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Combined Immune Checkpoint Therapies Impressive in Advanced Melanoma

Summary and Comment |
June 27, 2013

Combined Immune Checkpoint Therapies Impressive in Advanced Melanoma

  1. Hensin Tsao, MD, PhD

Rapid tumor regression was noted in a substantial proportion of patients.

  1. Hensin Tsao, MD, PhD

Anti–CTLA-4 and anti–PD-1 therapeutics (ipilimumab and nivolumab, respectively) have demonstrated success in treatment of advanced melanoma. CTLA-4 inhibits T cells early in the sequence of activation, and PD-1 leads to later T-cell exhaustion in peripheral tissues. In previous preclinical studies, combined antagonism of both PD-1 and CTLA-4 led to more substantial antitumor activity than blockade of either pathway alone. In this Phase I trial, investigators assessed the synergy of combining nivolumab and ipilimumab in clinical use.

Of 86 patients, 53 (concurrent-regimen group) received 4 combined intravenous doses 3 weeks apart, followed by nivolumab alone every 3 weeks for 4 doses, followed by up to 8doses of combined treatment. The sequenced-regimen group of 33 previous ipilimumab recipients received up to 48 doses of nivolumab every 2 weeks. The overall objective-response rate in the concurrent-regimen group was 40%. This rate was 53% at the maximum tolerable dose, with tumor reduction of >80%. The sequenced-regimen group had an objective-response rate of 20%. Grade III or IV adverse treatment-related effects occurred in 53% and 20% of the two groups, respectively.

Comment

Because these agents block tumor immunity at different stages, combining anti–PD-1 and anti–CTLA-4 drugs makes biologic sense. This clinical trial provides further evidence that the model is correct in vivo. It is impressive that the maximum tolerated dose produced a tumor reduction of 80% or more in about half of the patients. As can be seen in this study and in another recent trial, immune checkpoint therapies have hit the ground running. Early results show that these checkpoint approaches are appropriate for patients who fail to benefit from selective BRAF inhibitors. This new pipeline of great drugs for melanoma is creating an extraordinary amount of excitement in the entire cancer community. Their success also speaks to the importance in all drug pursuits of having well-characterized mechanisms of disease.

  • Disclosures for Hensin Tsao, MD, PhD at time of publication Consultant / advisory board Genentech; Quest Diagnostics; WorldCare Clinical Grant / research support NIH; Department of Defense; American Skin Association Editorial boards British Journal of Dermatology; Journal of the American Academy of Dermatology; Journal of Investigative Dermatology Leadership positions in professional societies American Academy of Dermatology (Chair, Skin Cancer and Melanoma Committee); American Board of Dermatology (Director)

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Reader Comments (1)

ROBERT BONE Physician, Surgery, General, Vanderbilt University Medical Center

Hold for Advanced Melanoma Therapy

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