Advertisements

Novel Therapies in GI Oncology at ASCO22

Advertisements

Jun 27, 2022

Dr. Rachna Shroff, of the University of Arizona Cancer Center,
tells guest host, Dr. Shaalan Beg, of UT Southwestern’s Harold C.
Simmons Comprehensive Cancer Center and Science 37, about advances
in precision medicine for pancreatic cancer featured at the 2022
ASCO Annual Meeting. She also highlights compelling new data from
the FOLFOX, FOENIX-CCA2, and HERB trials in hepatocellular
carcinoma, cholangiocarcinoma, and biliary tract cancer.

 

Advertisements

TRANSCRIPT

Dr. Shaalan Beg: Hello and welcome to the
ASCO Daily News podcast. I’m Dr. Shaalan Beg, your guest
host of the ASCO Daily News podcast today. I’m an adjunct
associate professor at UT Southwestern Simmons Comprehensive Cancer
Center and vice president of oncology at Science 37.

I’m delighted to welcome Dr. Rachna Shroff, the associate dean
for clinical and translational research and the chief of
gastrointestinal (GI) medical oncology at the University of Arizona
Cancer Center where she’s also the interim chief of
Hematology-Oncology.

Advertisements

Dr. Shroff is also the chair-elect for the Gastrointestinal
Cancer Symposium. Today we’ll be discussing key abstracts in GI
cancer that were featured at the 2022 ASCO Annual Meeting.

Our full disclosures are available in the show notes and
disclosures of all our guests on the podcast can be found on our
transcripts at asco.org/podcasts.

Dr. Shroff, thank you for being on the podcast today.

Advertisements

Dr. Rachna Shroff: Thank you so much for having
me.

Dr. Shaalan Beg: Let’s begin by reviewing what
is new in the realm of precision medicine in GI cancers. One of the
diseases where precision medicine has not made adequate inroads is
pancreatic cancer. One of the most common mutations in pancreas
cancer is KRAS, but there haven’t been a lot of treatments
that can target the most common forms of KRAS. What did we
hear at ASCO22 regarding precision medicine and pancreatic
cancer?

Dr. Rachna Shroff: I agree, I think that the
area of precision oncology is, unfortunately, lagging behind a
little bit in pancreatic cancer. But I think as we have gotten
better and better with our comprehensive genomic profiling, we are
identifying subsets of patients within pancreas cancer who are
potentially amenable to targeted therapies.

Advertisements

You already mentioned KRAS mutations, and we obviously
have a number of inhibitors in development in that space, though,
we are still missing that key G12D mutation that we see in
pancreas cancer. But what I think was really interesting that came
out of ASCO22, was a lot of interest and emphasis on better
understanding the KRAS wild-type patients in pancreatic
cancer.

Now, this is obviously a smaller subset of patients, given that
the majority of patients have KRAS mutations. But there
was a really interesting abstract, LBA4011,
that looked at patients with locally advanced or metastatic
pancreatic cancer, who were KRAS wild-type. They actually
received gemcitabine in combination with a monoclonal antibody
targeting EGFR and nimotuzumab.

This was a study that was done entirely in Asia. It involved 92
Chinese patients that were randomly assigned to receive the
combination of nimotuzumab with gemcitabine. What was interesting
in this study is that the patients were found in the full analysis
set to have a significantly longer median overall survival of 10.9
months versus 8.5 months with a hazard ratio of 0.5.

Advertisements

So, that of course was intriguing and provocative for sure.
Similarly, the other endpoints were also somewhat intriguing in
terms of improvements in the median progression-free survival
(PFS), etc. And specifically, patients without biliary obstruction
had a longer PFS, which was an interesting finding as well.

The nimotuzumab overall was pretty well tolerated and not any
sort of surprising treatment-related adverse events (TRAEs) were
noted. And so, this is definitely a drug that, I think, piques our
interest in terms of being able to target patients with
KRAS wild-type pancreatic cancer.

