Neoadjuvant immunotherapy improves clinical outcome in resectable melanoma

The findings of the PRADO extension cohort study suggest that neoadjuvant immune therapy results in high pathological responses in stage III melanoma patients. These findings were published in the reputed journal Nature Medicine.

Immune checkpoint inhibitors (ICI) have received approval as adjuvant therapies for high-risk melanomas. Interestingly, the neoadjuvant use of ICIs has recently gained much attention. This includes the PRADO extension cohort of the OpACIN-neo trial, which has evaluated the use of neoadjuvant ipilimumab and nivolumab (Ipi-Nivo) on pathological response as a criterion for deciding upon further course of treatment.

Phase II PRADO: neoadjuvant ipilimumab and nivolumab

The phase III PRADO study enrolled 99 patients with stage IIIb-d nodal melanoma and treated them with six weeks of neoadjuvant Ipi-Nivo. Based on the observed major pathological response (MPR) in the index lymph node (ILN, largest lymph node metastasis), patients with MPR ≤10% viable tumour did not undergo therapeutic lymph node dissection (TLND) nor adjuvant therapy. Patients with pathologic partial response (pPR; >10 to ≤50% viable tumour) underwent TLND but not adjuvant therapy. Finally, patients with pathologic non-response (pNR; >50% viable tumour) underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy.

Improved quality of life

The primary objective was to see if TLND can be skipped in patients achieving MPR and if risk-free survival can be improved in subgroup showing pNR. An MPR rate of 61% and a pathological response rate (pRR) of 72% were observed using neoadjuvant Ipi-Nivo. Further, grade 3-4 toxicity was observed in 22 patients. Based on the MPR, TLND was skipped in 59 (out of 60) patients resulting in reduced surgical morbidity and improved quality of life. Notably, the two-year relapse-free survival (RFS, 93%) and distant metastasis-free survival rates (DMFS, 98%) were very high in patients with MPR. For patients with pPR and pNR, the RFS and DMFS were 64%, 64% and 71%, 76%, respectively.

Conclusion

In conclusion, the findings of the PRADO trial strongly support the use of neoadjuvant immunotherapy for patients with stage III melanoma. 

Reference

1. Reijers ILM, Menzies AM, van Akkooi ACJ, et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nat Med 2022;28:1178-88.
2. Karakousis GC, Mitchell TC. Personalizing the approach to neoadjuvant therapy: a promising path to improving outcomes of resectable melanoma. Nat Rev Clin Oncol 2022;19:679-80.