A phase II study of the cell cycle checkpoint kinases 1 and 2 (CHK1/2) inhibitor (LY2606368; prexasertib) in sporadic triple negative breast cancer (TNBC)

Background

CHK1/2 are major cell cycle regulators in tumors with p53 dysfunction, such as TNBC. Second-generation CHK1/2 inhibitor, prexasertib monomesylate monohydrate, showed preliminary single agent activity in advanced cancer pts. We hypothesize that prexasertib may yield clinical benefit in sporadic TNBC pts.

Methods

Eligible pts have recurrent TNBC with no deleterious germline BRCA mutation or no family history of hereditary breast and ovarian cancer syndrome; good end organ function and safely biopsiable disease. Prexasertib was administered at 105 mg/m² IV once every 14 days on a 28-day cycle. Response was assessed every 2 cycles by RECISTv1.1 and safety by CTCAEv4 per cycle. Primary endpoint is overall response rate (ORR). Optimal two- stage design was used; if ≥1 response is seen in the first 9 pts, then accrual continues to 24 pts per cohort.

Results

9 wild type BRCA TNBC pts have been treated in the first stage (median age 55.3 yrs [29-72 yrs] and median ECOG PS 1 [0-1]). The median number of prior therapies was 4 (2-10). 1 PR (3 mo) was observed (ORR 11%). 4 of 9 evaluable pts attained SD > 3 mo (median 4.5 mo [3-5]). Grade 3/4 AEs include neutropenia (89%), anemia (33%) and thrombocytopenia (22%). The median duration of grade 3/4 neutropenia was 5.5 (3-19) days. Grade 3/4 neutropenia resolved to less than grade 3/4 within 7 days in 5/9 pts. 1 pt required dose reduction to DL-1 (80 mg/m²) due to grade 4 neutropenia. 6 pts required GCSF support to avoid treatment delays. 3 pts received pRBC transfusion due to grade 2/3 anemia. 1 pt with grade 3 thrombocytopenia required platelet transfusion to avoid procedure-related bleeding.

Conclusions

Prexasertib monotherapy showed modest single agent activity in sporadic TNBC pts and continues to enroll in second stage. Tri-lineage marrow toxicity was observed. Prophylactic GCSF should be considered.

Clinical trial identification

NCT02203513

Legal entity responsible for the study

National Cancer Institute, NIH Rockville, MD USA

Funding

This work was funded by the Intramural Program of the Center for Cancer Research, NCI, National Institutes of Health, USA.

Disclosure

All authors have declared no conflicts of interest.