Ipilimumab Plus Nivolumab May Improve Outcomes in Patients With Refractory Metastatic Melanoma, Study Suggests

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Researchers have discovered that ipilimumab in combination with nivolumab may be an effective second-line therapy in patients with PD-1 blockade–refractory metastatic melanoma, according to a recent study published by VanderWalde et al in Nature Medicine. These findings demonstrated the combination therapy may extend progression-free survival and help patients overcome resistance to prior immunotherapies.


Ipilimumab and nivolumab are immune checkpoint inhibitors. Nivolumab is capable of blocking the PD-1 protein found on T cells, and ipilimumab is capable of blocking the CTLA-4 protein. Both inhibitors can help restore the natural ability of T cells to attack cancer cells.

Currently, patients with advanced metastatic melanoma are treated with PD-1 inhibitors as first-line therapy. Although these immune checkpoint inhibitors have been a significant advancement for treating patients with a variety of advanced cancers, more than 50% of metastatic melanoma tumors are resistant to the approach. When resistance occurs, patients are often switched to CTLA-4 inhibitors. Previously, it was unclear whether patients whose tumors are resistant to PD-1 inhibitors can continue the PD-1 agent in combination with a CTLA-4 inhibitor or if they should be switched to a CTLA-4 inhibitor alone.

Study Methods and Results

In this multicenter clinical trial, the researchers enrolled 91 patients with refractory metastatic melanoma who had already been treated with a PD-1 inhibitor and had not received a CTLA-4 inhibitor. The researchers randomly assigned 68 patients to receive ipilimumab and nivolumab and 23 patients to receive ipilimumab alone.

They then measured progression-free survival as the main endpoint and examined other factors such as the immune cells’ infiltration of the tumors, the cancer’s response to treatment, and any side effects the patients exhibited.

The researchers found that patients treated with the combination of ipilimumab and nivolumab demonstrated a 37% improvement in progression-free survival compared with those who received ipilimumab alone. Further, patients who received the combination of drugs experienced an overall response rate of 28% vs 9% among those who received ipilimumab monotherapy. The researchers also noted that one-third of the patients receiving ipilimumab and nivolumab had improved outcomes.

They found that the side effects were similar to previous reports on this drug combination. The most frequent severe adverse event being diarrhea, which occurred at the same rate in both groups.


"The combination had the potential to better activate the immune system against cancer by simultaneously blocking two main immune checkpoints, increase the immune infiltration in the cancer, and thereby overcome resistance to anti–PD-1 [therapy] alone,” explained senior study author Antoni Ribas, MD, Professor of Medicine at the David Geffen School of Medicine and Director of the Tumor Immunology Program at the University of California, Los Angeles Jonsson Comprehensive Cancer Center. "The results are practice-changing. Patients with advanced melanoma can get an anti–PD-1 treatment upfront and only add the anti–CTLA-4 ipilimumab if they do not respond—so, only the patients who need the combination are exposed to the increased toxicities. Sequencing immunotherapy treatments as was tested in this study is the next step forward in our efforts to better tailor the treatment options while limiting exposure to side effects,” he concluded.

Disclosure: For full disclosures of the study authors, visit

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