A multicenter Phase II clinical trial showed that combination immunotherapy drug therapy with ipilimumab (an anti-CTLA-4 drug) and nivolumab (an anti-PD-1 therapy) is an effective second-line therapy for patients with melanoma that has progressed on PD-1 inhibitors alone. It is the first randomized study showing that continuing PD-1 therapy beyond progression can be effective when combined with another appropriate drug.
To see if a combination approach is more effective than using CTLA-4 inhibitors alone as a second-line therapy, researchers in the multi-center clinical trial enrolled 91 patients who had already been treated with an anti-PD-1 immunotherapy drug and had not received an anti-CTLA-4 drug. All the patients enrolled had cancer that had not responded to the current therapy. Sixty-eight patients were randomly assigned to receive the combination of ipilimumab and nivolumab and 23 patients received just ipilimumab.
The team found the participants receiving combination therapy had a 37% improvement in progression-free survival compared to participants who received ipilimumab alone. Patients receiving the combination treatment also had higher response rates, with 28% of patients seeing their tumor shrinking compared to only 9% of those who received ipilimumab alone. The study results are published in Nature Medicine.
“The most important message from this study is that patients who have received single agent PD-1 therapy like nivolumab as first-line therapy and whose melanoma tumors did not respond, should absolutely receive the combination of ipilimumab plus nivolumab as second-line treatment,” explains first author Ari VanderWalde, MD, oncologist at the West Clinic in Tennessee. “This should be the new standard of care in those patients.”
Currently, patients with advanced metastatic melanoma are treated with PD-1 inhibitors as a first-line defense. While these checkpoint inhibitors have been a significant advancement, more than 50% of metastatic melanoma tumors are resistant to the drug. When resistance occurs, patients are often switched to CTLA-4 inhibitors.
Before this study, it was unclear whether patients whose cancers are resistant to the 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.
“It has been questioned whether continuing PD-1 therapy was worthwhile since it either did not work in the first place or stopped working,” says VanderWalde. But he says that the combination makes a lot of scientific sense.
He explains that when patients receive anti-PD1 therapy and their tumors do not respond, the thinking was that the T cells that PD-1 therapy effects were not present in the tumor. “And so if there are no white blood cells in the tumor to be able to be acted upon by PD-1 therapy, there is not going to be that checkpoint effect that’s going to allow the tumors to decrease and die,” VanderWalde says.
The addition of CTLA-4 antibodies takes those T cells that exist in the lymph nodes and helps move them into the tumors. “That makes them available to the PD-1 agents to actually have an effect,” he adds. If anti-CTLA-4 is given by itself without anti-PD-1 therapy, the T cells will go into the tumors, but they won’t really do anything when they get there. Likewise, if anti-PD-1 is given alone, like they were in the first line, they can’t do anything if the T cells are not in the tumors.
While this study was done in melanoma patients, theoretically this combination immunotherapy could be effective across all malignancies. “We believe that this study has implications for other cancers because it demonstrates an efficacy benefit with continued PD-1 or PD-L1 blockade therapy beyond progression compared to switching to a new agent altogether,” the authors write. “As such, this study serves as a proof of concept across tumor types and provides justification for investigators and drug developers to design studies in the second line or later that include continued PD-1 blockade therapy even when the patient may have already progressed on PD-1 blockade therapy in a previous line.
In clinical practice, the researchers hope to influence first-line metastatic melanoma therapy where combination immunotherapy therapy is widely practiced despite the lack of definitive evidence that it increases survival compared with single-agent PD-1 therapy. “The problem with combination therapy as evidenced both in the first-line studies as well as in our study is that it’s highly toxic,” says VandeWalde. “And so if we can use the combination therapy only in a rescue setting, such as here, we can get reserve the combination with anti-CTL4 only for those patients who do not respond to single-agent PD-1.”
