A randomised phase II trial of osimertinib and bevacizumab versus osimertinib alone as second-line treatment in stage IIIb-IVb NSCLC with confirmed EGFRm and T790M

Lung cancer has been the most common carcinoma in the world for several
decades. There were estimated 1.8 million new cases in 2012 (12.9% of the
total). It is also the most common cause of death from cancer worldwide.

Non-small cell lung carcinoma (NSCLC) represents approximately 80% to 85% of
all lung cancers. Unfortunately, at the time of diagnosis approximately 70% of
NSCLC patients already have advanced or metastatic disease not amenable to
surgical resection. Furthermore, a significant percentage of early stage NSCLC
patients who have undergone surgery subsequently develop distant recurrence and
die as a result of their lung cancer. Patients presenting with unselected
advanced NSCLC have a median overall survival of 10 to 12 months

Progress in molecular biology has changed the therapeutic approach to NSCLC,
and the treatment of advanced NSCLC can now be guided by the presence of
certain mutations, for example by mutations in the epidermal growth factor
receptor (EGFR). EGFR tyrosine kinase inhibitors (TKIs) (e.g. erlotinib) are
now the established first line therapy in patients with EGFRm NSCLC. Despite
achieving very good initial response rates and durable benefit following
treatment with approved TKI drugs targeting EGFRm, these patients will
eventually develop treatment-resistant disease after 9-14 months.

Survival rates of patients with advanced NSCLC who progress following treatment
with EGFR-TKI remain very low, with a median overall survival of 1-2 years.
Treatment following progression on EGFR TKI therapy is guided by patient
performance status, symptoms, and extent of disease. Patients have
traditionally been treated with chemotherapy. In patients able to tolerate
platinum-containing doublet chemotherapy, this is most often the preferred
second-line treatment. Median PFS with platinum-containing doublet chemotherapy
is generally reported to be in the range of 3-6 months. Following progression
on an EGFR TKI and doublet chemotherapy the only remaining options for patients
with EGFRm NSCLC are to re-challenge with EGFR TKI, or to receive salvage
chemotherapy.

A number of mechanisms of resistance that lead to the EGFR TKI failure have
been postulated, but the most frequently observed resistance mechanism is the
emergence of the T790M mutation in EGFR, which is detected in the tumours of
around 60% of patients after EGFR TKI failure

Osimertinib is a novel oral, potent, and selective third-generation
irreversible inhibitor of both EGFRm-sensitizing and T790M resistance mutants.
This compound is structurally distinct from other third-generation EGFR TKIs
and offers a pharmacologically differentiated profile from earlier first and
second generation EGFR TKIs

Vascular endothelial growth factor (VEGF) is a key angiogenic factor regulating
angiogenesis, the growth of new vessels from pre-existing vessels. This process
is fundamental to the growth of solid tumours , and it plays a significant role
in NSCLC; microvessel count is an independent predictor of poor prognosis in
patients with NSCLC.Moreover the Increased production of VEGF has been reported
to be associated with resistance to EGFR inhibition.


Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to
and inhibits the interaction of VEGF-A to its receptors on the surface of
endothelial cells.. Neutralising the biological activity of VEGF regresses the
vascularisation of tumours, normalises remaining tumour vasculature, and
inhibits the formation of new tumour vasculature, thereby inhibiting tumour
growth.

Clinically, the addition of anti-angiogenic agents such as bevacizumab to
chemotherapy in the treatment of advanced NSCLC have led to OS benefit. The
anti-angiogenic agent bevacizumab has been shown to provide additional efficacy
when used in combination with first-line platinum-based chemotherapy in several
trials in non-squamous NSCLC.

Pre-clinical studies suggest that erlotinib resistance may be associated with a
rise in both tumour cell and host stromal VEGF. Furthermore they suggest that
combined blockade of the VEGFR and EGFR pathways can abrogate primary or
acquired resistance to EGFR TKIs . Pre-clinical studies also indicate that
combination with anti-VEGF therapy could enhance antitumor activity of
anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by
increasing EGFR TKI concentration in specific tumours that express high levels
of VEGF protein.

2 clinical studies which examined the combination of erlotinib and bevacizumab
suggest that that combination treatments that target both tumour cells and
tumour microenviroment (such as angiogensis) may be a promising strategy for
further improving efficacy outcomes in patients with EGFRm NSCLC following
progression on EGFR TKI therapy and other lines of therapy.

There is thus a considerable unmet clinical need for novel therapeutic options
that can further extend the efficacy of targeted agents such as EGFR TKIs,
across all lines of therapy. Osimertinib is a new thirdgeneration EGFR-TKI wich
specifically targets the T790M resistence mutation, which is the most frequent
resistence mechanism to previous EGFR-TKI. There a strong rationale to combine
EGFR-TKI with anti-angiogenic therapies. Anti-angiogenic factors such as
bevacizumab could enhance the efficacy of EGFR-TKI and can delay and even
abrogate EGFR-TKI resistance. the main aim of this trial is to assess the
efficacy of the combination of Osimertinib with bevacizumab versus osimertinib
in terms of progression free survival

Primary objective
To assess the efficacy of the combination of osimertinib and bevacizumab versus
osimertinib alone in terms of progression-free survival (PFS) assessed by
RECIST 1.1.

