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

490s Lung Cancer—Non-small Cell Metastatic
7541 General Poster Session (Board #44G), Sat, 1:15 PM-5:15 PM
A phase II multicenter study of aflibercept (AFL) in combination with
cisplatin (C) and pemetrexed (P) in patients with previously untreated
advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC).
Presenting Author: Hongbin Chen, Roswell Park Cancer Institute, Buffalo,
NY
Background: AFL is a recombinant human fusion protein that acts as a
decoy receptor and prevents the interaction of vascular endothelial growth
factor (VEGF)-A, VEGF-B, and placental growth factor with their receptors.
This study evaluated the efficacy and safety of AFL in combination with
first-line chemotherapy of C and P in NSCLC. Methods: This phase II, single
arm, open label, multicenter trial in patients with previously untreated,
locally advanced, or metastatic NSCLC excluded patients with squamous
histology, cavitating lesions, ECOG � 1, uncontrolled hypertension, or
brain/CNS metastases. All patients received IV AFL 6 mg/kg, P 500 mg/m2 ,
and C 75mg/m2 , every 3 weeks for up to 6 cycles. For those who completed
the combined chemotherapy, Q3W administration of AFL was to continue
until disease progression, intolerable toxicity, or any other cause for
withdrawal. The primary endpoints were objective response rate (ORR) and
progression free survival (PFS). Planned sample size was 72 patients.
Results: The study was closed prematurely due to 3 confirmed cases of
reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42
patients were enrolled. Median age was 61.5 years; 54.8% were male,
85.7% white and 50% ECOG 0. A median of 4 cycles of AFL was
administered. The most common treatment-emergent adverse events
(TEAEs) of any grade were nausea (69%) and fatigue (67%), with
hypertension (36%) as the most common grade 3/4 TEAE. The 3 patients
with RPLS were Caucasian women. Two had a history of hypertension and
both experienced elevated BP and reduced CrCl. Of the 38 patients
evaluable for response, ORR was 26.3% (95% CI, 12.3-40.3%) and
median PFS was 5 months (95% CI, 4.3-7.1). Conclusions: The rate of
RPLS observed in this study with AFL � C � P was higher than anticipated.
A meta-analysis of safety from three large placebo-controlled studies
reported no RPLS among 1333 patient treated with AFL � chemotherapy,
and none was reported in prior combination studies of AFL � PorAFL� C
� docetaxel. Though the study was stopped early, ORR and PFS were in
accordance with most historical first-line NSCLC studies.
7543 General Poster Session (Board #45A), Sat, 1:15 PM-5:15 PM
Phase II study of the HSP90 inhibitor AUY922 in patients with previously
treated, advanced non-small cell lung cancer (NSCLC). Presenting Author:
Edward B. Garon, David Geffen School of Medicine, University of California
Los Angeles, Los Angeles, CA
Background: AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor.
A Phase I study in advanced solid tumors provided a recommended
Phase II dose of 70 mg/m2 . HSP90 acts as a chaperone of client proteins,
including those relevant in NSCLC pathogenesis. This Phase II study
assessed AUY922 in pts with previously treated advanced NSCLC stratified
by molecular status. Methods: Pts with advanced NSCLC who progressed
following �2 prior lines of chemotherapy, received AUY922 70 mg/m2 as a
1-hr infusion once-weekly. Pts were assigned to 4 strata: EGFR activating
mutations (EGFR mut), KRAS mut, ALK rearranged (ALK�), or EGFR/KRAS/
ALK wild type (wt). Phase II Bayesian hypothesis testing design allowed
sharing of information between strata based on assessing similarity in
observed response data. Primary endpoint was confirmed (RECIST) objective
response rate (ORR) or stable disease (SD) at 18 wks. Secondary
endpoints included OS, PFS, and safety/tolerability. Results: A total of 112
pts (median age 60 years; 45% male; 86% adenocarcinoma; 28 [25%] pts
KRAS mut; 35 [31%] EGFR mut; 14 [12%] ALK�; 31 [28%] EGFR/KRAS/
ALK wt) were treated at the December 16th 2011 cutoff. Most pts were
heavily pretreated: 61% had received �3 prior systemic regimens; 64%
had WHO PS 1 or 2. Mean duration of exposure was 9.1 wks. The most
frequent adverse events (AEs, any grade [Gr]) were diarrhea (73%), visual
AEs (71%), and nausea (43%). Most AEs were Gr 1/2; Gr 3/4 AE’s were rare
(all �10%). The study is ongoing, and 29 pts were still receiving treatment
at the cutoff date. Preliminary clinical activity of AUY922 (RECIST;
investigator assessed) was seen with partial responses in 13/101 (13%)
pts: 2/8 (25%) ALK� pts, 6/33 (18%) EGFR mut pts, 4/30 (13%)
EGFR/KRAS/ALK wt pts, 0/26 (0%) KRAS mut pts, and 1/4 (25%) pts of
unknown status. In ALK� pts, responses were seen in crizotinib (CRZ)naive
pts, and SD was seen with tumor shrinkage in CRZ-resistant pts. PFS
data will be presented. Conclusions: AUY922 had an acceptable safety
profile and demonstrated preliminary activity in heavily pretreated pts with
advanced NSCLC. This trial demonstrates clinical activity of AUY922 in
EGFR mut and EGFR/KRAS/ALK wt NSCLC pts in addition to ALK� pts.
