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

7512 Poster Discussion Session (Board #2), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Randomized phase II study of carboplatin and paclitaxel with either
linifanib or placebo for advanced nonsquamous NSCLC. Presenting Author:
Suresh S. Ramalingam, Winship Cancer Institute, Emory University,
Atlanta, GA
Background: Linifanib is a potent and selective inhibitor of VEGF and PDGF
receptors with modest single-agent activity in NSCLC. We evaluated the
combination of linifanib with carboplatin (C) and paclitaxel (P) for first-line
therapy of advanced non-squamous NSCLC. Methods: Patients (pts) with
stage IIIB/IV, non-squamous NSCLC, stratified by ECOG PS and gender,
were randomized to receive up to six 3-wk cycles of C (AUC 6 mg/ml/min)
and P (200 mg/m2 ) with daily placebo (Arm A), linifanib 7.5 mg (Arm B), or
linifanib 12.5 mg (Arm C). The primary endpoint was progression-free
survival (PFS); secondary endpoints included overall survival (OS), 12 m
survival rate, and objective response rate (ORR). Safety was assessed by
NCI-CTCAE v3.0. Results: 138 pts were randomized at 37 sites in 6
countries. Baseline characteristics were: median age, 61 y; men, 57%;
smoker, 84%. Efficacy results are shown in the table. Thrombocytopenia
was the only Grade 3/4 AE significantly higher on linifanib (Arm B: 16.7%;
Arm C: 29.8%) vs. placebo (2.1%). Other adverse events (AEs) related to
the dose of linifanib were diarrhea, thrombocytopenia, hypertension,
weight loss, palmar-plantar erythrodysaesthesia syndrome, and hypothyroidism.
Analysis of samples for predictive biomarkers including serum VEGF
and placental growth factor are underway. Conclusions: The addition of
linifanib to chemotherapy was tolerable at the doses tested and resulted in
a significant improvement in PFS, with a modest survival improvement for
Arm C in first-line therapy of advanced non-squamous NSCLC.
Arm A
N�47
Arm B
N�44
Arm C
N�47
Median PFS, m [95% CI] 5.4 [4.2, 5.7] 8.3 [4.2, 10.8] HR 0.51, P�0.022* 7.3 [4.6, 10.9] HR 0.64, P�0.118*
Median OS, m [95% CI] 11.3 [8.8, 17.0] 11.4 [6.6, 14.8]
13.0 [8.3, 18.9]
HR�1.08, P�0.779*
HR�0.89, P�0.650*
12 m survival rate, % 45 44 54
ORR, % 25.5 43.2 31.9
Received 2L therapy, n 26 13 18
*Stratified log-rank test; p value compared with CP � placebo.
7514 Poster Discussion Session (Board #4), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a
phase II randomized discontinuation trial (RDT). Presenting Author: Beth
A. Hellerstedt, US Oncology Research, LLC, McKesson Specialty Health,
The Woodlands, TX, and Texas Oncology, Central Austin Cancer Center,
Austin, TX
Background: Dysregulation of MET and VEGFR2 signaling has been observed
in NSCLC and MET upregulation has been implicated in resistance
to EGFR inhibitors. Cabozantinib (cabo) is an oral, potent inhibitor of MET
and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we
report on the metastatic NSCLC cohort which included patients who
received prior EGFR and VEGF pathway targeted therapy. Methods: All
eligible patients (pts) were required to have measurable disease at
baseline. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage.
Tumor response (mRECIST) was assessed q6 wks. Treatment � wk 12 was
based on response: pts with PR continued open-label cabo, pts with SD
were randomized to cabo vs placebo, and pts with PD discontinued. Results:
Enrollment to this cohort is complete (n � 60); all pts are unblinded.
Baseline characteristics: median age 67 years; adenocarcinoma 72% and
squamous cell 28%; 6 pts with known EGFR mutation (of 28 tested), all
having received prior erlotinib; bone metastases 20%; median prior lines of
therapy 3 (range 0 - 6); prior exposure to anti-EGFR therapy 50%, prior
exposure to anti-VEGF pathway therapy 32%. Median follow-up was 2
months (range 0.4 - 22.3 months). At Wk 12, ORR per RECIST was 10%
and overall disease control rate (PR�SD) was 40%. Objective tumor
regression was observed in 30/47 pts (64%) with post-baseline tumor
assessments, some of whom had known driver mutations in KRAS (3 pts) or
EGFR (4 pts). 24 pts (40%) completed Lead-in stage with 15 randomized
to continue cabo (N � 8) or to placebo (N � 7). No differences with respect
to PFS were observed between treatment arms in the randomized phase of
the study. Median PFS from study day 1 for all pts was 4.2 months. Most
common Grade 3/4 AEs were fatigue (13%), Palmar-plantar erythrodyesthesia
(8%), diarrhea (7%) and asthenia (7%); one related Grade 5 AE of
hemorrhage was reported during Lead-in stage. Conclusions: Cabo treatment
demonstrates activity in heavily pretreated metastatic NSCLC pts
with 4.2 months median PFS, 10% RECIST response, and 64% rate of
objective tumor regression. The safety profile of cabo was comparable to
that seen with other VEGFR TKIs. Future studies are warranted in NSCLC.
