Who this is for
“I have been diagnosed with metastatic colon cancer and my doctor told me that my cancer is MSI-high or related to Lynch syndrome. I have heard immunotherapy works well. Should I receive one immunotherapy drug or two?”
This article is for you.
Clinical observation
Few moments in medicine are more difficult than telling a young patient that their cancer has already spread.
One patient I remember particularly well was only 31 years old.
His mother had previously been diagnosed with endometrial cancer, but there was very little other family history. Genetic testing confirmed that he carried Lynch syndrome.
Several years later, he developed colorectal cancer.
Unfortunately, his scans showed metastatic disease. During a staging laparoscopy, the surgeons found multiple deposits of cancer throughout the lining of the abdomen (peritoneal metastases).
I still remember the conversation.
At the time, this was a young man with a young family, a promising future, and suddenly a diagnosis that seemed overwhelming.
Fortunately, his cancer was MSI-high.
This meant he was eligible for immunotherapy.
We treated him with a single-agent immunotherapy approach, which was considered standard treatment at that time.
The response was remarkable.
His cancer shrank dramatically.
He returned to work.
Travel became possible again.
Most importantly, he was able to spend meaningful time with his family.
For almost 18 months, life became relatively normal again.
Unfortunately, follow-up imaging eventually showed signs that the cancer was beginning to grow again.
What surprised me
What surprised me was not that immunotherapy worked.
We have known for several years that MSI-high colorectal cancers are among the most immunotherapy-sensitive cancers we treat.
What surprised me was that even patients who achieve excellent responses can eventually relapse.
That naturally raises an important question.
If immunotherapy works well, can we make it work even better?
That is exactly what the CheckMate 8HW study attempted to answer.
Why this study matters
Approximately 5% of metastatic colorectal cancers are MSI-high or mismatch-repair deficient (dMMR).
Some patients have Lynch syndrome, while others develop MSI-high or dMMR colorectal cancer for non-inherited reasons.
Unlike most colorectal cancers, these tumours contain thousands of genetic errors, making them highly visible to the immune system.
Because of this, immunotherapy has transformed outcomes for these patients.
For several years, treatments such as pembrolizumab or nivolumab alone became standard approaches.
The CheckMate 8HW study asked a very important question:
Can combining nivolumab and ipilimumab improve outcomes even further compared with nivolumab alone?
Understanding the background
Our immune system constantly patrols the body looking for abnormal cells.
Cancer develops ways to hide from these immune cells.
Immunotherapy removes these “brakes” on the immune system.
Nivolumab blocks the PD-1 pathway.
Ipilimumab blocks the CTLA-4 pathway.
These drugs work at different stages of immune activation.
The theory is simple:
- One immunotherapy drug activates the immune system.
- Two immunotherapy drugs may activate it more effectively.
- Stronger immune activation may lead to longer cancer control.
The trade-off is a higher risk of immune-related side effects.
The purpose of this study was to determine whether the additional benefit outweighed the additional risk.
What was the CheckMate 8HW study?
Study type
International Phase III randomized clinical trial.
Number of patients
707 patients with MSI-high or dMMR metastatic colorectal cancer.
Who was included?
Patients with:
- Metastatic colorectal cancer
- MSI-high disease
- dMMR disease
- No previous immunotherapy
Treatment groups
Group A
Nivolumab plus ipilimumab
Group B
Nivolumab alone
What was the main question?
The main question was simple:
Could two immunotherapy drugs keep the cancer controlled for longer than one immunotherapy drug alone?
The study measured progression-free survival.
In simple terms:
How long can we keep the cancer under control before it starts growing again?
Key results
- The cancer stayed controlled for longer with two immunotherapy drugs.
Patients who received nivolumab plus ipilimumab had a 38% lower risk of the cancer growing or the patient dying compared with patients who received nivolumab alone. - Many patients continued to do well years later.
After almost 4 years of follow-up, the average time before the cancer started growing again had still not been reached in the combination treatment group. - The benefit appeared to last over time.
The advantage of using two immunotherapy drugs continued with longer follow-up. This suggests the benefit may not only be about shrinking the cancer, but also about keeping it controlled for longer. - The trade-off is more side effects.
Two immunotherapy drugs can activate the immune system more strongly. However, this can also increase the risk of immune-related side effects, so the decision must be individualised.
What do these results mean for my patient?
When I think about the young man described earlier, this study immediately changes the discussion.
If he presented today, I would have a very different conversation with him and his family.
The goal would not simply be to shrink the cancer.
The goal would be to keep the cancer controlled for as long as possible.
For a young patient with Lynch syndrome and metastatic colorectal cancer, longer disease control can mean more time living normally.
It may mean returning to work.
Travel may feel achievable.
Family time may become less interrupted by cancer.
There may be more birthdays.
There may be more school events.
