Dutch research projects investigating immunotherapy for melanoma

Can you briefly tell us about the NADINA study?

"The standard treatment for patients with stage 3 melanoma is removal of the melanoma (which has often been done before) and local lymph nodes followed by multiple treatments with immunotherapy. Postoperative treatment with immunotherapy generally lasts a year. Despite the intensive treatment regimen, the disease recurs in nearly one-third to half of the patients. Prof. Dr. Blank, medical oncologist at the LUMC and Antoni van Leeuwenhoek, has conducted several studies in recent years to establish a safe and effective treatment plan in which patients undergo immunotherapy prior to surgery. The idea is that, by giving the immunotherapy before surgery, there may be a stronger immune response against the tumor."

"The LUMC is one of 14 melanoma centers in the Netherlands that participated in the NADINA study. The NADINA study is the first phase 3 study (study where a large group of patients is randomized and followed over a long period of time) that looked at the difference between immunotherapy before surgery (neoadjuvant) and immunotherapy after surgery (adjuvant). The adjuvant treatment is currently a standard treatment." Worldwide, 423 patients participated in this study. Two-thirds of these patients were from the Netherlands, and the LUMC provided a substantial portion of the Dutch patients. The results of this study were recently published in the prestigious New England Journal of Medicine.

What are the outcomes of the NADINA study?

"We now have the results after almost 1 year of completion of treatment. The outcome is overwhelming: 84% of patients in the neoadjuvant group are still tumor-free compared to 57% of patients who received the standard treatment. In almost 60%, the tumor even disappeared completely in the neoadjuvant group and no additional treatment was needed!" said Kapiteijn.

This means that not only the success rate of treatment increases, but also that the costs of treatment decrease. "This is because with standard treatment, 8 to 12 courses of immunotherapy are given after surgery. With neoadjuvant treatment, patients receive only two courses of immunotherapy. Because fewer treatments are needed, patients in the neoadjuvant group also experience a better quality of life, although there are also more side effects.”

So, three birds with one stone! Will all melanoma patients now be treated according to this new protocol?

“No, we have not reached that point yet. An application is currently pending with health insurers and the National Health Care Institute for the neoadjuvant treatment to be reimbursed. The study is also still ongoing for follow-up on outcomes. To truly get compelling evidence for the success of a treatment, we also look at the overall survival rate. We do not have this data yet, but Prof. Dr. Blank hopes to report the first results in two years’ time. The patients are closely monitored and have regular follow-up scans. Meanwhile, we continue with this and other research in the Netherlands.”

And by "we" you mean the members of WIN-O?

"Exactly. The WIN-O is part of the DMSCG* and is the national task force dedicated to research and systemic treatments for melanoma patients in the Netherlands. It is a large collaboration between the 14 melanoma centers where the systemic treatments of all stage 3 and 4 patients are registered in the Dutch Melanoma Treatment Registry (DMTR) database. By now, clinically relevant data of more than 12,000 melanoma patients are included in the database which is managed by the Dutch Institute for Clinical Auditing (DICA) in Leiden. In the field of registration of melanoma patients, we can honestly say that the DMTR database is leading worldwide."

"In addition to our large database, the strength of the WIN-O lies in our collaboration. Any melanoma specialist from the 14 melanoma centers can submit a research question and use the data from the database. In addition, there is openness about the ongoing studies and there is a collaborative effort to better understand and treat melanoma. The interest of the patient, and not that of the individual research institution, is paramount."

What other studies does the WIN-O have in mind?

“A next step is to offer personalized treatment based on the profile of the tumor. By looking closely at which types of tumors do/do not respond to treatment, we hope to be able to predict which treatment best suits the patient. No more standard protocol where everyone undergoes the same steps, but customization tailored to the type of tumor and the patient.

For example, as preventive treatment nowadays all lymph nodes are surgically removed in stage 3 melanoma. This is very burdensome for the patient. Especially if the lymph nodes are removed from the groin because it can lead to fluid accumulation in the leg. There are studies showing that it is safe to remove only the affected lymph node to assess the response to neoadjuvant treatment. And in the case that the tumor is (almost) gone, a previous small study showed it is even safe not to remove any lymph nodes. A larger study is now being set up to investigate this further.”

The WIN-O is also investigating specific patient groups, such as the elderly and patients with autoimmune diseases. "The elderly, because of their age and overall fitness, are often excluded from participation in clinical trials. In addition, it was assumed that the immune system works less well in the elderly and that immunotherapy in the elderly would lead to more side effects. So far, this has not proven to be the case. Furthermore, it was often thought that patients with autoimmune diseases could not receive immunotherapy because of the assumption that their autoimmune disease would get worse. Thanks to our research using data from the DMTR database, it appears that the majority of patients with autoimmune disease can safely receive immunotherapy for metastatic melanoma. The WIN-O aims to further close the knowledge gap and continues to conduct more research in these specific patient groups. Finally, the WIN-O investigates shorter immunotherapy treatment duration because of the notion that once the immune system is enabled, it is activated for a long time.”

“In conclusion, tailored cost-effective treatments with less surgical intervention and shorter time of treatment is what we are aiming for at the WIN-O!”

More information (in Dutch) about melanoma can be found on the website of the LUMC and the website of the Melanoma Foundation.

*Dutch Melanoma Skin Cancer Group