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

7595 General Poster Session (Board #51E), Sat, 1:15 PM-5:15 PM
Survival outcome segregated by KRAS mutation status in newly diagnosed
stage IV non-small cell lung cancer (NSCLC) patients (pts) treated with
first-line chemotherapy. Presenting Author: Anna K. Brady, University of
Pennsylvania, Philadelphia, PA
Background: KRAS mutations (MT) form a distinct subset of NSCLC,
generally considered to have poor prognosis. Although KRAS MT is a
well-establised prognostic and predictive marker in colorectal cancer, its
role in NSCLC remains ambiguous. Pts with KRAS MT NSCLC do not
respond well to epidermal growth factor receptor (EGFR) directed tyrosine
kinase inhibitor therapy, but little is known about the ability of KRAS MT to
predict outcome after first-line chemotherapy in newly diagnosed advanced
or recurrent NSCLC. Methods: We analyzed outcomes of consecutive pts
with newly identified Stage IV non- squamous NSCLC treated at University
of Pennsylvania (Penn) between 05/2008 and 7/2010 and then compared
survival based on KRAS status [MT vs wild type (WT)] using chi square,
Kaplan-Meier methods, and Cox regression models. Results: Of 106
consecutive new pts with Stage IV non squamous NSCLC treated at Penn,
49 (46%) underwent molecular analysis for KRAS MT. Fifteen (34%) were
KRAS MT. Of 34 KRAS WT pts, 6 were positive for EGFR MT. The median
age of all 49 pts was 61 years; 83% were Caucasian, 45% male and 60%
had a �10 pack year smoking history. Median duration of follow up is 16.4
mos. Majority of pts (92%) had adenocarcinoma histology. Most pts (88%)
had ECOG PS 0-1 at presentation. Forty three pts received first line
platinum-based combination chemotherapy (platinum and pemetrexed in
31 pts). KRAS MT was associated with smoking (p�0.04), but not with
gender or age. Overall survival (OS) of pts with KRAS MT was similar to
KRAS WT pts [median OS 15.6 vs. 19.0 mos; HR 1.24 (95% CI
0.57-2.67)]. Univariate analyses demonstrated superior OS among women
compared to men (HR 0.40, 95% CI 0.20-0.85) in the entire pt cohort.
Conclusions: In our population of stage IV non squamous NSCLC, pts with
KRAS MT had similar OS to those with KRAS WT tumors. OS was slightly
higher in KRAS WT pts, but this may have been confounded by the
inclusion of 6 EGFR MT pts in this cohort. The potential prognostic or
predictive role of KRAS MT in NSCLC pts undergoing chemotherapy
requires further prospective study.
7597 General Poster Session (Board #51G), Sat, 1:15 PM-5:15 PM
Insulin-like growth factor 1 (IGF-1R) protein expression (PE) and gene copy
number (GCN) for discrimination of response and outcome to figitumumab
in NSCLC. Presenting Author: Murry W. Wynes, Division of Medical
Oncology, University of Colorado Denver, Aurora, CO
Background: Early clinical data suggested figitumumab (F), an anti-IGF-1R
antibody, had clinical activity in several tumor types. However, two phase
III studies, A4021016 carboplatin/paclitaxel (CP) �/- F in 1st line
treatment or A4021018 erlotinib (E) �/- F in 2nd line therapy for patients
with advanced NSCLC, were closed prematurely due to futility. Neither
study used biomarker driven selection criteria. The aim of this study was to
retrospectively examine the phase III specimens in order to determine if
IGF-1R PE or GCN could discriminate response and/or outcome to F.
Methods: IGF-1R PE was determined by immunohistochemistry (IHC) and
the tumor specimens were scored using the H-score method (0-300) with
separate enumeration of membranous and cytoplasmic components and
then combination of these scores. GCN was evaluated by bright field silver
in situ hybridization (SISH) with recording the average copy number for 50
tumor cells. Results: IHC was evaluable in 25 CP�F, 20 CP, 27 E�F and
26 E specimens whereas SISH was evaluable in 24, 17, 21 and 22
specimens, respectively. Median PE for membrane, cytoplasm and both in
A4021016 were 130, 110 and 120 and in A4021018 they were 135, 140
and 140. Median GCN was 1.88 and 1.98 for A4021016 and A4021018,
respectively. There were no significant differences in PE or GCN between
treatment arms within each study. Neither PE nor GCN were able to
discriminate between response/non-response or disease control/progression
in either study. Likewise, neither study showed a significant difference
in OS or PFS when using the median cut-points for either PE or GCN.
Conclusions: Neither IGF1R PE or GCN were able to discriminate response
or outcome in the limited quantity of specimens available from two studies
that examined the IGF-1R targeted therapy figitumumab.
Lung Cancer—Non-small Cell Metastatic
7596 General Poster Session (Board #51F), Sat, 1:15 PM-5:15 PM
Visual effects in anaplastic lymphoma kinase (ALK)-positive advanced
non-small cell lung cancer (NSCLC) patients treated with crizotinib.
