Ipilimumab
Ipilimumab was the first checkpoint inhibitor (2011), and proved the immune system could be unleashed against cancer.
Monotherapy improved OS in melanoma (2010 NEJM); now mostly used with nivolumab in melanoma, RCC, MSI-H CRC, HCC, mesothelioma, and NSCLC. Immune-related adverse events are frequent (colitis, hypophysitis).
1.Antibody binds CTLA-4 on T cells in lymph nodes and tumour
- Route
- IV infusion
- Schedule
- Melanoma monotherapy 3 mg/kg every 3 weeks ×4; with nivolumab 3 mg/kg (melanoma) or 1 mg/kg (RCC, NSCLC, HCC, MSI-H CRC) every 3 or 6 weeks
- Dose modifications
- Permanently discontinue for grade 3-4 colitis, hepatitis, hypophysitis with severe symptoms
- Monitoring
- LFTs, thyroid, cortisol/ACTH; colitis education; early steroids
Source: US prescribing information (DailyMed). Doses are for orientation; the current label governs.
- Medicare
- Part B (clinician-administered)
Given by infusion or injection in a clinic or hospital outpatient department, so it is a Part B drug: Medicare pays 80% after the Part B deductible and the patient owes 20% coinsurance, uncapped in Original Medicare unless a Medigap policy applies. HCPCS J9228.
- Commercial insurance
- covered with prior authorisation
Covered under the medical benefit with prior authorisation confirming diagnosis, biomarker status and line of therapy; site-of-care policies may steer infusions away from hospital outpatient departments.
- Assistance programmes
- BMS Access Support
- Bristol Myers Squibb Patient Assistance Foundation
- PAN Foundation — Disease-specific co-pay and premium funds; open and closed funds change monthly.
- HealthWell Foundation
- CancerCare Co-Payment Assistance Foundation
- Patient Advocate Foundation Co-Pay Relief
20% Part B coinsurance on a high-cost infusion adds up quickly: Medigap Plan G or N, Medicare Advantage maximum out-of-pocket, Medicaid dual eligibility, or a charity fund are the usual buffers.
Sources: Medicare.gov: Chemotherapy · Medicare.gov: Prescription drugs (outpatient, Part B). Not medical or financial advice; verify with your plan.
- Appraised for
- Previously untreated advanced melanoma
- Notes
- TA268 (previously treated melanoma, 2012) was the first checkpoint inhibitor NICE recommended; combinations with nivolumab in TA400 (melanoma) and TA655 (RCC).
- NHS England
- Routinely funded for the appraised indication (or via managed access)
Sources: NICE TA319 · SMC advice: ipilimumab. Funding decisions are indication-specific and change monthly; verify with NICE and your treating team.
- 25 Mar 2011ApprovalUS
Metastatic melanoma: first checkpoint inhibitor approved anywhere source
- 28 Oct 2015ApprovalUS
Adjuvant stage III melanoma (10 mg/kg; later superseded) source
- 16 Apr 2018ApprovalUS
With nivolumab in RCC source
- 15 May 2020ApprovalUS
With nivolumab in first-line NSCLC (CheckMate 227) and HCC source
- 2 Oct 2020ApprovalUS
With nivolumab in mesothelioma (CheckMate 743) source
- Apr 2025ApprovalUS
With nivolumab first-line MSI-H/dMMR colorectal cancer (CheckMate 8HW) source
Approvals
| Region | Year | Indication |
|---|---|---|
| US | 2011 | Metastatic melanoma |
| Adverse event | Any grade | Grade 3+ |
|---|---|---|
| Colitis (with nivolumab 1+3) | 25% | 14.4% |
| Hepatitis (with nivolumab) | 15% | 13.4% |
| Hypothyroidism (with nivolumab) | 20% | 0.4% |
| Rash (with nivolumab) | 28% | 4.8% |
| Adrenal insufficiency (with nivolumab) | 8% | 2.6% |
| Hyperthyroidism (with nivolumab) | 9% | 0.9% |
Nivolumab 1 mg/kg + ipilimumab 3 mg/kg, melanoma. Rates read from the US prescribing information. Blank cells mean the figure was not sourced, not that it is zero.
| Country | Reimbursement | List price | Assistance |
|---|---|---|---|
| United States | Medicare Part B (physician-administered); commercial plans per formulary | not disclosed | bmsaccesssupport.com |
| United Kingdom | NICE: recommended with nivolumab in melanoma, RCC, MSI-H CRC, mesothelioma, HCC | not disclosed | — |
List prices are manufacturer or Medicare figures where publicly disclosed; net prices after rebates are usually lower. Reimbursement changes; check the payer.
