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

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7595 General Poster Session (Board #51E), Sat, 1:15 PM-5:15 PM<br />

Survival outcome segregated by KRAS mutation status in newly diagnosed<br />

stage IV non-small cell lung cancer (NSCLC) patients (pts) treated with<br />

first-line chemotherapy. Presenting Author: Anna K. Brady, University <strong>of</strong><br />

Pennsylvania, Philadelphia, PA<br />

Background: KRAS mutations (MT) form a distinct subset <strong>of</strong> NSCLC,<br />

generally considered to have poor prognosis. Although KRAS MT is a<br />

well-establised prognostic and predictive marker in colorectal cancer, its<br />

role in NSCLC remains ambiguous. Pts with KRAS MT NSCLC do not<br />

respond well to epidermal growth factor receptor (EGFR) directed tyrosine<br />

kinase inhibitor therapy, but little is known about the ability <strong>of</strong> KRAS MT to<br />

predict outcome after first-line chemotherapy in newly diagnosed advanced<br />

or recurrent NSCLC. Methods: We analyzed outcomes <strong>of</strong> consecutive pts<br />

with newly identified Stage IV non- squamous NSCLC treated at University<br />

<strong>of</strong> Pennsylvania (Penn) between 05/2008 and 7/2010 and then compared<br />

survival based on KRAS status [MT vs wild type (WT)] using chi square,<br />

Kaplan-Meier methods, and Cox regression models. Results: Of 106<br />

consecutive new pts with Stage IV non squamous NSCLC treated at Penn,<br />

49 (46%) underwent molecular analysis for KRAS MT. Fifteen (34%) were<br />

KRAS MT. Of 34 KRAS WT pts, 6 were positive for EGFR MT. The median<br />

age <strong>of</strong> all 49 pts was 61 years; 83% were Caucasian, 45% male and 60%<br />

had a �10 pack year smoking history. Median duration <strong>of</strong> follow up is 16.4<br />

mos. Majority <strong>of</strong> pts (92%) had adenocarcinoma histology. Most pts (88%)<br />

had ECOG PS 0-1 at presentation. Forty three pts received first line<br />

platinum-based combination chemotherapy (platinum and pemetrexed in<br />

31 pts). KRAS MT was associated with smoking (p�0.04), but not with<br />

gender or age. Overall survival (OS) <strong>of</strong> pts with KRAS MT was similar to<br />

KRAS WT pts [median OS 15.6 vs. 19.0 mos; HR 1.24 (95% CI<br />

0.57-2.67)]. Univariate analyses demonstrated superior OS among women<br />

compared to men (HR 0.40, 95% CI 0.20-0.85) in the entire pt cohort.<br />

Conclusions: In our population <strong>of</strong> stage IV non squamous NSCLC, pts with<br />

KRAS MT had similar OS to those with KRAS WT tumors. OS was slightly<br />

higher in KRAS WT pts, but this may have been confounded by the<br />

inclusion <strong>of</strong> 6 EGFR MT pts in this cohort. The potential prognostic or<br />

predictive role <strong>of</strong> KRAS MT in NSCLC pts undergoing chemotherapy<br />

requires further prospective study.<br />

7597 General Poster Session (Board #51G), Sat, 1:15 PM-5:15 PM<br />

Insulin-like growth factor 1 (IGF-1R) protein expression (PE) and gene copy<br />

number (GCN) for discrimination <strong>of</strong> response and outcome to figitumumab<br />

in NSCLC. Presenting Author: Murry W. Wynes, Division <strong>of</strong> Medical<br />

