A phase II trial evaluating the safety and efficacy of the addition of concurrent anti-PD-1 nivolumab to standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B Non-Small Cell Lung Carcinoma

Over the past decade, concomitant chemotherapy and radiotherapy has become the
first choice treatment for most patients with stage III non-small-cell lung
carcinoma (NSCLC). Currently, approximately 30% of patients are alive 5 years
after concomitant therapy. This figure remains approximately the same with the
addition of surgery. After chemo-radiotherapy, at least 30-40% of the patients
show local tumour progression on CT scans as first site of relapse.
Also after surgery, about 30% of patients fail locally as a first site of
recurrence. In addition, more than half of the patients eventually develop
distant metastases that may have been present but undetected at the time of
staging or that may have come from persistent or recurring local disease. It is
thus obvious that new approaches that preferentially tackle both local and
distant disease sites are needed to improve long-term survival and cure rates.
Dose-limiting toxicity of thoracic radiotherapy includes radiation pneumonitis
(RP). Starting from two months after the end of radiotherapy, about 15% of the
patients develop increasing dyspnoea and cough, provoked by a mixed
T-lymphocyte infiltrate in lung areas that have been irradiated. RP may happen
up to 6 months post-treatment, however about three quarters of RP cases occur 3
months after radiotherapy. Besides dose and volume parameters of the
radiotherapy, such as the mean lung dose (MLD) or the V20 (that is the
percentage of the lungs that received more than 20 Gy), the most important risk
factor for developing RP is the inflammatory status of the lungs before
therapy. The more baseline inflammation, the higher is the risk of RP.
Inflammation in the lungs can be visualized and quantified by measuring the
18F-fluoro-D-deoxyglucose (FDG) in the lung parenchyma by standard FDG-PET-CT
scans obtained at the time of staging. As the relative FDG uptake in the lung
vs. the aorta is used,
no specific calibration of the PET-scanner is required. Attempts to improve the
long-term survival include radiotherapy dose escalation/acceleration,
new chemotherapy combinations, and adding biological agents and cancer vaccines
to standard regimens. At present, none of these have demonstrated an improved
outcome. Improved understanding of the immune profile of NSCLC has led to
immunotherapeutic strategies, including inhibitory molecules responsible for
abrogating an anti-cancer immune response such as PD-1 and CTLA-4.
Bristol-Myers Squibb*s nivolumab, an investigational monoclonal antibody that
inhibits the immune checkpoint receptor PD-1 expressed on activated T cells,
has demonstrated positive results in several trials of previously treated
patients with advanced NSCLC. However, rare cases of severe or fatal
pneumonitis have been
reported throughout clinical trials using anti-PD-1 or anti-PD-L1 compounds.
Pre-clinical data show a clear beneficial effect by combining local
radiotherapy and anti-PD-1. Not only was the local tumour control increased,
but an *abscopal* effect on distant metastases could be observed. Radiotherapy
clearly acted as an *in situ* tumour vaccination resulting in the induction of
specific anti-tumour immunity in all sites of the body that could result in a
clinical anti-tumour effect because of the combination with anti-PD-1. The
initial dose and schedule of nivolumab will be 360 mg i.v. The rational for
flat dosing is based on the expected similarity of safety and efficacy to the
approved 3 mg/kg dose. Based on a wide therapeutic window of nivolumab
monotherapy, the range of exposures with flat dosing are not expected to affect
the efficacy because the exposures predicted for the 360 mg Q3W is on the flat
part of the exposure response curve. For safety, doses up to 10 mg/kg nivolumab
Q2W have been well tolerated across multiple tumours and an increase in
exposure is not associated with a probability of increasing adverse events.
Therefore, flat dose of 360 mg Q3W for nivolumab monotherapy is recommended for
further investigation in this trial. From cycle five on, nivolumab will be
administered at 480 mg Q4W for up to 1 year from commencement of nivolumab
treatment. Based on pharmacokinetic modelling, the 480 mg Q4W will provide
similar steady-state average concentrations as 3 mg/kg. The 4-weekly schedule
will be more convenient for patients. While the role of immunotherapy is
currently being evaluated as monotherapy or in combination with chemotherapy or
tyrosine kinase inhibitors in all lines of treatment of advanced NSCLC, as
monotherapy in early NSCLC adjuvant setting as well as monotherapy in
consolidation after completion of definitive chemo-radiotherapy, it has not yet
been assessed in combination with radiotherapy. Historical data of concurrent
treatment in the palliative setting suggest acceptable safety and a good
tolerability of such combination. Initially the NICOLAS trial was set up as
prospective evaluation of the safety of the checkpoint inhibition concurrent
with chemoradiotherapy.
In summary, there is a definite unmet need in the multidisciplinary care to
improve the prognosis of patients diagnosed with stage III NSCLC, with a strong
rationale supporting the combination of chemo-radiotherapy with anti-PD-1. A
major theoretical concern is the development of pneumonitis, a rare toxicity of
both radiotherapy and checkpoint inhibitors. The main aim of the current trial
proposal is therefore to evaluate the pneumonitis rate in patients being
treated with chemotherapy and radiotherapy in combination with concomitant or
sequential nivolumab treatment.
Rational for protocol amendment 2:
Since the NICOLAS trial was initiated, the landscape of combining
chemo-radiotherapy with immune-checkpoint inhibition, such as anti-PD-1
antibodies, has changed rapidly, opening a new window of opportunity.
There is a very strong interest of the multidisciplinary lung cancer community
to investigate the optimal integration of anti-PD-1 treatment into
chemo-radiotherapy. Currently, 11 sites from 5 countries are activated for the
NICOLAS trial and recruiting strongly (ahead of schedule). Using this momentum
will allow us to rapidly recruit additional patients in order to reach the
power to not only determine the feasibility in terms of pneumonitis grade 2 and
abouve, but also to evaluate the efficacy of the concurrent treatment.
So far, during the regular safety review, the ETOP IDMC did not observe any
additional toxicity compared the chemo-radiotherapy alone.
Additionally, a first planned analysis of the PACIFIC trial (stage III NSCLC
treated with concurrent chemotherapy and radiotherapy, followed by the
anti-PD-L1 durvalumab or observation, NCT02125461) showed an increased
progression-free survival (PFS), which was co-primary endpoint together with
overall survival (OS). The full details are not known, yet, but it appears that
the pre-clinical rationales of combined chemo-radiotherapy and anti-PD-1
treatment can be successfully transferred into clinical trials, without serious
toxicities.
A recent secondary analysis of the Keynote 001 trial indicates synergistic
affects of radiotherapy and immunotherapy. This international, multicentre
phase I trial assessed the effect of pembrolizumab monotherapy in patients with
progressive locally advanced or metastatic NSCLC. Patients were assigned to
multiple expansion cohorts to allow for the inclusion of patients who were
naïve to systemic therapy and those who had progression after one or two
previous regimens.
The results from this study showed that the effect of pembrolizumab was
significantly higher in patients who received previous radiotherapy than in
patients without previous radiotherapy (median PFS: 4.4 months versus 2.1
months, hazard ratio 0.56, p=0.019; median OS: 10.7 months versus 5.3 months,
hazard ratio 0.58, p=0.026).
These findings were well in line with pre-clinical studies that underlined the
ability of radiotherapy to enhance antitumour immune response.
In the absence of of serious pulmonary toxicity, the apperant benefit of
chemo-radiotherapy and anti-PD-1 and the high interest of the NICOLAS study
group, we propose to amend the NICOLAS trial protocol to expand on the number
of patients in order to reach sufficient power for an efficacy readout
(progression-free survival).

