Phase Ib, multicenter, open label study of PDR001 in combination with platinum-doublet chemotherapy in PD-L1 unselected, metastatic NSCLC patients

Although chemotherapy has led to clinical improvements in patients with locally
advanced or metastatic non-small cell lung cancer (NSCLC), the outcome of
chemotherapy treatment in the first-line setting remains poor.
For patients with NSCLC that does not have EGFR or ALK or ROS1 gene mutation
current chemotherapy treatments are not considered satisfactory and the
prognosis continues to be poor despite chemotherapy treatment, with a 5-year OS
rate of only 15%.
PD-1 inhibitors have provided remarkable clinical benefit for patients with
advanced NSCLC. As a result, PD-1 inhibitors have become the preferred option,
in first line, for NSCLC that does not have a EGFR or ALK or ROS1 gene mutation
but does have PD-L1 expression on greater than 50% of tumor cells, and in
second line irrespective of PD-L1 expression but without a *druggable* gene
rearrangement, having demonstrated superior overall survival when compared to
standard chemotherapy. However, a large fraction of patients do not respond to
single agent PD-1 inhibitor. One potential approach to increase response rate
is based on the observation that chemotherapy-induced tumor cytotoxicity can
result in the release of tumor antigens, which can trigger anti-tumor Tcell
immunity. Preclinical studies have confirmed that chemotherapy leads to antigen
release in the tumor microenvironment.
Results from other PD1 inhibitors in combination with platinum-doublet
chemotherapy in the first line setting in phase Ib/II have shown promising
results, including tumor shrinkage in the majority of patients, durable
responses, and acceptable safety profiles. Recent data indicate that, in the
first-line setting, single agent PD-1 inhibitors are superior to
platinum-doublet chemotherapy with respect to PFS and OS in patients with high
levels of PD-L1 expression (>50%) on tumor cells. However, the population with
high level expression of PD-L1 expression may be relatively small. Preliminary
data suggest that even in this population combination with chemotherapy may
increase Overall Response Rate (ORR). Taken together these data indicate that
further exploration of PD-1 inhibitors in combination with platinum-doublet
chemotherapy is warranted in patients with PD-L1 unselected NSCLC.
An unanswered question is the choice of second-line therapy in patients whose
disease progresses following first line PD-1 inhibitor therapy. Based on the
demonstrated efficacy of platinum-doublet chemotherapy in the first line
setting, it can be assumed that platinumdoublet chemotherapy would provide some
benefit to this chemotherapy naive population. However, given the preclinical
data suggesting that chemotherapy leads to tumor antigen release creating an
immunogenic *feedback loop*, the addition of a PD-1 inhibitor may provide
improved efficacy over chemotherapy alone.
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody
that blocks the binding of PD-L1 and PD-L2 to PD-1. PDR001 shows functional
activity in vitro/ex vivo. In the mean time 11 early phase studies with PDR001
as a monotherapy or in combination with LAG525 (an anti-LAG3 antibody) are
ongoing. By the end of March 2016, a total of 58 patients had been treated in
the first in human study. No patient experienced a dose limiting toxicity and
the toxicity profile appears to be similar to that of marketed inhibitors of
PD-1.

Primary:
Dose confirmation part: To establish the Maximum Tolerated Dose (MTD) and/or
Recommended dose for expansion (RDE) of PDR001 with platinum-doublet
chemotherapy in treatment naïve patients with PD-L1 unselected, advanced NSCLC
of squamous or non-squamous histology, lacking EGFR, ALK or ROS1 gene changes
in the first 6 weeks of therapy for groups A, B, C.
Dose expansion part: To assess the antitumor activity (as measured by ORR) of
PDR001 with platinum-doublet chemotherapy in treatment naïve patients with
PD-L1 unselected, advanced NSCLC of squamous or non-squamous histology, lacking
EGFR, ALK or ROS1 gene changes for groups A, B, C.
Secondary:
Antitumor activity in groups A, B, C and D. Safety and tolerability.
Pharmacokinetics (PK). Immunogenicity.

Multicenter phase Ib open-label non-comparative study.
Part I: Dose confirmation part.
Dose escalation of PDR001 (starting dose 300 mg i.v. on day 1 of every course
of 3 weeks).
In combination with fixed dose chemotherapy up to first 4 cycles: group A:
(squamous): gemcitabine/cisplatin; group B: (non-squamous):
pemetrexed/cisplatin; group C: (squamous or non-squamous):
paclitaxel/carboplatin.
Part 2: Dose expansion part.
PDR001: MTD or RDE from part 1.
Groups A-C as in part 1.
Group D: (non-squamous): randomization to
* Arm 1: Investigator*s choice pemetrexed/cisplatin or pemetrexed/carboplatin +
PDR001 (up to 4 cycles) followed by maintenance with pemetrexed + PDR001.
* Arm 2: Investigator*s choice pemetrexed/cisplatin or pemetrexed/carboplatin
(up to 4 cycles) followed by maintenance with pemetrexed alone.
Treatment until progression or unacceptable toxicity.
Follow-up for safety 5 months. Follow-up for survival.
Part 1: up to 60 subjects.
Part 2: 120 subjects.
See also protocol pages 37-38.

Treatment with PDR001 and platinum-doublet chemotherapy (see protocol pages
37-38).

Risk: Adverse effects of PDR001 plus chemotherapy.
Burden: Cycles of 3 weeks. Visits on day 1, 8, 15 of the first 4 cycles and day
1 of every cycle thereafter. Visit duration mostly 1-4 hours. 2x patient will
be admitted to the hospital for 8-9 hour duringPK days.

IV infusions of PDR001 and chemotherapy on day 1 of every cycle (PDR001) or of
the first 4 cycles (chemotherapy), in case of gemcitabine also on day 8 of the
first 4 cycles. Infusions of 250 mL. Duration of PDR001 infusion standard 0,5
hour (up to 2 hours is accepted).
Physical examination: day 1 of (nearly) every cycle, screening, once during
follow-up.
Blood tests (5-50 mL/occasion): day 1, 8, 15 of cycle 1-4, once during every
cycle thereafter, screening, once during follow-up.
ECG: every 3rd cycle, screening, once during follow-up.
Echocardiography: twice.
CT-/MRI scan: every 6-12 weeks.
2 tumor biopsies (1st may be replaced by recent archival material).
Optional: tumor biopsy at disease progression.
Optional: extensive PK blood sampling.
Optional: pharmacogenetic blood sample (6 mL).
Optional: biomarker and immunological blood sampling in case of adverse event
(2 tubes).
Optional use of the remaining blood and tissue for future research.