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Annals of Oncology
814P A PHASE IB CLINICAL TRIAL OF THE MULTITARGETED
KINASE INHIBITOR LENVATINIB (E7080) IN COMBINATION
WITH EVEROLIMUS FOR TREATMENT OF METASTATIC
RENAL CELL CARCINOMA (RCC)
A.M. Molina 1 , T.E. Hutson 2 , J. Larkin 3 , A. Gold 4 , C. Andresen 4 , K. Wood 5 ,
R.J. Motzer 1 , M.D. Michaelson 6
1 Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center,
New York, NY, UNITED STATES OF AMERICA, 2 GU Oncology Program, Baylor
Sammons Cancer Center, Dallas, TX, UNITED STATES OF AMERICA,
3 Department of Medicine, Royal Marsden Hospital, London, UNITED KINGDOM,
4 PCU, Eisai Inc, Woodcliff Lake, NJ, UNITED STATES OF AMERICA, 5 Oncology
Pcu, Eisai Ltd, Hatfield, UNITED KINGDOM, 6 Medical Oncology, Massachusetts
General Hospital Cancer Center, Boston, MA, UNITED STATES OF AMERICA
Background: Lenvatinib (L) is an oral tyrosine kinase inhibitor targeting VEGFR1-3,
FGFR 1-4, RET, KIT, and PDGFβ. Everolimus (E) is an oral mTOR inhibitor
approved for RCC. This Phase (Ph) 1b/2 study investigates the combination of L plus
E in RCC patients (pts) (NCT01136733). The Ph 1b component reported here
assessed safety, tolerability, and maximum tolerated dose (MTD). The 3-arm
randomised Ph 2 comparing PFS of L plus E and L alone versus E alone is ongoing.
Methods: Pts with advanced unresectable or metastatic RCC, ECOG PS 0-1, age ≥18
y were eligible for Ph 1b. Pts received L plus E, daily, in 28-day cycles. A standard
3 + 3 dose-escalation design with expansion cohort was used to identify the MTD.
Results: 20 pts (M/F: 14/6; median age: 59 y [range 46-72]; median of 2 prior
therapeutic regimens [range 0-5]; 17/20 pts [85%] had received prior anti-VEGF
treatment (tx); 7/20 pts [35%] had also received prior mTOR-targeted tx) were
treated at 3 dose levels of L (12 mg [n = 7]; 18 mg [n = 11]; 24 mg [n = 2]) in
combination with E 5 mg. 4 DLTs were observed: G3 nausea and vomiting (1 pt) and
G2 mucositis (1 pt) at 24 mg; G3 elevated CPK at 18 mg; G3 abdominal pain at 12
mg. The MTD was L 18 mg plus E 5 mg. Median duration of tx was 14.5 wk (range
1-68, 7/20 (35%) pts ongoing). The most common tx-related adverse events (AEs),
all grades were fatigue 45% (G3, 5%); mucosal inflammation 40%; proteinuria 35%
(G3, 10%); diarrhoea 30% (G3, 5%); rash 30%; hypertension 25%; nausea, vomiting
each 25% (each G3 5%); constipation, decreased appetite, epistaxis each 20%. There
was 1 G4 related AE of hypercholesterolemia. PR was observed in 6/18 (33%) pts in
the MTD and lower dosing cohorts. Durable stable disease (≥23 wk) or PR were
achieved in 8/16 (50%) pts with postbaseline tumor assessments (and 3 pts ongoing
with SD $10,000. M.D. Michaelson: Dr.
Michaelson discloses institutional research funding from: EISAI, Pfizer, Abbott,
GlaxoSmithKline, Genentech Consultant or advisory role (UNCOMPENSATED):
Pfizer, EISAI. All other authors have declared no conflicts of interest.
815P SUNITINIB (SU) DOSING SCHEDULE AND DATA COLLECTION
TIMEPOINTS: IMPACT ON QUALITY OF LIFE (QOL)
OUTCOMES IN METASTATIC RENAL CELL CARCINOMA
(MRCC)
A. Bushmakin 1 , J.C. Cappelleri 1 , B. Korytowsky 2 , R. Sandin 3 , E. Matczak 4 ,
D. Cella 5
1 Statistics, Pfizer Inc., Groton, CT, UNITED STATES OF AMERICA, 2 Oncology
Health Economics Outcomes Research, Pfizer Global Pharmaceuticals,
New York, NY, UNITED STATES OF AMERICA, 3 Global Health Economics and
Outcomes Research, Pfizer Oncology, Sollentuna, SWEDEN, 4 Oncology, Pfizer,
New York, NY, UNITED STATES OF AMERICA, 5 Medical Social Sciences,
Northwestern University Feinberg School of Medicine, Chicago, IL, UNITED
STATES OF AMERICA
Background: In a randomized phase III trial, SU was associated with superior QoL
compared with interferon-alfa (IFN). Here, we report implications related to the
timing of collection of QoL data as it relates to SU-approved dosing in mRCC
(4 weeks on treatment, 2 weeks off treatment; Schedule 4/2) and the extent to which
such timing affects reported outcomes.
Methods: 750 treatment-naïve patients with mRCC were randomized 1:1 to receive
SU 50 mg orally once daily on Schedule 4/2 or IFN 9 MU subcutaneously thrice
weekly. QoL measures included FACT-G, FKSI-15, FKSI-DRS, EQ-5D, and EQ-VAS.
Higher scores indicated better outcomes (better QoL or fewer symptoms). Patients
completed QoL questionnaires on Days 1 and 28 of each cycle, up to a maximum of
30 cycles. SU data were analyzed to describe how the timing of QoL collection may
affect results. Random coefficients mixed-effects models were used.
Results: Data were used from all assessments collected (Days 1 and 28 at every
cycle). The model indicated that QoL results based on Day 28 collection were
consistently and statistically worse (lower QoL scores) than results based on Day 1
(table). Based on a comparison with previously reported between-arm differences
with SU vs. IFN, such variation could potentially diminish or increase the observed
treatment effect by 38% to 62%.
Conclusions: To account for overall patient QoL experience on therapy, in this case,
SU on Schedule 4/2, careful consideration must be given to the timing of QoL data
collection. For SU in mRCC, QoL data should be collected both on and off treatment
within a cycle. If QoL data are collected at only the last or first dose, scores will be
overly negative or positive, respectively. Hence, if QoL data are collected at only a
single timepoint within a cycle, it may not represent the full extent of QoL as
experienced by patients on SU and may lead to misinterpretation of the true QoL
outcomes.
Model means of QoL endpoints with SU by assessment day
Day 1 Day 28
Difference between
Day 1 and Day 28
(i.e., after (i.e., after Difference
as percentage of
2 weeks 4 weeks between Day
treatment effect*
Endpoint off drug) on drug) 1 and Day 28 P value (SU vs. IFN)
FKSI-15 46.3 44.3 2.0