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Neoadjuvant Combination Checkpoint Blockade in Advanced Melanoma


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Rodabe N. Amaria, MD

Rodabe N. Amaria, MD

Neoadjuvant combination checkpoint blockade showed activity among patients with high-risk stage III melanoma in a small study. However, a high incidence of side effects caused the trial to be closed early. These results were published by Rodabe N. Amaria, MD, Assistant Professor of Melanoma Medical Oncology at MD Anderson, and colleagues in Nature Medicine.

The phase II study was led by researchers at The University of Texas MD Anderson Cancer Center. Patients received either the programmed cell death protein 1 (PD-1) inhibitor nivolumab (Opdivo), or the combination of nivolumab and the CTLA-4 checkpoint inhibitor ipilimumab (Yervoy). All patients received adjuvant nivolumab.

Response

In the combination arm, 8 of 11 (73%) patients had their tumors shrink and 5 (45%) had no evidence of disease at surgery. However, 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 pathologic complete response, and only 8% had grade 3 side effects. Two patients progressed to stage IV 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,” noted Dr. Amaria, “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 pathologic 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.

Michael Tetzlaff, MD, PhD

Michael Tetzlaff, MD, PhD

“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 at MD Anderson.

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

The MD Anderson–led team is now working with other research teams worldwide in an international neoadjuvant melanoma consortium to harmonize efforts in neoadjuvant treatment.

Amaria RN, et al: Nat Med 24:1649-1654, 2018.


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