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RCC) was designed to address an unmet medical need by providing everolimus to
patients with mRCC prior to regulatory approval. UK results from the REACT trial
are reported here.
Methods: REACT was an open-label, international, expanded-access program.
Eligible patients had measurable or nonmeasurable mRCC of any histology, and had
progressed on, or were intolerant of, VEGFr-TKI therapy. Patients received a
once-daily oral 10 mg dose of everolimus. The primary objective of REACT was to
evaluate long-term safety of everolimus. Tumour response was also assessed
according to RECIST.
Results: A total of 120 patients were enrolled in the UK, 9% of worldwide
enrolment. Prior sunitinib was received by 76% of patients; only 5.8% of patients
received more than one VEGFr-TKI. Everolimus was received for a median duration
of 21.8 weeks (range, 2.0–59.0), numerically longer than reported overall for REACT
(14.0 weeks; range, 0.1–83.7). Safety findings and tumour responses were consistent
with those observed in the global patient population. The most commonly reported
grade 3/4 AEs were anaemia (20.8%), hyperglycaemia (10%), and lower respiratory
tract infection (7.5%). Stomatitis and pneumonitis occurred in 13.3% and 10% of
patients, respectively (all grades); grade 3 events were reported in 6.7% and 3.3% of
patients (no grade 4 events). Investigator-assessed best overall responses were stable
disease in 67 (55.8%) patients and a partial response in 1 patient (0.8%), comparable
with the overall population. No complete responses were documented in this trial.
Conclusions: The REACT trial provided everolimus in advance of regulatory
approval and commercial availability to mRCC patients in the UK who failed initial
VEGFr-TKI therapy. Everolimus was well tolerated, and safety findings were
consistent with those reported for global REACT.
Disclosure: S. Chowdhury: Consultant or Advisory: Novartis, Pfizer, GSK,
Sanofi-Aventis, Janssen-Cilag, Dendreon. All other authors have declared no conflicts
of interest.
822P A PHASE I DOSE ESCALATION STUDY INVESTIGATING
DOVITINIB AND EVEROLMUS IN COMBINATION IN
METASTATIC CLEAR CELL RENAL CANCER PATIENTS WHO
HAVE PREVIOUSLY FAILED VEGF TARGETED THERAPY
T.B. Powles 1 , R.J. Jones 2 , S. Crabb 3 , S. Sarker 1 , E. Boleti 4 , J. Shamash 1 ,
N. Sarwar 1 , S. Chowdhury 5
1 QMUL, Barts Cancer Insititute, London, UNITED KINGDOM, 2 Medical
Oncology, Beatson West of Scotland Cancer Centre Gartnavel General Hospital,
Glasgow, UNITED KINGDOM, 3 Oncology, Southampton University, London,
UNITED KINGDOM, 4 Oncology, Royal Free Hospital, London, UNITED
KINGDOM, 5 Oncology, Guys and St Thomas Hospital, London, UNITED
KINGDOM
Introduction: Both dovitinib and everolimus are agents used, or under investigation
in patients with renal cancer refractory to VEGF targeted therapy. It is potentially
attractive to use these agents in combination in patients with VEGF TKI refractory
disease. Together they target mTOR, VEGF and FGF-2. The purpose of this study is
to establish a dose for this combination to take forward in randomised trials.
Method: This phase I study (EUDRACT 2010-021250-19) followed a classic dose
escalation 3 + 3 designed. Sequential patients with metastatic clear cell renal cancer,
who had previously failed VEGF tyrosine kinase inhibitors were included. Patients
received fixed doses of drug in each escalating cohort (maximum n = 6) until dose
limiting toxicity (DLT) was reached. DLT included grade 3 toxicity during the first
6 weeks of therapy. If 2 episodes of grade 3 or more toxicity occurred in a specific
cohort the DLT cohort had been reached. The study has appropriate ethical approval.
Assement of response and progression free survival was by RECIST v1.1
Results: Patients were entered into 2 cohorts before DLT occurred (cohort 0:
dovitinib 200 mg/everolimus 5mg [n = 6]; cohort 1: dovitinib 300 mg/everolimus 5mg
[n = 3]) . DLT in cohort 1 included grade 3 fatigue (2/3) after 2 and 3 week of
therapy. In cohort 0 the following toxicity was identified: Lethargy grade 2 3/6 and
3 1/6; Diarrhoea Grade 2 2/6 and 3 0/6 mucositis; grade 2 0/6 and 3 0/6; nausea/
vomiting grade 2 0/6 and 3 1/6, pulmonary fibrosis grade 2 1/6 3 0/6 . Grade 3
toxicity after the first 6 weeks of therapy included pulmonary fibrosis 1/6, lipid
abnormalities 2/6. Overall 1 patient (11%) had a partial response to therapy. Of the
5 patients who did not stop therapy during the first 6 weeks due to toxicity,
3 continued for 6 months or more without progression.
