UCSF

Lessons learned

Fulvestrant is a selective estrogen receptor (ER)-downregulating antiestrogen that blocks ER transcriptional activity and is approved for ER-positive breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models.

Background

Fulvestrant is a selective estrogen receptor (ER)-downregulating antiestrogen that blocks ER transcriptional activity and is approved for ER-positive (+) breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models.

Methods

This is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses.

Results

Among nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) maximal concentration (C_max ) of 155 (122-171) ng/mL, time of maximal concentration (T_max ) of 1 (1-1.5) hour, terminal elimination half-life of 66.6 (57.3-102.6) hour after initial dose, and area under the curve (AUC) of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51 days (range, 47-137).

Conclusion

This drug combination has a favorable safety profile and antitumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing.