Ipilimumab, an antibody, blocks CTLA-4. That brake acts earlier, and somewhere else, than the PD-1 brake that pembrolizumab and nivolumab block. The cards below show where it works. The list after them spells out what that difference means for a patient, from the number of doses to the organs most at risk and the absence of any test that predicts who will respond.
Dosing runs in two phases. The first sets the length of a stay abroad.
Which cancers is it used for, and what did the trials find?
Six cancers appear on the European label, namely melanoma, kidney cancer, non-small-cell lung cancer, pleural mesothelioma, bowel cancer with a mismatch repair defect and squamous cancer of the esophagus, each treated with nivolumab alongside and in some with chemotherapy. The strength of the evidence differs a great deal between them.
Melanoma
CheckMate 067 randomized patients with untreated advanced melanoma to the combination, to nivolumab alone or to ipilimumab alone. At ten years, median survival was 71.9, 36.9 and 19.9 months. The risk of death was 47 percent lower with the combination than with ipilimumab alone and 37 percent lower with nivolumab alone. Among patients alive and without progression at three years, 96 percent of the combination group were still alive of melanoma at ten years. The trial was not designed to prove the combination better than nivolumab alone, and whether the added survival justifies the added toxicity for a given patient is the central question in the consultation.
Melanoma that has reached the brain
CheckMate 204 treated 94 patients with melanoma spread to the brain, without symptoms and without prior brain radiotherapy, with the combination. In 57 percent the brain deposits disappeared, shrank or stayed stable for at least six months, and they disappeared completely in 26 percent. Before this trial such patients were routinely excluded from immunotherapy studies and treated with radiation first.
Kidney cancer
CheckMate 214 randomized 1,096 patients with untreated clear-cell kidney cancer to the combination or to the tablet sunitinib. Among the patients at intermediate or poor risk, survival at 18 months was 75 against 60 percent, the response rate 42 against 27, and complete disappearance of the cancer 9 against 1 percent. Grade 3 or 4 treatment-related side effects were less frequent with the combination, 46 against 63 percent, while more patients stopped treatment because of them, 22 against 12 percent. Patients at favorable risk gained less, and other combinations compete for them.
Bowel cancer with a DNA repair defect, lung, mesothelioma, esophagus
The combination is licensed first-line for bowel cancer with a mismatch repair defect, where pembrolizumab alone is the alternative, for non-small-cell lung cancer with two cycles of chemotherapy, and for pleural mesothelioma and squamous esophageal cancer. In each, other immunotherapy options exist, and the tumor board weighs them for the individual patient.
What are the side effects?
Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment.
Conclusion of the first ipilimumab survival trial, New England Journal of Medicine, 2010
Go to a hospital the same day
Diarrhea more than four times a day, or any blood in the stool, or abdominal pain. Severe headache, visual change, extreme tiredness, dizziness on standing or confusion, which can mean the pituitary gland is inflamed. Breathlessness or a new cough. Chest pain or palpitations. Yellow eyes. Muscle weakness. Say that you are on ipilimumab and nivolumab, because a doctor who does not know may treat colitis as an infection.
This table scrolls sideways on a narrow screen. Swipe or drag to see every column.
Immune side effects of ipilimumab with nivolumab, by organ
| Organ |
What happens |
How it compares with a PD-1 drug alone |
What is done |
| Bowel |
Diarrhea and colitis, from mild loose stools to bleeding and perforation |
Far more frequent and more severe, the signature toxicity of ipilimumab |
Steroids at once, infliximab or vedolizumab if steroids fail within days |
| Pituitary and other hormone glands |
Headache, tiredness, low blood pressure, low sodium, from an inflamed pituitary. Thyroid failure or overactivity |
Pituitary inflammation is characteristic of ipilimumab and rare with PD-1 drugs alone |
Hormone replacement, often for life, and steroids for the acute phase |
| Skin |
Itchy rash, sometimes widespread |
More frequent |
Creams, antihistamines, steroids for severe rash |
| Liver |
Rising enzymes on the blood test |
More frequent |
Steroids, and treatment paused or stopped |
| Lung, heart, nerves, kidneys |
Pneumonitis, myocarditis, nerve and muscle inflammation, nephritis |
Similar or somewhat more frequent, rare but dangerous |
Admission, high-dose steroids, specialist care |
Why the combination is harder to take
Treatment-related grade 3 or 4 adverse events occurred in 55 percent of patients, and one patient died of immune-related myocarditis.
CheckMate 204, melanoma metastatic to the brain, New England Journal of Medicine, 2018
Half of patients on the combination, or more, have a serious side effect. Many stop before the fourth dose. That does not undo the benefit. In the melanoma trials, patients who stopped early because of side effects did as well as those who completed the course, because the immune response had already been set off. Nor do steroids, given properly and promptly, cancel the treatment. What undoes the benefit is a side effect caught late, when colitis has perforated the bowel or pituitary failure has caused a collapse, and the whole of the safety plan is built to prevent that.
Do steroids stop the treatment from working?
High-dose steroids given for an immune side effect do not, in the published analyses, reduce the chance that the cancer responds. Doctors start them without delay when the guideline calls for them, and tapered over four to six weeks, since stopping them too fast brings the side effect back.
- Blood tests before every dose, including thyroid, cortisol, liver, kidney, sugar and sodium.
- A diary of bowel movements during the four doses, and a same-day call for any rise.
- An alert card naming both drugs.
- Nothing started on your own.
- Follow-up of hormone levels for years, since pituitary and thyroid failure can surface late.
Hormone failure, the side effect that lasts
Most immune side effects resolve with steroids. Failure of the pituitary, thyroid or adrenal glands tends not to resolve, and the patient takes replacement hormones for life. Replacement works well, and life on it is normal, provided the patient knows to double the steroid dose in a fever or before surgery. The discharge letter spells that out.
