Immune Checkpoint Inhibitors: The New Breakout Stars in Cancer Treatm | Page 11

Although the majority of combination studies are
focusing on the combination of an anti-PD-1 or antiPD-L1 agent, at least one current study is investigating
the combination of an anti-PD-1 agent with an
anti-PD-L1 agent (Table 6). Although all of the
therapeutic agents in the anti-PD-1 antibody family
target the binding of PD-L1 to PD-1, there may be
differences in their clinical benefit, based on affinity
and antibody isotype.24 A greater affinity for PD-1
should theoretically result in efficacy at lower
concentrations.
The combination approach might stimulate an
antitumor immunological memory,10 combining
the higher response rate of a targeted drug and the
longer-lasting response of immunotherapies.9
Despite the successes with combination treatment,
significantly more toxicities were experienced with
the combination than with either drug alone in all
of the studies investigating the combination of
ipilimumab and nivolumab. In the CheckMate-069
study, 62% of the patients undergoing combination
therapy had serious adverse reactions, versus 39%
with monotherapy. Further, adverse reactions leading
to permanent discontinuation occurred for 43% of
the combination therapy group and only 11% of the
monotherapy group; discontinuation was the result of
colitis, diarrhea, pyrexia, and pneumonitis. Therefore,
immunotherapy combinations might be limited by
their toxicity; these side effects might be largely
manageable with immunosuppressants.10

‘‘
62% of the patients
undergoing combination
therapy had serious
adverse reactions, versus
39% with monotherapy.

Considerations with combined immune
checkpoint therapy:
• Sequence:
– The choice of sequential or simultaneous
administration can affect the outcome
– A decision must be made regarding which
inhibitor will be administered first with
sequential administration; for example, in
the CheckMate-064 study, the ORR was 41%
when nivolumab was administered before
ipilimumab and 20% when ipilimumab was
administered before nivolumab.
• Doses
– Because of the increased risk of toxicities
with combination treatment, the most
appropriate doses for efficacy, while
minimizing toxicities need to be determined.

The observed durations and response rates with
the combination of nivolumab and ipilimumab for
melanoma has prompted combination with multiple
other immune modulators, both novel and FDA
approved (anti-LAG-3, anti-killer Ig-like receptors
[KIR], anti-4-1BB, and, as already discussed, IL-21
and pegylated IFN).24
Of these, the second-generation immune checkpoint
inhibitors represent additional treatment options
targeted at the large number of receptors and ligands
that help to control the immune response at various
levels. One of these second-generation agents is
LAG-3, a CD-4 homologue, which is required for
optimal T cell activation. Monotherapy with antiLAG-3 therapy (BMS-986016) is currently being
evaluated in a Phase I study for hematologic neoplasms
(chronic lymphocytic leukemia, lymphomas, and
multiple myeloma) (NCT02061761) and has completed
evaluation, as IMP321, for stage IV renal cell carcinoma
(NCT00351949) and metastatic breast cancer
(NCT00349934). As part of combination therapy,
dual blockade of PD-1 and LAG-3 helped to overcome
the anergy, or state of exhaustion, that can occur due
to high levels of persistent PD-1 expression in the
presence of a chronic viral infection or cancer.25,26
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