Patient information session melanoma trials by Christian Blank

The OpACIN study, initiated in 2015, was the first to compare neoadjuvant treatment (ipilimumab + nivolumab) with adjuvant treatment. The study showed that neoadjuvant immunotherapy was indeed feasible: surgery did not have to be postponed due to side effects of immunotherapy, but high rates of serious side effects were nevertheless observed (in 90% of patients). Neoadjuvant therapy also led to a greater increase in T cells in the tumor. More than three-quarters of patients responded to the therapy.

Researchers involved in the OpACIN-neo trial tried to find the ideal dose of ipilimumab and nivolumab that would lead to fewer side effects while retaining its anti-tumor efficacy. They achieved the right balance by administering a lower dose of ipilimumab together with a higher dose of nivolumab; this combination led to serious side effects in 20% of patients, and three-quarters of patients still responded well to the therapy. Additionally, pathologic response to the neoadjuvant immunotherapy appeared to be predictive of long-term outcomes: Patients with a good or partial response to the neoadjuvant therapy hardly ever experienced recurrence, while two-thirds of patients with insufficient responses developed a recurrence after 2 years post-surgery.

The PRADO study investigated whether follow-up treatment could be further personalized with surgery and the possibility of adjuvant treatment depending on the response to neoadjuvant immunotherapy (ipilimumab and nivolumab). Patients who responded well to the neoadjuvant immunotherapy would forego major lymph node surgery, while patients with a partial or insufficient response still underwent surgery. In patients showing an insufficient response, additional adjuvant therapy was administered after major lymph node surgery.

The study showed that lymph node surgery could be omitted in about 60% of patients, resulting in a better quality of life and little melanoma recurrences. Patients with inadequate responses saw less frequent recurrences of melanoma with the addition of adjuvant therapy.

evious trials had shown that something known as interferon-gamma (IFN-γ) signature could predict a patient’s response to neoadjuvant therapy. This IFN-γ signature is a genetic characteristic of tumor tissue that provides information about immune activation in the tumor. A high signature leads to a greater likelihood of a good response to the therapy than a low signature.

The DONIMI trial used this IFN-γ signature to test the feasibility of different combinations of immunotherapy with the new drug domatinostat. The study showed that these different combinations of immunotherapy were feasible (surgery did not have to be postponed), but not all treatment cycles could be administered due to the side effects, most notably skin rash. The IFN-γ signature successfully predicted who would be likely to respond to immunotherapy, with patients with high signatures responding equally well to only one immunotherapy agent (nivolumab) as to a combination of nivolumab and ipilimumab (as tested in previous trials). Since the addition of domatinostat did not improve response rates in patients with a low signature, new combinations will need to be investigated in the future to improve the efficacy of neoadjuvant therapy in this patient group.

This large comparative phase 3 study led by the NKI started last year and will include a total of 420 patients. Groups are randomized between neoadjuvant treatment with ipilimumab and nivolumab, and standard adjuvant treatment with nivolumab. Participating parties will include hospitals from the Netherlands, Australia, Poland, America and potentially France and Italy.

This trial will use an app (Kaiku) to regularly monitor the patients' side effects and quality of life, and provide quick and targeted feedback and instructions when side effects are reported. These results will contribute to the future plans for the Center for Early Diagnostics. If the results are promising, patient checkups can be done primarily through digital monitoring, which would allow patients to avoid journeys to the hospital.