Aptitude Health interviewed Dr Alexander Eggermont to gain his unique perspectives on recent advances and strategic insights in the management of melanoma. Dr Eggermont is Chairman of the Board of the Comprehensive Cancer Center Munich (CCCM) in Germany, the Chief Scientific Officer of the Princess Máxima Center for Pediatric Oncology in the Netherlands, Professor of Clinical & Translational Immunotherapy at the University Medical Center Utrecht in the Netherlands, and emeritus professor of oncology at Paris-Sud University, and emeritus professor of surgical oncology at Erasmus University Rotterdam. He has a PhD in tumor immunology and is a Fellow of the National Cancer Institute Surgery Branch (Steve Rosenberg).
Dr Eggermont has many years of international experience researching and treating cancer and has won a plethora of international awards in recognition of his work, particularly in the field of immunotherapy. His past roles include being president of the European Organisation for Research and Treatment of Cancer (EORTC), the European CanCer Organisation (ECCO), and the European Academy of Cancer Sciences (EACS). In Germany, Dr Eggermont is closely involved in the comprehensive cancer center program of the Deutsche Krebshilfe. He is also editor-in-chief of the European Journal of Cancer.
In your opinion, what is the most important achievement in the treatment of melanoma in the last 5 years?
There are 2. First for me is without doubt neoadjuvant immunotherapy development with the combination of anti–CTLA-4 and anti–PD-1 therapies in melanoma patients with palpable nodal involvement. The 2018 Nature Medicine paper by Christian Blank, et al, from the Netherlands Cancer Institute, provided the biologic understanding of the efficacy of treating such patients with 2 cycles of ipilimumab 3 mg/kg and nivolumab 1 mg/kg. They demonstrated that neoadjuvant treatment expanded T-cell clones already present at baseline multifold in comparison to adjuvant therapy after surgery, and moreover, that neoadjuvant therapy induced a much greater variety of new T-cell clones than adjuvant therapy. With that basic observation, we understood and expected the results in the subsequent trial that demonstrated major responses in about 75% of patients and complete pathologic response (pCR) or near complete pathologic responses (npCR) in about 60%. It then became clear that <10% of these patients relapse and that most of them are cured and do not need further treatment. In the PRADO trial, they went on to demonstrate that if the largest indicator node had a pCR/npCR, therapeutic lymph node dissection could be omitted. That means that the management of melanoma is most likely going to change profoundly – more cures, shorter treatments, and less surgery.
The second major achievement is the rollout of neoadjuvant immunotherapy into other tumors. The ramifications are enormous as Dr John Haanen’s group went on to demonstrate a >90% complete pathologic response rate in microsatellite instability (MSI) colorectal cancers, published in Nature Medicine in 2020. These patients still underwent a resection of their (mostly rectal) MSI cancers, but with this kind of efficacy, those resections will disappear as patients will be followed by endoscopy and magnetic resonance imaging. This development is ongoing in stage T3 muscle layer-invasive bladder cancer, where roughly 45% to 50% pCR rates are seen with PD-1–based approaches, which is expected to lead to a reduction of mutilating bladder resections. Similarly, we will see this development for cutaneous squamous cell carcinomas in the face and in other tumor types. There are now neoadjuvant anti–PD-1–based trials in lung, head and neck, esophageal, esophagogastric junction, gastric, renal, hepatocellular, and other tumor types.
What is your biggest disappointment in melanoma management in the last 5 years?
The biggest disappointment was our failure to break the anti–PD-1 ceiling with agonist antibodies – failure to develop a macrophage checkpoint inhibitor to break their profound immunosuppressive functions. There are some new developments with anti-CD47, anti-SIRP alpha, galectin-3 inhibitors, and other treatment mechanisms, but these are yet to be proven in solid tumors.
What is the most important medical need in melanoma management?
The most important medical need is to cure more melanoma patients. There are a number of developments that will contribute to that:
- Neoadjuvant immunotherapy that will cure more patients and will lead to shorter treatments and less surgery (resectable stage IV metastases, palpable nodal stage III, expansion into sentinel-node positive disease).
- Identification of patients who, despite relatively low-risk stage IB–IIA, will still relapse and about 50% will die. These patients can be identified by an algorithm of age and Breslow thickness with a gene expression profile of 8 “metastasis-propensity genes”. We published this in the European Journal of Cancer in 2020. This patient population is as large as the whole stage III patient population that is now routinely treated with adjuvant therapy.
- Avoiding overtreatment. I think gene expression profiling will one day replace sentinel-node staging and will help clinicians decide whom to treat (neo)adjuvantly. In the end, that will maximize the percentage of melanoma patients that will be cured.
What is the most interesting strategic direction of further development in melanoma?
Neoadjuvant immunotherapy is the most important development, at the moment, that will cure more patients, shorten treatment periods, and reduce surgery.
Do you think we can start talking about cure in patients with melanoma?
We are talking about cure from melanoma right now. The immunotherapy revolution is by far the most important component in that discussion.
How has COVID changed your perspective?
COVID has changed perspectives on life and society . . . the Internet has been taken over by misinformation, manipulation, lying, conspiracy theories, ignorance, and so on. “Liberty and freedom” to not get vaccinated are claimed, but this limits the freedom of those who are vaccinated and prolongs the societal problems, the healthcare problems, and the increased backlog in all the other necessary medical interventions, including cancer management. All this is mainly driven by ignorance, misunderstanding, and manipulation; we should know better and should put societal values and individual societal responsible behavior first. Regarding melanoma, it is clear that in Western Europe and in North America, data show that 20% to 50% fewer melanomas were diagnosed during the peak COVID periods and as a consequence, the thickness of the primary melanomas that are diagnosed has increased and costs lives. I expect these numbers to normalize over the next 12-18 months.