A single arm phase II trial evaluating the activity of alectinib for the treatment of pretreated RET-rearranged advanced NSCLC

Despite advances in the treatment of non-small cell lung cancer (NSCLC) over
the past several decades, only small incremental overall survival benefits have
been demonstrated and treatments beyond first-line remain limited in unselected
NSCLC.

In 2004 the discovery of the Epidermal Growth Factor Receptor (EGFR) mutations
in NSCLC and their predictive value for therapy with EGFR tyrosine kinase
inhibitors (TKIs) opened the way to an intense program of research on lung
cancer, aiming at identifying other genomic or protein alterations that could
be used as target for treatment. Subsequently, genetic rearrangements of the
anaplastic lymphoma kinase (ALK) gene in lung cancer and its oncogenic features
were discovered in 2007. The impressive clinical results obtained with the
inhibition of ALK and EGFR kinases compared to classical chemotherapy further
supported the hypothesis that targeting signaling pathways aberrantly active in
cancer cells, might lead to a better outcome of therapy for molecularly
selected lung cancer patients. However, EGFR mutations and ALK translocations
cover only 15-20% of NSCLC in Western populations, calling for discovery and
development of novel targets. Studies on molecular alterations of lung tumours
highlighted specific differences of biomarkers expression and role in the
several histotypes of lung cancer. Adenocarcinoma (ADC) is the most prevalent
histologic subtype among lung tumours and certainly the most characterized for
its molecular features. To date, a targetable alteration may be recognized in
20-30% of adenocarcinomas in Caucasian patients.

After the discovery of ALK fusions, other genes have been to be found
genetically rearranged in lung cancer. The RET gene is located on chromosome 10
and encodes for a transmembrane receptor with tyrosine kinase activity.
Mutations of RET are known to be involved in the multiple endocrine neoplasia
type 2 (MEN2) syndrome, sporadic medullary thyroid cancer and sporadic and
radiation induced papillary thyroid carcinoma. RET fusions are transforming in
vitro and in vivo, and inhibition of RET in RET-rearranged lung cancer cells
leads to suppressed viability.

RET rearrangements have been identified in lung ADC as well, with a prevalence
of 1-2%. RET-positive lung carcinomas are more common in poorly differentiated
tumours and in never-smokers. Therapeutically, several multiple kinases
inhibitors, such as vandetanib (Astrazeneca, London, England), cabozantinib
(Exelis Inc. USA), ponatinib (Ariad, USA), axitinib (Pfizer, USA), sunitinib
(Pfizer, USA), sorafenib (Bayer Healthcare, Germany), and alectinib (Roche,
Switzerland) are potentially able to inhibit RET kinase function. Phase III
trials data in biologically unselected NSCLC are available for some of these
agents both as monotherapy and in combination. However, all the results from
these studies were negative and none of the drugs was approved for lung cancer
treatment, probably due to the absence of genotypic selection. On the other
hand, some case reports describe anecdotal responses to treatment with
vandetanib and cabozantinib in RET-positive lung cancer patients.

Preclinical studies have recently shown that alectinib has potent anti-tumour
activity in RET rearranged NSCLC. To date, a unique small clinical report of
alectinib activity in RET-rearranged NSCLC is available. Recently, in the
Journal of Thoracic Oncology, the Massachusetts General Lung Group reported on
four RET-rearranged advanced NSCLC patients who were treated with alectinib
(600 mg twice daily, N=3; 900 mg twice daily, N=1) as part of single-patient,
compassionate use protocols or off-label use of the commercially available
drug. Three of the four had received prior RET TKIs including cabozantinib and
experimental RET inhibitors. In total, they describe two (50%) objective
radiographic responses following treatment with alectinib (one confirmed and
one unconfirmed), with durations of therapy of 6 months and 5+ months
(treatment ongoing), respectively. Notably, one of these two patients was dose
escalated to alectinib 900 mg twice daily and had clinical improvement in
central nervous system metastases. In addition, one patient (25%) experienced a
best response of stable disease lasting ~6 weeks (drug discontinued for
toxicity). A fourth patient who was RET TKI-naïve had primary progression on
alectinib. Therefore, alectinib demonstrated preliminary antitumour activity in
advanced RET-rearranged NSCLC patients.

The primary objective is to assess the efficacy of alectinib in terms of best
overall response (OR) assessed by RECIST v1.1.

The secondary objectives are to evaluate secondary measures of clinical
efficacy including disease control, progression-free survival (PFS), and
overall survival (OS) as well as to assess safety and tolerability of the
treatment and to describe the association of primary and secondary outcomes
with tumour characteristics.

