Concurrent checkpoint inhibitor therapy, radiation feasible in advanced melanoma

In patients with regionally advanced melanoma, concurrent administration of ipilimumab and radiation therapy (RT) is safe and beneficial, producing high response rates and converting unresectable disease to operable, as shown in a study.

“In the adjuvant cohort, the 6- and 12-month relapse free survival (RFS) was 85 percent and 69 percent, respectively, which is similar to other adjuvant studies using ipilimumab,” according to the researchers. [New Engl J Med 2016;375:1845-1855]

“Additionally, the combination of ipilimumab and RT appeared to be active in patients with unresectable/locally advanced disease, with an overall response rate (ORR) of 64 percent and a disease control rate (DCR) of 73 percent, higher than historic response rates for ipilimumab alone, with all patients alive at 2 years,” they added. [New Engl J Med 2010;363:711-723]

The analysis included 24 patients who received ipilimumab at 3 mg/kg every 3 weeks for four doses in conjunction with RT (median dose, 4,000 cGy). Treatment was given in an adjuvant setting for patients in cohort 1 (n=13; median age, 63.6 years) and was based on either neoadjuvant or definitive approach for patients in cohort 2 (n=11; median age, 56.2 years).

Concurrent administration of treatments was safe, with adverse event (AE) profiles in line with those established for checkpoint inhibition and RT. Only 15 percent of patients in cohort 1 and 18 percent in cohort 2 experienced a grade 3 treatment-related AE; no grade 4 or 5 events were reported. The most common AE was fatigue, followed by pruritis and rash. Grade 1 or 2 radiation dermatitis occurred in 46 percent and 73 percent of patients in cohorts 1 and 2, respectively. Diarrhoea was the most common gastrointestinal AE, and all cases were grade 1. [Clin Cancer Res 2021;doi:10.1158/1078-0432.CCR-20-2452]

Ten relapses or progressions occurred over a median follow up of 25.8 months in cohort 1 and 25.3 months in cohort 2.

In the neoadjuvant/definitive cohort, four out of 10 evaluable patients achieved a radiographic complete response (CR). Another three had a partial response and went on to surgical resection.

With 2 years of follow-up, the 24-month RFS in the adjuvant cohort was 62 percent. All patients in the neoadjuvant/definitive cohort and 10/13 patients in the adjuvant cohort were still alive.

Finally, there were differences in peripheral blood mononuclear cells (PBMCs), with responders more likely to carry PD-1+HLA-DR- CD4+ T cells.

From unresectable to surgery-eligible

“One of the most important findings from our study was the promising signal that in unresectable patients, the combination of ipilimumab and RT was associated with favourable disease control and survival,” the investigators pointed out. “Not only were high local response rates seen with RT, but also no patient in this study recurred within the radiation field.”

The use of systemic therapies in melanoma has continued to evolve since the initiation of the current study. Ipilimumab, which was considered standard first-line therapy at trial commencement, was subsequently replaced by anti-PD-1 owing to better efficacy and tolerability. [Lancet 2017;390:1853-1862]

In line with this, the sequencing of systemic therapies as part of the management of regionally advanced melanoma has begun to shift, according to the investigators. Systemic therapies have taken a more prominent role in the initial management of stage III disease.

“The concept of a neoadjuvant approach, long considered standard of care in many other malignancies, is emerging as a promising strategy in the management of high risk, but potentially resectable, patients with regionally advanced melanoma,” they said.

“While our study focused on a patient population with unresectable disease, the integration of local therapy with modified doses of newer systemic agents could be applicable in the neoadjuvant setting where the risks of systemic therapies should be carefully considered,” they added.