Annual Meeting Proceedings Part 1 - American Society of Clinical ...

224s Gastrointestinal (Colorectal) Cancer
3585 General Poster Session (Board #32F), Mon, 8:00 AM-12:00 PM
FOLFOXIRI plus bevacizumab as first-line treatment of BRAF-mutant
metastatic colorectal cancer patients. Presenting Author: Lisa Salvatore,
U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto
Toscano Tumori, Pisa, Italy
Background: BRAF V600E mutation plays a negative prognostic role in
metastatic colorectal cancer (mCRC) patients, leading to a median PFS of
4-6 months with first-line conventional treatments. Recently, results from a
retrospective exploratory analysis suggested that an up-front intensive
treatment with FOLFOXIRI plus bevacizumab could improve the outcome
of BRAF mutant mCRC. Methods: Fifteen consecutive BRAF mutant mCRC
patients treated with first-line FOLFOXIRI plus bevacizumab were included
in a validation set. The primary endpoint was 6-months progression free
rate (6m-PFR). Secondary endpoints were: overall survival, response rate
and the pooled analysis of all main outcome parameters in both the
exploratory and validation set. Results: In the validation set, 11 out 15
patients included were progression-free at 6 months, for a 6m-PFR of
73.3%. Primary endpoint was met. At a median follow-up of 21.6 months,
median progression-free survival was 9.2 months while median OS has not
yet been reached. In the pooled data analysis of the validation set and the
initial retrospective cohort 24 out 25 total patients were evaluable for
response: partial or complete response was obtained in 17 (68%) and in 1
(4%) patient, respectively, for an overall response rate of 72%. At a median
follow-up of 34.1 months, the pooled set of patients showed a median PFS
of 11.8 months and a median OS of 23.8 months. Conclusions: These data
suggest that FOLFOXIRI plus bevacizumab could be a reasonable option for
the first-line treatment of BRAF mutant metastatic colorectal cancer
patients.
3587 General Poster Session (Board #32H), Mon, 8:00 AM-12:00 PM
Activity of the anti-IGF-1R antibody dalotuzumab (MK-0646) in KRASmutant
colorectal cancer: Preclinical and clinical data. Presenting Author:
Sriram Sathyanarayanan, Merck Research Laboratories, Boston, MA
Background: KRAS mutated metastatic colorectal cancer (mCRC) is inherently
resistant to EGFR targeted therapy and carries an inferior prognosis to
wild-type disease with a median survival of approximately 16 months.
Methods: The activity of dalotuzumab (Dz) has been investigated in KRAS
mutant pre-clinical colon cancer models. In addition efficacy data relating
to a sub-set of KRAS mutant mCRC patients enrolled in a randomized
phase II/III study (initiated prior to the introduction of KRAS genotyping) of
Dz in combination with cetuximab (Cx) and irinotecan (Ir) are reported. All
patients had received Cx and Ir with either placebo (n�20), weekly Dz
(n�18), or 2 weekly Dz (n�31). Results: In pre-clinical models, Dz was
found to be effective in inhibiting IGF-1 mediated cellular growth.
Furthermore, in colorectal cancer xenograft models high IGF-1 was found
to identify a sub-set of Dz responsive tumours. Combination studies
demonstrated that Irinotecan exposure resulted in the activation of IGF-1R
and PI3K signaling pathways, representing a possible cellular survival
mechanism. In xenograft models the combination of Dz with irinotecan
produced lasting tumor growth inhibition that persisted even after treatment
withdrawal. Outcome data are reported for 69 patients with KRAS
mutant mCRC enrolled in the randomized study. Efficacy data demonstrated
differential activity between colon versus rectal tumours with
evidence of activity in the rectal subgroup. Molecular analysis suggests that
this observation may be mediated by differential IGF-1 expression.
Conclusions: These data suggest that Dz in combination with irinotecan may
have utility in the treatment of KRAS mutated colorectal cancer patients.
Based on these data Dz is being further evaluated in a molecularly selected
population of mCRC.
