Immunotherapy drug may help ‘cure’ advanced colorectal cancer without surgery

By Staff 10 Min Read

  • 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.

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.

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.

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.

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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