Citations

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.

Abstract Background Vedolizumab effectiveness estimates immediately after Food and Drug Administration (FDA) approval for ulcerative colitis (UC) and Crohn’s disease (CD) are limited by use in refractory populations. We aimed to compare treatment patterns and outcomes of vedolizumab in 2 time frames after FDA approval. Methods We used 2 data sets for time trend analysis, an academic multicenter vedolizumab consortium (VICTORY) and the Truven MarketScan database, and 2 time periods, May 2014–June 2015 (Era 1) and July 2015–June 2017 (Era 2). VICTORY cumulative 12-month clinical remission, corticosteroid-free remission, and mucosal healing rates, and Truven 12-month hospitalization and surgery rates, were compared between Eras 1 and 2 using time-to-event analyses. Results A total of 3661 vedolizumab-treated patients were included (n = 1087 VICTORY, n = 2574 Truven). In both cohorts, CD and UC patients treated during Era 2 were more likely to be biologic naïve. Compared with Era 1, Era 2 CD patients in the VICTORY consortium had higher rates of clinical remission (31% vs 40%, P = 0.03) and mucosal healing (42% vs 58%, P < 0.01). These trends were not observed for UC. In the Truven database, UC patients treated during Era 2 had lower rates of inflammatory bowel disease–related hospitalization (22.4% vs 9.6%, P < 0.001) and surgery (17.2% vs 9.4%, P = 0.008), which was not observed for CD. Conclusion Since FDA approval, remission and mucosal healing rates have increased for vedolizumab-treated CD patients, and vedolizumab-treated UC patients have had fewer hospitalizations and surgeries. This is likely due to differences between patient populations treated immediately after drug approval and those treated later.

AbstractObjectivesTo evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation.MethodsData were pooled from four NDMM phase I/II studies; patients received induction therapy with once‐ or twice‐weekly ixazomib plus lenalidomide‐dexamethasone (IRd), melphalan‐prednisone (IMP), or cyclophosphamide‐dexamethasone (ICd), followed by single‐agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity.ResultsA total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice‐weekly IRd, n = 18; weekly or twice‐weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug‐related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance.ConclusionsIxazomib maintenance following ixazomib‐based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long‐term administration. Phase III investigation of ixazomib maintenance is ongoing.

PURPOSE The Congress of Neurological Surgeons (CNS) has developed a series of guidelines for the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS Two CNS guidelines were reviewed for developmental rigor by methodologists, and an independent multidisciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The Expert Panel voted to endorse the two guidelines, and ASCO and Society for Neuro-Oncology (SNO) independently reviewed and approved the ASCO/SNO guideline endorsement. RESULTS The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. RECOMMENDATIONS Key recommendations include the following: prophylactic antiepileptic drugs were not recommended for routine use; and corticosteroids, specifically dexamethasone, were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases. Additional information is available at www.asco.org/neurooncology-guidelines .