Immunotherapy drug shows promise in potentially curing advanced colorectal cancer without the need for surgery

1. Colorectal Cancer Prevalence: With over 1.9 million new cases diagnosed in 2020 and projections pointing to a rise to 3.2 million by 2040, colorectal cancer represents a serious and growing global health challenge.
2. Genetic Mutation: A subset of patients with colorectal cancer has tumors characterized by being mismatch repair deficient (dMMR) with high microsatellite instability (MSI-H). Normally, mismatch repair is a crucial process that corrects DNA replication errors. Deficiencies in MMR lead to MSI-H tumors, which are present in about 15% of all colorectal cancer cases.
3. Clinical Challenges: Traditionally, MMR deficient/MSI-High colorectal cancer tumors have proven challenging to treat effectively.
4. Pembrolizumab Trial: A clinical trial has shown promising results by administering pembrolizumab, an immunotherapy drug, prior to surgery in patients with stage two or three MMR deficient/MSI-High colorectal cancer. Notably, this treatment was given in lieu of the conventional approach of chemotherapy.
5. Study Presentation: These findings were showcased at the ASCO Annual Meeting in 2024, suggesting that the results are both recent and relevant to current medical practices.
6. Significance: The study signifies a potential paradigm shift in treatment for the specified patient group, offering an alternative to chemotherapy which could lead to improved outcomes.

This development, encompassing a move towards personalized medicine based on genetic profiling of tumors, represents the cutting edge of oncology treatment. It holds profound implications not only for the management of colorectal cancer but also underscores the importance of genomic insights in guiding therapeutic decisions across various cancer types. Further research and long-term data are essential to validate these initial findings and to potentially integrate immunotherapy as a standard pre-surgical treatment option for MMR deficient/MSI-High colorectal cancers.

Focusing on stages 2 and 3 colorectal cancer

The clinical trial led by Kai-Keen Shiu aimed to address the challenges associated with stages 2 and 3 mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) colorectal cancer. Traditionally, treating this type of cancer, particularly when it’s reached stages 2 and 3, is difficult due to the risk of disease recurrence or metastasis to other body parts, which is classified as stage 4.

Shiu explains that stage 4 cancer, once established, may have already spread, and despite the early detection of stages 1-3, the risk of recurrence persists. Conventional treatments like chemotherapy, radiotherapy, and certain targeted therapies might extend life but often don’t cure the disease. Eventually, the cancer may become resistant and incurable, leading to the patient’s death.

Immunotherapy, according to Shiu, offers a ‘smarter’ approach, especially for treating dMMR bowel cancers that are in stage 4. This type of treatment has become preferred over chemotherapy for dMMR bowel cancers as it can induce remission in about one-third of patients, with them being alive and well five years later, as opposed to the mere 10% or less survival rate seen with conventional treatments.

By focusing on stages 2 and 3 colorectal cancer patients for the clinical trial, Shiu and his team aim to see if immunotherapy could be as effective in earlier stages of cancer as in stage 4. The potential of immunotherapy to induce remission in these stages and improve long-term survival rates could be transformative for the treatment paradigm of colorectal cancer.

Why pembrolizumab?

Pembrolizumab, known by its brand name Keytruda, is chosen as the immunotherapy drug for the NEOPRISM-CRC phase II clinical trial due to its unique and effective mode of action against certain types of cancer, including mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer. Here are the reasons why it is being used:

1. FDA Approval: Pembrolizumab has been approved by the U.S. FDA for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer, providing a regulatory endorsement based on evidence of its efficacy and safety.
2. Immune System Enhancement: The drug functions by upregulating or stimulating the patient’s immune system. It particularly enhances the activity of T cells, which are adept at killing viruses and damaged tissue. By boosting their activity, pembrolizumab assists these cells in recognizing and eliminating cancer cells that they would otherwise not target effectively.
3. Cancer Cell Elimination: Pembrolizumab enables the immune system to recognize cancer cells as ‘not self’ and subsequently eradicate them. This interaction leverages the body’s natural defense mechanisms to combat cancer more effectively.
4. Long-term Benefits: The immune response augmented by pembrolizumab is durable and, to some extent, has a ‘memory’. This allows it to protect the body from cancer recurrence beyond the actual duration of the treatment, which could be as short as a few weeks or months. It’s also generally well-tolerated with fewer side effects.
5. Favorable Side Effect Profile: Compared to traditional treatments like chemotherapy or radiotherapy, which can have numerous side effects, pembrolizumab is typically more tolerable. Its side effects are often less severe, allowing patients to undergo treatment with minimal disruptions to their quality of life.
6. Targeted Action: Unlike chemotherapy or radiotherapy, which are non-targeted and can kill rapidly dividing cells indiscriminately, pembrolizumab offers a more targeted approach, sparing the normal, healthy cells while focusing on the cancerous ones.

