Is pembrolizumab plus ipilimumab combination therapy safe and effective for the treatment of advanced melanoma after failure of anti-PD-1/L1 therapy?

This study aimed to investigate the effectiveness and safety of combining pembrolizumab (PEM; Keytruda)) and ipilimumab (IPI; Yervoy) for the treatment of advanced-stage melanoma in patients that have progressed after previous PD-1/L1 therapy. The study concluded that this combination was well tolerated and improved the outcomes of these patients. 

Immunotherapy is a type of cancer treatment that makes use of the immune system to fight cancer. The cancer cell has some proteins present on the surface that help to turn off the immune system by binding proteins on the surface of the immune cells such as PD-1/PD-L1 or CTLA4. Immune checkpoint inhibitors (ICI) such as IPI and PEM block these interactions and turns on the immune system to attack and kill the cancer cells.

Melanoma is one of the most aggressive forms of skin cancer. Recent use of anti-PD-1/L1 (ICI) treatment showed effective results in melanoma. However, some patients still experience disease progression after these immunotherapies. Combinations of anti-PD-1 (PEM) and anti-CTLA-4 (IPI) treatment demonstrated improved survival in patients with advanced melanoma. However, there is no detailed report of the safety and effectiveness of this combination in patients who previously failed anti-PD-1/L1 therapy.

The study involved 70 patients who had progression of melanoma even after anti-PD-1/PD-L1 therapy (without anti-CTLA-4). Patients received 200mg PEM along with low-dose IPI (1mg/kg) intravenously once every three weeks for four doses. The average follow-up for the patients was 12 months.

29% of the patients showed a response on combination immunotherapy with IPI and PEM. 7.2% of the patients showed complete response (complete absence of cancer) and 21.4 had a partial response (decrease in cancer growth). The average duration of response is 16.6 months.

The average survival without cancer worsening was 5 months. The average overall survival was 24.7 months.

87% of patients experienced side effects. The most common side effects were increased liver enzymes, rash, diarrhea, fatigue, and nausea.

Patients with PD-L1-negative (absence of PD-L1 protein on cancer cells) were more likely to respond to the combination immunotherapy (38% vs 15%).

The results showed the combination of pembrolizumab and low-dose ipilimumab led to improved survival in patients with advanced melanoma that failed previous immunotherapy. 

The study was supported by Merck, the manufacturer of pembrolizumab. This study had a small number of participants and did not include a comparison group.