COLON CANCER: Highlights AIOM POST ASCO-GI Review Updates and news from the Gastrointestinal Cancer Symposium in San Francisco, CA, USA Roma, 5-6 Febbraio 2016 Alfredo Falcone Dipartimento di Ricerca Traslazionale e Nuove Tecnologie in Med. e Chir., Università di Pisa Polo Oncologico – Azienda Ospedaliero Universitaria Pisana Istituto Toscano Tumori Italy
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COLON CANCER: Highlights
AIOM POST ASCO-GI Review
Updates and news from the Gastrointestinal Cancer Symposium in San Francisco, CA,
USA
Roma, 5-6 Febbraio 2016
Alfredo Falcone Dipartimento di Ricerca Traslazionale e Nuove Tecnologie in Med. e Chir., Università di Pisa
Polo Oncologico – Azienda Ospedaliero Universitaria Pisana
Istituto Toscano Tumori
Italy
OUTLINE
Studio STEAM (abst. 492)
Studio MAVERICC (abst. 493)
CDX2 (Keynote Lecture)
OUTLINE
Studio STEAM (abst. 492)
Studio MAVERICC (abst. 493)
CDX2 (Keynote Lecture)
Overall response rate in STEAM, a randomized,
open-label, phase 2 trial of sequential and
concurrent FOLFOXIRI-bevacizumab vs
FOLFOX-bevacizumab for the first-line treatment of
healing wound, active peptic ulcer, or untreated bone fracture
Statistical Considerations
• Efficacy analyses were conducted in all randomized patients (intent-to-treat population). Safety analyses
were conducted in all patients who received ≥1 dose of study medication; treatment group based on
treatment received
• Sample size (280 patients), based on the following assumptions, and 5% type I error (1-sided) will
provide 80% power:
– cFOLFOXIRI-BEV and FOLFOX-BEV exhibit ORRs of 70% and 50%, respectively
– An improvement of 43% from median PFS1 14.3 months in (concurrent and sequential)
FOLFOXIRI-BEV to median PFS1 of 10 months in FOLFOX-BEV
• Fixed-sequence hypothesis testing adjusted for co-primary endpoints (ORR1 and PFS1)
– ORR1: 1-sided alpha of 5% to compare cFOLFOXIRI-BEV with FOLFOX-BEV
– If the test of ORR1 is significant, then PFS1 will be tested for cFOLFOXIRI-BEV and
sFOLFOXIRI-BEV vs FOLFOX-BEV with a 1-sided alpha of 5%
• Here we present preliminary efficacy data from STEAM (final ORR1 and interim PFS1)
Patient Disposition (N=280, ITT Population)
cFOLFOXIRI-
BEV
sFOLFOXIRI-
BEV
FOLFOX-BEV
Randomized (ITT population), n 93 92 95
Treated (safety population),a n 91 90 90
Median duration of follow-up,
months (range)
13.7
(0.4, 28.9)
13.1
(0.1, 27.0)
12.4
(0.1, 25.7)
Remaining on study at data cut-off
for present analysis, n (%)
64 (69%) 62 (67%) 60 (63%)
First patient in: January 23, 2013
Last patient in: December 26, 2014
Data cutoff: July 1, 2015 (when the last patient completed the induction phase)
aSafety population is grouped according to treatment received.
Baseline Characteristics (ITT)
cFOLFOXIRI-BEV
(n=93)
sFOLFOXIRI-BEV
(n=92)
FOLFOX-BEV
(n=95)
Age, years (median, range) 58.0 (23–75) 56.0 (25–74) 58.0 (34–73)
Sex, n (%)
Male 51 (55) 52 (57) 59 (62)
Female 42 (45) 40 (43) 36 (38)
ECOG performance status, n (%)
0 62 (67) 52 (57) 51 (54)
1 31 (33) 40 (43) 44 (46)
Cancer type at initial diagnosis, n (%)
Colon 68 (73) 64 (70) 76 (80)
Rectal 25 (27) 28 (30) 19 (20)
Prior cancer surgery, n (%) 48 (52) 55 (60) 61 (64)
Baseline Characteristics (ITT, Continued)
cFOLFOXIRI-BEV
(n=93)
sFOLFOXIRI-BEV
(n=92)
FOLFOX-BEV
(n=95)
Extent of metastatic disease, n (%)
Liver-limited disease 28 (30) 28 (30) 27 (28)
Non-liver-limited disease 65 (70) 64 (70) 68 (72)
Tumor location, n (%)a
Right 43 (46.2) 38 (41) 40 (42)
Left 50 (54) 54 (59) 55 (58)
KRAS status, n (%)
Wild-type 25 (27) 23 (25) 25 (26)
Mutant 23 (25) 22 (24) 20 (21)
Unknown or not done 45 (48) 47 (51) 50 (53)
aRight included the right colon and transverse up to splenic flexure. Left included everything distal from the
splenic flexure, including rectal cancer.