I think that questions, however, that remain, and I think
require further study is really understanding what this drug could
do in combination with the chemotherapy combinations that we use
more frequently in metastatic pancreatic cancers such as
gemcitabine and paclitaxel or 5FU-based regimens like
FOLFIRINOX.

I think given that it is a relatively well-tolerated drug, it
would be a very reasonable thing to investigate this drug further
in the KRAS wild-type population with the kind of
modern-day chemotherapy regimens that we use. And I think, of
course, we all know that it is useful to be able to look at these
types of drugs in a more global population. And so, a larger
patient set I think would be very useful as well, but at least it
tells us that there is a way to think about our KRAS
wild-type patients with pancreas cancer and that perhaps we really
need to understand and identify those patients’ potential for
precision oncology.

Dr. Shaalan Beg: One of the GI cancers that has
been a hotbed for precision medicine is cholangiocarcinoma, a
disease that’s very close to your heart. What updates did we hear
at ASCO22 regarding cholangiocarcinoma and precision medicine?

Dr. Rachna Shroff: This space of targeted
therapy and cholangiocarcinoma has been incredibly exciting for the
last few years and I think drug development has been rapid-fire in
that space.

The oldest, if you will, target that we’ve been thinking about
for some time is the FGFR2 fusion patient population. And
in Abstract
4009 by Dr. Goyal and colleagues, we saw the results of the
FOENIX-CCA 2 trial which was looking at an oral FGFR inhibitor
(futibatinib) in patients with intrahepatic cholangiocarcinoma, who
harbor FGFR2 fusions and gene rearrangements.

We had initially seen some of this data presented a few years
back, but this was the updated data set. It was a single-arm phase
2 study that involved patients with advanced intrahepatic
cholangiocarcinoma who had identified FGFR2 gene fusions,
and they received futibatinib daily until progression.

See also  Disparities Conference Unites Researchers, Patients, and Policymakers 

This was a traditional single-arm phase 2 study with a primary
endpoint of overall response rate. At the final data cut, with a
median follow-up of 25 months, there’s actually a confirmed overall
response rate of 41.7%. And I think that what was really exciting
about this is this is a refractory patient population.

So, in patients who have refractory cholangiocarcinoma, the
other drugs, the non-targeted therapy drugs that we think through,
really have response rates more in the single-digit to 10% range
and so to have a confirmed overall response (OR) over 40% is truly
exciting.

The duration of the response was also exciting. This is not just
a drug that works briefly, it has a duration of response of 9.5
months. And the mature median overall survival was 20 months. And
in a disease which we talk about with the ABC-02 data of GemCis, a
median OS in advanced disease of 11.7 months. This is really,
really exciting for patients who harbor this fusion or gene
rearrangement.

We know that that’s seen in about 10 to 15% of patients. So,
again, we’re dealing with a smaller subset, but it clearly
demonstrates the need to identify FGFR2 gene fusions, so
that we can offer these types of targeted therapies.

This was not the first FGFR inhibitor that we have seen data on
and in fact, we have 2 drugs already U.S. Food and Drug
Administration (FDA) approved. And so, when we look at the common
treatment-related adverse events that were identified with the
futibatinib, there are really class effects related to FGFR
inhibition like hyperphosphatemia, alopecia, dry mouth, nothing
that really stood out or that was concerning.

And so, I think this final analysis for the FOENIX study really
just reaffirms the utility of futibatinib in patients with
FGFR2 gene fusions, and the mature OS data, the duration
of response, all of this really aligns with the need to identify
patients with this alteration so that we can, post-gemcitabine
based therapies, offer this targeted therapy or an FGFR inhibitor
in general to these patients.

I think the other really exciting abstract in the glandular
carcinoma or biliary tract cancer space was
Abstract 4006. This was the updated data from the HERB trial,
which was an investigator-initiated multicenter phase 2 trial
looking at trastuzumab deruxtecan (T-DXd) in patients who have
HER2 expressing unresectable or recurrent biliary tract
cancer.

