Combination Immunotherapy Helps Heavily Pretreated Melanoma Patients

Best Practices in Immunotherapy – June/July 2017 Vol 8

A new study has shown that combination immunotherapy can yield significant clinical benefits—even in heavily pretreated populations.

According to data presented at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, administration of nivolumab plus ipilimumab produced promising results in patients with advanced melanoma previously treated with checkpoint blockade inhibitors. The overall response rate was 21%, and more than one-quarter of patients are still without treatment failure.

In addition, said Claire Friedman, MD, the combination therapy was well tolerated by patients. Only 16% of patients experienced grade 3 immune-related adverse events, compared with 50% of patients in the frontline setting.

“These results show that combination therapy can really help patients who are heavily pretreated,” said Dr Friedman, a physician-scientist at the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center. “The patient with the longest partial response had 7 prior lines of treatment. These are patients who you would not really expect to respond.”

As Dr Friedman reported, in treatment-naive patients with advanced melanoma, the combination of nivolumab plus ipilimumab is associated with an impressive 52% to 58% overall response rate, but toxicity can be an issue; according to recent data, there is a 53% incidence of high-grade immune-related adverse events.

Despite this success in treatment-naive patients, the efficacy and tolerability of the combination therapy in patients previously treated with checkpoint blockade inhibitors remains unknown.

Study Design

For this phase 1 study, 19 patients, previously treated with ipilimumab or anti–PD-1 as single agents, were treated with nivolumab plus ipilimumab from December 2015 to September 2016 at Memorial Sloan Kettering Cancer Center.

Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) were administered every 3 weeks for 4 doses, with the option to continue anti–PD-1 maintenance.

The primary end points were investigator-assessed overall response rate using RECIST v1.1, time to treatment failure, and overall survival. Dr Friedman and colleagues also collected and graded immune-related adverse events per CTCAE v4.0 and recorded the immunosuppressive drugs used to treat these events.

Nivolumab plus Ipilimumab Well Tolerated

As Dr Friedman reported, 16 patients (84%) had stage M1c disease, 2 patients (11%) had stage M1b, and 1 patient (5%) had stage IIIc. In addition, 63% of patients had cutaneous melanoma, 27% had an elevated lactate dehydrogenase level, and 26% and 21% had brain and liver metastases, respectively. The median number of prior systemic treatments was 2, with 7 being the highest.

The overall response rate was 21%—3 partial responses (16%) and 1 complete response (5%). In addition, said Dr Friedman, 5 patients (26%) treated with the combination are still without treatment failure at the time of the reporting.

“After treatment with the combination, many patients are on PD-1 maintenance therapy, and some continued on monotherapy,” Dr Friedman added.

Most remarkable about the results, however, was how well-tolerated the treatment was in this vulnerable population. Nearly half of patients (47%) received 4 cycles of nivolumab plus ipilimumab, while 5 patients (26%) stopped early for disease progression, and 4 patients (21%) stopped for toxicity.

Although 12 patients (63%) experienced an immune-related adverse event, only 3 patients (16%) had a grade 3 immune-related adverse event (rash, elevated ALT, and diarrhea). The most common grade 1/2 immune-related adverse events were diarrhea (11%), elevated ALT/AST (16%), thyroiditis/hypophysitis (21%), rash (26%), and pneumonitis (5%).

According to Dr Friedman, 6 patients (32%) required at least 1 course of steroids, and 2 patients (11%) required infliximab for steroid-refractory diarrhea.

“When compared to a 53% incidence of high-grade immune-related adverse events in treatment-naive patients, these are impressive results and suggest that combination therapy is very well tolerated,” said Dr Friedman, who hypothesized that these more advanced patients could have a less reactive immune system.

According to Dr Friedman, the investigators hope to determine whether there is a benefit to continuing PD-1 blockade with ipilimumab in combination for PD-1 refractory disease. The combination therapy is currently being evaluated in a prospective, multicenter, randomized phase 2 trial.

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Last modified: June 9, 2018

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