Stage III disease seems susceptible to immunotherapy, and these patients may be the perfect ones for this treatment.— Christian U. Blank, MD
As neoadjuvant or adjuvant therapy for stage III melanoma patients with palpable disease, the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) was shown to be a promising, though also toxic, combination in a phase Ib study reported at the 2016 European Society for Medical Oncology (ESMO) Congress by Christian U. Blank, MD, of The Netherlands Cancer Institute.1
Patients received either two courses of the combination before surgery and two after surgery or four courses after surgery. “(Neo)adjuvant therapy [ie, before and after surgery] with ipilimumab plus nivolumab is feasible, and surgery can be performed without delay. The combination induces an unexpectedly high frequency and depth of response,” Dr. Blank said.
The OpACIN trial enrolled 20 high-risk patients with stage IIIB/C melanoma and palpable lymph nodes. Patients received ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg, either as 4 courses after surgery (adjuvant arm) or as 2 courses prior to surgery and 2 after surgery ([neo]adjuvant arm). This subset of patients is at high risk for recurrence, with 5-year survival rates ranging from 20% to 59%, depending on the study, Dr. Blank said.
Other investigators have also been addressing the need to protect against recurrences in this subset. Also at the ESMO Congress, Eggermont et al presented the results of a larger study of adjuvant ipilimumab alone, showing an improvement in overall survival with a hazard ratio of 0.72 and resulting in an absolute overall survival benefit of 11% at 5 years.2 Currently, blockade of programmed cell death protein 1 (PD-1) with nivolumab or pembrolizumab (Keytruda) is being tested in phase III adjuvant trials. But it is possible that combinations of immunotherapeutic agents may be even more protective, as has been shown in stage IV melanoma, where the combination of ipilimumab plus nivolumab improves response rates and progression-free survival compared to ipilimumab alone and improves response rates over nivolumab alone.
“T-cell checkpoint inhibition is of greatest value at the moment of T-cell receptor triggering. As the amount of antigen that can provide that triggering correlates with tumor load, we postulated that adjuvant immunotherapy will work most efficiently when initiated prior to surgery,” Dr. Blank said.
Dr. Blank presented data on the feasibility and safety of the treatment in 18 patients, and the initial efficacy for the first 10 patients in the (neo)adjuvant arm only. The study’s primary endpoints were safety, feasibility, and alteration in magnitude or breadth of the neoantigen-specific T-cell response in the time interval pre- to post-adjuvant therapy in the peripheral blood.
Feasibility and Surgery-Related Adverse Events
All patients in the (neo)adjuvant arm were able to undergo lymph node dissection at the preplanned time point of week 6. No differences were observed in the rates of surgery-related adverse events between the adjuvant and (neo)adjuvant arms, and no surgery-related adverse events were attributed to the immunotherapy.
“However, only 2 of 18 patients received all 4 courses. Fifteen patients stopped due to grade 2 to 4 toxicity, and one stopped due to progressive disease after 2 courses of adjuvant ipilimumab/nivolumab,” Dr. Blank reported.
Treatment-related adverse events of any grade were observed in all 18 patients and were grade 3/4 in 16 of them. The most common toxicities were elevated liver enzymes, which were observed in 15 patients and were grade 3/4 in 4; diarrhea, observed in 11 patients and was grade 3/4 in 6 patients, respectively; and elevated lipase, observed in 10 patients and grade 3/4 in 7 patients, respectively.
At a median follow-up of 34 weeks, 6 of 18 patients have recovered fully from immune-related adverse events, and 12 are experiencing ongoing adverse events. Of these 12 patients, 8 require hormonal substitution and 4 have other ongoing immune-related adverse events, including low-grade diarrhea, elevated lipase, and hyperglycemia.
“Most patients managed to recover, but it took time, and it took several lines of immunosuppressive therapy to achieve recovery,” he commented.
Initial Efficacy in Neoadjuvant Arm
“Of 10 patients in the (neo)adjuvant arm, 8 (80%) had a profound reduction of tumor burden,” he reported.
This included 3 patients with pathologic complete responses, 4 with near-complete responses, and 1 who had metastatic disease but still had a 75% tumor reduction. Only 2 patients had no response; 1 had stable disease, and the other, disease progression at week 6. Interestingly, only the two patients not responding in the (neo)adjuvant arm have relapsed so far, whereas in the adjuvant arm, three patients have relapsed.
Dr. Blank concluded, “Grade 3/4 toxicity was more frequent than expected from stage IV melanoma study data. But in parallel, response rate and depth of response also may be higher than in stage II melanoma…. Stage III disease seems more susceptible to immunotherapy, and these patients may be the perfect ones for this treatment.”
Ipilimumab plus nivolumab as neoadjuvant treatment in stage III melanoma will be tested in the upcoming phase II OpACIN-neo trial, with the aim of preserving efficacy but reducing toxicity. The three-arm study will evaluate various doses and schedules of this combination as neoadjuvant therapy and will start at the end of this year in six melanoma centers (Netherlands Cancer Institute, Amsterdam; Royal Marsden NHS Foundation Trust, London; University of Vienna; Gustave Roussy, Paris; Karolinska Institute, Stockholm; and Melanoma Institute Australia, Sydney). ■
Disclosure: Dr. Blank reported serving in an advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, Lilly, and Pfizer.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Ipilimumab versus placebo after complete resection of stage III melanoma: Final overall survival results of the EORTC 18701 randomized double-blind, phase 3 trial. 2016 ESMO Congress. Abstract LBA2_PR. Presented October 8, 2016.
Celeste Lebbé, MD
Invited discussant Celeste Lebbé, MD, of the Hospital Saint Louis in Paris, noted that the study met its primary endpoints and produced “very impressive data”; however, “major toxicity” was a concern.
She said that in this small study of 18 patients (10 for efficacy),...!-->!-->