Milea Timbergen

10 spontaneous regression is observed in up to 20% of patients 21 . Especially for DTF tumours located in the chest wall, head, neck and upper limb, this active surveillance approach is beneficial since these “unfavourable locations” are generally considered challenging to treat, yielding severe morbidity 22 . Forms of ‘active treatment’ like surgery, radiotherapy and systemic therapy, are indicated in case of a symptomatic and/or progressive DTF tumour 19 . Surgery is first in line in case of failure of the active surveillance approach 22, 23 . Radiotherapy as a single treatment modality has not shown any improvement of the risk of progression compared to surgery with adjuvant radiotherapy 24, 25 . It can decrease symptoms and cause disease stabilization or even a partial or a complete response in patients with inoperable DTF 26 . Adjuvant radiotherapy is only given in cases with a high chance of recurrence, which would be difficult to treat due to the unfavourable tumour location. Several systemic treatment options are available to treat symptomatic and progressive DTF, for which surgery and/or radiotherapy is not a suitable option. Systemic options include non- steroidal anti-inflammatory drugs (NSAID’s) alone or in combination with anti-hormonal agents such as tamoxifen 27-29 , low dose chemotherapy such as a doxorubicin 30, 31 , or a combination of methotrexate low dose with either vinblastine or vinorelbine 32-36 , gamma- secretase inhibitors such as Nirogacestat 37 , and tyrosine kinase inhibitors such as imatinib 38-40 , sorafenib 41, 42 , pazopanib 43, 44 , or nilotinib 19 . There is no consensus about the sequence of systemic treatments and the exact working mechanisms of these systemic agents in DTF remains unclear. Randomized data is currently only available for tyrosin kinase inhibitors (sorafenib vs. placebo (phase 3) 42 and pazopanib vs. methotrexate-vinblastin (phase 2) 43 and gamma-secretase inhibitors (Nirogacestat vs. placebo) 45 . The first trial reported an advantage for sorafenib in the 2-year progression-free survival (PFS) over placebo (81% (95% confidence interval [CI], 69-96) versus 36% (95% CI, 22-57). The second trial reported an advantage for pazopanib over methotrexate-vinblastin in progression-free proportion of patients measured at 6 months (83.7% (95% CI 69.3–93.2) vs 45% (95% CI 23.1–68.5). Gamma-secretase inhibitors, such as Nirogacestat, form an attractive therapeutic option as they inhibit the final step in the Notch signalling pathway, a pathway which is also known for its cross talk with the Wnt signalling pathway 46 . Clinical phase 1 and 2 trials of the gamma- secretase inhibitor PF-03084014 (later named Nirogacestat) showed promising results in which a substantial part of patients experienced partial response or disease stabilisation 47, 48 . These results led to a phase 3 trials of which the inclusion is already closed and the results 1