Dr. Kai-Keen Shiu’s explanation shines light on the rationale behind the selection of pembrolizumab for this clinical trial. Its effectiveness at bolstering the body’s innate immune response against cancer cells, coupled with its potential to induce a long-lasting remission with tolerable side effects, makes it a compelling candidate for treating certain populations of colorectal cancer patients.

50%+ taking pembrolizumab before surgery cancer-free afterward

The information provided unfolds a significant advancement in the treatment of colorectal cancer patients with specific genetic alterations. Let’s process the details disclosed:

1. Immunotherapy Pre-surgery: The research involved administering three cycles of pembrolizumab, an immunotherapy agent, before surgical intervention. This approach deviates from the standard treatment which generally includes surgery followed by chemotherapy.
2. Remarkable Response: The trial revealed that over 50% of the participants who received pembrolizumab pre-surgery showed no signs of cancer post-operatively. This is a stark contrast to the 4% remission rate in patients who underwent pre-surgery chemotherapy in previous studies.
3. Long-term Goals: The principal investigator, Dr. Kai-Keen Shiu, elucidated that the traditional treatment might not prevent relapse in a significant portion of patients, who may then develop metastatic disease and become incurable. The goal of giving immunotherapy before surgery is to shrink the cancer and potentially obliterate microscopic cancer cells that could cause relapses, thus ‘curing’ the disease ‘upfront’ and possibly circumventing the need for follow-up chemotherapy.
4. Further Research: The next step for Shiu and his team involves expanding the trial to enrol approximately 70-80 patients to substantiate that the observed three-year relapse survival rate is credible. The aim is not just to shrink the tumors but to ensure they do not recur in the patient’s lifetime.
5. Understanding Cancer Biology: Additionally, the trial encompasses translational objectives to deepen the understanding of the biology of dMMR cancers and the workings of immunotherapy. The team is particularly interested in individualizing the treatment to determine the necessary quantity and duration of immunotherapy to achieve long-term remission or cure.

These findings suggest a potentially transformative change in treating this subset of colorectal cancer patients, offering a less invasive yet more effective treatment modality. The successful implementation of such treatments can not only improve patient outcomes but also enhance their quality of life by avoiding the long-term consequences of chemotherapy and invasive surgeries. As the trial progresses, it will be pivotal to observe if these initial results hold up and lead to a new standard of care.

Long-term follow-up needed

The comments from Dr. Anton Bilchik underscore the groundbreaking nature of the study in question. His insights offer several key perspectives:

1. Unique Research Approach: The study stands out for being the first of its kind to examine the impact of pre-surgical immunotherapy in colorectal cancer patients at stages 2 and 3. This diverges from the more common practice of administering immunotherapy in advanced stages of the disease.
2. High Response Rate in Advanced Cancer: Dr. Bilchik points out that there is already a well-documented high response rate, reaching 80-90%, when using immunotherapy in advanced colorectal cancer cases with high microsatellite instability. This existing knowledge heightens the interest in investigating whether similar benefits can be extended to earlier stages of the illness.
3. Conventional Treatment Sequence: Typically, patients undergo surgical tumor removal followed by a pathologic assessment of lymph nodes to inform the decision on subsequent chemotherapy. The new approach upends this sequence by introducing immunotherapy upfront.
4. Need for Long-term Follow-up: While the initial results are promising, Dr. Bilchik emphasizes the importance of ongoing and long-term follow-up data to validate the efficacy and durability of immunotherapy when administered before surgery for these patients. Such data will be crucial for determining whether this treatment can definitively improve patient outcomes and become a new standard of care.

Dr. Bilchik’s response reflects a cautious enthusiasm within the medical community. While the study’s preliminary findings are encouraging, rigorous long-term data is needed to confirm the full impact and potential benefits of this innovative treatment approach for colorectal cancer patients.