Patients with advanced skin cancer often have to reckon with relapses and the occurrence of metastases. But the prognosis could improve if they receive combined immunotherapy before and after the surgical removal of the melanoma. This is shown by a phase II study with 30 patients. This therapy is already approved for inoperable forms of skin cancer. The current study suggests that it can also be useful in combination with surgery, among other things to prevent recurrence.
Cancer cells use a variety of tricks to spread through our body and evade the immune system. Among other things, many malignant tumors modulate the reactions of the body's own T cells and in this way ensure that the immune system does not attack them. So-called immune checkpoint inhibitors are often used in cancer therapy. They block the inhibitory effect of the immune checkpoints located on the T cells and thus strengthen the immune system's defense reaction against the tumor cells. One area of application is, for example, end-stage (stage IV) melanoma that has already formed metastases and is inoperable. In March 2022, the US Food and Drug Administration (FDA) approved a combination of two immune checkpoint inhibitors, relatlimab and nivolumab, for this indication.
Supportive immunotherapy
In a clinical phase II study, a team led by Rodabe Amaria from the University of Texas MD Anderson Cancer Center in Houston has now investigated the extent to which immunotherapy can also help patients whose tumor can still be surgically removed. The 30 subjects in the study had stage III melanoma. At this stage, the tumor has already invaded the lymphatic system, but surgery is still possible. However, one problem so far has been the risk of relapse. "In clinical stage III melanoma, the risk of the cancer returning after surgery can be as high as 50 percent," explains Amaria. "One of the goals of neoadjuvant immunotherapy is to reduce the likelihood of recurrence."
As part of the study, the patients received the combination of relatlimab and nivolumab twice before the operation, four weeks apart. In addition, they were treated with ten more doses after the operation. During the neoadjuvant therapy, i.e. the treatment before the operation, the researchers did not observe any serious side effects of the immunotherapy in any of the patients. One patient developed brain metastases prior to the planned surgery and was therefore not treated further according to the study protocol. The remaining 29 patients could be operated on as planned, with the immunotherapy not delaying the operation.
"Safe and effective treatment option"
According to the researchers, the results are promising: 17 of 29 patients showed a complete response to the neoadjuvant immunotherapy. At the time of the operation, there were no longer any viable tumor residues detectable in them. In four others, the tumor had regressed by at least more than half. At two years, 91 percent of the fully responding patients had survived recurrence-free, compared to 69 percent of the non-responders. "Our results support the combination of relatlimab and nivolumab as a safe and effective treatment option in the neoadjuvant treatment of stage III melanoma," summarizes Amaria.
However, only 15 patients completed all ten adjuvant therapy doses of immunotherapy. In contrast, the therapy was terminated prematurely in twelve test persons due to side effects, and three withdrew their consent. The most common side effects included secondary adrenal insufficiency and elevated liver enzymes. "This raises the question of whether continued dosing in the adjuvant period is necessary after a pathologic response to neoadjuvant therapy," the researchers write. "Furthermore, none of the patients who prematurely discontinued therapy due to toxicity have had a recurrence."
In further studies, the researchers want to clarify in more detail how immunotherapy can best help patients with skin cancer and which biomarkers can provide information on how well a patient is responding to the therapy.
Source: Rodabe Amaria (The University of Texas MD Anderson Cancer Center, Houston) et al., Nature, doi: 10.1038/s41586-022-05368-8