Trastuzumab deruxtecan, I’m sure everybody has been hearing
about because it has been incredibly effective in HER2
alterations across a myriad of different disease sites. And so, not
wanting to be left out, biliary tract cancers were investigated in
this study with patients who had HER2 expression, so, that
was HER2-positive IHC3+ or IHC2+/ISH+, and they also looked at
HER2-low expressing patients, and [whose disease] were refractory
or intolerant to gemcitabine-based therapy with the primary
endpoint of overall response rate.

So, in the HERB trial, a total of 32 patients were enrolled. 24
of them were HER2-positive and 8 were HER2-low and they all
received trastuzumab deruxtecan. When you look at the efficacy
data, the confirmed overall response rate in the patients with
HER2-positive was 36.4%, which again, as I said, in a refractory
patient population is certainly very exciting data. And the overall
disease control median, PFS, and median OS were all pretty
encouraging in terms of efficacy.

What was also kind of intriguing was that there was some
efficacy seen even in the patients who are HER2-low. Now, this is,
in my opinion, a slightly less exciting amount of efficacy, but
still important to note that the overall response rate in HER2-low
was 12.5% with a median PFS that was also somewhat exciting at 4.2
months.

And so, there is a potential clearly for targeting patients with
HER2-high or HER2-positive with trastuzumab deruxtecan, and I think
in the patients who are HER2-low, we need to better understand the
potential utility.

The common treatment-related adverse events that we see were the
typical things that we’ve heard about with trastuzumab deruxtecan,
but I think the one thing that was really worth noting was 8
patients or 25% of patients had interstitial lung disease (ILD),
which we know is an important identified safety concern for
patients who receive trastuzumab deruxtecan, and I think that’s a
pretty sizable number of 25%, so, I think that’s going to really
require a little bit more fleshing out for us to understand the
safety for these patients.

One question that a lot of us have had is whether these are
patients who have received gemcitabine, which we know can also
cause pneumonitis. And so, I don’t know if we’re seeing a higher
percentage of ILD because of, ‘priming’ with prior gemcitabine.

But regardless, I think this is just proof of principle that
again, we need to identify patients with biliary tract cancers that
have HER2-positivity because we now have a number of drugs
including potentially trastuzamab deruxtecan to target [their
disease] with after gemcitabine-based treatments

Dr. Shaalan Beg: Absolutely. Any new biomarkers
to keep on the radar for our listeners?

Dr. Rachna Shroff: I think there are a lot of
really exciting targets. One that was talked about and that we saw
data on at ASCO [Annual Meeting] was from Abstract
4048, which looked at claudin [18]. Claudin is basically a
transmembrane protein that kind of helps maintain the tight
junctions between cells.

In gastric cancer, in particular, we look at claudin 18 isoform
2, and there are 18.1 and 18.2 gene expressions that have been
identified in gastric cancer. So, there was a very comprehensive
abstract that was presented of over 1,900 samples that underwent
comprehensive profiling by next-generation sequencing.

See also  Fighting Prostate Cancer Through Diet and Nutrition

And the patients were identified with claudin 18.1, and 18.2,
high versus low. Claudin 18.2 expression was actually detected in
97% of the samples. It’s slightly lower with claudin 18.1 at 63%.
It’s important to note that the primary tumors had higher
expression levels than the metastatic tumors, so those were really
the tumors in which they did a deeper dive.

And in the process of doing this deeper dive, they did a really
interesting kind of better understanding of the immune
microenvironment and the immune profile in the samples that had
claudin expression. And what was identified is that there was an
inverse relationship basically between claudin 18.1 and 18.2
expression and correlation with PD-L1 positivity, tumor mutational
burden (TMB)-high, M1 macrophages expression, NK cell presence, CD4
positive T-cells, myeloid dendritic cells.

