High Response Rates Observed with Ipilimumab Plus Nivolumab in Advanced Melanoma

Christian Blank, MD, PhD

Combined ipilimumab and nivolumab administered pre- and post-surgery reduced the tumor burden in patients with Stage III B/C melanoma, according to first results from the OpACIN trial reported at the ESMO 2016 Annual Congress.

Tumor load was reduced after 6 weeks of ipilimumab plus nivolumab immunotherapy in 8 of 10 patients. Pathologic complete response (pCR) was achieved by 3 patients; and 5 patients showed minimal remaining micro metastases, including one partial response (PR) with remaining metastasis of 0.5 mm. One patient showed stable disease and 1 patient experienced progressive disease.

The objective response rate (ORR) was 78%. So far, none of the responding patients within the neoadjuvant arm has relapsed.

Christian Blank, MD, PhD, of the Netherlands Cancer Institute, and colleagues conducted this two-arm Phase 1b trial consisting of 18 high-risk stage III B/C melanoma patients who had palpable nodes. The mean age of the patients was 54 years old, and the median number of lymph nodes involved was 2 (range, 1-4) and 1 (range, 1-5) in the respective arms.

“The outcome of patients with high-risk stage III macroscopic/palpable melanoma is poor with 5-year survival rates of 20 to 59%,” according to Blank. “Adjuvant radiotherapy after lymph node dissection improves the local control but has no effect on relapse free survival or overall survival.”

The co-primary endpoints of the study were safety and feasibility, as measured by adverse events (AEs), adherence to timelines, and alteration in the magnitude or breadth of the neoantigen-specific T cell response between pre- to post-adjuvant therapy.

Secondary endpoints included relapse-free survival (RFS) per RECIST 1.1, rate and type of late AEs, and a correlation between RFS and the magnitude and breath of the T cell population.

“The amount of antigen that can provide the first signal to trigger T cell activation correlates with tumor load, which led us to postulate that immunotherapy will work most efficiently when it is initiated prior to surgery,” Blank explained.

All patients received ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg; however, patients were randomized to receive either adjuvant immunotherapy for 4 courses after surgery, or 2 courses each of split neo-adjuvant and adjuvant immunotherapy.

Blank discussed feasibility, safety, and initial efficacy findings from patients in the neo-adjuvant arm at ESMO. All 10 patients in the neo-adjuvant arm have undergone lymph-node dissection at the pre-planned week 6 timepoint.

No differences in surgery-associated AEs between adjuvant and neo-adjuvant immunotherapy were observed and no surgery-related AEs were attributed to the neoadjuvant immunotherapy.

Only 2 of 18 patients received all 4 courses of immunotherapy: 15 patients halted treatment due to toxicity grades 2 to 4 and one patient due to progressive disease after receiving 2 courses of adjuvant ipilimumab and nivolumab.

All patients experienced an immunotherapy-related AE and 16 patients had a grade 3/4 AE. The most commonly reported immunotherapy-related AEs greater than grade 3 were diarrhea in 4 patients, elevated lipase in 7 patients, and colitis in 6 patients. Four patients reported elevated ALT, 3 patients each experienced rash and vomiting, and headache, adrenal insufficiency, and fever each occurred in 2 patients. One case of hyperthyroidism was also reported.

At a median follow-up of 34 weeks, 7 of 8 patients had recovered from AEs and 12 patients had ongoing AEs; of these, 8 require hormonal supplementation. The remaining 4 patients had low-grade AEs of diarrhea, elevated lipase, or hyperglycemia.

“Neo-adjuvant ipilimumab plus nivolumab is feasible, results in on-time surgery, and induces and unexpected high frequency and depth of responses,” Blank said.

In discussing these results, Blank posed the questions of whether stage 3 melanoma may be more susceptible to immunotherapy, and whether late-stage melanoma may induce systemic immune suppression.

An OpACIN-NEO study is planned in collaboration with several melanoma institutes worldwide, Blank said.

Reference:

Blank C.U., Van Akkooi A, Rozeman E, et al., (Neo-)adjuvant ipilimumab + nivolumab (IPI + NIVO) in palpable stage 3 melanoma — initial data from the OpACIN trial. Presented at: 2016 ESMO Congress; October 7-11 2016; Copenhagen, Denmark. Abstract LBA39.