Triple combination shows promise against advanced melanoma

Combining two types of drugs that, separately, have extended the lives of people with metastatic melanoma has yielded higher response rates in three early phase clinical trials reported in Nature Medicine, one led by MD Anderson Cancer Center investigators.

“These are the first clinical trials that combine targeted therapy and immunotherapy that are maturing, with promising durable results for patients so far,” says Patrick Hwu, M.D., head of the Division of Cancer Medicine, professor of Melanoma Medical Oncology and senior author of one of the papers.

Results among 39 evaluable patients, all with BRAFV600 mutations in their tumors, who received the immune checkpoint inhibitor atezolizumab, which blocks the PD-L1 ligand that activates the PD-1 off-switch on T cells, the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib include:

• Overall response rate of 71.8%
• Complete responses in 20.5%
• Ongoing responses in 39.3% after 29.9 months
• Median duration of response of 17.4 months
• Median progression-free survival of 12.9 months
• Median overall survival not reached, with one-year survival of 83% and two-year survival of 75%.

Hwu said the high response rate and durability at 29.9 months are promising results. “The key question is how durable these responses ultimately prove to be and how many patients are cured,” he says.

Strong two-year survival rate

The two-year overall survival rate of nearly 75 percent “is as good as any published data in unresectable stage III or stage IV melanoma and supports further study of this combination,” the study authors note.

The researchers also note the limits of a Phase Ib clinical trial with a small number of participants and lack of a control arm. A randomized, Phase III study is under way, Hwu says, comparing the triple therapy to a control arm of vemurafenib plus cobimetinib plus placebo.

About half of advanced-stage melanoma patients have the BRAF mutation in their tumors. The 71.8% response rate to the triple combination is similar to that of patients who receive vemurafenib and cobimetinib in the frontline setting.  The durability of the triple combination is comparable to the greater durability seen with anti PD-L1/PD-1 checkpoint blockade compared to that of the targeted therapy combination.

Research results led to combination trials

Research by Hwu’s lab, a group led by Jennifer Wargo, M.D., associate professor of Surgical Oncology at MD Anderson, and an Australian group found that treatment with BRAF inhibitors increased the penetration of immune T cells in tumors, providing a scientific basis for testing the combination.

Seventeen patients were treated with atezolizumab and vemurafenib in the initial cohorts of the study, in which the researchers found that it was better to treat first with vemurafenib and then add atezolizumab to reduce treatment toxicity.  After a Phase III study found vemurafenib plus cobimetinib was superior to vemurafenib alone, the investigators added cobimetinib to the trial.

All 39 patients in the triple combination cohort experienced at least one treatment-related side effect. The more serious grade 3-4 treatment emergent adverse events occurred in 26 patients (66.7%).

Overall, the investigators note that adverse events were managed with dose delays and reductions. Eleven events led to discontinuation of a study drug with eight of those involving elevated liver enzymes.

Three fatal adverse events were reported, caused by sepsis, respiratory distress and inflammation of the duodenum, none of which were considered related to treatment.

Nature Medicine also published two other studies that used a different combination of drugs against the same targets (PD-1 inhibitor pembrolizumab plus BRAF inhibitor dabrafenib and MEK inhibitor trametinib) that reported similar results.