The objective response rate with neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) was almost tripled compared with nivolumab alone in patients with high-risk resectable melanoma, according to preliminary findings from a phase II study presented during the 32nd SITC Annual Meeting.
Sangeetha M. Reddy, MD, MSci
The objective response rate (ORR) with neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) was almost tripled compared with nivolumab alone in patients with high-risk resectable melanoma, according to preliminary findings from a phase II study. However, a significant degree of added toxicity was demonstrated with the combination compared with nivolumab monotherapy, Sangeetha M. Reddy, MD, MSci, said in a presentation during the presidential session at the Society for Immunotherapy of Cancer’s 32nd Annual Meeting.
“Treatment with combination ipilimumab/nivolumab is associated with higher response rates in the neoadjuvant setting, but also with significant toxicity, suggesting we need to optimize this regimen further in this setting,” said Reddy, a medical oncologist at The University of Texas MD Anderson Cancer Center. Reddy worked on this trial with co-investigators Rodabe Amaria, MD, and Jennifer Wargo, MD.
Researchers in the Wargo Laboratory at MD Anderson sought to study the effects of immune checkpoint inhibitors in the neoadjuvant setting after obtaining positive results using this approach with combination targeted therapies.
Investigators randomized patients with high-risk resectable metastatic melanoma to 8 weeks of neoadjuvant BRAF/MEK targeted therapy versus standard-of-care upfront surgery. Those who received neoadjuvant therapy achieved higher response rates and improved outcomes compared with those who had upfront surgery, according to results scheduled to be published inLancet Oncology.
In the immunotherapy trial, patients were stratified by stage and PD-L1 status for the combination of neoadjuvant nivolumab and ipilimumab for up to 3 doses or neoadjuvant nivolumab monotherapy for up to 4 doses. Following resection, patients in both arms were then given adjuvant nivolumab for 6 months.
In the neoadjuvant setting, the primary endpoint was pathological complete response (pCR) rate at surgical resection, and secondary endpoints were RECIST responses and toxicity. In the adjuvant setting, secondary endpoints included relapse-free survival (RFS), overall survival, and immune monitoring.
Forty patients with resectable stage IIIB/C or oligometastatic stage IV melanoma were expected to be enrolled in the study, with 20 in each arm. However, the trial was stopped early after 23 patients were enrolled due to concerns from the data and safety monitoring board regarding efficacy and toxicity, Reddy said.
Among the 23 enrolled patients, the median age was 49 in the combination arm and 55 in the monotherapy arm. All patients had an ECOG performance status of 0. Many of the patients had received prior surgery (64% in the combination arm and 42% in the monotherapy arm) and few had received prior systemic therapy (18% and 8%, respectively). A majority of the patients demonstrated PD-L1 expression (≥1%; 64% and 75%, respectively); patients were also tested forBRAF(36% and 58%, respectively) andNRASmutations (27% and 8%, respectively).
In the combination arm (n = 11), the ORR was 73%, and 45% achieved a pCR. With nivolumab alone (n = 12), 3 patients achieved a pCR for an ORR of 25%. “Of note, 2 of the patients developed significant progression of disease while they were receiving their neoadjuvant treatment and therefore were deemed unresectable,” Reddy said.
RFS was improved with the combination compared with nivolumab alone (P= .140) and among patients who achieved a pCR versus those who did not (P= .048). Those findings were “consistent with what we demonstrated in our targeted neoadjuvant trial, and this was maintained in both arms,” Reddy commented.
With combination nivolumab and ipilimumab, 73% of patients demonstrated a grade 3 adverse event (AE), including transaminitis, colitis, hyperthyroidism, and myositis, compared with 8% overall in the monotherapy arm, where the only grade 3 AE was tumor-related pain. No grade 4 toxicities were noted in the neoadjuvant portion of the trial. Seven patients in the combination arm were unable to receive the full dose, 6 required steroids, and 3 required a delay in their surgery.
Patients also underwent molecular and immune profiling for translational studies, and the researchers noted higher CD8 and PD-L1 expression in responders at baseline and following treatment, as well as enhanced immune infiltrates in these patients. “Preliminary biomarkers of response are in line with those already identified, and additional analyses are underway to identify novel biomarkers of response,” Reddy said.
In addition, greater clonality of T-cell populations was demonstrated in patients who achieved a response, and less remodeling of the T-cell repertoire was noted in patients who received nivolumab alone and achieved a response.
Reddy noted that further analysis is ongoing and is expected to be shared in the next few months that will determine the next steps with this study.
Reddy SM, Amaria RN, Spencer CN, et al. Neoadjuvant nivolumab versus combination ipilimumab and nivolumab followed by adjuvant nivolumab in patients with resectable stage III and oligometastatic stage IV melanoma: preliminary findings. Presented at: 32nd SITC Annual Meeting; November 8-12, 2017; National Harbor, MD. Abstract O15.