And so, there’s clearly something between the presence of this
claudin expression and the effect it has on the immune
microenvironment. I think that’s very relevant to keep in mind
because as we all know, there’s a whole space of drug development
focused right now on anti-claudin 18.2 monoclonal antibodies, as
well as a target for antibody-drug conjugates (ADC) and cellular
therapies with CAR T-cell therapies being developed specifically
against claudin 18.

And so, understanding the immune microenvironment and the
interaction between the claudin expression will be really important
as we continue to charge forward in that space.

Dr. Shaalan Beg: Absolutely. Very, very
exciting. Sticking with the liver pancreas theme, what other
studies piqued your interest with regards to hepatocellular
carcinoma (HCC)?

Dr. Rachna Shroff: It’s a really exciting time
in HCC. I mean, we actually have drugs that are working in the
advanced space. And so, now there’s a lot of interest in shifting
to looking at preoperative neoadjuvant, and adjuvant approaches and
what we can do to improve disease-free survival and overall
survival in patients who are able to undergo prior resection.

So, Abstract
4013 looked specifically at the efficacy and safety of adjuvant
hepatic arterial infusion chemotherapy with FOLFOX. And this was a
randomized open-label phase 3 trial. It actually included a total
of 315 patients between 5 different centers and patients were
randomly assigned to receive either 1 to 2 cycles of adjuvant HAIC
FOLFOX (Hepatic Arterial Infusion Chemotherapy FOLFOX) versus just
follow up, the control group had no adjuvant treatment, and the
primary endpoint was disease-free survival here and in the
intention to treat population, there was a significantly improved
median disease-free survival at 27 months versus 11 months in the
patients who were on the control arm. And there was a protocol
analysis, there were a number of other efficacy endpoints including
disease-free survival rates at 1, 2, and 3 years.

And everything kind of leaned towards and or suggested an
improvement with the utility of HAI FOLFOX in patients who undergo
complete resection. It should be noted that this included patients
specifically who had microvascular invasion on their resection. And
so, these are patients who are at higher risk for recurrence as we
know.

This to me suggests that there could be a role for adjuvant
treatment in patients who undergo complete resection with
microvascular invasion (MVI). HAI is a very specific technique and
it requires a highly skilled center in the placement of HAI pumps.
And we’re seeing more and more trials across the U.S. as well
investigating the role of HAI in advanced disease and in
perioperative approaches.

And so, I think this is an area of much-needed continued
research. There are, of course, a number of ongoing adjuvant
studies looking at immunotherapy in the adjuvant setting. And so,
it’ll be really important to see how those read out and then to try
to put all of these in context so that we can better understand
local therapy like HAI FOLFOX versus more systemic adjuvant
approaches like immunotherapy.

Dr. Shaalan Beg: Thank you very much, Dr.
Shroff for sharing your valuable insights with us. I really
appreciate you taking the time to spend with us and our
listeners.

Dr. Rachna Shroff: Thanks so much. I enjoyed
it.

Dr. Shaalan Beg: And thank you to our listeners
for your time today. You will find links to the abstracts discussed
today in the transcript of this episode. Finally, we’d really like
to hear your feedback. If you could please take a moment to rate,
review, and subscribe wherever you get your podcasts. Thank you
very much!

 

Disclosures:

Dr. Shaalan Beg:

Employment: Science 37

Consulting or Advisory Role: Ipsen, Array BioPharma,
AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation
Medicine

Research Funding (Inst.): Bristol-Myers Squibb,
AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics,
MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals

Dr. Rachna Shroff:

Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics,
Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim,
SERVIER, Genentech, Basilea

Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical,
Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals,
Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure,
Nucana, Loxo/Lilly, Faeth Therapeutics

Disclaimer:

The purpose of this podcast is to educate and inform. This is
not a substitute for professional medical care and is not intended
for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience,
and conclusions. Guest statements on the podcast do not express the
opinions of ASCO. The mention of any product, service,
organization, activity or therapy should not be construed as an
ASCO endorsement.

 

Advertisements

Leave a Reply

Your email address will not be published.