Neuwirth, Rachel

Abstract Background: TAK-228 is an investigational, oral and highly selective ATP-competitive inhibitor of TORC1/2. Targeting the PI3K/AKT/mTOR pathway with the dual TORC1/2 inhibitor TAK-228 may restore sensitivity to endocrine therapies in patients (pts) with breast cancer who have progressed on the combination of an endocrine agent plus a TORC1 inhibitor. Here we report data from the phase 2 portion of a phase 1b/2 study of TAK-228 plus exemestane (E) or fulvestrant (F). Methods: Postmenopausal women with ER+ and HER2-, inoperable or metastatic breast cancer (MBC) following everolimus (EVE) plus E or F after progression, received oral TAK-228 (4 mg QD) plus E (25 mg QD) or F (500 mg monthly) for 28-day cycles until progressive disease (PD) or unacceptable toxicity (NCT02049957). Pts were enrolled into parallel cohorts based on prior response to EVE plus E or F and were given the same prior therapy (E or F) at their established dose: EVE-sensitive, defined as disease progression after complete response (CR), partial response (PR), or ≥6 mos stable disease (SD); or EVE-resistant, defined as disease progression without a CR or PR, or after <6 mos SD. Primary endpoint was clinical benefit rate at 16 wks (CR, PR, or SD at 16 wks; CBR-16). Secondary endpoints included CBR at 24 wks (CBR-24), overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Results: From Oct 2015 to Dec 2017, 94 pts were enrolled. Median age was 58 y (range 32–83). At baseline, most pts (67%) had stage IV disease and others were stage IA–IIIC (24%), other (3%) or unknown (5%); 94% of EVE-sensitive (93% E vs 100% F) and 88% of EVE-resistant pts (91% E vs 75% F) had received ≥4 prior lines of therapy. Pts received a median of 3 cycles (1–15) of TAK-228. At data cutoff (24 Apr 2018), 98% of pts had discontinued treatment, mainly due to PD (76%) or adverse events (AEs; 14%). CBR-16 was 41% (n=21) in EVE-sensitive and 26% (n=11) in EVE-resistant pts (table). CBR-24 was 24% in EVE-sensitive (19% E vs 50% F) and 23% in EVE-resistant (23% E vs 25% F) pts. Eleven of 21 pts who achieved CBR-16 also achieved CBR-24 (6 SD, 5 PR) in the EVE-sensitive cohort and 8 of 11 pts in the EVE-resistant cohort (6 SD, 2 PR). The ORR was 12% in EVE-sensitive pts and 9% in EVE-resistant pts (table). Median PFS (95% CI) was 4.1 mos (2.2–5.5) and 3.4 mos (1.9–5.4), and median OS (95% CI) was 15.9 mos (14.1–19.5) and 14.0 mos (13.0–16.0) in the EVE-sensitive and -resistant cohorts, respectively. Drug-related any grade and grade ≥3 AEs were seen in 90% and 29% of pts, respectively. Most common drug-related any grade AEs were nausea (50%), fatigue (38%), hyperglycemia and diarrhea (each 29%); 22% of pts reported a serious AE. No deaths were reported. Treatment is ongoing in two pts. Conclusion: TAK-228 plus E or F showed modest clinical benefit in pts with previously treated, EVE-sensitive or -resistant MBC, with an acceptable safety profile. EVE-sensitive (N=51)EVE-resistant (N=43) TAK-228+TAK-228+Best response, n (%)E (n=43)F (n=8)E (n=35)F (n=8)ORR=CR+PR4 (9)2 (25)3 (9)1 (13)CR001 (3)0PR4 (9)2 (25)2 (6)1 (13)CBR-1617 (40)4 (50)9 (26)2 (25) Citation Format: Diamond JR, Potter D, Salkeni M, Silverman P, Haddad T, Forget F, Awada A, Canon J-L, Danso M, Lortholary A, Bourgeois H, Tan-Chiu E, Patel C, Neuwirth R, Leonard EJ, Lim B. Phase 2 safety and efficacy results of TAK-228 in combination with exemestane or fulvestrant in postmenopausal women with ER-positive/HER2-negative metastatic breast cancer previously treated with everolimus [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-09.

SummaryPeripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib‐induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1–4, 8–11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient‐level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules.