Discussion
NEC, tumours, NENs, tumour, NECs
TUMOURS, CARCINOIDS, DISEASE, TUMOUR, CPS
Treatment with durvalumab plus tremelimumab showed modest antitumor activity in this large cohort (The long-term clinical benefit rate was chosen as the primary endpoint to include long-term stabilisation of the disease as a therapeutic success. The overall CBR (56.1% by RECIST 1.1) was not significantly better than that previously reported with a single ICI with pembrolizumab (59.8%) or spartalizumab (63.2%)DoR achieved by immunotherapy in our trial and in previous reports involving low-grade NENs was shorter than that recently reported with targeted therapies such as lenvatinib, with a median DoR of 21.5 months (range: 8.4–38.3)The median overall PFS was 5.3 months, which is in the range of that reported with single-agent pembrolizumab after progression to standard therapies (median 4.1 months; 95% CI: 3.5–5.4)Two trials in patients with low-grade NENs with single-agent pembrolizumab reported a median OS between 21 and 24 months, which was in the range of the OS among patients with low-grade NENs in our study, suggesting a small benefit with the addition of CTLA-4 blockadeThe differences observed in the efficacy and activity of immunotherapy between low- and high-grade NENs across trials may rely on the higher PD-L1 expression, TMB, and enhanced neoantigen presentation, which has been positively correlated to tumour gradeRegarding safety, our findings are consistent with those of previous reportsThe main limitation of the DUNE trial was the lack of randomisation and a parallel control group comparing single ICI or alternative treatment options. There is limited information on prognosis and survival in such a heavily pre-treated population of NENs, which may have led to an overestimation of the expected primary endpoints. Despite the overall sample size being relevant, the sample size for each cohort limited the exploratory research of potential prognostic factors in the stratified analysis. The small sample size also limited the comparison between G3 NET vs NEC histology, which are tumours with very different behaviour. However, a centralised review by an experienced pathologist showed that long-term survivors included both NECs and NETs. The lack of a centralised review for the tumour assessment was another caveat. In contrast, histological differentiation and PD-L1 CPS were centrally reviewed, and differences in ORR attributable to the use of RECIST 1.1 or irRECIST criteria were excluded.In summary, our findings support a potential modest use of dual ICI in high-grade NENs and atypical lung carcinoids. Further research with ICI in this setting may focus on long-term survival endpoints, and potentially shifting to a first-line setting in combination with chemotherapy. Prognostic and predictive biomarkers need to be further characterised in patients treated with ICI.