The immunotherapy drug pembrolizumab could increase cancer-free outcomes for some patients with colorectal cancer.
- Some
people with colorectal cancer have a genetic mutation causing them to have
an MMR deficient/MSI-High tumor.
- Past
research shows that treating MMR deficient/MSI-High colorectal cancer
tumors can sometimes be difficult.
- A
new clinical trial has found that giving the immunotherapy drug
pembrolizumab before surgery instead of chemotherapy can help improve
outcomes for people with stage two or three MMR deficient/MSI-High
colorectal cancer.
In 2020, more than 1.9 million people globally were diagnosed with colorectal
cancer, also known as colon cancer or bowel cancer. That number is
projected to jump to 3.2 million colorectal cancer cases by 2040.
Some people with
colorectal cancer may have what’s known as mismatch
repair deficient (dMMR) tumors with high
microsatellite instability (MSI-H).
Mismatch repair (MMR) is
a normal process that occurs in the body’s cells to correct any errors during
DNA replication. Defects in the MMR process can lead to tumors with high
microsatellite instability (MSI-H). Microsatellites are a short segment of DNA
that repeats a number of times in a specific genomic location and are prone to
mutations.
About 15% of all colorectal cancer tumors are MSI-H.
Past research shows that treating MMR
deficient/MSI-High colorectal cancer tumors can sometimes be difficult.
Now, a new clinical
study has found that giving the immunotherapy drug pembrolizumab before
surgery instead of chemotherapy can
help improve outcomes for people with stage two or three MMR deficient/MSI-High
colorectal cancer.
The study was
recently presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2024.
Focusing
on stages 2 and 3 colorectal cancer
For this study,
researchers recruited 32 study participants with stage two or stage three MMR deficient/MSI-High
colorectal cancer.
“Once a cancer is
established in a person’s body it can already have spread to other parts of the
body (stage 4) and even if detected early (stages 1-3), there is always a risk
of disease recurrence afterward,” Kai-Keen Shiu, FRCP, PhD, consultant medical oncologist at
University College London Hospitals NHS Foundation Trust, honorary associate
professor at the University College London Cancer Institute, and chief
investigator of this clinical trial explained to Medical New Today.
“Although we can use (a)
traditional non-targeted treatment like chemotherapy and radiotherapy and
certain targeted therapies to extend life, it usually becomes incurable and
most patients will eventually die from that cancer becoming resistant to these
treatments,” Shiu continued.
“So we want to give
‘smarter’ drugs such as immunotherapy which has been particularly successful in
treating patients with deficient dMMR bowel cancers which are stage 4, and is
now the preferred treatment over chemotherapy as we can induce a remission in
around a third of patients who are alive and well five years later rather than
10% or less,” he added.
Why
pembrolizumab?
The NEOPRISM-CRC phase
II clinical trial focused on the immunotherapy drug pembrolizumab, sold under
the brand name Keytruda.
In June 2020, the U.S.
FDA approved the use of pembrolizumab for treating
patients with unresectable or metastatic MSI-H or dMMR colorectal cancer.
“Most cancer cells seem
to be able to evade the patients’ normal immune system and keep growing and
spreading,” Shiu detailed.
“Pembrolizumab
upregulates/stimulates the patient’s own immune system — including T cells which
are good already at killing viruses and damaged tissue which is foreign to the
body. By ramping up their activity they are powerful enough to recognize the
cancer cells to be ‘not self’ and eliminate them.”
— Kai-Keen Shiu, FRCP, PhD
“The immune system is
very powerful as (it) is durable and to a degree has ‘memory’ to protect the
body from cancer recurring — beyond the duration of treatment which can be as
short as a few weeks/month/years and very tolerable in terms of side effects,”
he continued.
“This is unlike
chemotherapy or radiotherapy which although do kill rapidly growing cancer
cells, are not targeted, (and) have many side effects so patients can usually
only have (a) short course of this for a few months at a time,” he said.
50%+
taking pembrolizumab before surgery cancer-free afterward
Shiu and his team
administered three cycles of pembrolizumab, in which a dose of pembrolizumab
was given every three weeks, to study participants before their surgery instead
of the standard treatment of surgery and chemotherapy.
Researchers found that more than 50% of participants
treated with pembrolizumab before surgery had no signs of cancer after their
surgery. The scientists compared these findings to previous studies showing
only 4% of participants treated with chemotherapy before surgery were cancer-free
after the surgery.
“When we do traditional surgery for early stage dMMR
CRC and cut out whole cancer and their associated lymph nodes, then give three
to six months of two drugs — FOLFOX or CAPOX chemotherapy
— we think around 20-30% of those patients will still relapse with metastatic
disease within three years of surgery, so (they) are no longer ‘curable’,” Shiu
said.
‘Curing’ Future Cancer Upfront
“If
we consider another approach by giving immunotherapy prior to surgery to shrink
the cancer down significantly and perhaps completely away — called a
pathological complete response — we are also eliminating any microscopic cancer
cells in the bloodstream or lymphatic system which would have (been the) future
cause of relapse. So we (are) potentially curing them ‘up front’ and also
avoiding any need for post-operative standard chemotherapy.”— Kai-Keen Shiu,
FRCP, PhD
With these promising
results, Shiu said they now have two main aims for continuing their research.
“Firstly, to enroll more
patients to a total of around 70-80 so we can generate enough data and
confidence that the three-years relapse survival rate is ‘true’ and become the
primary endpoint. This is much more meaningful for patients and doctors as we
don’t just want to shrink the cancer away, but see if that means it will never
come back in that patient’s lifetime,” he explained.
“Secondly, we built in
many translational objectives into the trial to learn more about the biology of
dMMR cancers and how immunotherapy works, including for the future how to
select which patients need more or less immunotherapy to get to long term
remission or hopefully cure,” Shiu added.
Long-term
follow-up needed
After reviewing this
study, Anton Bilchik, MD, PhD, surgical oncologist, chief of
medicine, and director of the Gastrointestinal and Hepatobiliary Program at
Providence Saint John’s Cancer Institute in Santa Monica, CA, told MNT he
found the study to be very interesting because this is the first time that
immunotherapy has been studied in these stages of colon cancer given before
surgery.
“It’s well known that
immunotherapy given in patients with advanced colon cancer that have high
microsatellite instability have an up to 80-90% response, so this is the first
time it’s been looked at in people who typically undergo an operation and then
after the operation and evaluation of the lymph nodes, the determination is
made whether to get chemotherapy or not,” Bilchik continued.
“And
this study shows that a high percentage of patients in that earliest stage — so
we’re talking about stage two or three — that get immunotherapy before surgery,
50% of them had no tumor in the specimen, and that makes the study very novel
and provocative.”— Anton Bilchik, MD, PhD
MNT also spoke with Glenn S. Parker, MD, FACS, FASCRS, vice chairman of surgery
and chief of the Division of Colon and Rectal Surgery at Hackensack Meridian
Jersey Shore University Medical Center in New Jersey, who commented that these
promising results of immunotherapy cannot be translated to treat all colon
cancers and long-term follow up is needed to assess the duration of response.
“However, as more drugs
for both chemotherapy and immunotherapy are developed on the horizon,
additional clinical trials will continue to play a role in the molecular
genetic profile for individual patients, their tumors, and greater precision
medicine in the future,” Parker said.
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