Dz vs placebo arm
Hazard ratio (95% CI)
PFS OS
Weekly Dz 2 weekly Dz Weekly Dz 2 weekly Dz
Mean normalized IGF-1
Cq values (rtPCR)
All patients (n�69) 0.75 (0.35, 1.58) 1.14 (0.59, 2.20) 0.88 (0.42, 1.84) 0.96 (0.49, 1.90)
Colon (n�37) 1.50 (0.60, 3.74) 1.63 (0.67, 3.94) 1.21 (0.47, 3.07) 1.31 (0.54, 3.19) 5.22
Rectal (n�32) 0.17 (0.04, 0.79) 0.31 (0.08 1.22) 0.32 (0.09, 1.20) 0.37 (0.11, 1.18) 4.52
p�0.043
3586 General Poster Session (Board #32G), Mon, 8:00 AM-12:00 PM
Neoadjuvant capecitabine, oxliplatin, and bevacizumab (CAPOX-B) in
intermediate-risk rectal cancer (RC) patients defined by magnetic resonance
(MR): GEMCAD 0801 trial. Presenting Author: Carlos Fernandez-
Martos, Medical Oncology Department, Fundacion Instituto Valenciano De
Oncologia, Valencia, Spain
Background: Retrospective data suggest that RT might not be needed in all
patients with stage II/III RC. Modern systemic therapy might have local
efficacy similar to chemoradiation (CRT). Methods: A multicenter phase II
trial was undertaken to evaluate safety and efficacy of neoadjuvant
CAPOX-B in patients with T3 middle third rectal adenocarcinoma. Eligible
patients (pts) had measurable disease at the baseline and candidate for R0
total mesorectal escision (TME) with intermediate-risk defined by pelvic
MR a) T3 with distal border of tumor � 5 cm from the anal verge and below
the sacral promontory. b) tumor �2 mm from the mesorectal fascia. Pts
received 4 cycles of Cap 2000 mg/m2 (d1-14), Ox 130 mg/m2 (d1) and B
7.5 mg/kg (d1) every 3 weeks (last cycle without B). Pts undergo re-staging
with MR. One radiologist reviewed all pre- and post-treatment MR scans
independently. Pts without progression proceed to TME 4-6 weeks from the
last cycle. If progression, pts were to be referred for pre-op cap/RT followed
by TME. 1º Endpoint: Tumor Response (RECIST). Design: Simon 2-stage;
28 pts 1st stage and 46 pts 2nd stage. We report data on the planned
analysis of pts included for 1st stage. Results: 28 eligible pts (10F/18M)
were enrolled from 7/09-5/11. Tumor response, compliance and toxicity
details are shown in table below. Two pN2 pts received postop Cap/RT.
Conclusions: Neoadjuvant CAPOX-B is active and safe. Early parameters of
efficacy are encouraging and seem similar to those observed with CRT.
Efficacy
MR response
MR overall response
MR complete response
MR partial response
MR stable disease
p response
pCR ( ypT0N0)
pLN�
TRG intermediate � total regression �
Downstaging
CRM free
R0 resection
Compliance
4 cycles
24*
21 (87.5%) 95%; CI 68%-97%
1 (4%)
20 (83%)
3 (13%)
27v
4 (15%)
10 (37%)
17 (63%)
10 (37%)
26 (96%)
27 (100%)
24 (86%)
Toxicity G3� 14 (50%)
Surgical complications G3� 3 (11%)
Abbreviations: pCR, pathologic complete response; CRM, circumferential resection margin;
TRG, tumor regression grade. � Dworak 2�3�4;*4MRnotdone. 1 died (diarrhea/renal
failure), 1 perforation after 3th cycle, 2 withdrawal;v pts underwent surgery.
3588 General Poster Session (Board #33A), Mon, 8:00 AM-12:00 PM
Early tumor shrinkage in patients with metastatic colorectal cancer
receiving first-line treatment with cetuximab combined with either CAPIRI
or CAPOX: An analysis of the AIO KRK 0104 trial. Presenting Author:
Dominik Paul Modest, Department of Hematology and Oncology, Klinikum
Grosshadern and Comprehensive Cancer Center, LMU Munich, Munich,
Germany
Background: This study investigated the impact of early tumor-shrinkage
(ETS) on progression-free (PFS) and overall survival (OS) in patients with
metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104trial.
ETS was previously shown to be a predictor of treatment response to
cetuximab. The present analysis, for the first time, evaluates the correlation
of ETS with outcome parameters in patients undergoing capecitabinebased
therapy. It also aims to correlate the predictive value of ETS and
cetuximab-induced skin toxicity. Methods: The AIO KRK0104 trial was
performed as a randomised study comparing capecitabine/oxaliplatin
(CAPOX) plus cetuximab to capecitabine/irinotecan (CAPIRI) plus cetuximab
in the first-line treatment of mCRC. 121 patients were available for
evaluation of ETS at 6 weeks. ETS was defined as a relative change of
�20% in the sum of the longest diameters of target lesions compared to
baseline. Results: Tumors of 63 patients (71% KRAS wild-type (wt), 100%
skin reactions) developed ETS, 58 tumors did not develop ETS (53% KRAS
wt, 86% skin reactions). ETS was associated with prolonged PFS (8.9 vs.
4.7 months, p�0.001, hazard ratio: 0.37) and OS (31.6 vs. 15.8 months,
p�0.005, hazard ratio: 0.48) in patients with KRAS wt tumors but not in
patients with KRAS mutant mCRC. ETS occurred more frequently with
CAPOX- vs CAPIRI-based therapy (p�0.05). There was a highly significant
correlation between the occurrence of ETS and cetuximab-related skin
toxicity of any grade (I-III) (p�0.002). ETS was documented more
frequently in patients with liver metastasis (p�0.09), metastatic involvement
of �2 organs (p�0.09), KRAS wild-type tumors (p�0.06) and no
previous adjuvant chemotherapy (p�0.06). Conclusions: In patients with
KRAS wild-type mCRC receiving capecitabine- and cetuximab-based firstline
therapy ETS correlates with prolonged PFS and OS. ETS also correlates
with cetuximab-induced skin toxicity. Both parameters may therefore serve
as post-randomisation surrogate markers of favourable outcome for cetuximab-based
treatment.
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