Patient information session melanoma trials by Christian Blank

11-07-2022

“Now I am sitting here, six years after participating in the first neoadjuvant trial, and hearing about all the results, I understand how important our role has been, and that feels good”.

In medical oncologist Christian Blank’s experience, patients who have participated in a clinical trial investigating neoadjuvant immunotherapy for melanoma would like to be informed about the results of these studies. They also appreciate being able to meet each other to discuss their experiences. That’s why Blank and his team have been inviting all patients who have participated in their trials to visit the Netherlands Cancer Institute for an information session followed by drinks. They hosted one of these sessions on Saturday, June 25 – the first in quite a long time due to COVID-19.

Pioneers

Blank is a pioneer in neoadjuvant immunotherapy (immunotherapy prior to surgery) for stage III melanoma. In stage III melanoma, cancer has spread to the lymph nodes, but not to the other organs. The current standard treatment for stage III melanoma is surgery in which all lymph nodes are removed, followed by post-treatment (adjuvant) immunotherapy or targeted therapy. The idea behind neoadjuvant immunotherapy is that the immune response against melanoma will be stronger when the entire tumor is still in the body because that allows the immune system to learn to recognize the whole tumor while receiving more signals that something is not right in the body.

"Not all patients will be invited to these kinds of sessions. You hear many relatable stories, some of which you can read about or see elsewhere, but sharing them in person is immensely valuable." - Patiënt from OpACIN trial

The first study design – the OpACIN trial – had been conceived over a cup of coffee on a Friday afternoon in 2014 together with cancer researcher Ton Schumacher. Because this trial involved an entirely new approach, the first patients that were treated as part of this trial were true pioneers as well. The fifth trial has recently been launched: the NADINA study. This comparative phase 3 study will need to provide proof that neoadjuvant immunotherapy (before surgery) is more effective than adjuvant immunotherapy (after surgery).

The future

If the results of the NADINA trial are positive, Blank hopes to see neoadjuvant immunotherapy being approved as a standard treatment for stage 3 melanoma. His ultimate goal is to develop a personalized treatment for every patient, with neoadjuvant immunotherapy at its foundation.

"We have made tremendous progress over the last few years thanks to all the patients who have participated in our trials. When I started working here 15 years ago, nearly all of the patients we saw had stage IV melanoma and very few of them survived. Our goal is to ensure that 95% of patients with stage III melanoma don't develop a recurrence, preventing stage IV melanoma, so we can cure a large number of patients.”

- Christian Blank, medical oncologist

Blank hopes to be able to set up a neoadjuvant outpatient clinic one day, in which patients can get their scans, blood tests, and a consultation with their specialist done on the same day. The results of the genetic tests will also be available within a few days, at which point a decision for personalized therapy can be made: the (at that point potentially) standard neoadjuvant immunotherapy, or a trial involving new immunotherapy combinations.

The OpACIN trial: is neoadjuvant immunotherapy feasible?

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.

The OpACIN-neo trial: can we minimize the side effects?

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 trial: can we omit major surgery following a good response to neoadjuvant immunotherapy?

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.

The DONIMI trial: can we personalize neoadjuvant therapy and test new combinations based on the tumor characteristics?

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.

The NADINA trial: the ultimate proof that neoadjuvante immunotherapy is more successful than adjuvant therapy?

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.