Primary objective: To assess the feasibility of the addition of nivolumab
consolidation to standard first-line chemotherapy and radiotherapy in locally
advanced stage IIIA/B NSCLC, as defined by the rate of grade *3 pneumonitis
(CTCAE V4.0) 6 months post-radiotherapy (see section 17:
Statistical Considerations).

Most important secondary objective:
* Progression free survival after 1 year

Other secondary objectives
* To evaluate secondary measures of clinical efficacy including time to first
grade *3 pneumonitis (TFP3), progression-free survival (PFS), objective
response rate (ORR), time to treatment failure (TTF) and overall survival (OS).
* To assess the safety and the tolerability of the treatment.

This is a multicenter phase II trial evaluating the addition of anti-PD1
nivolumab consolidation to standard first-line chemotherapy and radiotherapy in
locally advanced stage IIIA/B non-small cell lung cancer.

The trial consists of the following phases:
* Screening: within 28 days prior to enrolment
* Standard chemo-radiotherapy. Radiotherapy is given concurrent with
chemotherapy. Chemotherapy will consist of cisplatin and vinorelbine or
etoposide or pemetrexed given every 3 weeks for 3 cycles. If cisplatin cannot
be used, it will be replaced by carboplatin. Radiotherapy (5 days per week) is
delivered concurrent with cycle 2 and 3 of chemotherapy.
* Trial treatment with nivolumab, which should start together with
radiotherapy. Nivolumab is to be administered as a 30-minute infusion. The
first 4 doses (360mg) are administered every 3 weeks. As from dosis 5,
nivolumab (480mg) will be administered every 4 weeks. The treatment duration
with nivolumab is 1 year from start of nivolumab treatment, unless treatment
stops earlier due to unacceptable toxicity, disease progression or withdrawal
of consent.
* Follow-up visits after trial treatment stop but before progression will take
place every 9 weeks (first year after completion of chemo-radiotherapy), 12
weeks (year 2) or 6 months from year 3. Follow-up visits after progression will
take place every 6 months (starting from date of progression). Follow-up will
continue until 2 years from start of nivolumab treatment of the last recruited
patient in the trial.