Trials
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Landmark trials in OnCo
Before 2011 median survival in metastatic melanoma was under a year; this trial shows that roughly half of patients treated with combination checkpoint blockade are now long-term survivors, effectively cured. It anchors first-line treatment of advanced melanoma and sets the benchmark for every new regimen, including nivolumab-relatlimab. The combination's toxicity means nivolumab alone or newer doublets remain reasonable for some patients.
For patients with advanced melanoma, immunotherapy offers a realistic chance of long-term survival and probably cure, and the ten-year data show that patients who are alive and progression-free at three years rarely die of melanoma afterwards. Nivolumab plus ipilimumab gives the best long-term results but at a high price in serious side effects; nivolumab alone or nivolumab plus relatlimab are alternatives for patients at lower risk or with autoimmune concerns. The trial is also a caution about surrogate endpoints: the survival plateau took years to become visible.
Patients with melanoma that has spread to palpable lymph nodes should now be offered immunotherapy before rather than only after surgery: two cycles of low-dose ipilimumab with nivolumab, then surgery, with the pathology result deciding whether any more treatment is needed. Most patients respond well and are spared a year of adjuvant therapy. Serious side effects are more common than with nivolumab alone, mostly endocrine, and the approach requires close coordination between oncologists, surgeons and pathologists.
For colon cancer that is mismatch-repair deficient (about 10-15% of colon cancers, more in older patients), a single short course of immunotherapy before surgery is now a reasonable standard and is far more effective than chemotherapy, which barely works in this subtype. It requires testing every colon cancer for mismatch repair at diagnosis, before surgery. Whether some patients can safely skip surgery, as in dMMR rectal cancer, is the next question.
NICHE-2 shows that a month of immunotherapy before surgery can effectively cure locally advanced dMMR colon cancer, where chemotherapy after surgery has limited benefit. It is changing guidelines towards neoadjuvant checkpoint blockade for this group and raises the question of whether surgery can be omitted altogether, as in dMMR rectal cancer. Whether the same applies to MMR-proficient tumours is being tested but is not established.
This trial supplied the randomised proof that was missing for TIL therapy and showed academic centres can run cell-therapy phase 3 trials without industry. It supports TIL as a standard option after checkpoint inhibitor failure in melanoma and underpinned reimbursement in the Netherlands. The comparator, ipilimumab, is itself only modestly effective in this setting, and overall survival did not differ significantly.
Checkpoint inhibitors are now given to hundreds of thousands of patients a year, many in community clinics and emergency departments, so a common, explicit playbook for their autoimmune side effects saves lives. The guideline standardised when to stop, when to give steroids and when to escalate, and made multidisciplinary toxicity teams routine. It does not remove the judgement needed for rare events or for patients whose cancer is responding.
Patients with newly diagnosed advanced stomach or oesophageal adenocarcinoma whose tumour is HER2-negative and PD-L1 positive (CPS 5 or more, or at least 1 in some regions) should receive chemotherapy with nivolumab (or pembrolizumab, from KEYNOTE-859), which adds about three months of median survival and doubles the chance of being alive at three years. The benefit in PD-L1-negative tumours is doubtful, and these patients may be better served by chemotherapy alone or by trials.
This paper launched the immunotherapy era. It was the first randomised evidence that taking a brake off the immune system could extend life in a solid cancer, and it introduced clinicians to immune-related adverse events and to responses that arrive late or after apparent progression. Ipilimumab alone has since been superseded by PD-1 antibodies and combinations, but every checkpoint programme traces back to this result.
Every checkpoint inhibitor, from ipilimumab to pembrolizumab, rests on this idea: the immune system can already recognise cancer and just needs its brakes released. It changed the goal of immunotherapy from vaccinating against tumours to unleashing existing T cells.
Latest papers
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