This is a single arm, multicentre phase II trial evaluating the activity of
alectinib as second-line treatment of pretreated RET-rearranged advanced
non-small cell lung cancer (NSCLC).

Patients must have histologically or cytologically documented advanced NSCLC
(recurrent stage IV) with locally tested RET rearrangement after at least one
previous line of platinum-based systemic therapy. RET rearrangement will later
be centrally confirmed.

If the subject meets the criteria to take part in the study, he/she will
receive alectinib 600 mg orally, twice per day (1200 mg per day in total) until
progression, refusal or unacceptable toxicity. Trial treatment may also
continue beyond progression, with physician and patient agreement, for as long
as the patient may still derive clinical benefit as per investigator decision.

Treatment has to start as soon as possible after enrolment, ideally within 7
days. Treatment visits are planned at treatment start (week 0) and then every 2
weeks (±3 days) for the first 12 weeks and every 4 weeks (±3 days) thereafter.
Radiological tumor assessments by CT scans of thorax/upper abdomen will be done
at baseline and repeated every 8 weeks (±4 days) after first dose of alectinib
until disease progression. At the end of trial treatment and irrespective of
the reason for stopping treatment, an end of treatment visit should be
performed within 30 days following the decision to stop trial treatment.

Patients who discontinue trial treatment before progression will perform
follow-up visits every 8 weeks (±4 days). Patients with progression that ends
trial treatment will be followed up every 12 weeks (±2 weeks) starting from
date of progression until trial end.

All patients in this study will be treated in the same way. If the subject
meets the criteria to take part in the study, he/she will receive alectinib 600
mg (4 x 150 mg capsules) orally, twice per day (total 1200 mg, 8 capsules
daily)until progression, refusal or unacceptable toxicity. The capsules must be
swallowed whole at the same time each day with food. Trial treatment may also
continue beyond progression, with physician and patient agreement, for as long
as the patient may still derive clinical benefit as per investigator decision.
Treatment has to start as soon as possible after enrolment, ideally within 7
days. Treatment visits are planned at treatment start (week 0) and then every 2
weeks (±3 days) for the first 12 weeks and every 4 weeks (±3 days) thereafter.

Distinct subtypes of non-small cell lung cancer are driven by a specific
genetic alteration and are known to be sensitive to inhibition of the
corresponding activated oncogenic pathway. RET rearrangements have been
identified in lung adenocarcinoma with an incidence of 1-2% and several
multiple kinases inhibitors (such as alectinib) are potentially able to inhibit
RET kinase function. Recently, alectinib demonstrated preliminary antitumour
activity in advanced RET-rearranged NSCLC patients. Alectinib has been
administered in several clinical trials and it has been shown that it was
generally well tolerated and had an acceptable safety profile.

At study entry, subjects will have a physical examination, radiological
examination (MRI or CT of the brain and CT of thorax and upper abdomen within 6
weeks prior to enrolment), electrocardiogram (ECG), blood and urine tests. A
pregnancy test will be done in women of childbearing potential. The subjects
will also be asked questions about their medical history and medication they
take. During the treatment with alectinib, the subject should visit the study
doctor every 2 weeks for the first 12 weeks and every 4 weeks thereafter for a
physical examination and blood and urine analyses. The subject will also be
asked questions about side effects, medications, treatments and hospital stays.
The doctor will assess the performance status by asking questions about his/her
general wellbeing. Radiological examinations (CT thorax and upper abdomen) will
be done every 8 weeks until disease progression.

Patients will receive alectinib 600 mg (4 capsules of 150mg) orally, twice per
day (total 1200 mg) until disease progression, refusal or unacceptable
toxicity. Trial treatment may also continue beyond progression, with physician
and patient agreement, for as long as the patient may still derive clinical
benefit as per investigator decision. Patients will be given a diary to fill
in the day and time they take alectinib capsules and to note any side effects
they experience. The completed diary should be brought to each clinic visit,
together with all empty, full and partly used bottles of alectinib.

At the end of trial treatment and irrespective of the reason for stopping
treatment, an end of treatment visit should be performed within 30 days
following the decision to stop trial treatment. During this visit, a physical
examination, ECG, blood and urine tests will be performed. A CT of thorax and
upper abdomen needs to be performed if not done within 6 weeks prior to the end
of treatment visit. Patients who discontinue trial treatment before progression
will perform follow-up visits every 8 weeks. Patients with progression that
ends trial treatment will be followed up every 12 weeks starting from date of
progression until trial end.