Treatment with Opdivo (nivolumab) plus Yervoy (ipilimumab) improved response rates in patients with melanoma, but not without some severe side effects.
Pre-surgical (neoadjuvant) treatment with the immunotherapy combination Opdivo (nivolumab) plus Yervoy (ipilimumab) nearly tripled objective response rates (ORR) in patients with high-risk resectable melanoma, compared to single-agent therapy with the PD-1 inhibitor.
However, the treatment regimen did come with a cost, carrying a significantly higher rate of grade 3 adverse events (AE), according to a small study presented at the 2017 SITC Annual Meeting.
In the combination arm (11 patients), the ORR was 73 percent and 50 percent of patients achieved a pathological complete response (pCR). With Opdivo alone (12 patients), the ORR was 25 percent and the pCR rate was 25 percent. Unfortunately, these gains in response were accompanied by 73 percent of patients in the combination arm having a grade 3 AE compared with just 8 percent in the single-agent arm. This high level of toxicity led the researchers to close the study early, according to Sangeetha M. Reddy, M.D., MSci. Reddy worked on this trial with co-investigators Rodabe Amaria, M.D. and Jennifer Wargo, M.D.
"The initial trial was designed with 20 patients in each arm; however, the trial was stopped early after a data safety monitoring board review identified differences in efficacy and toxicity between treatment arms,” Reddy, a medical oncologist at The University of Texas MD Anderson Cancer Center, said during a presentation of the results. “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.”
In the trial, patients were stratified by stage and PD-L1 status for the combination of neoadjuvant Opdivo and Yervoy for up to three doses or neoadjuvant Opdivo monotherapy for up to four doses. Following resection, patients in both arms were then given adjuvant Opdivo for six 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.
Twenty-three patients were enrolled when the trial was halted. The median age of patients 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 percent in the combination arm and 42 percent in the monotherapy arm) and few had received prior systemic therapy (18 percent and 8 percent, respectively). A majority of the patients demonstrated PD-L1 expression (at least 1 percent; 64 percent and 75 percent, respectively); patients were also tested for BRAF (36 percent and 58 percent, respectively) and NRAS mutations (27 percent and 8 percent, respectively).
RFS was improved with the combination compared with Opdivo alone and among patients who achieved a pCR versus those who did not. 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 Opdivo alone and achieved a response.
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.
The most common grade 3 AEs with the combination were transaminitis, colitis, hyperthyroidism and myositis, compared with monotherapy, 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, six required steroids, and three required a delay in their surgery.
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.