* Chemotherapy:
Cisplatin 80 mg/m2 as an infusion on day 1 and vinorelbine 30 mg/m2 (20 mg/m2
during cycle 2 and 3) as an infusion days 1 and 8 , given every 3 weeks for 3
cycles
OR
Cisplatin 80 mg/m2 as an infusion on day 1 and etoposide 100 mg/m2 as an
infusion days 1 * 3 given every 3 weeks for 3 cycles
OR
Cisplatin 75 mg/m2 as an infusion on day 1 and pemetrexed 500 mg/m2 as an
infusion on day 1, given every 3 weeks for 3 cycles
Please note, if for some reason cisplatin cannot be used, it will be replaced
by carboplatin as an infusion on day 1 given every 3 weeks for 3 cycles.
* Radiotherapy will consist of a physical dose of at least 60 Gy i delivered
concurrent with chemotherapy cycles two and three.
* Nivolumab (experimental treatment) will start concurrently with chemotherapy
cycles two and three.
The first 4 doses of nivolumab will be administered at 360 mg in 30-minute
intravenous infusions every 3 weeks. From dose 5 on, nivolumab will be
administered at 480 mg every 4 weeks for up to 1 year from the start of
nivolumab treatment.
Treatment with nivolumab will continue for up to 1 year unless unacceptable
side effects, disease progression, or withdrawal of consent.

At the time of study entry, physical, radiological and lab examinations will be
performed. In addition, an electrocardiogram will be taken and pulmonary
function will be measured. In women who could become pregnant, a pregnancy test
will be done (on serum or urine) prior to receiving study treatment. During the
study treatment, patients must visit the study doctor every 3 weeks during the
chemotherapy phase and every 4 weeks during the treatment with nivolumab for a
physical examination and routine blood analyses. Inpatient admission into a
hospital is not envisaged, but can potentially become necessary.
Nivolumab will start concurrently with chemotherapy cycles two and three. The
first 4 doses of nivolumab will be administered at 360 mg in 30-minute
intravenous infusions every 3 weeks. From dose 5 on, nivolumab will be
administered at 480 mg every 4 weeks for up to 1 year from the start of
nivolumab treatment. Treatment with nivolumab will continue for up to 1 year
unless unacceptable side effects, disease progression, or withdrawal of consent.
Follow-up visits after trial treatment stop but before progression will take
place every 9 weeks (first year after completion of chemo-radiotherapy), 12
weeks (year 2) or 6 months from year 3. Follow-up visits after progression will
take place every 6 months (starting from date of progression). Follow-up will
continue until 2 years from start of nivolumab treatment of the last recruited
patient in the trial.

FDG-PET-CT must be performed at study entry. The FDG-PET exam is part of the
standard practice. The patient will have to be fasting for at least 6 hours
(drinking of water is allowed). After injection of a radioactive substance into
a vein, the patient will have to wait for about one hour. Then the scanning
session will start which may take up to 30 minutes.

After completion of the chemotherapy and radiotherapy, a CT of the thorax and
upper abdomen will be performed. This will be repeated every 9 weeks in the
first year after chemotherapy and radiotherapy, every 12 weeks in the second
year, and later every 6 months.These examinations can be carried out more
frequently, if the doctor considers this appropriate. The study doctor may also
suggest other tests, such as CT of the brain.

Although many attempts were made to improve the long-term survival of patients
with locally advanced non-small cell lung cancer, none of these have
demonstrated improved outcome. Improved understanding of the immune profile of
non-small cell lung cancer has led to immunotherapeutic strategies, including
inhibitory molecules responsible for abrogating an anti-cancer immune response
such as PD-1. Nivolumab is a monoclonal antibody that inhibits the immune
checkpoint receptor PD-1 and it has demonstrated positive results in several
trials of previously treated patients with advanced non-small cell lung cancer.
Nivolumab was never tested in the context of definitive radio-chemotherapy for
stage III disease. It was not specifically described to date to interact with
palliative radiotherapy in the stage IV setting. The unmet need in this
curative context presents a favourable risk/benefit ratio with as major concern
the cumulative risk of radiotherapy induced pneumonitis and nivolumab-related
pneumonitis. Since 2014 nivolumab has been approved in US and Japan for the
treatment of malignant melanoma, in Europe since June 2015. For the treatment
of non-small cell lung cancer nivolumab has recently gained approval in US and
Europe and is now available for compassionate use for 2nd line treatment of
non-small cell lung cancer.