Study Shows Efficacy of Neoadjuvant Combo Therapy in Melanoma, Cautions Toxicity

Neoadjuvant therapy with a combination checkpoint blockade produced a high response rate among patients with melanoma.

A neoadjuvant therapeutic approach demonstrated a clinical benefit for patients with high-risk melanoma, but toxicity concerns suggest the need for further optimization to reduce adverse effects, according to a new study.

In the phase 2 study, which was published in Nature Medicine, researchers at The University of Texas MD Anderson Cancer Center evaluated a combination checkpoint blockade in 23 patients with high-risk stage 3 melanoma.

Patients included in the trial received either the PD-1 inhibitor nivolumab or a combination of nivolumab and the CTLA-4 checkpoint inhibitor ipilimumab before surgery. All patients received nivolumab after surgery.

Seventy-three percent of patients treated with the combination therapy had their tumors shrink, 45% had no evidence of disease at surgery (pathological complete response), and 73% had grade 3 adverse effects, which caused dosing delays in 64% and delayed surgery in some cases.

In patients who were treated with nivolumab, 25% experienced tumor shrinkage and a pathological complete response. Only 8% had grade 3 adverse effects. Two patients progressed to stage 4 metastatic disease before they could get to surgery.

All patients who achieved a pathological complete response in either arm remain without evidence of disease recurrence, with an overall survival rate of 100% at 24 months in the combination arm and 75% in the nivolumab arm, according to the study.

“The advantage of a neoadjuvant approach in this setting is that it enables an interval evaluation of the tumor cells after therapy to determine the extent to which those tumor cells responded to the therapy in real time and predict which patients are likely to experience durable responses going forward,” study author Michael Tetzlaff, MD, PhD, associate professor of Pathology and Translational and Molecular Pathology, said in a press release.

Analysis of biopsies and blood samples taken throughout the trial allowed researchers to identify biomarkers of response, mechanisms of resistance, and differential effects of the 2 treatment regimens, according to the study. The analysis found that responders to both treatments demonstrate higher lymphoid infiltrates and responders to nivolumab monotherapy had a more clonal and diverse T cell infiltrate.

Based on the results of this study, the researchers re-designed the trial to evaluate nivolumab plus relatlimab, an inhibitor of the LAG3 immune checkpoint, which the researchers think may also be effective and have a better adverse effect profile.

“These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers,” the researchers concluded.

References

Amaria RN, Reddy SM Wargo JA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nature Medicine. 2018. https://www.nature.com/articles/s41591-018-0197-1.

Neoadjuvant combination checkpoint blockade trial yields high response rates for patients with high-risk stage 3 melanoma [news release]. MD Anderson’s website. https://www.mdanderson.org/newsroom/2018/10/neoadjuvant-combination-checkpoint-blockade-trial-yields-high-response-rates-for-melanoma-patients.html. Accessed October 8, 2018.