Who it suits, how long to stay, and what decides the cost
Among patients alive and free of progression at three years, ten-year melanoma-specific survival was 96 percent with nivolumab plus ipilimumab.
CheckMate 067 ten-year report, New England Journal of Medicine, 2024
The combination suits patients with melanoma or kidney cancer who are fit, without active autoimmune disease or an organ transplant, and willing to accept a high chance of a serious side effect in exchange for a better chance of long survival. It suits patients with melanoma in the brain who have no symptoms from it. Frail or elderly patients are harder cases, as are those with serious heart or bowel disease and those for whom a PD-1 drug alone offers a similar result with less risk. Patient and tumor board decide together.
Who should not receive it
Patients with an active autoimmune disease needing immune suppression, an organ transplant, uncontrolled infection including hepatitis B or C, pregnancy, and severe heart, bowel or liver disease are poor candidates. Earlier severe side effects from a PD-1 drug count against it. Each is weighed, and the reply to your file says plainly when we advise against it.
Grade 3 or 4 treatment-related events occurred in 46 percent with nivolumab plus ipilimumab and 63 percent with sunitinib, while discontinuation for adverse events was 22 against 12 percent.
CheckMate 214, kidney cancer, New England Journal of Medicine, 2018
Send these five things.
- The pathology report, and the BRAF result for melanoma, the risk category for kidney cancer, or the mismatch repair result for bowel cancer.
- Staging scans with images, including a brain MRI.
- Every treatment so far, and any side effects from earlier immunotherapy.
- Blood tests with thyroid, cortisol, liver, kidney and hepatitis serology, and your weight.
- Any autoimmune disease, bowel disease, heart disease or transplant.
How long to stay in Istanbul
Nine to ten weeks.
That covers the four combination doses and the two weeks after the last one, when side effects are most frequent. Patients who can manage it stay for the whole phase in a hotel or apartment near the hospital, because a colitis or pituitary crisis is best recognized by the team that gave the drug. Others return every three weeks for each dose. Blood tests happen at home in between. Nivolumab maintenance continues at home, and a local oncology unit can give it from the written plan without any change to the drug, the dose or the interval. Fly at any point, provided no side effect is active.
What decides the cost
The drugs set the price.
Weight sets the ipilimumab dose, so a heavier patient receives more milligrams and pays more, and the combination phase adds nivolumab at each visit. Four combination cycles form most of the first-phase drug bill. Maintenance is separate. At home it costs less. Baseline scans, the blood tests before every dose, the day-unit time and the scan at twelve weeks are separate lines. An admission for colitis or hormone failure, with intravenous steroids and sometimes infliximab, is the largest unknown and should be priced in advance. Few hospitals in Istanbul publish a package for this combination, and quotes found online are nearly always for pembrolizumab, a different drug with a different schedule. Ask for three written figures. One per combination cycle, one per maintenance cycle, one for an admission. Your own figure follows the free review of your file.
Language, companions and follow-up once you are back home
One coordinator from the international patients team is assigned from your first message and stays with you through the combination phase. English, Arabic, French, Russian, Serbian, Romanian and Spanish are covered. Other languages are interpreted on request. An invitation letter naming the hospital and the treating oncologist goes out ten days before travel, with a longer visa requested for a stay of nine to ten weeks. The international patients office arranges the airport transfer, an apartment or hotel for you and a companion, and the rides to the day unit, and a companion is strongly advised for this treatment. Rooms for anyone admitted have a companion bed, a prayer room is on site, and halal, vegetarian and diabetic meals come from the hospital kitchen, while a request for a female doctor is passed to the department and met wherever the rota allows, which for a course of this length is a request worth making in the very first message. Back home, the coordinator stays reachable on the same WhatsApp number, the maintenance plan and the side-effect instructions go to your own oncologist, and hormone tests continue for years.
Ipilimumab FAQ
How does ipilimumab differ from pembrolizumab or nivolumab?
Ipilimumab blocks CTLA-4, a brake that acts when T cells are trained in the lymph nodes. Pembrolizumab and nivolumab block PD-1, a brake that acts in the tumor. Ipilimumab is now given mainly with nivolumab, for four doses, and its side effects are more frequent, especially colitis and pituitary inflammation.
What is the success rate of ipilimumab with nivolumab in melanoma?
In the ten-year report of CheckMate 067, median survival was 71.9 months with the combination against 36.9 with nivolumab alone and 19.9 with ipilimumab alone. Among patients alive and progression-free at three years, 96 percent were alive of melanoma at ten years.
How often is Yervoy given?
In most regimens, every three weeks for four doses together with nivolumab, followed by nivolumab alone. In lung cancer and mesothelioma, every six weeks with nivolumab for up to two years.
What are the side effects of Yervoy?
Immune inflammation of healthy organs, above all the bowel, skin, liver and hormone glands. With nivolumab, about half of patients have a serious side effect. Most are treated with steroids, and pituitary or thyroid failure may need lifelong hormone tablets.
How long do I need to stay in Istanbul?
Nine to ten weeks for the four combination doses and the period after them, or a return trip every three weeks. Nivolumab maintenance continues at home.
Can my family come with me?
Yes, and a companion is strongly advised. The international patients office arranges an apartment or hotel for you both, and rooms for admitted patients have a companion bed.
References
- Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine. 2010;363(8):711-723.
- Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. New England Journal of Medicine. 2025;392(1):11-22.
- Tawbi HA, Forsyth PA, Algazi A, et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. New England Journal of Medicine. 2018;379(8):722-730.
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New England Journal of Medicine. 2018;378(14):1277-1290.
- Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology. 2018;36(17):1714-1768.
