Ipilimumab + Nivolumab for Colorectal Cancer

Overseen By Nicholas D Klemen, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Autoimmune disorders, Immunodeficiency, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 23

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drugs nivolumab and ipilimumab can help individuals with colorectal or gastroesophageal cancer avoid or delay surgery. Researchers aim to determine if these drugs can effectively manage the cancer, potentially reducing the need for major surgical procedures. Participants will receive either both drugs or just nivolumab to compare outcomes. Suitable candidates for this trial include those diagnosed with colorectal or gastroesophageal cancer who wish to explore non-surgical treatment options. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does exclude participants taking steroids or other immunosuppressive agents that could affect the study drugs. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the drugs nivolumab and ipilimumab have been tested in people with colorectal cancer. Nivolumab, also known as Opdivo, can cause serious side effects like diarrhea and pneumonia, but these occur in only a small number of patients. When combined with ipilimumab (known as Opdivo and Yervoy), the chance of serious side effects increases compared to nivolumab alone. About 22% of patients experienced serious side effects with the combination treatment, compared to 14% with just nivolumab. The most common side effects when using both drugs are tiredness and diarrhea, affecting more than 20% of patients.

Both drugs have FDA approval for treating certain types of colorectal cancer, indicating they have been well-studied and are monitored for safety. However, as with any treatment, individual experiences can vary, so discussing potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Ipilimumab and Nivolumab for colorectal cancer because these drugs work differently than traditional chemotherapy. Unlike standard treatments, which often attack cancer cells directly, Ipilimumab and Nivolumab are immunotherapies that empower the patient's own immune system to recognize and fight the cancer. Nivolumab blocks a protein called PD-1, which cancer cells use to hide from the immune system, while Ipilimumab targets CTLA-4, another immune checkpoint. This dual action potentially enhances the body's natural defenses to tackle tumors more effectively.

What evidence suggests that this trial's treatments could be effective for colorectal cancer?

In this trial, participants will receive either nivolumab alone or a combination of nivolumab and ipilimumab. Research has shown that using nivolumab and ipilimumab together holds promise for treating colorectal cancer. One study found that patients taking both drugs had a 38% lower risk of cancer progression or death compared to those taking only nivolumab. Additionally, about 68% of patients on the combination treatment were alive without cancer worsening three years after starting. Nivolumab alone has also proven effective, particularly for patients with certain genetic traits. Overall, both treatments show potential, but the combination appears more effective. ^{1 2 3 4 6}

Who Is on the Research Team?

Nicholas D Klemen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

This trial is for adults with colorectal or gastroesophageal cancer. For gastroesophageal cancer, a specific gene change is required. Participants will undergo numerous clinic visits and tests including blood, urine, imaging scans, and tissue samples from the digestive tract.

Inclusion Criteria

Breastfeeding participants must discontinue breastfeeding during study treatment

Participants must understand and sign a written informed consent document

My medical records show special reasons for my MMR proficient colon cancer treatment.

Exclusion Criteria

I am not on medications that could interfere with the study treatment.

Participants receiving any other investigational agents

Uncontrolled intercurrent illness limiting compliance with study requirements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive nivolumab every 3 weeks for up to 8 cycles, with some receiving additional ipilimumab every 6 weeks for up to 4 cycles

24 weeks

8 visits (in-person)

Evaluation

Participants are evaluated every 6 weeks for response to treatment, which dictates further management

24 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits every 6 months for up to 5 years

5 years

10 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab

Trial Overview The study evaluates if nivolumab alone or combined with ipilimumab can delay or avoid surgery in patients. Treatments are given through an IV every 3 weeks for up to 24 weeks. Patients responding well may continue treatment; otherwise, they'll consider surgery.

How Is the Trial Designed?

Group I: 2: nivolumab Experimental Treatment 1 Intervention

Nivolumab (3 mg/kg) every 3 weeks for up to an initial 4 cycles (an additional 4 cycles may be given depending on response, for a total of 8 cycles).

Group II: 1: nivolumab and ipilimumab Experimental Treatment 2 Interventions

Nivolumab (3 mg/kg) every 3 weeks for up to an initial 4 cycles (an additional 4 cycles may be given depending on response, for a total of 8 cycles); low-dose ipilimumab at 1 mg/kg every other cycle (every 6 weeks) for up to an initial 2 doses (an additional 2 doses may be given depending on response, for a maximum of 4 doses).

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

In a meta-analysis of 8 studies involving 1727 patients with advanced cancers (excluding melanoma), the combination of nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone, with some studies even showing lower median survival with the combination.

