SAN ANTONIO – The combination of the checkpoint inhibitor ipilimumab with palliative doses of radiation therapy was not associated with any unexpected toxicities, and half of the patients with metastatic melanoma who were treated showed a promising clinical response in a phase II study.
The trial included 22 patients with stage IV disease aged a median of 62 years, of whom 11 (50%) responded to the immunotherapy.
ASTRO/Adam Donohue
Dr. Susan Hiniker
So far 3 (14%) of the 11 patients who responded have achieved a complete response (CR) at a median 55 weeks’ follow-up, and 3 (14%) had a partial response at a median 40 weeks’ follow-up, reported the lead study investigator, Dr. Susan Hiniker of Stanford University, during a press briefing at the annual meeting of the American Society for Radiation Oncology. The remaining five (23%) patients who responded had stable disease at a median 39 weeks’ follow-up.
The trial is one of the first prospective studies to report on the combined use of radiation with systemic immunotherapy in this patient population, she observed, noting that the idea behind the combination was that radiation might enhance the immunogenicity of tumors, that may then in turn make systemic immunotherapy more potent.
“Multiple trials have shown that there is still a minority of patients who respond to ipilimumab, with response rates of approximately 15%”, Dr. Hiniker said.
“As such, new methods of potentiating ipilimumab-induced responses are needed,” she added. “Local irradiation can modulate the local tumor environment such as to promote immune responses in a number of ways,” and other preliminary data have suggested that it may be able to increase overall response rates to ipilimumab.
Patients were recruited for the trial if they had stage IV melanoma and were aged between 18 and 65 years. Treatment consisted of palliative radiation delivered to one or two metastatic sites and at least one nonmetastatic site within 5 days of initial immunotherapy treatment with ipilimumab at a dose of 3 mg/kg every 3 weeks for a total of four treatment cycles. The dose and fractionation schedule was at the discretion of the treating physician.
Tumors were assessed for response using Response Evaluation Criteria in Solid Tumors (RECIST) and Immune Response Criteria (IRC) at baseline, 2-4 weeks after the last dose of ipilimumab was given, and then every 3 months thereafter until disease progression.
This being a phase II trial, the primary objective was to look at the safety of the approach; no additional or unexpected toxicities were seen.
“We saw approximately a 14% rate of grade 3-4 toxicity, which is really on par with what has been reported for ipilimumab monotherapy – on the order of 20%,” Dr. Hiniker said in an interview. “But that being said, we don’t believe that radiation itself caused any additional toxicity.”
One of the patients did have a perforated colon, she acknowledged, and for this reason future research may look at the combination of radiation therapy with the PD-1 (programmed T-cell death) inhibitors.
“I think right now everyone is so excited about the PD-1 inhibitors, and think that they’re safer,” Dr. Hiniker suggested. “It’s hard to give someone ipilimumab alone as the first line at this point; although many patients may not experience toxicity, [in] the ones that do, it can be severe.”
Dr. Hiniker also reported that IRC (independent review committee) analysis results suggested that several proinflammatory cytokines were elevated in some patients who responded to treatment. Higher levels of interleukin 2 at baseline, and at two time points during the study, for example, were associated with better response rates than lower levels. The findings also suggested that there might be a relationship between an increased number of elevated CD8-positive T cells and response.
“I think that we will find biomarkers, but we are not there yet, and it would need to be confirmed in a longer, larger study,” Dr. Hiniker said.
From a practical perspective, if a patient is already being treated with ipilimumab, and a physician is considering radiotherapy, then these results suggest that there will be no additional toxicity, she suggested.
“This combination approach does appear to be promising,” she said. “So for a subset of carefully selected patients – and the problem is we don’t totally know how to select them yet – this can be extremely promising.”
Dr. Hiniker had no disclosures to report.