The immune checkpoint inhibitors nivolumab and ipilimumab have transformed the treatment of melanoma, but thus far their use has been limited mostly to therapy for unresectable metastatic disease. An ongoing clinical trial may show that the two drugs can also be used as neoadjuvant treatment for patients with resectable stage III or oligometastatic melanoma.
Patients with resectable stage III or oligometastatic (i.e., resectable stage IV disease in three or fewer sites excluding the bone and central nervous system) melanoma have a 70% chance of disease recurrence after standard treatment with surgery followed by systemic therapy, according to Rodabe Amaria, M.D., an assistant professor in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center. She thinks that neoadjuvant therapy could improve outcomes for such patients.
“Neoadjuvant therapy doesn’t have a track record in melanoma,” Dr. Amaria said. “And many patients don’t see a medical oncologist until after the surgery is done. I think that’s a missed opportunity for this population of patients who have such high-risk disease.”
Neoadjuvant immunotherapy trial
Dr. Amaria is the principal investigator of a phase II clinical trial (No. 2015-0041) of neoadjuvant therapy with nivolumab alone or combined with ipilimumab. Nivolumab, which inhibits PD-1 (programmed cell death protein 1), and ipilimumab, which inhibits CTLA-4 (cytotoxic T lymphocyte antigen 4), are each approved by the U.S. Food and Drug Administration as monotherapy for metastatic melanoma; and the combination of nivolumab and ipilimumab was approved in 2016 for patients who have unresectable metastatic melanoma. But the current trial is one of the first studies to use these agents as neoadjuvant therapy for resectable melanoma.
Patients in the trial’s monotherapy arm receive up to four doses of nivolumab (3 mg/kg intravenously every 2 weeks) before surgery; patients in the combination therapy arm receive up to three doses of nivolumab (1 mg/kg intravenously every 3 weeks) and ipilimumab (3 mg/kg intravenously every 3 weeks) before surgery. After surgery, patients in both arms receive nivolumab (3 mg/kg intravenously) every 2 weeks for 6 months.
Outcome measures and concerns
The trial’s primary outcome measure is pathological response, which is determined by the number of viable tumor cells on hematoxylin and eosin staining of a surgical sample. “Our hypothesis is that the more tumor necrosis or the less viable melanoma you have at the time of surgery, the better the patients’ long-term outcomes,” Dr. Amaria said. She added that the hypothesis was derived from the success of neoadjuvant therapy for breast cancer, in which complete pathological responses correlate with better survival outcomes.
The secondary outcome measures are the 12-month recurrence-free and overall survival rates as well as the objective response rate to neoadjuvant therapy. Responses are assessed using imaging and the Response Evaluation Criteria in Solid Tumors.
The safety of nivolumab and ipilimumab is also being evaluated, and patients are monitored closely for adverse events. “Any of these immunotherapy drugs can cause side effects related to overactivation of the immune system,” Dr. Amaria said. The side effects—which typically resolve with treatment—may include rash, pneumonitis, diarrhea, and thyroid or pituitary gland dysfunction.
Another concern is tumor progression. “These drugs don’t work as quickly as targeted therapies,” Dr. Amaria said. “So there’s a possibility that some patients’ tumors will grow during treatment. But we’re seeing good responses in both treatment arms.” Although not enough patients have been treated to enable a preliminary analysis, Dr. Amaria said that about half the patients have had a good response to neoadjuvant immunotherapy—including multiple patients who had no viable tumor cells in their surgical specimens—while half the patients have gone to surgery with a considerable volume of viable tumor cells.
The trial’s randomization process is set up to assign equal numbers of patients whose tumors express PD-L1 (the PD-1 ligand) to the two treatment arms. Previous studies have identified PD-L1 expression as a potential biomarker for response to nivolumab and ipilimumab, so the researchers want to see whether PD-L1 expression affects outcomes in either arm.
Dr. Amaria—along with Jennifer Wargo, M.D., an associate professor in the Department of Surgical Oncology, and other collaborators in the trial—also hopes to discover new biomarkers for response to immune checkpoint inhibitors. “Our trial is heavy on the collection of blood and tumor tissue so that we can assess what happens in the tumor and blood over the course of therapy,” Dr. Amaria said.
For each patient, tumor biopsy samples are taken before treatment and at least once during treatment. These samples and those from the surgical specimen undergo immune and molecular assays. “The serial samples will generate data that may help us understand why some patients have excellent responses and other patients do not respond as favorably,” Dr. Amaria said.
Building a neoadjuvant therapy program
The immunotherapy trial is the second MD Anderson trial to investigate neoadjuvant therapy for stage III or oligometastatic melanoma. The first trial, led by Dr. Wargo, is ongoing but is no longer enrolling patients, and the preliminary results are promising (see “Neoadjuvant Therapy with BRAF Inhibitors for Patients with Melanoma,” below).
“We’re working to build a neoadjuvant therapy program for melanoma patients,” Dr. Amaria said. “With the advances in treatment we’ve seen in recent years, neoadjuvant therapy has become a viable option.”
For more information, call Dr. Rodabe Amaria at 713-792-2921 or Dr. Jennifer Wargo at 713-745-1553. For more information about clinical trials for melanoma patients, visit www.clinicaltrials.org.
OncoLog, January 2017, Volume 62, Issue 1
Neoadjuvant Therapy with BRAF Inhibitors for Patients with Melanoma
Early results from a clinical trial indicate that neoadjuvant therapy with BRAF inhibitors improves recurrence-free survival in melanoma patients who have resectable stage III or oligometastatic melanoma with BRAF V600E or V600K mutations compared with a group of patients who were offered standard therapy.
In the trial (No. 2014-0409), which is ongoing but no longer enrolling patients, patients were randomly assigned to a control arm to receive the standard of care or an experimental arm to receive neoadjuvant and adjuvant therapy with the oral BRAF inhibitors dabrafenib and trametinib. Patients in the control arm underwent surgery within 4 weeks of enrollment followed by standard adjuvant therapy selected by the treating physician. Patients in the experimental arm received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) for 8 weeks followed by surgery, and they will continue to receive the study drugs for up to 44 weeks after surgery.
An interim analysis showed an overall response rate of 77% on imaging and a pathological complete response rate of 58% at week 8 for the patients in the experimental arm. The estimated 6-month recurrence-free survival rates were 100% for the experimental arm but only 28% for the control arm, so enrollment was closed.
Drs. Amaria and Wargo and their colleagues presented these results at the 2016 Society for Melanoma Research International Congress in November.