Assessment of Short Immunotherapy After Radical Surgery of High-risk Malignant Melanoma

1. Rational Every year, around 5,000 people in Sweden are diagnosed with malignant skin melanoma. In the early stages of malignant skin melanoma, the chance of cure with surgery is very good. At a later stage, when the melanoma has become thick and/or has spread, the risk of recurrence is greater despite radical surgery. Therefore, in these cases (even in cases of recurrence after radical surgery), additional treatment with immunotherapy is often given, as it has been shown to reduce the risk of recurrence. Immunotherapy is given for one year based on previous research studies, but it has not been investigated whether a shorter treatment period has the same effect. The hypothesis is that six months of treatment is equally effective, which would have several advantages. The main advantage of a shorter treatment period is that the risk of severe side effects is reduced. A shorter treatment period also means fewer hospital visits for patients. In addition, significant drug costs and other healthcare resources could be saved. 2. Aim/objective The aim of the study is to investigate whether 6 months of treatment with immunotherapy, in addition to radical surgery, for malignant skin melanoma at high risk of recurrence, is as effective in preventing recurrence as 12 months of treatment. Secondary objectives: To investigate overall survival after 6 versus 12 months of treatment with immunotherapy. To investigate the health economic effects of a shorter treatment. 3. Primary endpoints The two primary endpoints of the study are relapse-free survival (RFS) and distant metastatic-free survival (DMFS) and they will be analyzed for the first time in the interim analysis conducted after 2/3 of the estimated number of patients have been included in the study. 4. Secondary outcome measures Overall survival will be analyzed for the first time in the interim analysis. Health economic calculations are planned only at the final stage of the study. 5. Study design This is a randomised phase 3 study, with the aim of showing that treatment in the experimental arm (6 months of immunotherapy) is not inferior to the treatment in the standard arm (12 months of immunotherapy). Patients will be followed up to five years. The visits in the study follow clinical routine. 6. Study population Patients aged ≥18 years undergoing radical surgery for stage IIb-c, III or IV cutaneous malignant melanoma, with a WHO general condition score of 0-1 and deemed tolerable to immunotherapy. 7. Study treatment The study treatment consists of immunotherapy according to clinical routine, currently nivolumab or pembrolizumab given intravenously for either 6 months (experimental treatment) or 12 months (standard treatment). For patients receiving neoadjuvant treatment (additional treatment before surgery), the neoadjuvant treatment time is added to the adjuvant treatment time (additional treatment after surgery) to give a total treatment time of 6 or 12 months. Treatment is followed up according to routine, with imaging (CT or PET-CT) at baseline and after 6 months and at an additional time beyond clinical routine, after 36 months, as well as medical examination at baseline, 6, 12, 18, 24 and 36 months. In case of any signs of relapse, additional examinations are performed as needed. If relapse is detected, the patient is discussed at a local multidisciplinary conference to select the best available treatment for each patient. All study patients are followed for survival status for up to five years. 8. Risk-benefit and ethical issues If this study shows that a shorter treatment period is as effective as the current one-year treatment, it would greatly benefit patients by reducing the risk of side effects and reducing the number of hospital visits. It would also save healthcare resources, which could then be used in other areas. The Swedish Melanoma Patient Association (Melanompatientföreningen) has been consulted and is positive about the study, however they expect that patients may be reluctant to participate for fear of receiving inferior treatment. However, none of the pivotal studies conducted to date have shown that adjuvant systemic treatment of patients with malignant melanoma significantly prolongs overall survival, but its routine use is based on prolonged relapse-free survival. In addition, a recent cohort study indicated no survival benefit after the introduction of immunotherapy. To ensure that the experimental arm is not clearly inferior to the standard arm, an interim analysis will be conducted in this study (see above). It is worth mentioning that similar studies to Grand SLAM have been conducted in breast and colon cancer where additional treatment after surgery has been introduced as it not only reduces the risk of recurrence but also prolongs overall survival. These studies have shown that shorter treatment is equally effective.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Provision of written informed consent for participation.
2. ≥ 18 years of age.
3. Performance status ECOG/WHO 0-1.
4. Adequate organ functions as per standards for immunotherapy.
5. Radical surgery for CMM (including acral) stage IIb-c, III (including in transit) and IV. Stage III CMM patients with unknown primary and stage IIb-c CMM patients who have not undergone sentinel node procedure are eligible.
6. A complete physical examination within 28 days prior to randomization
7. Previous adjuvant treatment with BRAF + MEK inhibitors is allowed.
8. Neoadjuvant treatment with immunotherapy for two months (currently pembrolizumab every third weeks three times or nivolumab every fourth week two times) is allowed providing that a complete or near complete pathological response was not achieved and patients with clear progressive disease according to the pathology report are not eligible.
9. All participants who have not received neo-adjuvant treatment must have disease-free status documented by radiological assessment within 28 days prior to randomization while 6 weeks is sufficient for neo-adjuvant treated patients.
10. Participants must be off immunosuppressive doses of systemic steroids (\>10 mg/day prednisone or equivalent) for a minimum of 14 days prior to study drug administration.
11. Sufficient renal function for radiological assessments with i.v. contrast.
12. Peri-operative radiation therapy is allowed.
13. Patients who experience a locoregional lymph node relapse, i.e. stage III disease or operable stage IV at a time-point later than primary diagnosis are welcome to participate.

Exclusion Criteria:

1. The patient is, in the opinion of the investigator, assessed as unfit to receive systemic adjuvant treatment.
2. Serious and/or uncontrolled medical disorder that in the opinion of the investigator is contraindicated.
3. An active, known, or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism requiring hormone replacement only and skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are eligible.
4. Life-expectancy less than 2 years due to concurrent disease (e.g., cardiac disease and liver cirrhosis).
5. Inability to provide informed consent or refusal to do so.
6. Inability to comply with the study protocol.
7. Participation in other clinical trials interfering with the current study protocol.
8. Existing or previous malignancies within the past 5 years (except for in situ breast and in situ cervical cancer, melanoma in situ, malignant melanoma, non-melanoma skin cancer and low risk prostate cancer).
9. Pregnancy or planned pregnancy.
10. Ocular and mucosal melanoma.

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• RESULTPatel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. doi: 10.1056/NEJMoa2211437.