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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 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.

Objectives: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved as maintenance treatment for patients (pts) with newly diagnosed advanced or recurrent ovarian cancer following a response to platinum-based chemotherapy (CT) doublet. The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study showed that niraparib following first-line treatment improved progression-free survival (PFS) in the overall intention-to-treat (ITT) population (hazard ratio [HR] 0.62; 95% CI 0.50-0.76). Methods: This double-blind, placebo (PBO)-controlled, phase 3 trial evaluated niraparib in pts with newly diagnosed, advanced, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response to first-line CT. Pts were considered to be at a high risk for disease progression based on their clinical characteristics. This post-hoc analysis presents the efficacy of niraparib, measured by PFS, based on time of surgery and residual disease status, and was not powered to determine differences among the subgroups. Results: Data cutoff was May 2019. In total, 733 pts were randomized in the PRIMA study. Efficacy outcomes by surgical timing, either primary debulking surgery (PDS) or interval debulking surgery (IDS), and postoperative residual disease status, either no visible residual disease (NVRD) or visible residual disease (VRD), are shown in Table. Pts who underwent PDS or IDS had similar efficacy with niraparib maintenance treatment versus PBO in the ITT population (PFS HRs were 0.67 and 0.57, respectively). Niraparib treatment reduced risk of progression by 42% in pts who received PDS and had VRD, 35% in those with IDS and NVRD, and 59% in those with IDS and VRD. Efficacy was not evaluable for pts with PDS and NVRD due to low sample size. Download : Download high-res image (142KB) Download : Download full-size image Conclusions: In this post-hoc analysis, the impact of residual disease after PDS or IDS on the efficacy of niraparib was comparable across subgroups. Pts with IDS and VRD had the highest reduction in the risk of progression

Objective AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS. Methods Of 940 AGO-OVAR 16 participants, 664 had BRCA1 / 2 exon sequencing data (pazopanib, n =335; placebo, n =329). A Cox model was used to test the association between genetic variants and PFS. Results Ninety-seven of 664 patients (15%) carried clinically important BRCA1 / 2 mutations ( BRCA1 / 2 carriers: pazopanib 14%, placebo 16%). Median PFS was longer in BRCA1 / 2 mutation carriers than in BRCA1 / 2 non-carriers in the placebo arm (30.3 vs 14.1months, hazard ratio, 0.48; 95% confidence interval [CI]: 0.29–0.78; P =0.0031); a similar non-significant trend was noted with pazopanib (30.2 vs 17.7months, hazard ratio, 0.64; 95% CI: 0.40–1.03; P =0.069). Among BRCA1 / 2 non-carriers, PFS was longer for pazopanib-treated patients than placebo-treated patients (17.7 vs 14.1months, hazard ratio, 0.77; 95% CI: 0.62–0.97; P =0.024). Among BRCA1 / 2 carriers, there was no significant PFS difference between treatments, although numbers were small (pazopanib, 46; placebo, 51), resulting in a wide CI (hazard ratio, 1.36; 95% CI: 0.66–2.82). Conclusions Patients with clinically important BRCA1 / 2 mutations had better prognosis. BRCA1 / 2 mutation status might be added as strata in future trials in primary ovarian cancer.

MafB oncoprotein detected by immunohistochemistry as a highly sensitive and specific marker for the prognostic unfavorable t(14;20) (q32;q12) in multiple myeloma patients