While there was a statistically significant but clinically marginal improvement in progression-free survival with the combination therapy, it was associated with a substantially higher risk of severe treatment-related adverse events and discontinuations, indicating a need for careful consideration of the risks versus benefits in nonmelanoma cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Ipilimumab vs Nivolumab Alone in Advanced Cancers Other Than Melanoma: A Meta-Analysis. Serritella, AV., Shenoy, NK.[2023]

In a review of 129 oncology patients treated with immune checkpoint inhibitors, 51.9% experienced at least one immune-related adverse event (irAE), highlighting the common occurrence of these side effects.

Nearly half of the irAEs were managed according to established guidelines, but there was significant variability in documentation and management practices, indicating a need for improved adherence as immunotherapy use increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. Teimouri, A., Minard, LV., Scott, SN., et al.[2022]

In a phase II study involving 45 patients with MSI-H/dMMR metastatic colorectal cancer, the combination of nivolumab and low-dose ipilimumab showed a high objective response rate of 69% and a disease control rate of 84%, indicating strong efficacy as a first-line treatment.

The treatment was well tolerated, with only 22% of patients experiencing grade 3-4 treatment-related adverse events, and 74% of responders maintained their response at the time of data cutoff, suggesting durability of the treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. Lenz, HJ., Van Cutsem, E., Luisa Limon, M., et al.[2022]

A systematic review of 14 randomized controlled trials found that combining nivolumab (NIVO) with ipilimumab (IPI) significantly increases the risk of treatment-related adverse events (TRAEs) compared to NIVO alone, with an overall risk ratio of 1.11 for any grade TRAEs and 1.95 for severe (grade 3 or 4) TRAEs.

Specific adverse events were notably higher with the combination therapy, including colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68), indicating that while the combination may be effective, it comes with increased safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. Kamat, S., Patel, J., Brown, BR., et al.[2022]

The combination of nivolumab and ipilimumab resulted in an overall objective response rate (ORR) of 34.5% among 2,114 patients, indicating its efficacy in treating advanced malignancies.

Patients receiving nivolumab at 3 mg/kg with ipilimumab at 1 mg/kg experienced significantly fewer high-grade adverse events (39.9% incidence) compared to those receiving nivolumab at 1 mg/kg with ipilimumab at 3 mg/kg (55.9% incidence), suggesting a safer dosing strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity and Treatment-Related Toxicity Associated With Nivolumab Plus Ipilimumab in Advanced Malignancies: A Systematic Review and Meta-Analysis. Xu, H., Tan, P., Ai, J., et al.[2023]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

In a study of 274 elderly patients with advanced melanoma, the risk of developing colitis was similar for those treated with anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab or pembrolizumab) therapies.

However, when considering patients across all stages of melanoma, anti-PD1 treatment was associated with a significantly lower risk of colitis compared to anti-CTLA4, suggesting a safer profile for anti-PD1 in this broader patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. Almutairi, AR., Slack, M., Erstad, BL., et al.[2022]

Citations

1. opdivohcp.com opdivohcp.com/efficacy/crc

Efficacy Data for Colorectal Cancer (CRC) - Opdivo In Checkmate 8HW, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with ipilimumab were fatigue, diarrhea, ...

2. news.bms.com news.bms.com/news/details/2025/Bristol-Myers-Squibb-Presents-Results-from-CheckMate--8HW-Analysis-Evaluating-Opdivo-nivolumab-plus-Yervoy-ipilimumab-Compared-to-Opdivo-Monotherapy/default.aspx

8HW Analysis Evaluating Opdivo® (nivolumab) plus ... Patients experienced a 38% reduction in the risk of disease progression or death when treated with Opdivo plus Yervoy versus Opdivo monotherapy across all ...

3. cancer.gov cancer.gov/news-events/cancer-currents-blog/2025/fda-nivolumab-ipilimumab-dmmr-colorectal-cancer

Immunotherapy Combo Approved for dMMR Colorectal ... At 3 years after starting treatment, approximately 68% of patients in the combination group were still alive without their cancer having gotten ...

4. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer

FDA approves nivolumab with ipilimumab for unresectable ... The major efficacy outcome measure was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1. 1 ...

5. drugs.com drugs.com/medical-answers/how-effective-opdivo-yervoy-when-taken-together-3577723/

How effective are Opdivo and Yervoy when taken together? Among patients who remained progression-free at 3 years, an remarkable 96% achieved 10-year melanoma-specific survival with the Opdivo plus ...

6. ono-pharma.com ono-pharma.com/en/news/20250825.html

Ono and Bristol-Myers Squibb KK Receive Supplemental ... The safety profile of Opdivo plus Yervoy remained consistent with previously reported data, with no new safety signals identified. Any one ...