Neoadjuvant Immune Checkpoint Blockade in Melanoma

Additional studies needed to optimise treatment regimens and validate biomarkers

Two letters published on 8 October 2018 in the Nature Medicine describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimise treatment regimens and to validate putative biomarkers. 

In first letter, corresponding authors Christian U. Blank and Ton N. Schumacher of the Netherlands Cancer Institute, Amsterdam, The Netherlands and collaborators wrote that preclinical studies suggest that neoadjuvant checkpoint inhibitors may be superior to adjuvant therapy. To address that question and test feasibility, they randomised 20 patients with palpable stage III melanoma to receive ipilimumab and nivolumab, as either four courses after surgery or two courses before surgery and two courses postsurgery. 

They found that neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However, in both arms, 9 of 10 patients experienced one or more grade 3/4 adverse events. 

Pathological responses were achieved in 7 of 9 (78%) patients treated in the neoadjuvant arm. Median follow-up is 25.6 months and none of these patients have relapsed so far. 

The study team found that neoadjuvant ipilimumab plus nivolumab expand more tumour-resident T cell clones than adjuvant therapy. 

The authors concluded that the current regimen induced high toxicity rates and further investigation is needed to preserve efficacy but reduce toxicity. 

In second letter, Jennifer A. Wargo of the MD Anderson Cancer Center, Houston, TX, USA and collaborators reported results from a randomised phase II study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma. 

They assessed overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response. 

Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). 

Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. 

References

Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nature Medicine; Published online 8 October 2018. doi: 10.1038/s41591-018-0198-0. 

Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nature Medicine; Published online 8 October 2018. doi: 10.1038/s41591-018-0197-1.