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

210s Gastrointestinal (Colorectal) Cancer
3528 Poster Discussion Session (Board #20), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
BRAF V600 mutant colorectal cancer (CRC) expansion cohort from the
phase I/II clinical trial of BRAF inhibitor dabrafenib (GSK2118436) plus
MEK inhibitor trametinib (GSK1120212). Presenting Author: Ryan Bruce
Corcoran, Massachusetts General Hospital Cancer Center, Boston, MA
Background: BRAF V600 mutations occur in 10-15% of CRC and may
predict lack of response to standard chemotherapy and anti-EGFR treatment.
There have been no significant recent changes in the treatment of
CRC. Novel therapeutic strategies for BRAF mutant CRC are critically
needed. To collect preliminary efficacy data, an expansion cohort of 25
BRAF mutant CRC patients (pts) was included in part 2 of a phase I/II study
evaluating the combination of dabrafenib (BRAFi) and trametinib (MEKi).
Methods: Eligible pts had BRAF V600 mutant CRC, measurable disease per
RECIST 1.1, and previous treatment with anti-cancer therapies. Pts were
treated with established dose of dabrafenib (150mg BID) and trametinib
(2mg QD). Results: Data for 23 pts are available at data cut-off: median age
54 years, 74% female, ECOG performance status 0 (48%) or 1 (52%).
39% had received prior EGFR inhibitor treatment. 74% had received � 2
prior chemotherapy regimens; 48% had � 1 biologic therapy. 48% had
� 3 metastatic sites. Three of the 23 pts were non-evaluable at data cut-off
as they had not reached the first restaging assessment. Among the 20
evaluable pts, 1 (5%) achieved partial response and 10 (50%) stable
disease. Minor responses (�10% to �30% tumor shrinkage) were observed
in 4/10 patients (40%) with stable disease. The most frequent
adverse events observed in all Part 2 patients who received the same dosing
combination (n�75) included pyrexia (65%), fatigue (47%), nausea
(44%), chills (41%), vomiting (31%), constipation (28%), diarrhea (24%)
and rash (21%). Conclusions: Dabrafenib at 150 mg BID combines safely
with trametinib 2 mg QD in this BRAF mutant CRC cohort. Based on the
preliminary anti-tumor activity seen, further investigation is warranted in
BRAF mutant CRC pts. Updated safety and efficacy data and an analysis of
the relationship between efficacy and potential predictive biomarkers,
including microsatellite status, PTEN loss, PIK3CA mutation, and total and
phosphorylated EFGR levels, will be presented.
3530 Poster Discussion Session (Board #22), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Overall survival (OS) of advanced colorectal cancer (aCRC) patients (pts)
treated with the multipeptide vaccine IMA910: Results of a matched-pair
analysis with arm C pts from COIN. Presenting Author: Tim S. Maughan,
Gray Institute for Radiation Oncology and Biology, University of Oxford,
Oxford, United Kingdom
Background: IMA910 is a novel cancer vaccine consisting of 10 class I and
3 class II tumor-associated peptides (TUMAPs), naturally presented on
HLA molecules of CRC. Vaccine-induced immune responses are associated
with prolonged OS of renal cell carcinoma pts treated with IMA901, a
multi-peptide vaccine identified by the same antigen discovery platform.
Methods: 92 HLA-A*02� aCRC pts with stable or responding disease after
12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase
I/II trial. After immunomodulation with cyclophosphamide (300 mg/m2 )to
reduce regulatory T cells, pts were immunized intradermally (up to 16
vaccinations) with IMA910 in combination with GM-CSF without (cohort 1;
n�66) or with (cohort 2; n�26) topically applied imiquimod. Safety and
PFS data was recently presented [Mayer et al., ASCO-GI 2012]. OS of
IMA910 pts was compared to matched pts from arm C (intermittent
chemotherapy) of the COIN trial [Adams et al., Lancet Oncology 2011].
Matching was performed in a prospectively defined, fully blinded fashion
based on a propensity score involving all available prognostic factors. T-cell
responses to individual IMA910 peptides were analyzed by HLA multimer
and intracellular cytokine assays. Results: At a median follow up of 1.7 yrs,
OS of IMA910 vaccinated pts was significantly longer in comparison to 1:1
matched HLA-A*02� COIN pts (HR 0.675, 95% CI 0.458-0.995,
p�0.047; 1 yr OS: 69% vs 55%; 2 yr OS: 40% vs 24%). Multi-TUMAP
responders (�2 CD8� and �2 CD4� vaccine-induced T cells) had a
significantly longer OS (HR 0.45, p�0.04) compared to matched COIN pts
while non-multi-TUMAP responders showed similar OS compared to
matched COIN pts (HR 0.76, p�0.22). Conclusions: OS of IMA910 pts was
significantly longer in comparison to matched COIN pts with separation of
survival curves at ~9 months and increasing OS difference over time.
Multi-TUMAP immune responders had a significantly longer OS compared
to non-multi-TUMAP responders and compared to matched COIN pts.
These clinical and immune response data strongly suggest clinical activity
of IMA910 in 1st line CRC pts and warrant further development.
