American Melanoma Institute · 5 min read
How adjuvant immunotherapy and targeted therapy work after surgery for stage IIB, IIC and III melanoma, what trials found, and the side effect trade-off.
Surgery removes every bit of melanoma the surgeon can find. For thicker tumors, and for melanoma that has reached the lymph nodes, doctors know that a few cancer cells may already have traveled elsewhere in the body in numbers too small for any scan to pick up. Adjuvant therapy is medicine given after surgery to go after those hidden cells.
No test can show whether those cells exist. The decision rests on risk: how often melanomas like yours return, how much a drug lowers that chance, and what the drug may cost you in side effects.
Doctors mainly discuss adjuvant therapy for stage IIB and IIC melanoma and for stage III melanoma. Stage IIB and IIC tumors are thick, often with ulceration (the skin over the tumor has broken down), and have not reached the lymph nodes. Stage III means melanoma has reached nearby lymph nodes or the skin on the way to them.
The researchers who ran the CheckMate 76K trial pointed out that stage IIB and IIC melanomas return about as often as stage IIIA and IIIB melanomas do. Stage I and IIA tumors return much less often, so surgery alone remains the standard for them.
Pembrolizumab (Keytruda) and nivolumab (Opdivo) are PD-1 checkpoint inhibitors. Both are given every 2 to 6 weeks, depending on the drug and dose, for about 1 year, and both are FDA approved for use after surgery in stage IIB, IIC and III melanoma.
Dabrafenib (Tafinlar) plus trametinib (Mekinist) is a pair of pills taken every day for 12 months. This option exists only for stage III melanomas that carry a BRAF V600 mutation, a gene change found in about half of skin melanomas.
A person with a BRAF-mutated stage III melanoma can often choose between the pills and a PD-1 drug. No trial has compared the 2 approaches directly, so the choice usually turns on side effects and other health conditions. An older drug, ipilimumab, is now rarely used after surgery, because nivolumab worked better and caused far fewer serious side effects in the 906-patient CheckMate 238 trial (Weber and colleagues, New England Journal of Medicine, 2017).
In stage IIB and IIC melanoma, the KEYNOTE-716 trial (Luke and colleagues, The Lancet, 2022) assigned 976 patients to pembrolizumab or a placebo for up to about 1 year. After a median follow-up of about 21 months, melanoma had returned, or the patient had died, in 15% of the pembrolizumab group and 24% of the placebo group. In CheckMate 76K (Kirkwood and colleagues, Nature Medicine, 2023), which tested nivolumab in 790 similar patients, 89% of the nivolumab group and 79% of the placebo group were free of recurrence at 12 months.
For stage III melanoma, KEYNOTE-054 randomized 1,019 patients to pembrolizumab or placebo. A 7-year analysis (Eggermont and colleagues, European Journal of Cancer, 2024) found 50% of the pembrolizumab group free of recurrence compared with 36% of the placebo group. In COMBI-AD, 870 patients with BRAF-mutated stage III melanoma took dabrafenib plus trametinib or placebo pills for 12 months. The final report (Long and colleagues, New England Journal of Medicine, 2024), with more than 8 years of follow-up, showed the drug pair cut the risk of relapse roughly in half.
Picture 100 people with stage IIB or IIC melanoma. Without the drug, about 24 had a recurrence in the first 21 months or so. With the drug, about 15 did.
So treatment spared roughly 9 people in 100 a recurrence during that window. About 76 would have been fine with surgery alone, and about 15 had a recurrence despite treatment. Doctors cannot yet tell in advance which group a person belongs to.
Staying free of recurrence is also different from living longer, because melanoma that returns can be treated with the same drugs. In COMBI-AD, survival favored the treated group, but the difference did not reach statistical significance. For the PD-1 drugs, more data is needed before anyone can say whether treating everyone early extends life compared with treating only those whose melanoma returns.
Checkpoint inhibitors can push the immune system to attack healthy organs. A pooled safety analysis of 4 trials of pembrolizumab after surgery for melanoma, lung cancer and kidney cancer (Luke and colleagues, European Journal of Cancer, 2024) found immune-related side effects in about 36% of people on the drug and 8% of those on placebo. In about 9% of people on the drug, the reaction was severe.
Most of these problems settle with steroids or a pause in treatment. An underactive thyroid, a failed pituitary gland, or type 1 diabetes caused by immunotherapy usually lasts for life and requires daily hormone replacement. Deaths are rare. In CheckMate 76K, 1 death was linked to nivolumab.
A person who was already cured by surgery gains nothing from the drug yet carries the same chance of a permanent side effect. Dabrafenib plus trametinib has a different pattern: fevers, chills, fatigue and nausea are common, and they generally fade once the pills stop.
Close follow-up without a drug is an accepted choice. The NCCN patient guideline says the decision at stage IIB and IIC should take personal factors into account, including age and any history of autoimmune disease.