7542 General Poster Session (Board #44H), Sat, 1:15 PM-5:15 PM
Skin toxicity associated with outcome to erlotinib in non-small cell lung
cancer (NSCLC) patients (p) with EGFR mutations in the EURTAC study.
Presenting Author: Cristina Buges, Catalan Institute of Oncology, Hospital
Germans Trias i Pujol, Barcelona, Spain
Background: Rash is reported in 75% of p treated with erlotinib and has
been associated with improved overall and progression-free survival (PFS)
in unselected p although not specifically in p with EGFR mutations.
Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized
174 p with EGFR exon 19 deletions or L858R mutations to receive
erlotinib or chemotherapy. Overall PFS was 9.7 months (m) vs 5.2 m,
respectively (P�0.0001). Rash was defined according to NCI CTC v3.0 and
dichotomized by grades 0-1 vs 2�. Grade 2 is macular or popular eruption
or erythema with pruritus or other associated symptoms, localized desquamation
or other lesions covering �50% of body surface area. We examined
outcome in the erlotinib arm according to rash grade. Results: 16pinthe
erlotinib arm had no rash (grade 0), 30 had grade 1, and 40 had grade 2�.
80% of cases of rash grade 2� occurred in p with exon 19 deletions, while
only 20% were in p with L858R mutations (P�0.039). There were no
differences in rash grade according to sex, age or smoking status. PFS was
11.2 m in p with rash grade 2� and 8.4 m in p with grade 0-1 (HR, 0.52;
P�0.018). There was no correlation between rash grade 0-1 vs 2� and
response or overall survival (OS). Interestingly, when p were divided into
those with no rash (16 p) and those with grade 2� (40 p), PFS was 11.2 m
for p with grade 2� vs 2.7 m for p with no rash (P�0.031), and OS was
24.9 m for p with grade 2� vs 16.1 m for p with no rash (P�0.033).
Conclusions: Although the biological reasons for the association of skin rash
with better outcome to erlotinib have not been elucidated, this sub-analysis
of the EURTAC trial has enabled us to confirm for the first time that skin
rash – especially grade 2� - can predict better outcome to erlotinib in p
with EGFR mutations. In addition, the correlation between rash and type of
EGFR mutation warrants further investigation.
7544 General Poster Session (Board #45B), Sat, 1:15 PM-5:15 PM
GAIN-(L): Efficacy and biomarker findings of RG7160 (GA201), a novel,
dual-acting monoclonal antibody (mAb) designed to enhance antibodydependent
cellular cytotoxicity (ADCC), in combination with first-line
cisplatin and pemetrexed in metastatic nonsquamous NSCLC. Presenting
Author: James F. Spicer, King’s College London, Guy’s Hospital Campus,
London, United Kingdom
Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth
Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown
promising clinical activity in phase I and in the neoadjuvant treatment of
head and neck cancer. This phase Ib study (NCT01185847) aimed to
determine the safety, pharmacokinetics (PK), activity and recommended
phase II dose (RP2D) of GA201 in combination with chemotherapy in
non-squamous NSCLC. Methods: Successive cohorts received GA201
1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with
chemotherapy at standard doses. Data cut off was 7 months after enrolling
the last patient. Results: 14 patients (4 female) with performance status
0-1 were enrolled. No maximum tolerated dose was reached. Most common
adverse events (AEs – all grades) included rash (100%), hypomagnesaemia
(71%), infusion-related reactions (64%), mucosal inflammation (57%)
and anemia (50%). AEs of � grade 3 included rash (71%), skin fissure
(21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median
timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction
for 4 patients and discontinuation for 1 patient. There were 6 confirmed
partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with
stable disease ��9 weeks. Duration of response ranged between 5 and 42
weeks (3 patients still ongoing). Preliminary biomarker analysis shows a
correlation between tumor-infiltrating CD16� immune cells and target
lesion shrinkage at first tumor assessment [R(spear)�-0.65 (p�0.02)]; no
apparent correlation between EGFR H-score and response was found. PK
data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The
RP2D of GA201 in combination with chemotherapy was established to be
1400 mg. The incidence of EGFR associated rash was high and guidelines
to reduce its severity were implemented with a noted improvement in
tolerability. Promising antitumor activity was observed. Biomarker data
support the mode of action of GA201 via ADCC. A randomized phase II trial
of this combination is ongoing and fully recruited.
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