“New drugs are approved in the metastatic setting first because those patients have the greatest need and fewest options,” Amaria says. “As we’ve made progress in melanoma and new drugs have been approved for metastatic disease, we then start to study them in people with earlier stages of the disease, to provide an effective treatment so that their cancer never progresses to stage IV.”
Introducing immunotherapy for earlier-stage melanoma
The goal of neoadjuvant immunotherapy is to give it before surgery, so it’s only available to patients whose tumors are still contained enough to be successfully removed through surgery.
About 50% of patients with regional or lymph-node-involved melanoma will see their cancer return after surgery, due to microscopic cancer cells that have spread beyond the tumor and can’t be removed by surgery. The goal of adding immunotherapy to surgery is to kill any remaining cancer cells and reduce the chance of the cancer coming back. But the order of treatment matters.
Timing is important based on how immunotherapy works
“Checkpoint inhibitors rely on the presence of T cells in physical contact with the tumor to prompt the immune system to kill the cancer,” Patel says. “The idea behind neoadjuvant immunotherapy is that the immune system will have a bigger effect if treatment is given before the cancer and its resident T cells are removed, rather than only after.”
That’s why neoadjuvant immunotherapy clinical trials are designed to give patients a short round of immunotherapy before surgery (typically one to four doses spread out over several weeks). For some cancers, additional immunotherapy is given after surgery – typically once every 3 to 4 weeks for a year or more.
In recent studies led by Patel and Amaria, neoadjuvant immunotherapy was safe and worked well for patients with high-risk, operable melanoma:
The SWOG Cancer Research Network study led by Patel compared giving the same checkpoint inhibitor before and after surgery versus only after surgery. In the randomized clinical trial, patients who received neoadjuvant immunotherapy had a significantly lower risk of cancer recurring than patients who received the drug only after surgery.
In Amaria's study, most patients had no active cancer cells left in their resected tumors. Giving a combination of two different checkpoint inhibitors before surgery did not cause any surgery-delaying side effects.
Neoadjuvant immunotherapy can be used for some other cancer types
Neoadjuvant immunotherapy may shrink the cancer before surgery for some cancers, like cutaneous squamous cell carcinoma, which most frequently grows in the head and neck region. This allows surgeons to do a less invasive, function-preserving operation. If it’s effective, it could also spare patients from needing other adjuvant therapies that bring more side effects, such as chemotherapy and radiation therapy.
Drugs used for neoadjuvant immunotherapy
Researchers have studied several types of immunotherapy in the neoadjuvant setting, including:
Single-agent or combined immune checkpoint blockade that targets PD1 (pembrolizumab, nivolumab) or CTLA4 (ipilimumab, tremelimumab)
The combination of nivolumab, an anti-PD1 checkpoint inhibitor, and relatlimab, a novel antibody that inhibits the newest immune checkpoint, LAG-3
Monoclonal antibodies with various targets (cemiplimab, durvalumab, oleclumab, monalizumab)
Sometimes a clinical trial uses a single drug. Other times, clinical trials compare a single drug to a combination of drugs to find out which approach produces the best results with the fewest side effects. Different drugs may work better in different cancer types.
Future questions about neoadjuvant immunotherapy
As research teams continue to study neoadjuvant immunotherapy in clinical trials, they’ll look to answer the questions that remain about this type of cancer therapy, including:
What’s the optimal number of doses of neoadjuvant immunotherapy?
Are there patients who may not need surgery or additional immunotherapy after surgery – and how do we determine who those patients are?
How does neoadjuvant immunotherapy affect overall survival after long-term follow-up?
“As physicians and researchers, we want to be able to provide our patients with the best chance for a cure without sacrificing quality of life,” says Gross. “Neoadjuvant immunotherapy is a promising advancement, particularly for those with serious, but operable cancers, and we look forward to learning even more about how to use this therapy to give our patients the best possible outcomes.”