Discussion
tumor, melanoma, toxicity, inflammation, tumors, loss of whiskers/irritated skin, skin toxicities, alopecia, dermatitis
TUMOR, MELANOMA, INFLAMMATION, TUMORS, STAGE IV MELANOMA, SKIN CONDITION, SKIN TOXICITIES, TUMOR GROWTH, ALOPECIA, DERMATITIS, INFILTRATED, STAGE III MELANOMA
To our knowledge, DONIMI is the first neoadjuvant immunotherapy trial that used a biomarker to allocate therapy in melanoma by prospectively testing an IFN-γ signature gene expression score to allocate patients with stage III melanoma to different combinations of neoadjuvant ICB with domatinostat. The trial design was informed by results from our preclinical melanoma tumor model that showed enhanced tumor growth control, prolonged survival of mice and an increased IFN-γ response upon the combination of anti-PD-1 + anti-CTLA-4 with domatinostat. The DONIMI trial showed that the combination of neoadjuvant ICB with domatinostat was feasible and that the IFN-γ signature score in a baseline tumor biopsy was associated with pathologic response to neoadjuvant ICB. Patients with a high IFN-γ score had higher pathologic response rates (despite treatment de-escalation) compared to patients with a low score.This IFN-γ signature–driven approach was based on results from our previous neoadjuvant trials that showed that the baseline IFN-γ score was a predictive biomarker for pathologic response (While we have not fully excluded the possibility of mild subclinical dermatitis that might have been concealed by the fur, we did not observe any visible skin toxicities (such as signs of alopecia, loss of whiskers/irritated skin on face and limbs, excessive grooming, or bad skin condition) in our murine model upon treatment with domatinostat. In contrast to the results of our preclinical melanoma model and the SENSITIZE trial testing domatinostat + pembrolizumab in stage IV melanoma (Furthermore, the addition of domatinostat did not seem to increase the pathologic response rate of the neoadjuvant therapy for patients with a high IFN-γ score (80 versus 90% for nivolumab monotherapy) or with a low IFN-γ score (40–50 versus 49% seen in the historical data for ipilimumab + nivolumab; A major finding of DONIMI is that patients with a high IFN-γ score can achieve high pathologic response rates with nivolumab monotherapy, thus might not need treatment with ipilimumab + nivolumab or other combinations, e.g., nivolumab + relatimab (anti-LAG-3 antibody; Our data indicate that the concept of tumor immune inflammation by division into immune infiltrated, immune excluded, and immune desert tumors (Biomarker analyses from larger trials testing neoadjuvant anti-PD-1 monotherapy are needed to confirm the high pathologic response rates of the DONIMI patients with a high IFN-γ score. This could be assessed in the phase II SWOG S1801 trial (NCT03698019) that tested neoadjuvant plus adjuvant pembrolizumab compared to adjuvant pembrolizumab in resectable stage III–IV melanoma and recently demonstrated an EFS benefit of 23% at 2 yr for the neoadjuvant arm (One of the limitations of our murine study was that this was not conducted in a neoadjuvant setting, making direct comparisons of pathological responses between the murine model and the clinical trial challenging.The DONIMI trial was limited by its small sample sizes. Therefore, our trial can only be seen as hypothesis-generating. Moreover, DONIMI did not randomize patients to the combination of ipilimumab + nivolumab, which is currently the most widely investigated neoadjuvant treatment regimen. Thereby, it allows for only indirect comparisons to historical cohorts with regard to efficacy and the additive effect of domatinostat for patients with a low baseline IFN-γ score treated with combination ICB.Future clinical trials in stage III melanoma should focus on alternative (triple) treatment combinations for patients with an IFN-γ low→low score who are less likely to respond to ipilimumab + nivolumab. Combined nivolumab + relatlimab has shown promising efficacy with tolerable toxicity in advanced melanoma and as neoadjuvant therapy in stage III melanoma (