FM NOVEMBER 2018 ISSUE - digital edition

IMMUNE CHECKPOINT
BLOCKADE: THE NEW RAGE
Drugs that inhibit PD-1/PD-L1 pathway have been
rapidly getting adopted into clinical practice
NSCLC tumours overexpress the
immunosuppressive checkpoint
protein programmed death ligand 1
(PD-L1) to evade detection and attack
by immune cells. Inhibiting the PD-1/
PD-L1 axis with monoclonal antibodies
has significantly changed the treatment
approach in lung cancer during the last
5 years.
Immune checkpoint inhibitors that
block the PD-1/PD-L1 pathway, such
as nivolumab, pembrolizumab and
atezolizumab, have become a standard
treatment option for patients with
advanced non-small-cell lung cancer
(NSCLC).
NIVOLUMAB
Nivolumab is a fully human monoclonal
immunoglobulin G4 antibody targetting
PD-1. The treatment won US FDA
approval in March 2015 for the treatment
of squamous cell lung cancer. Marketed
by Bristol-Myers Squibb under the
brand name Opdivo, its efficacy to treat
squamous NSCLC was established in a
randomized trial of 272
participants of whom
135 received nivolumab
and 137 received
docetaxel.
In October 2015,
FDA expanded
nivolumab's approval to
advanced (metastatic)
nonsquamous nonsmall
cell lung cancer in
cases where the disease
progressed during or
after platinum-based chemotherapy.
Patients who received nivolumab
lived longer than those who received
docetaxel in the study. However, it was
found that the level of PD-L1 expression
in NSCLC tumours may help identify
the patients who are more likely to
live longer with the help of nivolumab
treatment. Therefore, the FDA also
approved the PD-L1 IHC 28-8 pharmDx
test to detect PD-L1 protein expression
levels and help physicians determine
which patients may benefit most from
treatment with nivolumab.
Currently, several studies are
underway to determine whether
nivolumab, in combination with other
therapies, is effective in patients with
advanced NSCLC. Among them are
Biomarker-Targeted Second-Line Therapy
in Treating Patients with Recurrent Stage
IV Squamous Cell Lung Cancer (The
Lung-MAP Screening Trial) and Alchemist
treatment trial. Studies using nivolumab
in NSCLC patients are ongoing in India as
well, according to ClinicalTrials.gov
“We are continuing to
explore the potential of
Opdivo through our broad
development programme in
thoracic malignancies, including
early- and late-stage NSCLC,
SCLC and malignant pleural
mesothelioma,'' says Sabine
Maier, M D, Development
Lead, Thoracic Cancers,
Bristol-Myers Squibb.
In October, BMS
announced topline results
from the Phase 3 CheckMate-331 study
evaluating nivolumab versus the current
standard of care, topotecan or amrubicin,
in patients with SCLC who relapsed
following platinum-based chemotherapy
did not meet its primary endpoint of
overall survival.
Earlier, in 2016, BMS said nivolumab
failed to achieve its endpoint in a study
and was no better than traditional
chemotherapy at treating newly
diagnosed lung cancer.
Nivolumab has been approved for
second-line NSCLC in more than 65
countries, including the US, Europe,
Japan and China.
PEMBROLIZUMAB
Pembrolizumab is a highly selective IgG4-
kappa humanized monoclonal antibody
against PD-1 receptor.
Pembrolizumab was approved
by the US FDA on October 2015 for
the treatment of metastatic NSCLC in
patients whose tumours express PD-L1
and who have failed treatment with
other chemotherapeutic agents.
Merck sells the drug under the brand
name Keytruda.
Following the results of Keynote
024 trial, the initial approval of
pembrolizumab as a second-line
treatment was extended to first-line
treatment in NSCLC patients with high
PD-L1-expressing tumours (PD-L1 >50%)
with no EGFR or ALK mutations.
The study found treatment with
pembrolizumab prolonged progressionfree
survival (PFS) and overall survival
(OS) and improved objective response
remarkable results in patients who are deemed untreatable
otherwise. It resulted in the complete remission of disease
even in cases of melanoma which has metastasised. However,
it fails to do the trick in all patients with the same condition.
PD-1/PD-L1 inhibitors also share some of the debilitating
adverse effects which are common to this class of
immunotherapies.
“There’s a substantial toxicity because when we remove
the brakes, the immune system will also attack normal tissue.
There is, especially with the anti-CTLA4 therapy, a tendency to
get autoimmune diseases like thyroiditis and hypopituitarism,”
points out Dr Dixit. But that, fortunately, has been largely
managed by dose alterations and other supportive care, he
adds.
26 / FUTURE MEDICINE / NOVEMBER 2018