ORR During First-Line Treatment (ORR1-Confirmed)a
cFOLFOXIRI-BEV
(n=93)
sFOLFOXIRI-BEV
(n=92)
Pooled
FOLFOXIRI-BEV
(n=185)
FOLFOX-BEV
(n=95)
ORR, % 60.2 62 61.1 47.4
Odds ratio vs
FOLFOX-BEV (90% CI)b
1.7 (1.05, 2.77)
p=0.077c
1.8 (1.12, 2.97)
p=0.040c
1.8 (1.16, 2.68)
p=0.025c
CR, % 4.3 0 2.2 1.1
PR, % 55.9 62.0 58.9 46.3
SD, % 31.2 32.6 31.9 40
PD, % 2.2 1.1 1.6 6.3
Unable to evaluate, % 6.5 4.3 5.4 6.3
aConfirmed response (sensitivity analysis, ITT population), defined as a CR or PR, as assessed by the investigator,
on two consecutive assessments at least 4 weeks apart. bStratified by extent of metastatic disease and tumor location after randomization. c1-sided Cochran-Mantel-Haenszel p-value (no multiplicity adjustments).
Interim PFS1 (ITT): cFOLFOXIRI-BEV and
sFOLFOXIRI-BEV vs FOLFOX-BEV cFOLFOXIRI-
BEV
(n=93)
sFOLFOXIRI-
BEV
(n=92)
FOLFOX-
BEV
(n=95)
Median PFS,
months (90% CI)a
11.7
(9.9, 16.6)
10.7
(8.7, 12.7)
9.3
(7.7, 10.4)
Stratified HR vs
FOLFOX-BEV (90%
CI)b
0.672
(0.489, 0.922)
0.738
(0.537, 1.012)
cFOLFOXIRI-BEV
sFOLFOXIRI-BEV
FOLFOX-BEV
100
80
60
40
20
0
Pro
gre
ss
ion
-fre
e S
urv
iva
l (%
)
0 3 6 9 12 15 18 21 24 27
Time (months)
aPFS1 is defined as the time from randomization to first occurrence of disease progression or death from any cause during first-line treatment,
whichever occurs first. Patients without an event are censored at their last tumor assessment. bStratified by extent of metastatic disease and tumor location after correction post randomization.
HR, hazard ratio.
cFOLFOXIRI-Bev
FOLFOX-Bev
Liver Resection Rates During First-Line Treatment (ITT)
cFOLFOXIRI
-BEV
(n=93)
sFOLFOXIRI
-BEV
(n=92)
Pooled
FOLFOXIRI-
BEV
(n=185)
FOLFOX-
BEV
(n=95)
Liver resection rates, % 15.1 9.8 12.4 7.4
R0 resection 15.1 8.7 11.9 6.3
Percent difference in
resection rates vs
FOLFOX-BEV (90%
CI)a
7.7
(0.2, 15.2)
2.4
(-4.3, 9.2)
5.1
(-0.9, 11.0)
p-valueb 0.094 0.555 0.195
aNormal approximation to the binomial distribution. bPreliminary and exploratory p-value (2-sided Pearson’s chi squared test, no multiplicity
adjustments).
Overview of Treatment-Emergent Adverse Eventsa
cFOLFOXIRI-
BEV
(n=91)
sFOLFOXIRI-
BEV
(n=90)
FOLFOX-
BEV
(n=90)
Any TEAE, % 100 99 100
Grade ≥3 TEAE, % 90 87 82
TEAEs of special
interest, % 82 77 69
TEAE leading to
withdrawal from study
treatment, %
41 33 38
TEAE leading to study
discontinuation, % 15 3 6
Fatal TEAE, % 3 4 3
aSafety population.
TEAE, treatment-emergent adverse event.