Presenting Author: Ravi Salgia, The University of Chicago, Chicago, IL
Background: Crizotinib is an ALK inhibitor indicated in the US for advanced
ALK-positive NSCLC. Visual effects reported by patients treated with
crizotinib were characterized using the Visual Symptom Assessment
Questionnaire (VSAQ). Methods: Patients with previously treated, advanced
ALK-positive NSCLC were administered 250 mg BID crizotinib in an
ongoing phase II study (PROFILE1005, NCT00932451; Pfizer). Patients
completed the VSAQ at day 1 of each 21 day cycle and at end of treatment.
The VSAQ has a recall period of 3 weeks and consists of 7 questions
assessing presence, frequency, timing, duration and degree of bother of
visual effects and their impact on Activities of Daily Living (ADL). The
visual effects assessed included appearance of overlapping shadows/after
images, flashing lights and streamers/strings/floaters, difficulty adapting to
lights and seeing at night. Patients rated degree of bother on a 5-point scale
ranging from ‘not at all’ to ‘extremely’. Impact on ADL was measured using
a 10-point scale (0: no effect; 10: completely prevented ADL). Frequency
analyses were performed. Results: As of June 1 2011, visual effects as
identified by VSAQ were reported by 63% (114/182) of patients at cycle 2
(C2), 57% at C3 (85/149), 52% at C4 (64/123) and 41% at C5 (46/112).
The most commonly experienced visual events were appearance of flashing
lights (C2:81%; C3:82%; C4:84%; C5: 76%), streamers/strings/floaters
(C2: 83%; C3:78%; C4: 81%; C5:87%) and overlapping shadows/after
images (C2:70%; C3:77%; C4:87%; C5:84%). Most patients reported
each event to last �1 minute (C2:61%; C3:71%; C4:77%; C5: 70%).
Majority of patients reported event frequency at each cycle of � 7 days/wk
(50–78%). Patients reported that the visual effects occurred mostly in the
morning (52–62%) and/or evening (62–73%). Majority of patients reported
that visual effects were not at all or a little bothersome (C2:62%;
C3:61%; C4:66%; C5:65%). Majority of patients indicated no or minimal
impact on ADL (C2:80%; C3:80%; C4:83%; C5:87%). Conclusions: Visual
effects identified by VSAQ in patients treated with crizotinib were frequent,
but were reported to be transient with no or minimal impact on ADL.
7598 General Poster Session (Board #51H), Sat, 1:15 PM-5:15 PM
Clinical presentation of hepatotoxicity-associated crizotinib in ALKpositive
(ALK�) advanced non-small cell lung cancer (NSCLC). Presenting
Author: Patrick Schnell, Pfizer Inc., New York, NY
Background: Severe hepatotoxicity has been observed with most receptor
tyrosine kinase inhibitors. Crizotinib, a first-in-class oral inhibitor of ALK,
was recently FDA approved for the treatment (tx) of advanced (ALK�)
NSCLC. We provide a review of hepatotoxicity in the crizotinib clinical
development program. Methods: Relevant tx-emergent adverse event (AE)
reports from 2 pooled single-arm trials in patients (pts) with ALK� NSCLC
who received crizotinib 250 mg BID (n�588) up to Jun 2011 were
reviewed. Five reports of severe hepatotoxicity received through Dec 13,
2011 were also evaluated. Results: Incidence of elevation in ALT and AST
lab values by CTCAE grade are shown in the table. Additionally, 16
all-grade (7 grade 3 or 4) cases of pertinent hepatic events have been
reported. Transaminase elevations generally occurred in the first 2 months
of tx and were usually reversible. Pts usually resumed tx at a lower dose
without recurrence; however, 4 (�1%) required permanent discontinuation
from tx. Five (�1%) cases of severe, potentially drug-related hepatotoxicity
(2 fatal) were reported through Dec 13, 2011, with an estimated exposure
of 1400 pts. Pts presented with fatigue, nausea, anorexia, weakness, and
abdominal pain. Time from starting crizotinib to onset of hepatotoxicity was
�6 weeks in 4 cases, while significant transaminase elevation was
observed after 6 months in the fifth case. Significant hepatic metastases
and abnormal enzymes at baseline were present in 1 (fatal) case, while
baseline transaminases were normal in 3 cases, or just above the upper
limit of normal in 1 case. Conclusions: Crizotinib is uncommonly associated
with severe hepatotoxicity and was reported in �1% of pts. Nausea,
malaise, decreased appetite, vomiting, and abdominal pain may indicate
hepatic toxicity. ALT and total bilirubin should be monitored monthly and
as clinically indicated. Discontinuation of crizotinib is recommended when
severe drug-induced hepatic toxicity is suspected or diagnosed.
Causality/grade
N � 588
Increased ALT
n (%)
503s
Increased AST
n (%)
All causality
All grade 86 (14.6) 63 (10.7)
Grade 3/4 30 (5.1) 14 (2.4)
Tx related
All grade 73 (12.4) 52 (8.8)
Grade 3/4 24 (4.1) 10 (1.7)
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