PracticeUpdate: Haematology & Oncology

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Predictors of
immunotherapy response
in lung cancer: biomarkers,
mutational load and
tumour biology
Roy S. Herbst MD, PhD,
Ensign Professor of
Medicine and Chief of
Medical Oncology at
the Yale Cancer Center
and Smilow Cancer
Hospital in New Haven,
Connecticut, speaks with Dr Farzanna
Haffizulla on immunotherapy for lung
cancer and advances in biomarker
studies.
Dr Haffizulla: We know that immunotherapy
agents have truly come of age in lung cancer.
What is your opinion about the advances in
biomarker studies?
Dr Herbst: Immunotherapy clearly has become
a new modality for treating lung cancer, just
like chemotherapy, radiation therapy, and tar-
geted therapy. The question now is how can
we benefit more patients. We know that 1 out
of 4, 1 out of 5 patients has a truly remarka-
ble outcome, but the remainder don’t, so we
need to develop newer and better biomark-
ers. We’re doing that. There’s PD-L1, which
gives an okay, not great biomarker.
Some studies, including one that I led with
pembrolizumab, do clearly show that higher
levels of PD-L1 do predict a better outcome,
so I think that PD-L1 will be used in some
settings. But what is also known is some
patients who don’t have any PD-L1 on their
tumour, still do have benefit, so it’s not the
whole story. Now what’s being done is immu-
no-sequencing, meaning people are looking
at tumours, sequencing those tumours, either
looking at either the number of mutations,
or the quality of the mutations, meaning is
there a specific mutation. I think those signa-
tures might be important, and then remember
there’s another part of the whole component.
It’s not enough to have a tumour that’s driv-
ing the process. You have to have the immune
system at the tumour. So, is the tumour
becoming inflamed and are the immune cells
coming to the tumour? I think both are being
looked at right now.
Dr Haffizulla: The PD-L1 status itself, would
you consider that a dynamic biomarker? And
you mentioned the tumour infiltrating lym-
phocytes themselves, and how they stain, and
how quickly you’re able to get that particular
specimen stained in the right fashion, and
how old that particular specimen is.
Dr Herbst: You bring up some good points.
It’s the interferon that stimulates the whole
process. It’s a real time marker, so archival
biopsies have their limits, so we’re going to
need to really cast a wide net here. Look at
signatures in the tumour, look at signatures
in lymphocytes, look at blood-based markers,
and all that’s being done, and we’re seeing
that in the literature now, and it’s a very big
area of research. We’re doing that in our own
group at Yale on a daily basis.
Dr Haffizulla: Still on the immunology thread
here. What is your opinion of some of the
immunologic biomarkers and immune neoan-
tigen signatures, and looking at the mutational
load of the tumour itself? How does that play
in, and I know that we want to get as detailed
as possible, but I know that there is also a
progression of change that happens with the
tumour as it’s being treated. So, how does
that all play in?
Dr Herbst: Well, you know, mutational load
certainly plays a role. Actually, if you look,
it’s really smoking. It’s patients who smoke
that tend to have a better outcome proba-
bly because they have more mutations. So, I
think mutational load can be a guide. I don’t
think it’s the whole story. We are going to
have to look at exactly what mutations are
there. Are there specific neoantigens? One
way we’re trying to figure this out at Yale is
we have a re-biopsy protocol as part of lung
SPORE grant, where we have patients who
get a biopsy before they’re treated, and then
they’re treated with an immune therapy.
Then, if they become resistant, we get a sec-
ond biopsy. The reason why that’s important
is then we can compare the genetic profile
before and after in the same patient. So, you
remove some of the noise that you see when
you check between patients, and try and iden-
tify what’s gained, what’s lost from the tumour
when it becomes resistant. These types of
studies are happening at many places now.
There’s so much we know, but there’s even
more we don’t know and I think this is an
Go to
to watch the
full video
interview with
Roy S. Herbst.
LUNG 28
PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY