Combination checkpoint blockade before surgery (neoadjuvant therapy) produced a high response rate among patients with high-risk stage 3 melanoma, with nearly half having no sign of disease at surgery, but a high incidence of side effects caused the trial to be closed early.

The phase 2 study was led by researchers at The University of Texas MD Anderson Cancer Center. Results of the study, the first randomized neoadjuvant clinical trial of immune checkpoint blockade for melanoma patients, are reported in Nature Medicine.

Patients received either the PD-1 inhibitor nivolumab or the combination of nivolumab and the CTLA-4 checkpoint inhibitor ipilimumab. Each drug blocks a separate off-switch on T cells, freeing the immune system to attack cancer. All patients received nivolumab after surgery.

On the combination arm, 8 of 11 (73%) patients had their tumors shrink, 5 (45%) had no evidence of disease at surgery (pathological complete response), and 73% had grade 3 side effects, causing dose delays in 64% and delaying surgery for some. There were no grade 4 side effects.

In the nivolumab arm, 3 of 12 (25%) had their tumors shrink and had pathological complete response, only 8% had grade 3 side effects. Two patients progressed to stage 4 metastatic disease before they could get to surgery.

“In this trial, treatment with single-agent anti-PD-1 was associated with modest response rates, and we were concerned that two patients on that arm progressed and could not go to surgery,” said co-first author Rodabe Amaria, MD, assistant professor of melanoma medical oncology. “Treatment with combined checkpoint blockade was much more effective, but at the expense of significant toxicity. It is clear from this trial that we need to further optimize this treatment approach.”

All of those who achieved pathological complete response in either arm remain without evidence of disease recurrence. Overall survival was 100% at 24 months in the combination arm and 75% in the nivolumab arm.

“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. It also provides us the tissue resources to determine why tumors may not respond to therapy and thus tailor therapies going forward as we learn more about resistance,” said co-senior author on the study, Michael Tetzlaff, MD PhD, associate professor of pathology and translational and molecular pathology.

Checkpoint blockade has been effective against metastatic melanoma and in reducing the risk of relapse after surgery for high-risk stage 3 disease. However, there is evidence in pre-clinical models that treatment before surgery may be superior to giving these agents in the adjuvant setting (after surgery).

Amaria and senior author Jennifer Wargo, MD, associate professor of surgical oncology and genomic medicine, launched the investigator-initiated trial through MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Due to the results of this study, the team re-designed the study to explore the safety and efficacy of nivolumab plus relatlimab, an inhibitor of the LAG3 immune checkpoint, a combination that Amaria notes thinks may be more effective than nivolumab alone with a better side effect profile than treatment with combined CTLA-4 and PD-1 blockade.

“This presurgical platform provides an ideal setting to study biomarkers of response, mechanisms of resistance, and differential effects of these two commonly used treatment regimens,” said co-first author Sangeetha Reddy, MD, instructor in cancer medicine. “In this study, we confirmed known biomarkers of response and observed novel biomarkers of therapeutic response that we are now studying further.”