3529 Poster Discussion Session (Board #21), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with
AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal
carcinoma (CRC). Presenting Author: Giovanna Speranza, National Cancer
Institute, Bethesda, MD
Background: The RAF/MEK/ERK and PI3K/AKT signaling pathways are commonly
deregulated in CRC. Each can serve as a compensatory mechanism
mediating resistance to single pathway blockade. Combined inhibition with
MK-2206 and selumetinib (AZD6244) could enhance antitumor activity.
Tolerable doses for the combination in solid tumors (ASCO 2011, abstr 3004)
are less than single agent MTDs. We conducted a biomarker driven trial of
MK-2206 and selumetinib at the established combination doses to determine
extent of pERK and pAKT inhibition in tumor biopsies (bx), using new, clinically
validated immunoassays for pERK and pAKT. Methods: Patients (pts) with
advanced CRC, refractory to standard therapy, ECOG � 2, adequate organ
function, and disease amenable to bx were treated with oral MK-2206, 90 mg
QW and selumetinib, 75 mg daily, stratified for KRAS mutation status (� or WT).
For each strata, pAKT and pERK levels from paired tumor bx, baseline and 3-6
hrs post-dose in 3 pts each on C1D1 or C1D22, were measured using a
quantitative, chemiluminescence immunoassay (dilution linearity R2 � 0.985
pERK, 0.995 pAKT; % CV at 0 � 6). 70% inhibition was considered biologically
significant based on levels observed in preclinical models that demonstrated
antitumor activity. Results: 11 pts enrolled to date (KRAS �, 6 pts; WT, 5 pts).
2/9 pts had SD after 2 cycles. Gr 1/ 2 toxicities: rash, reversible retinal
detachment, liver abnormalities, hypoalbuminemia, lymphopenia. Target protein
inhibition data are available for 8 paired bx samples (Table). Conclusions:
Although 4/8 pts demonstrated biologically significant inhibition in one marker,
at the MTD for this combination no pt had � 70% inhibition of both targets. If
repeated dosing does not produce the desired inhibition of pERK and pAKT, we
will conclude that the dose reductions for each agent necessitated by the toxicity
of the agents used in combination preclude the possibility of providing adequate
dual pathway inhibition. Loss of PTEN and DNA mutation analyses (KRAS,
BRAF, PIK3Ca, AKT) are planned.
% Inhibition of phosphorylation
pt pERK pAKT
C1D1
KRAS � 1 46 15
2 �77 4
3 61 23
C1D1
KRAS WT 4 53 19
5 �70 34
6 48 78
C1D22
KRAS � 7 77 20
8 0 60
3531 Poster Discussion Session (Board #23), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Molecular analysis of the randomized phase II/III study of the anti-IGF-1R
antibody dalotuzumab (MK-0646) in combination with cetuximab (Cx) and
irinotecan (Ir) in the treatment of chemorefractory KRAS wild-type metastatic
colorectal cancer (mCRC). Presenting Author: David J. Watkins, The
Royal Marsden Hospital, London and Surrey, United Kingdom
Background: Previously reported results of this randomized study demonstrated
that the addition of dalotuzumab (Dz) worsened the PFS and OS of
chemofractory mCRC patients receiving Cx and Ir (Watkins et al; ASCO
2011). Comprehensive molecular analysis has been undertaken retrospectively
to identify possible predictors of Cx resistance and Dz response.
Methods: Quantitative RT-PCR for IGF-1, IGF-2, immunohistochemistry for
IGF-1R and microarray expression profiling was conducted on archival
tumor tissue. All patients had received Cx and Ir with either placebo
(n�107), weekly Dz (n�112), or 2 weekly Dz (n�110). Results: Data from
292 and 206 patients was successfully obtained by RT-PCR or microarray
respectively. Within the placebo arm, high IGF-1 expression was found to
be associated with resistance to Cx (IGF-1-/IGF-1�; PFS 6.7/3.7 months,
OS 15.5/9.6 months). High IGF-1 expression was associated with benefit
from the addition of weekly Dz (placebo/weekly Dz; PFS 3.7/5.7 months,
OS 9.6/18.2 months). By contrast the addition of Dz was not effective in
tumors with high IGF-2 expression (placebo/weekly Dz; PFS 8.4/2.7
months). Microarray analysis revealed distinct populations that differentially
correlated with Cx and Dz response. An epithelial phenotype appeared
more associated with Cx response, whereas a mesenchymal phenotype
more associated with Dz response. Rectal cancers showed greater association
with increased IGF-1 expression, EMT gene signature and Dz response.
Conclusions: These data support IGF-1 and IGF-2 as potential biomarkers
for response to Dz therapy and high IGF-1 as a marker of resistance to Cx
therapy. Based on these data Dz is being further evaluated in a molecularly
selected population of mCRC.
Weekly Dz vs placebo arm
Hazard ratio (95% CI)
Difference
in response rate%
All patients
n�191
Colorectal
high IGF-2
n�25
Colorectal
high IGF-1
n�48
Rectal
high IGF-1
n�23
- 7.4% - 13.3% � 14.6% � 24.6%
PFS 1.30 (0.95, 1.78) 2.94 (1.09, 7.9) 0.59 (0.28, 1.24) 0.35 (0.10, 1.19)
OS 1.37 (0.96, 1.95) 3.48 (0.97, 12.54) 0.67 (0.31, 1.45) 0.49 (0.15, 1.56)
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