Most importantly, there may be more ordinary days that cancer does not take away.
This is why the CheckMate 8HW study matters.
It suggests that for selected patients with MSI-high or dMMR metastatic colorectal cancer, using two immunotherapy drugs together may give a better chance of long-lasting cancer control than using one immunotherapy drug alone.
This does not mean dual immunotherapy is right for everyone.
However, it does mean that patients with MSI-high metastatic colorectal cancer should have a careful discussion with their oncologist about whether single-agent or dual immunotherapy is the better option for their situation.
Does immunotherapy cause hair loss?
This is one of the most common questions I hear in clinic.
The answer is usually no.
Unlike traditional chemotherapy:
- Hair loss is uncommon
- Nausea is often less severe
- Many patients continue working
- Many patients continue travelling
- Quality of life is often maintained
Every patient is different, but immunotherapy is generally much easier to tolerate than conventional chemotherapy.
Who may not be suitable for dual immunotherapy?
Dual immunotherapy is not appropriate for everyone.
Extra caution may be needed if you have:
- Severe autoimmune disease
- Previous organ transplantation
- Active inflammatory bowel disease
- Significant prior immunotherapy toxicity
These decisions should always be individualized.
What about access in Australia?
This is an important practical question.
In Australia, access to nivolumab plus ipilimumab in Australia depends on the patient’s diagnosis, MSI-high or dMMR status, previous treatments and current PBS criteria.
Because access pathways can change over time, patients should discuss this directly with their treating oncologist.
In some situations, treatment may be available through PBS criteria, private funding, clinical trials, compassionate access programs or other mechanisms.
The most important first step is confirming whether the cancer is MSI-high or dMMR, because this result may open the door to immunotherapy options.
What this means for patients today
If you have:
- MSI-high metastatic colon cancer
- MSI-high metastatic rectal cancer
- Lynch syndrome-associated colorectal cancer
- dMMR colorectal cancer
then dual immunotherapy may represent an important treatment option.
The decision depends on:
- Your overall health
- Previous treatments
- Autoimmune conditions
- Funding and access
- Personal preferences
This is exactly the type of discussion that should occur with a specialist medical oncologist experienced in gastrointestinal cancers and immunotherapy.
For patients from Australia, Sri Lanka, Maldives, Indonesia and the Philippines who have been diagnosed with MSI-high metastatic colon cancer, this is an important treatment discussion to have with an oncologist experienced in gastrointestinal cancers and immunotherapy.
Key takeaways
- MSI-High Colorectal Cancer Responds Exceptionally Well to Immunotherapy
This remains one of the biggest advances in colorectal cancer treatment over the past decade.
- Combining Nivolumab and Ipilimumab Appears Better Than Nivolumab Alone
The CheckMate 8HW study demonstrated significantly improved progression-free survival.
- The Biggest Benefit May Be Preventing Later Relapses
For patients already doing well on immunotherapy, dual treatment may further improve the chances of long-term disease control.
References
- André T, Elez E, Van Cutsem E, et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer. N Engl J Med. 2024;391(21):2014-2026. doi:10.1056/NEJMoa2402141
- André T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383-395. doi:10.1016/S0140-6736(24)02848-4
- André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/NEJMoa2017699
- US Food and Drug Administration. FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. Published April 8, 2025. Accessed July 1, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer
- eviQ. Colorectal metastatic ipilimumab and nivolumab. Accessed July 1, 2026. https://www.eviq.org.au/medical-oncology/colorectal/metastatic/5001-colorectal-metastatic-ipilimumab-and-nivoluma
- Bowel Cancer Australia. Opdivo + Yervoy listed on the PBS. Published March 1, 2026. Accessed July 1, 2026. https://www.bowelcanceraustralia.org/opdivo-yervoy-listed-on-the-pbs/
Frequently asked questions (FAQs)
- What is MSI-high colon cancer?
MSI-high cancers have defects in DNA repair pathways. These cancers are particularly sensitive to immunotherapy.
- Is MSI-high the same as Lynch syndrome?
No.
Many Lynch syndrome cancers are MSI-high, but some MSI-high cancers occur without Lynch syndrome.
- Will I lose my hair?
Hair loss is uncommon with immunotherapy and far less frequent than with chemotherapy.
- Is dual immunotherapy more toxic?
Yes.
There is a higher risk of immune-related side effects compared with single-agent treatment.
Most side effects can be managed if recognized early.
- Could this become the new standard of care?
Many international experts now view nivolumab plus ipilimumab as a leading treatment option for MSI-high metastatic colorectal cancer.
Dr Dilanka De Silva
MBBS, MRCP(UK), MRCP(UK SCE Oncology), FRACP, PhD
Medical Oncologist & Cancer Genetics Physician
Memorial Sloan Kettering Cancer Center Fellow (New York, USA)