Pembrolizumab alone versus pembrolizumab-chemotherapy in first line NSCLC

Lung cancer is the leading cause of cancer mortality. Non-small cell lung
cancer (NSCLC) accounts for more than 85% of all lung cancers. Historically,
platinum-based doublet chemotherapy was the standard first-line treatment for
metastatic NSCLC in the absence of targetable alterations. Chemotherapy alone
produces response rates ranging only between 15-30%. Since the introduction of
immunotherapy, the treatment landscape for patients with NSCLC has
fundamentally changed. Monoclonal antibodies targeting programmed death-1
(PD-1) and programmed death ligand-1 (PD-L1) have received regulatory approval
for first-line treatment in patient with non-small cell lung cancer (NSCLC).
Pembrolizumab (a PD-1 monoclonal antibody) significantly improved
progression-free survival (PFS) and overall survival (OS) compared with
platinum-based chemotherapy in patients with a PD-L1 tumor proportion score of
50% or greater. In addition; adding pembrolizumab to standard chemotherapy
resulted in significantly longer OS and PFS than chemotherapy alone regardless
of PD-L1 expression. Therefore, the combination of pembrolizumab with
chemotherapy has replaced cytotoxic chemotherapy as the first-line treatment of
choice in patients with a tumor PD-L1 of less than 50%. In patients with PD-L1
>=50%, however, both pembrolizumab monotherapy and pembrolizumab combined with
chemotherapy can be given as a first line option. In these patients, usually
pembrolizumab monotherapy is chosen as it has less toxicities as compared to
pembro-chemotherapy.

In the population of patient with a high tumor burden it may be assumed that
the combination of pembrolizumab and chemotherapy will result in a higher
response rate and may lead to an improvement in progression free survival and
possibly overall survival.

The aim of this project is to determine whether patients with high tumor burden
and high PD-L1 expression respond better to the combination of pembrolizumab
with platinum-based chemotherapy rather than to pembrolizumab alone.

This study has been transitioned to CTIS with ID 2024-516581-11-00 check the CTIS register for the current data.

Primary Objective:
- to assess the effect of chemotherapy given concurrently with pembrolizumab on
overall response rate (ORR) in NSCLC patients with high PD-L1 and high tumor
burden

Secondary Objectives:
- to examine the effect of chemotherapy given concurrently with pembrolizumab
on progression free sur-vival (PFS) and overall survival (OS) in patients with
high PD-L1 and high tumor burden as compared to pembrolizumab monotherapy
followed by chemotherapy at progression
- to compare the PFS of concurrent chemo-pembrolizumab with sequential
pembrolizumab followed by chemotherapy at progression (i.e. PFS-1 plus PFS-2)

Exploratory Objectives: The tumor biopsy prior to start of therapy and
additional blood samples will be used for translational research.
- If sufficient tumor material is available, tumor mutational burden will be
performed.
- Immunoprofiling of tumor micro-environment will be performed on the tumor
biopsy using multiplex immunohistochemistry panels.
- Blood samples obtained at baseline and after 6 weeks of therapy will be
analyzed for markers associated with tumor inflammation, immune system
activation and exhaustion and circulating tumor DNA.

A phase 3, multicenter, randomized controlled trial.
Patients will be evaluated for study end points with follow-up at 6, 12 weeks
and subsequently 3 month intervals with history and physical examination,
imaging including CT of the chest and/or abdomen, and laboratory testing
including complete blood cell counts and/or comprehensive metabolic panels as
needed.

Treatment regimen (Arm 1): Sequential pembrolizumab followed by chemo at
progression
- Pembrolizumab monotherapy in first line
• Pembrolizumab monotherapy 3 or 6-weekly until progression at fixed dose of
200mg IV.
- Chemotherapy, subsequently in second line after PD
In non-squamous cell:
• Chemotherapy will be given using platinum/pemetrexed (4 cycles 3-weekly),
followed by pemetrexed monotherapy 3 or 6-weekly until progression.
• Platinum: either carboplatin ([Glomerular Filtration Rate (ml/min) + 25] x (5
mg/ml x min) IV) on day 1 of each cycle or cisplatin 75 (or80) mg/m2
administered IV on day 1 according to local protocol. Pre-hydration and post
hydration schedule is mandatory as described by local proto-col with NaCl 2.5
or 0.9%.
• Pemetrexed (500 mg/m2 IV) on day 1 of each cycle. Pemetrexed cycles will be
repeated until progression, unacceptable toxicity or patient withdrawal.
• Dexamethasone (8 mg IV) on day 1 of each cycle to prevent allergic reactions
to pemetrexed.
• Patients will receive folate (500 µg 1x/day orally) and hydroxocobalamin
(1000 µg 1x/9weeks intramuscularly) during the whole course of pemetrexed
therapy.
In squamous cell:
• Chemotherapy will be given using carboplatin/paclitaxel (4 cycles 3-weekly)
• Carboplatin ([Glomerular Filtration Rate (ml/min) + 25] x (5 mg/ml x min) IV)
on day 1 of each cycle
• Paclitaxel 200 mg/m2 administered IV on day 1.of each cycle.

Treatment regimen (Arm 2): Concurrent pembrolizumab and chemotherapy
- Pembrolizumab plus chemotherapy
• In non-squamous cell: combination of Platinum/pemetrexed and pembrolizumab (4
cycles 3-weekly), followed by pemetrexed/pembrolizumab monotherapy 3-weekly
until progression
• In squamous cell: combination of Platinum/paclitaxel and pembrolizumab (4
cycles 3-weekly), followed by pembrolizumab monotherapy 3 or 6-weekly until
progression
• Dosing as described above

Patients will undergo one of two accepted routine first line therapies. As
such, there are no additional risks nor is there an additional benefit
associated with participation in this study, other than the benefit for future
patients that will derived from the knowledge gained in this study.