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Research Project

Investigating Checkpoint Inhibitor Resistance in Melanoma Patients

Combination immunotherapy for melanoma patients showing resistance to checkpoint inhibitors targeting PD-1 or CTLA-4 

The MAHLER Trial


Checkpoint inhibitors have emerged as a breakthrough treatment, extending the lives of patients with advanced skin and lung cancers. Unfortunately, a significant number of cancer patients still do not respond to these immunotherapies or develop resistance to them.

This phase II randomized clinical trial (NCT02731729) is designed to help researchers understand why some patients with melanoma benefited from the treatment and why others did not. In addition, investigators will evaluate whether additional treatment, including a combination of two checkpoint inhibitors, can help patients who initially did not respond.

Both PD-1 and CTLA-4 are proteins involved in the immune checkpoint system and can dampen the immune system’s response, shutting down the body’s own ability to fight cancer. Checkpoint inhibitor treatments remove these brakes on the immune system so it can attack tumor cells. In this trial, Parker Institute scientists aim to uncover why inhibitors of PD-1 and CTLA-4 worked for some patients and not for others.


This study includes 70 patients with inoperable, advanced and metastatic skin melanoma who didn’t respond or progressed after treatment with therapy targeting PD-1 or CTLA-4. Half of these patients will receive a single immunotherapy agent, ipilimumab (Yervoy), while the other half will be treated with a combination of ipilimumab and nivolumab (Opdivo).

In addition, scientists are examining an extensive group of biomarkers to help understand the reasons why certain patients responded to treatment. For example, they will look at the number and type of mutations in the tumor and how that correlates with response to treatment.

These findings could help determine which patients may make better candidates for one type of treatment over another in the future, or if some patients might benefit more from combination treatments from the start.

where the trial is open

This study began enrolling patients in fall of 2016 at Memorial Sloan Kettering Cancer Center and later opened at the University of Pennsylvania, M.D. Anderson Cancer Center, the University of California, Los Angeles and the University of California, San Francisco. The trial is no longer enrolling patients at this time.

Research Team

Other researchers include Hussein Tawbi (MD Anderson) and Katy Tsai (UCSF)

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