Conclusion: The maximum tolerable dose for this combination was dovitinib 200mg
and everolimus 5mg. This dose is being taken forward in an expansion cohort which
will explore efficacy.
Disclosure: T.B. Powles: Novarits Has supplied an educational grant for this project.
Advisroy role for Novratis. S. Chowdhury: Advisory role. All other authors have
declared no conflicts of interest.
Annals of Oncology
823P SURVIVAL AMONG ADVANCED RENAL CELL CARCINOMA
(ARCC) PATIENTS WITH >2 PRIOR TARGETED THERAPIES
E. Calvo 1 , R. Casciano 2 , L. Stern 2 , T. Brechenmacher 3 , S. Stergiopoulos 3 ,
J. Coombs 4
1 Start Madrid, Early Clinical Drug Development Unit, Hospital Madrid Norte San
Chinarro Centro Integral Oncologico Clara Campal, Madrid, SPAIN, 2 Global
Outcomes Research and Pricing, Analytica LA-SER, New York, NY, UNITED
STATES OF AMERICA, 3 Oncology, Novartis Pharmaceuticals, East Hanover, NJ,
UNITED STATES OF AMERICA, 4 Global Health Economics and Market Access,
Novartis Oncology, East Hanover, NJ, UNITED STATES OF AMERICA
Background: Despite the emergence of VEGFR-TKIs and mTORs in aRCC,
considerable unmet medical needs remain. There are no published guidelines for 3rd
line treatment in aRCC and, despite significant advances, these patients have limited
treatment options. This analysis examines the overall survival of patients after
discontinuation from a phase III, randomized, double-blind, placebo-controlled trial
(RECORD-1), who received at least two targeted therapies.
Methods: All patients in RECORD-1 received at least one prior VEGFR-TKI before
randomization to everolimus (EVE) or placebo. Demographics, treatment sequence
and overall survival were reported for patients who discontinued EVE for reasons
other than death and received additional targeted therapy with either sorafenib or
sunitinib.
Results: Of the 416 patients in RECORD-1, 274 received EVE, 258 discontinued
EVE for reasons other than death and approximately one third of those (N = 87)
received sunitinib or sorafenib as additional targeted therapy following EVE (49.4%
sorafenib only, 40.2% sunitinib only and 10.3% both). Baseline patient demographics
at RECORD-1 enrollment are provided in the Table. Median time from EVE
discontinuation to additional sunitinib or sorafenib therapy was 0.9 months (mean
1.7, SD 2.5). The median overall survival for patients from start of the additional
sunitinib or sorafenib therapy after EVE discontinuation was 13.9 months (95% CI
10.6–17.2 mo).
Baseline Characteristics Patients receiving sorafenib or sunitinib post-EVE
N=87
Male, n (%) 73 (83.9%)
>= 65 years, n (%) 35 (40.2%)
MSKCC Intermediate Risk n (%) 52 (59.8%)
MSKCC Favorable Risk n (%) 29 (33.3%)
KPS— > =90 n (%) 63 (72.4%)
KPS—80 n (%) 20 (23.0%)
Conclusions: In this heavily pre-treated sub-population, following EVE
discontinuation in RECORD-1, some patients experienced meaningful rescue therapy
with a TKI, with a median overall survival of more than a year Clinical trials with
investigational targeted therapies are ongoing, and may provide additional treatment
options.
Disclosure: R. Casciano: Roman Casciano is an employee of Analytica LA-SER,
which received funding for the research. L. Stern: Lee Stern is an employee of
Analytica LA-SER, which received funding for the research. T. Brechenmacher:
Thomas Brechenmacher is employed by Novartis Pharmaceuticals, which provided
funding for the research. S. Stergiopoulos: Sotirios Stergiopoulos is employed by
Novartis Pharmaceuticals, which provided funding for the research. J. Coombs: John
Coombs is employed by Novartis Pharmaceuticals, which provided funding for the
research. All other authors have declared no conflicts of interest.
824P OVERALL SURVIVAL (OS) IN METASTATIC RENAL CELL
CARCINOMA (MRCC) SEQUENTIALLY TREATED WITH
DIFFERENT TARGETED THERAPIES (TTS): RESULTS
FROM A LARGE COHORT OF PATIENTS
G. Procopio 1 , E. Verzoni 1 , I. Testa 1 , R. Iacovelli 2 , E. Garanzini 1 , F.G.M. De Braud 1
1 Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano,
ITALY, 2 Dipartimento di Medicina Sperimentale, Policlinico Umberto I, Roma,
ITALY
Introduction: Targeted Therapies (TTs) have improved survival in patients with
mRCC. However expert opinion on the optimal therapeutic strategy is not entirely
shared. This study was performed to assess the overall survival (OS) in a consecutive
series of mRCC patients receiving TTs.
ix272 | Abstracts Volume 23 | Supplement 9 | September 2012