Secondary Objectives:
To compare short and long term clinical efficacy outcomes as well as
tolerability of the two treatments.

This is a randomised controlled phase II multinational, multi-center trial of
osimertinib and bevacizumab versus osimertinib alone as second-line treatment
in patients with stage IIIb-IVb NSCLC harbouring activating EGFR (exon 19
deletion or L858R) and T790M resistance mutation.
This randomised phase II trial, with block stratified randomisation balanced by
institution with a total of 154 patients randomised 1:1 to the experimental and
control arm.
The following stratification factors will be used: Ethnicity (Asian, Non-asian)
and material used for T790M testing (tumour vs circulating DNA)

• screening: within 28 days prior to enrolment
• Treatment period; for both arms study visits will take place every 3 weeks,
tumour assessment by CT scan will be done every 9 weeks.
o Experimental arm: Osimertinib, 80 mg p.o., once daily plus bevacizumab 15
mg/kg i.v. on day 1 of every 3-week cycle.
o Control arm: Osimertinib, 80 mg p.o., once daily
• end of treatment: end of treatment visit at the centre is to be scheduled
within 30 days following the decision to stop trial treatment or within 30 days
after planned treatment start.if treatment never started.
• Follow up visits:
1)Patient who discontinues trial treatment before disease progression should be
assessed every 9 weeks from end of treatment visit until tumour progression or
until the end of trial, whichever occurs first
2)Follow-up visits after progression will take place every 12 weeks until
trial end ( up to 2 years after randomisation of last patient)

During enrolment patient will be randomized in one of the following arms;

Experimental arm: Osimertinib, 80 mg p.o., once daily plus bevacizumab 15 mg/kg
i.v. on day 1 of every 3-week cycle. The initial infusion of bevacizumab should
be given over 90 minutes. If the initial infusion is well tolerated, the second
infusion can be given over 60 minutes. If the second infusion is again well
tolerated, all subsequent infusions can be given over 30 minutes.
Control arm: Osimertinib, 80 mg p.o., once daily

At the time of study entry, physical radiological land lab examinations will be
performed. In addition to the routine lab examinations, tumour and blood
samples are necessary for central confirmation of T790M. An electrocardiogram
will be taken and the patient will be submitted to ophthalmologic testing. In
woman who could become pregnant a pregnancy test will be done ( on serum or
urine) prior to randomisation. During the study treatment, patients must visit
the study doctor every 3 weeks during for a physical examination and routing
blood analyses. In addition blood samples for translational research have to be
collected within 3 days prior to cycle 4 (in the experimental arm) or 9 weeks
after treatment start (in the control arm) also at time of progression there
will be extra blood samples for central testing. If the patient is randomised
in the control arm ; the patient will administer osimertinib (80mg, p.o.) each
day.
If the patient is randomised in the experimental arm ; the patient will receive
on the first day of each cycle ( 3 weeks) 15mg/kg bevacizumab per infusion. The
first infusion will be administered over 90 minutes, the second over 60 minutes
and the subsequent infusions will be administered over 30 minutes. Both
treatments will be administered until disease progression, unless unacceptable
toxic effects or consent withdrawal. Treatment can be continued beyond
progression if the patient shows clinical benefit. A end of treatment visit
should be done within 30 days following the last dose of trial treatment.

Follow-up visits for patients who discontinues trial treatment before
progression will take place every 9 weeks starting from the end of treatment
visit, until disease progression or until end of trial ( whichever occurs
first). Patients with progression that ends trial treatment will be followed
up every 12weeks starting from date of progression until trial end.

A recent CTs-scan ( within 5 weeks prior to enrolment) should be available, at
baseline before randomisation and then every 9 weeks from randomisation until
progressive diseases.

Form earlier clinical trials Osimertinib monotherapy, at the dose to be
evaluated in this trial, has shown consistent and high objective response rates
in patients with non-small cell lung cancer (NSCLC). The European Medicines
Agency has approved the use of osimertinib in patients with a T790M mutation.
Bevacizumab is approved for a broad range of cancer, including non-small cell
lung cancer.

In earlier studies it has been shown that anti-angiogenic agents provide
additional efficacy when used in combination with erlotinib in EGFRm positive
NSCLC patients. This with acceptable safety profile. Preclinical studies
suggested that anti-angiogenic agents may increase intra tumoural uptake of
anti-cancer drugs by changing the tumour vessel physiology and therefore delay
subsequent treatment resistance.
The combination of osimertinib with bevacizumab may have the potential to
provide additional clinical benefit in terms of increased and/or prolonged
disease control and a delay in the emergence of resistance in patients with
advanced EGFRm NSCLC who have progressed following a prior EGFR TKI agent

In summary, combined osimertinib -bevacizumab treatment offers a significant
survival benefit in patients with stage IIIb-IVb NSCLC with confirmed EGFRm and
T790M.