Oncology, University <strong>of</strong> Colorado Denver, Aurora, CO<br />

Background: Early clinical data suggested figitumumab (F), an anti-IGF-1R<br />

antibody, had clinical activity in several tumor types. However, two phase<br />

III studies, A4021016 carboplatin/paclitaxel (CP) �/- F in 1st line<br />

treatment or A4021018 erlotinib (E) �/- F in 2nd line therapy for patients<br />

with advanced NSCLC, were closed prematurely due to futility. Neither<br />

study used biomarker driven selection criteria. The aim <strong>of</strong> this study was to<br />

retrospectively examine the phase III specimens in order to determine if<br />

IGF-1R PE or GCN could discriminate response and/or outcome to F.<br />

Methods: IGF-1R PE was determined by immunohistochemistry (IHC) and<br />

the tumor specimens were scored using the H-score method (0-300) with<br />

separate enumeration <strong>of</strong> membranous and cytoplasmic components and<br />

then combination <strong>of</strong> these scores. GCN was evaluated by bright field silver<br />

in situ hybridization (SISH) with recording the average copy number for 50<br />

tumor cells. Results: IHC was evaluable in 25 CP�F, 20 CP, 27 E�F and<br />

26 E specimens whereas SISH was evaluable in 24, 17, 21 and 22<br />

specimens, respectively. Median PE for membrane, cytoplasm and both in<br />

A4021016 were 130, 110 and 120 and in A4021018 they were 135, 140<br />

and 140. Median GCN was 1.88 and 1.98 for A4021016 and A4021018,<br />

respectively. There were no significant differences in PE or GCN between<br />

treatment arms within each study. Neither PE nor GCN were able to<br />

discriminate between response/non-response or disease control/progression<br />

in either study. Likewise, neither study showed a significant difference<br />

in OS or PFS when using the median cut-points for either PE or GCN.<br />

Conclusions: Neither IGF1R PE or GCN were able to discriminate response<br />

or outcome in the limited quantity <strong>of</strong> specimens available from two studies<br />

that examined the IGF-1R targeted therapy figitumumab.<br />

Lung Cancer—Non-small Cell Metastatic<br />

7596 General Poster Session (Board #51F), Sat, 1:15 PM-5:15 PM<br />

Visual effects in anaplastic lymphoma kinase (ALK)-positive advanced<br />

non-small cell lung cancer (NSCLC) patients treated with crizotinib.<br />

Presenting Author: Ravi Salgia, The University <strong>of</strong> Chicago, Chicago, IL<br />

Background: Crizotinib is an ALK inhibitor indicated in the US for advanced<br />

ALK-positive NSCLC. Visual effects reported by patients treated with<br />

crizotinib were characterized using the Visual Symptom Assessment<br />

Questionnaire (VSAQ). Methods: Patients with previously treated, advanced<br />

ALK-positive NSCLC were administered 250 mg BID crizotinib in an<br />

ongoing phase II study (PROFILE1005, NCT00932451; Pfizer). Patients<br />

completed the VSAQ at day 1 <strong>of</strong> each 21 day cycle and at end <strong>of</strong> treatment.<br />

The VSAQ has a recall period <strong>of</strong> 3 weeks and consists <strong>of</strong> 7 questions<br />

assessing presence, frequency, timing, duration and degree <strong>of</strong> bother <strong>of</strong><br />

visual effects and their impact on Activities <strong>of</strong> Daily Living (ADL). The<br />

visual effects assessed included appearance <strong>of</strong> overlapping shadows/after<br />

images, flashing lights and streamers/strings/floaters, difficulty adapting to<br />

lights and seeing at night. Patients rated degree <strong>of</strong> bother on a 5-point scale<br />

ranging from ‘not at all’ to ‘extremely’. Impact on ADL was measured using<br />

a 10-point scale (0: no effect; 10: completely prevented ADL). Frequency<br />

analyses were performed. Results: As <strong>of</strong> June 1 2011, visual effects as<br />

identified by VSAQ were reported by 63% (114/182) <strong>of</strong> patients at cycle 2<br />

(C2), 57% at C3 (85/149), 52% at C4 (64/123) and 41% at C5 (46/112).<br />

The most commonly experienced visual events were appearance <strong>of</strong> flashing<br />

lights (C2:81%; C3:82%; C4:84%; C5: 76%), streamers/strings/floaters<br />

(C2: 83%; C3:78%; C4: 81%; C5:87%) and overlapping shadows/after<br />

images (C2:70%; C3:77%; C4:87%; C5:84%). Most patients reported<br />

each event to last �1 minute (C2:61%; C3:71%; C4:77%; C5: 70%).<br />

Majority <strong>of</strong> patients reported event frequency at each cycle <strong>of</strong> � 7 days/wk<br />

