A phase II randomized, double-blind placebo controlled, study of letrozole with or without BYL719 or
buparlisib, for the neoadjuvant treatment of postmenopausal women with hormone receptor-positive
HER2-negative breast cancer (CBYL719A2201)

Letrozole is indicated for adjuvant and first line therapy for hormone receptor
(HR)+ breast cancer (BC) patients and is considered a valid therapeutic option
for neoadjuvant treatment of postmenopausal HR+ BC patients. While the
introduction of adjuvant treatment of estrogen receptor (ER)+ postmenopausal
breast cancer patients with hormonal therapy has led to improved long term
outcomes, there remains a nonnegligible percentage of patients relapsing after
standard adjuvant treatment with 5 years of letrozole (16%), justifying the
need for more efficient treatments. Because efficacy of adjuvant treatment is
based on long term outcomes, neoadjuvant testing offers a quick way to identify
which combination may lead to a better outcome over a single agent endocrine
treatment. Pathological complete response (pCR) is one of the indicators of
response to neoadjuvant treatment and it has been shown to be linked to long
term outcomes for neoadjuvant chemotherapy treatment in certain BC diseases.
However, pCR rate remains low with endocrine single agent. As a general
concept, the inhibition of the PI3K-AKT-mTOR pathway has already been shown to
lead to improved clinical outcomes when everolimus was added to letrozole.
Promising pre-clinical data showing potential for cell death in addition to
decreased proliferation have been observed when PI3K inhibitors are given in
combination with hormonal therapy. Furthermore, clinical activity has been
observed with single agent BYL719 or buparlisib in heavily pre-treated ER+ BC
patients and when buparlisib was given in combination with letrozole to
metastatic breast cancer patients.
The PI3K pathway might be activated via different routes. Within the given
ER+/PR+ subtype, activation can be seen via PIK3CA mutations or PTEN
alterations. Hence the use of an alpha-specific PI3K inhibitor like BYL719 or a
pan-PI3K inhibitor like buparlisib in combination with letrozole may improve
letrozole single agent outcomes by increasing the rate of tumor cell apoptosis.
It is hypothesized that inhibiting the PI3K pathway upfront in combination with
estrogen deprivation might be sufficient to lead to an increase in pathologic
response and might prove to be an effective treatment in neoadjuvant treatment
for postmenopausal HR+ HER2- BC patients.
In addition, in theory, an alpha specific inhibitor would demonstrate superior
efficacy in the PIK3CA-mutant cancer population, with a potentially improved
safety profile as compared to pan class I PI3K inhibitors. On the other hand, a
pan PI3K inhibitor may offer benefit over an alpha specific one by being
possibly active in circumstances where PI3K is activated via other subunits
such as PTEN or INPP4B altered breast cancer.
However, there is lack of sufficient preclinical data to predict respective
impact of alpha versus pan-PI3K inhibition in ER positive breast cancer in the
clinic and only a trial using both compounds in the same patient population
could provide additional preliminary information to help differentiate the
compounds in this context.
The purpose of the study is to determine whether treatment with a PI3K
inhibitor (BYL719 or buparlisib) plus letrozole leads to an increase in
pathologic response compared to treatment with placebo plus letrozole in
patients with hormone receptor-positive HER2-negative breast cancer for the
following populations: i) in patients with tumors harboring a mutation in the
PIK3CA gene ii) in patients with tumors harboring a wild type PIK3CA gene.
Update AM5:As part of a program-wide assessment of Buparlisib (BKM120) in
breast cancer across different indications, and considering the modest efficacy
observed in the Belle-2 study (Baselga, 2015), Novartis has decided not to
pursue further the development of buparlisib in early-stage breast cancer.
Ongoing patients receiving buparlisib/buparlisib-placebo and letrozole may
continue the treatment based on the investigator*s clinical judgement. Patients
recruited under buparlisib/buparlisib-placebo will still be part of the
statistical analysis. However, the assessment of the anti-tumor activity of
buparlisib/buparlisib-placebo plus letrozole will now become an exploratory
objective.

Primary objective: Determine whether treatment with a PI3K inhibitor (BYL719 or
buparlisib) plus letrozole leads to an increase in pathologic response compared
to treatment with placebo plus letrozole in patients with hormone
receptor-positive HER2-negative breast cancer for the following populations: i)
in patients with tumors harboring a mutation in the PIK3CA gene ii) in patients
with tumors harboring a wild type PIK3CA gene based on tumor tissue.
Update AM5: assess the anti-tumor activity of BYL719 QD plus letrozole versus
letrozole alone in increasing the Objective Response Rate (ORR) during
neo-adjuvant treatment among postmenopausal patients with HR+, HER2-negative
breast cancer for each of the two cohorts: i) PIK3CA mutated and ii) PIK3CA
wild tumor types based on tumor tissue.
Secondary objective: pCR and ORR (complete + partial) based on cDNA, safety
and tolerability, rate of breast conserving surgery, association between
changes in Ki67 from baseline to day 15, and baseline to surgery, with pCR for
each of the two cohorts, namely PIK3CA mutated and PIK3CA wild type, PEPI score
in both cohorts, pharmacokinetics.

Double blind randomized phase II study. Approximately 360 patients (180 PIK3CA
mutated and 180 wild type).
Randomization (1:1:1) to
* BYL 719 plus letrozole
* Placebo plus letrozole (50% placebo to BYL719, 50% placebo to buparlisib)
Neoadjuvant treatment for 24 weeks.
Follow-up for survival.

Treatment with letrozole ± BYL719

Risk: Adverse events of study medication.
Burden:
4 visits during cycle 1, 2 during cycle 2 and 1 during cycles 3-6. Duration 2-3
h. If separate consent for participation to PK has been obtained: 2 visits of
9h duration and 2 extra visits.
Fasting blood tests during every visit (except day 1 cycle 1) 20-35 ml per
occasion.
ECGs: day 1 of every cycle.
Echocardiography or MUGA-scan at screening and end of treatment.
Tumor evaluations after cycle 3 and 6.
Tumor biopsy at screening (in principle archived sample), during treatment and
at end of treatment (during surgery).
Diary about medication intake.
Follow-up for survival.