Serious Chemotherapy-Associated TEAEs
TEAE, % cFOLFOXIRI-
BEV
(n=91)
sFOLFOXIRI-
BEV
(n=90)
FOLFOX-BEV
(n=90)
Diarrhea 6 1 4
Nausea 3 0 0
Vomiting 3 0 3
Neutropenia 2 2 0
Febrile
neutropenia
2 2 2
Stomatitis 0 0 0
Peripheral
neuropathy
0 0 0
TEAEs of Special Interest for Bevacizumab
aGrade ≥3. bAny grade. cGrade ≥3 (any grade central nervous system bleeding, grade ≥2 hemoptysis). dGrade ≥2.
1University of Southern California, Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA; 2University of New Mexico Cancer Center, Albuquerque, NM, USA; 3Genentech, Inc., South San Francisco, CA, USA;
4Southern California Permanente Group, Bellflower, CA, USA; 5Illinois Cancer Center, Peoria, IL, USA; 6Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, USA;
7F. Hoffmann-La Roche, Ltd., Basel, Switzerland
Presented by: Dr HJ Lenz, University of Southern California, Norris
Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA,
USA
Study Design and Patient Eligibility
Key inclusion criteria
• Histologically confirmed mCRC with ≥1
measurable and unresectable lesion
• Age 18–75 years
• Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1
• Adequate hematologic, liver, and renal function
Key exclusion criteria
• Prior systemic treatment for mCRC (except
palliative radiosensitizers)
• Adjuvant chemotherapy completed <12 months
prior to study enrollment
• Surgery within 28 days prior to randomization
Untreated mCRC
(N=376)
Stratification factors:
• ERCC-1 (high vs low)
• Geographic area (US vs ex-US)
R
A
N
D
O
M
I
Z
E
mFOLFOX6-BV
(n=188)
FOLFIRI-BV
(n=188)
1:1 Progressive
Disease (PD)
Objectives and Statistical Methods
Primary objectives:
• Assess whether tumor ERCC1 is associated with progression-free survival (PFS) in first-line therapy
with mFOLFOX6-BV vs FOLFIRI-BV
• Assess pVEGF-A as a potential biomarker for response to BV or, used in combination with tumor
ERCC1, as a potential biomarker for response to chemotherapy
Secondary objectives:
• Evaluate the effect of tumor ERCC1 and pVEGF-A on overall survival (OS), objective response rate
(ORR), liver resection rate, or risk of specific toxicities
• Assess other potential biomarkers (including KRAS), as well as biomarker subgroups and their
association with clinical outcomes
Statistics:
• Efficacy analyses were based on the ITT population
• Median time to PFS and OS were estimated by the Kaplan–Meier method
• Hazard ratios (HR) were estimated by Cox regression (stratified by tumor ERCC1 level and region)
• The study was powered at 80% to detect a HR of 0.7 on PFS for FOLFIRI-BV vs mFOLFOX6-BV at the
2-sided 0.05 significance level
ITT: Baseline Characteristics
mFOLFOX6-BV
(n=188)
FOLFIRI-BV
(n=188)
Median age, years (range) 61.0 (31–87) 61 (34–81)
Sex, n (%)
Male 122 (64.9) 117 (62.2)
Female 66 (35.1) 71 (37.8)
ECOG performance status, n
(%)
0 93 (49.5) 110 (58.5)
1 94 (50.0) 77 (41.0)
Cancer type, n (%)
Colon 131 (69.7) 135 (71.8)
Rectal 50 (26.6) 48 (25.5)
Colon and rectal 7 (3.7) 5 (2.7)
Prior cancer surgery, n (%) 118 (62.8) 112 (59.6)
Prior adjuvant therapy, n (%) 22 (11.7) 20 (10.6)
Liver-limited disease, n (%) 44 (23.4) 36 (19.1)
ITT: Baseline Characteristics (continued)
mFOLFOX6-BV
(n=188)
FOLFIRI-BV
(n=188)
Tumor location, n (%)
Right 75 (39.9) 79 (42.0)
Left 113 (60.1) 109 (58.0)
Tumor ERCC-1 (x 10-3 ERCC1/-actin
mRNA), mean (SD)
1.6 (1.34) 1.8 (1.32)
High (>1.7), n (%) 64 (34.0) 67 (35.6)
Low (≤1.7), n (%) 124 (66.0) 120 (63.8)
pVEGF-A,(pg/mL), mean (SD) 9.4 (12.79) 9.1 (12.31)