Neoadjuvant Ipilimumab plus Nivolumab Demonstrates Promising Overall Survival and Relapse-free Survival in Stage III Melanoma

Updated data of the OpACIN study testing combined ipilimumab plus nivolumab administered as neoadjuvant or adjuvant therapy in patients with high-risk stage III melanoma demonstrated high response rates upon neoadjuvant therapy and very promising long term clinical outcome, according to findings presented at the ESMO Immuno-Oncology Congress 2018 in Geneva, Switzerland.

Patients with high-risk stage III melanoma generally have a poor outcome, with less than 50% of patients surviving 5 years. Adjuvant ipilimumab has been shown to improve 5-year relapse-free survival (RFS) and overall survival (OS) rates, and RFS was improved even more with adjuvant anti-PD1 therapy, according to Elisa A. Rozeman, MD, Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands. In stage IV disease the combination of ipilimumab plus nivolumab has been demonstrated to induce higher response rates. Therefore, dr Rozeman and colleagues conducted the phase Ib OpACIN feasibility trial to test this combination in stage III melanoma. 

From August 2015 to October 2016, the trial enrolled 20 patients with high risk, stage IIIB/IIIC melanoma, with palpable nodal disease. Patients were randomised to receive ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg, either in 4 adjuvant courses, or to receive the same doses split into 2 neoadjuvant plus 2 adjuvant courses. Pathological response was defined as <50% viable tumour cells as reviewed by a blinded pathologist.

High 30-month relapse-free and overall survival rates were demonstrated with combination neoadjuvant therapy

After follow-up of median 31.6 months (minimum 23.5 months) none of the 7 patients achieving a pathologic response in the neoadjuvant arm have relapsed. The two patients in this arm who did not achieve a pathological response have relapsed. The estimated 30-month RFS rate was 80% in the neoadjuvant arm. The OS rate at 30 months was 90% with neoadjuvant treatment.

In the adjuvant arm, 4 patients have relapsed and the 30-month RFS rate was 60%. The 30-month OS rate with adjuvant treatment was 67%.

One patient in the neoadjuvant arm and 3 patients in the adjuvant arm died. At the time of the analysis, 16 patients were alive.

Ninety percent of patients developed one or more grade 3/4 adverse events; all of these patients recovered to ≤ grade 1, except for 8 (50%) patients with ongoing endocrine toxicities, which required hormonal supplementation therapy.

Conclusion

The OpACIN trial was the first trail initiated to investigate the combination of ipilimumab plus nivolumab as neoadjuvant treatment in patients with macroscopic stage III melanoma and, therefore, represents the longest follow-up of this regimen. None of the patients demonstrating pathologic response has relapsed, which suggested to the authors, that pathologic response could become a primary read-out for subsequent neoadjuvant immunotherapy trials, as well as a surrogate marker for RFS and OS.

Reference

LBA3 – Rozeman EA, Sikorska K, van de Wiel BA, et al. 30 months relapse-free survival, overall survival, and long-term toxicity update of (neo)adjuvant ipilimumab (ipi) + nivolumab (nivo) in macroscopic stage III melanoma (OPACIN trial).