(50–78%). Patients reported that the visual effects occurred mostly in the<br />

morning (52–62%) and/or evening (62–73%). Majority <strong>of</strong> patients reported<br />

that visual effects were not at all or a little bothersome (C2:62%;<br />

C3:61%; C4:66%; C5:65%). Majority <strong>of</strong> patients indicated no or minimal<br />

impact on ADL (C2:80%; C3:80%; C4:83%; C5:87%). Conclusions: Visual<br />

effects identified by VSAQ in patients treated with crizotinib were frequent,<br />

but were reported to be transient with no or minimal impact on ADL.<br />

7598 General Poster Session (Board #51H), Sat, 1:15 PM-5:15 PM<br />

<strong>Clinical</strong> presentation <strong>of</strong> hepatotoxicity-associated crizotinib in ALKpositive<br />

(ALK�) advanced non-small cell lung cancer (NSCLC). Presenting<br />

Author: Patrick Schnell, Pfizer Inc., New York, NY<br />

Background: Severe hepatotoxicity has been observed with most receptor<br />

tyrosine kinase inhibitors. Crizotinib, a first-in-class oral inhibitor <strong>of</strong> ALK,<br />

was recently FDA approved for the treatment (tx) <strong>of</strong> advanced (ALK�)<br />

NSCLC. We provide a review <strong>of</strong> hepatotoxicity in the crizotinib clinical<br />

development program. Methods: Relevant tx-emergent adverse event (AE)<br />

reports from 2 pooled single-arm trials in patients (pts) with ALK� NSCLC<br />

who received crizotinib 250 mg BID (n�588) up to Jun 2011 were<br />

reviewed. Five reports <strong>of</strong> severe hepatotoxicity received through Dec 13,<br />

2011 were also evaluated. Results: Incidence <strong>of</strong> elevation in ALT and AST<br />

lab values by CTCAE grade are shown in the table. Additionally, 16<br />

all-grade (7 grade 3 or 4) cases <strong>of</strong> pertinent hepatic events have been<br />

reported. Transaminase elevations generally occurred in the first 2 months<br />

<strong>of</strong> tx and were usually reversible. Pts usually resumed tx at a lower dose<br />

without recurrence; however, 4 (�1%) required permanent discontinuation<br />

from tx. Five (�1%) cases <strong>of</strong> severe, potentially drug-related hepatotoxicity<br />

(2 fatal) were reported through Dec 13, 2011, with an estimated exposure<br />

<strong>of</strong> 1400 pts. Pts presented with fatigue, nausea, anorexia, weakness, and<br />

abdominal pain. Time from starting crizotinib to onset <strong>of</strong> hepatotoxicity was<br />

�6 weeks in 4 cases, while significant transaminase elevation was<br />

observed after 6 months in the fifth case. Significant hepatic metastases<br />

and abnormal enzymes at baseline were present in 1 (fatal) case, while<br />

baseline transaminases were normal in 3 cases, or just above the upper<br />

limit <strong>of</strong> normal in 1 case. Conclusions: Crizotinib is uncommonly associated<br />

with severe hepatotoxicity and was reported in �1% <strong>of</strong> pts. Nausea,<br />

malaise, decreased appetite, vomiting, and abdominal pain may indicate<br />

hepatic toxicity. ALT and total bilirubin should be monitored monthly and<br />

as clinically indicated. Discontinuation <strong>of</strong> crizotinib is recommended when<br />

severe drug-induced hepatic toxicity is suspected or diagnosed.<br />

Causality/grade<br />

N � 588<br />

Increased ALT<br />

n (%)<br />

503s<br />

Increased AST<br />

n (%)<br />

All causality<br />

All grade 86 (14.6) 63 (10.7)<br />

Grade 3/4 30 (5.1) 14 (2.4)<br />

Tx related<br />

All grade 73 (12.4) 52 (8.8)<br />

Grade 3/4 24 (4.1) 10 (1.7)<br />

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