Endpoint
Status
Pembrolizumab
Monotherapy
Response
Rate
Recruitin
g
Pembrolizumab
Monotherapy
IR-PFS &
Response
Rate
Recruitin
g
Nivolumab Alone or in
Combination with
Ipilimumab
Response
Rate
Recruitin
g
Summary/Conclusion
059
• Management of CRC involves multimodality strategies combining surgery, radiation
therapy, and chemotherapy
• Neoadjuvant/adjuvant chemotherapy for Stage II/III is an area of active study
particularly in rectal cancer
• Significant advances have been made over the last two decades in the treatment of
mCRC
– mOS for fluoropyrimine monotherapy: 12 months
– mOS for targeted agent + combination chemo: >25 months
• However, a number of challenges still remain (eg, treatment-emergent resistance, the
need for better tolerated, and effective therapy in later-line settings)
• More efforts are needed to better understand the underlying disease mechanisms of
mCRC and to identify novel, targetable driver mutations in order to improve disease
management
060
BACKUP
Treatment of Stage II/III Colon Cancer
(NCCN Guidelines): The Role of Adjuvant Chemotherapy
061
Stage
II
Stage
III
• Currently, there’s no role of targeted agents
associated with chemotherapy in the adjuvant setting for colon cancer
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015.
Treatment of Stage II/III Rectal Cancer
(NCCN Guideline)
062
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.3.2015.