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Guidance by molecular selection improves the outcome of early
phase treatment for gynecological (GYN) cancers
Background: Patients (pts) with advanced gynecological (GYN)
cancers have limited therapeutic options and the prognosis is poor.
Early phase trials may be a suitable option for pts with good
performance status. Increasingly, molecular characterisation guides
pt selection for early phase trials. We sought to determine the
outcome of GYN pts treated in a phase 1 unit and examined the role
of molecular selection to inform therapeutic decision making.
Methods: Medical records of all pts with a GYN malignancy treated
within an early phase trial between 2010 and 2016 were reviewed.
Data comprising patient and tumor characteristics, prior treatment,
trial therapy and outcome were analysed.
Results: 81 pts with a median age of 60 years (range 20-75) with a
diagnosis of ovarian (OC, 54), endometrial (EC, 15) or cervical/vulval
(CC, 12) cancer were identified. The median number of prior
therapies for advanced disease was 3 (OC) and 2 (EC and CC) (overall
range 1-6). 9 pts (11%) entered a second and 1 pt a third phase 1
study on disease progression. Next Generation Sequencing (NGS)
using a targeted panel was performed in 32 pts (40%) with an
actionable mutation identified in 9 including; KRAS (3pts), PIK3CA
(2pts) and EGFR (2pts). Germline BRCA (gBRCA) testing was
performed in 35 OC pts (65%) with 24 gBRCA mutations identified.
Pts were allocated, in order of priority, where available, to (1) a trial
selected on the basis of NGS or gBRCA (‘genomic’ 35%), (2) a ‘tumor
specific’ cohort within an early phase trial (15%) or (3) a ‘generic’
study (51%). For the whole cohort there was an overall response
rate (ORR) of 18% with 41% stable disease (SD) and median
progression free survival (PFS) and overall survival (OS) of 13 and 46
weeks respectively. Outcomes were best for pts in the genomic
group. Both PFS and OS were significantly longer with genomic
selection (p < 0.01 for both, Mantel-cox test) with median PFS of 29.7,
14.2, 8.0 weeks and OS of 84.1, 69.7, 33.6 weeks for genomics, tumor
specific and generic studies respectively. The ORR was also greatest
for the genomic cohort (32%) compared to the tumour specific (7%)
and generic (11%) groups.
Within the heavily pre-treated EC and CC cohorts there was an OS of
30 and 42 weeks respectively. 24% of EC pts had an ORR with a
further 24% with stable disease (SD). There was only 1 response
(9%) in the CC cohort, however SD was seen in 64%. The OS for the
OC was 55 weeks with an ORR of 20% and 46% SD.
Conclusions: Early phase trials represent a good option for pts with
advanced GYN malignancies. Whilst applicable to all GYN cancers,
this is particularly relevant for EC and CC pts as standard treatment
options are limited. For OC patients (median 3 prior lines of
chemotherapy in this cohort) where standard treatment options
exist, early access to phase 1 genomic trials may result in improved
response rates and allow further standard options to be given
subsequently. NGS is feasible in real time and may have a positive
impact on outcome.