A randomized study of 6 versus 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse.

BACKGROUND: The administration of adjuvant imatinib during 3 years is indicated after resection of primary localized GIST at high risk of recurrence, but many patients relapse afterwards. METHODS: IMADGIST (NCT02260505) was a multicenter, open-label, randomized phase III study evaluating the maintenance of imatinib for 3 more years (6-year arm) compared with interruption (3-year arm) from the day of randomization, conducted in the French Sarcoma Group. The primary endpoint was intent-to-treat disease-free survival. Secondary endpoints included overall survival, time to imatinib resistance, response after imatinib reintroduction at relapse, and safety. RESULTS: From 24 December 2014 to 4 April 2023, 136 patients aged ≥18 years, Eastern Cooperative Oncology Group performance status ≤2, with a localized gastrointestinal stromal tumor with an R0 or R1 surgery, and a risk of tumor recurrence ≥35% according to National Comprehensive Cancer Network (NCCN) risk classification were randomized in 14 centers. Sixty-five patients were randomized to the 3-year arm versus 71 to the 6-year arm. There were 68 males and females. Primary sites were gastric and small bowel in 60 (44%) and 64 (47%) patients, respectively. Respectively, 52 (38%) and 71 (52%) patients had a risk of relapse of 35%-70% and >70%. With a median follow-up of 55 months (interquartile range 46-59 months) after randomization, disease-free survival was significantly superior in the 6-year arm [hazard ratio: 0.40 (0.20-0.69), P = 0.0008]. Time to imatinib resistance, survival, adverse events, and quality of life were not different in the two arms. CONCLUSIONS: Three additional years of adjuvant imatinib reduces the risk of relapse in patients who have received 3 years of adjuvant imatinib with an acceptable tolerance.

Genome-wide CRISPR/Cas9 library screening identified ATM signaling network genes as critical drivers for resistance to ATR inhibition in soft-tissue sarcomas: synthetic lethality and therapeutic implications.

Soft-tissue sarcoma (STS) are a heterogeneous group of rare tumors with different biological behavior that are fatal in more than 40% of cases, due to their metastatic evolution and inadequate treatment options. ATR inhibition already showed an activity, even if modest, in broad pre-clinical models of STS. By using genome-wide CRISPR/Cas9 library screening, we identified ATM signaling network genes as critical drivers for resistance to the specific ATR inhibitor AZD6738. The role of such genes in resistance to AZD6738 was confirmed by using CRISPR/Cas9 knockout models. More strikingly, the ATM inhibitor AZD0156 works synergistically with AZD6738 in vitro and abolishes STS growth in vivo in our models of most frequent histotypes (such as dedifferentiated liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma among others). Moreover, the combination of AZD6738 and AZD0156 induced significantly higher levels of DNA damage than either drug used as single agent alone. In summary, our results demonstrate that targeting ATM is an effective approach to overcome resistance to ATR inhibition in different STS subtypes, including the most frequent histologies.