Discussion
NSCLC, neutropenia, CRC, RAD51C, RAD54L), cardiac toxicity, toxicities, Treatment-related haematological toxicity, tumour, HGSOC
NEUTROPENIA, DNA DAMAGE, DISEASE, TUMOUR, NSCLC
Multiple Chk inhibitors have been evaluated in Phase 1/2 trials. The development of an early intravenously administered Chk1 inhibitor AZD7762 was halted due to concerns about cardiac toxicity including a drop in ejection fraction [Haematological toxicities have been limiting for most Chk1 inhibitors when evaluated as single agents or in combination with standard dose gemcitabine. Treatment-related haematological toxicity such as neutropenia of NCI CTCAE Grade 3 or higher occurred in 60% of patients with GDC-0575 in combination with standard dose gemcitabine [This study was designed to enrich expansion cohorts with mutations that could theoretically sensitize cells to Chk1 inhibitors but did not result in identifying subpopulations of patients whose disease responded sufficiently to SRA737. Some reductions in tumour size (up to 29% reduction) were seen, however, there were no partial or complete RECIST responses observed in the study and therefore rigorous evaluation of associations between tumour response and genetic alterations was not possible. Interestingly, in the group of 29 patients with evidence of antitumour effect via a reduction or no increase in sum of RECIST target tumour diameters and/or stable disease for 4 or more cycles, a number of potential associations with genetic alterations were noted. For example, alterations in the oncogenic driver genes FBXW7 (a negative regulator of cyclin E, encoded by CCNE1) and CCNE1 were observed in 6 patients across multiple tumour types (CRC, HGSOC, NSCLC). PIK3CA, another frequently modified oncogenic driver gene, was observed in four patients. Similarly, alterations in DNA damage response genes such as ATM, CDK12, and those of the RAD family (RAD51C, RAD54L) were observed across multiple tumour types. Of note, a previously tested Chk inhibitor, GDC-0575, did not report partial or complete responses when used as a single agent [In the combination study [