Aim: Weekly paclitaxel (60mg/m2) and carboplatin (AUC 2.7) (TCw) has been shown to be an effective treatment in patients with recurrent or advanced gynaecological cancer (Vandenput Int J Gyn Cancer 2012; Torfs Eur J Cancer 2012; Cadron Gynecol Oncol, 2013). The main toxicity of the regimen has been neutropenia grade (G) 3-4 and or neutropenic fever. Methods: In this prospective study 108 patients were needed to detect a 15% reduction in the occurrence of G3-4 neutropenia (a: 0.05; b: 0.95) compared with the historical incidence of 84%, by using prophylactic filgrastim on day 5 of each of the 18 weekly planned courses. The main inclusion criteria were: measurable disease, platin-resistant or refractory epithelial ovarian carcinoma (OC), or recurrent or advanced endometrial (EC) or cervical cancer (CC), and no prior weekly or dose-dense TC. Results: 108 (3 cohorts of ovarian, endometrial and cervical cancer of each 36 patients) were included by 12 BGOG centers between February 20, 2012 and March 14, 2013. The median number of prior chemotherapy lines was 3 for OC, 2 for EC and 1 for CC, respectively. The percentage of G3-4 neutropenia was 34% (CI: 26%-44%; p Conclusions: TCw with G-CSF support is feasible with an acceptable toxicity in patients with platin-resistant or –refractory OC, and advanced or recurrent EC or CC. The incidence of G3-4neutropenia is lower with the addition of weekly G-CSF compared with earlier studies without the addition of prophylactic G-CSF. Disclosure: All authors have declared no conflicts of interest.

In patients with non-colon digestive carcinomas, various schedules and doses of 5-fluorouracil (5-FU) and leucovorin combined with cisplatin (CDDP) have been used extensively. The present study explored the toxicity and activity of a weekly 24-h infusion of high dose 5-FU modulated by high dose leucovorin with bi-weekly CDDP. 59 patients with measurable disease were treated with a weekly infusion of high dose 5-FU (2 or 2.6 g/m2)+leucovorin 500 mg/m2 for 6 weeks and a bi-weekly dose of CDDP (50 mg/m2). All patients had metastatic or locoregionally advanced disease and had a performance status < or =3. All patients were evaluable for toxicity and 58 for response. Toxicity was different according to the schedule of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2.6 g/m2 with a high incidence of grade 3/4 neutropenia (16%) and febrile neutropenia (13%), and led to dose reductions in both CDDP and 5-FU in 13 patients (34%). For patients who started 5-FU at a dose of 2 g/m2, no reduction in 5-FU was required, and only 4 patients required a dose reduction of CDDP (19%). Grade 3/4 neutropenia was seen in 10% of patients of this group and only 1 patient required hospitalisation for febrile neutropenia. Other grade 3/4 toxicities were rare in both groups. Renal toxicity was infrequent and mild and did not require dose adjustments. The overall response rate was 33%; 19 patients achieved a partial responses (PR). No patient had a complete response (CR). The median duration of response was 5.7 months (range 2-24 months) and the median survival was 7.9 months ( range: 1-30, 95% confidence interval (CI): 7-9). The combination of weekly 24-h infusion of high dose 5-FU with leucovorin and bi-weekly cisplatin seems a well-tolerated and active treatment in non-colon digestive carcinomas. A dose of 2 g/m2 of 5-FU seems to be recommended.

3162 Background: 15 Belgian oncology centers are participating in an open-label Phase II trial of gefitinib (IRESSA) 500 mg/day in patients (pts) with advanced epidermal growth factor receptor-positive solid tumors who had failed ≥1 previous chemotherapy regimen and had no further chemotherapy treatment options. Here we report interim data. Methods: Pts received gefitinib 500 mg/day until disease progression. Objective tumor assessments, by RECIST, were made every 8 weeks and confirmed by repeat assessments ≥4 weeks later. Disease control rate (DCR) was defined as objective response (confirmed complete response or partial response [PR]) plus stable disease (SD) for ≥8 weeks. All adverse events (AEs) were reported and assessed by NCI-CTC version 2.0. Results: 193 pts have been enrolled with pancreatic cancer [21%], cervical cancer (CC) [19%], ovarian cancer (OC) [17%], sarcoma (S) [12%], cancer of unknown primary origin (U) [10%], hepatocellular carcinoma (HC) [9%], bladder cancer (BC) [7%], and endometria...