Relationship between ipilimumab dose and response in patients with advanced melanoma

This study analyzed the efficacy and safety of ipilimumab (Yervoy) exposure in patients with advanced melanoma. It assessed the relationship between patient response and drug dosage (amount of drug administered) through the minimum steady-state concentration or Cminss (the lowest concentration that the drug reaches before the next dose is administered).

Patients with advanced melanoma (cancer of the pigmented cells of the skin, the melanocytes, that has spread beyond the skin, to the lymph nodes or to distant organs and tissues of the body) can benefit from several treatment options which include surgery, chemotherapy, radiotherapy or immunotherapy. Immunotherapy stimulates the patient’s own immune system to recognize and destroy cancer cells. Ipilimumab is an FDA approved immunotherapy drug that has shown significant survival benefits in patients with advanced melanoma. A drug’s effect on the body depends on the dose, how fast the drug is absorbed into the body and how fast it is eliminated. All these factors determine the Cminss or exposure, which is the lowest blood concentration that can be achieved by the drug at which it is still effective before the next dose is administered. The aim of this study was to assess the safety and efficacy of ipilimumab treatment in melanoma patients, through the relationship between the Cminss of the drug, patients response to treatment and adverse effects.

498 patients with advanced melanoma who were treated with ipilimumab alone were involved in this analysis. Patients received different dosages of the drug, of 0.3, 3, or 10 mg/kg. Results showed that a higher Cminss was associated with a higher response to treatment. Therefore, patients who received a 0.3mg/kg dose of ipilimumab had 0.6% response, patients who received a 3 mg/kg dose had 4.9% response, while those on a 10 mg/kg dose had 11.6% response. Patients with higher Cminss (exposure) levels experienced better survival than those with low exposure levels. Therefore, at the average Cminss determined for each dosage, patients who received 0.3mg/kg ipilimumab had a 0.85 fold and 0.58 fold lower survival compared to patients treated with 3mg/kg and 10mg/kg respectively. However, the risk of more severe adverse effects also increased with higher doses of ipilimumab. At the average Cminss for 0.3, 3 and 10mg/kg, the probabilities of experiencing adverse effects were 3%, 13% and 24% respectively. When Cminss increased from 43.9 mcg/ml (average) to 103 mcg/ml, the risk of adverse effects increased by 1.74 times.

In summary, increased doses of ipilimumab produce higher Cminss, which showed improved response and survival in patients with advanced melanoma, with a higher risk of developing adverse effects. 

This study was funded by Bristol-Myers Squibb Co., the manufacturer of Yervoy.

Consult with your physician on the most appropriate dosage for you and how to reduce adverse effects when using ipilimumab.