Lung Cancer—Non-small Cell Metastatic
483s
7513 Poster Discussion Session (Board #3), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
CALGB 30704: A randomized phase II study to assess the efficacy of
pemetrexed or sunitinib or pemetrexed plus sunitinib in the second-line
treatment of advanced non-small cell lung cancer (NSCLC). Presenting
Author: Rebecca Suk Heist, Massachusetts General Hospital Cancer
Center, Boston, MA
Background: Second line chemotherapy improves survival modestly and
new strategies are needed. This trial was designed to evaluate the paradigm
of an anti-VEGF strategy with or without standard chemotherapy in
previously treated NSCLC. Methods: Patients with Stage IIIB/IV NSCLC, PS
0-1 progressive after first-line chemotherapy were eligible for randomization
to P (pemetrexed 500 mg/m2 d1), S (sunitinib 37.5 mg d1-21), or
P�S (pemetrexed 500 mg/m2 d1 � sunitinib 37.5 mg d1-21). Pts were
stratified by PS (0/1), stage (IIIB/IV), and gender (M/F). Primary objective
was 18-week PFS rate; secondary objectives were response, OS, and
toxicity. Target accrual was 225. The study was terminated early due to
decreasing accrual rates. Results: Between 4/08 and 9/11, 130 pts
registered; 128 pts treated (P�41, S�46, P�S�41). Median follow-up
99 weeks. Baseline characteristics in the three arms (P/S/P�S) were well
balanced: Male (54%/54%/54%); PS 0 (32%/35%/34%); Stage IV (88%/
83%/93%). Histology was predominantly adenocarcinoma (66%/57%/
66%); squamous was allowed (10%/15%/15%). Toxicity was higher in the
S-containing arms: Grade 3/4/5 hematologic toxicity: P 5/0/0 (12%), S
8/1/0 (21%), P�S 5/9/0 (36%); Grade 3/4/5 non-hematologic toxicity
(excluding disease related deaths): P 6/2/0 (20%), S 21/3/1 (58%), P�S
21/3/1 (63%). The 18-week PFS rate in the three arms was: P 51%
(38-69), S 36% (24-54), P�S 47% (34-65). There is an overall statistically
significant difference in OS between the three arms (2-sided
p�0.0179) with HR 0.65 (95%CI: 0.38-1.13) for P/S; HR 0.47 (95%CI:
0.27- 0.82) for P/P�S. Median OS was 10.5 mo (8.3-22.5) for P, 7.0 mo
(6.0-13.0) for S, 6.7 (4.1-10.4) mo for P�S. Median PFS was 4.4 mo
(1.7-8.8) for P, 3.3 mo (2.7-4.3) for S, 3.7 mo (2.5-4.3) for P�S(p�0.3).
Fewer patients in the P�S arm received any subsequent therapy (29%)
than either P (54%) or S (57%). Conclusions: Pemetrexed had a superior
toxicity profile to either sunitinib or the combination of pemetrexed and
sunitinib. OS was significantly better with P alone compared to the two
S-containing arms, with P�S performing worst for OS.
7515 Poster Discussion Session (Board #5), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Randomized phase III trial of S-1 plus cisplatin versus docetaxel plus
cisplatin for advanced non-small-cell lung cancer (TCOG0701). Presenting
Author: Nobuyuki Katakami, Institute of Biomedical Research and Innovation,
Kobe, Japan
Background: Although molecularly targeted therapy improves outcome of
selected patients with advanced non-small-cell lung cancer (NSCLC), most
of the patients ultimately become candidates of cytotoxic chemotherapy,
which is the cornerstone of patient management. S-1 plus cisplatin (SP)
has shown activity and good tolerability in phase II settings. Docetaxel plus
cisplatin (DP) is the only third-generation regimen that demonstrated
statistically significant improvement of overall survival and quality of life by
head to head comparison with a second-generation regimen, vindesine plus
cisplatin, in patients with advanced NSCLC. Methods: Patients with
previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and
adequate organ functions were randomized to receive either oral S-1 80
mg/m2 /day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on
day 8 every 5 weeks or docetaxel 60mg/m2 on day 1 plus cisplatin 80
mg/m2 on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint is
overall survival (OS). Non-inferiority study design was employed as upper
confidence interval (CI) limit for HR�1.322. Secondary endpoints include
progression-free survival (PFS), response, safety, and quality of life (QOL).
Results: From April 2007 to December 2008, 608 patients from 66 sites in
Japan were randomized to SP (n�303) or DP (n�305). Patient demographics
were well balanced between the two groups. Two interim analyses were
preplanned. At the final analysis, total of 480 death events were observed.
The primary endpoint was met. OS for SP was non inferior to DP (median
survival, 16.1 v 17.1 months, respectively; HR�1.013; 96.4% CI,
0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the
DP arm. Statistically significantly lower rate of febrile neutropenia (7.4% v
1.0%), grade 3/4 neutropenia (73.4% v 22.9%), grade 3/4 infection
(14.5% v 5.3%), grade 1/2 alopecia (59.3% v 12.3%) were observed in the
SP arm than in the DP arm. QOL data investigated by EORTC QLQ-C30 and
LC-13 favored for the SP arm. Conclusions: S-1 plus cisplatin is a standard
first-line chemotherapy regimen for advanced NSCLC.
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