Background: In the Phase III MONALEESA (ML) trials, ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + endocrine therapy (ET) significantly improved progression-free survival (PFS) vs placebo (PBO) + ET in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). Here we report key patient-reported outcomes (PROs) for pts treated with RIB-based regimens of interest (i.e. with a non-steroidal aromatase inhibitor [NSAI] or fulvestrant [FUL]) in the ML-2, -3, and -7 trials. Methods: Postmenopausal pts with HR+, HER2– ABC and no prior ET for advanced disease received RIB (600 mg/day; 3-weeks-on/1-week-off) + letrozole (2.5 mg/day; ML-2 [NCT01958021]), or FUL (500 mg every 28 days, with an additional dose on Day 15 of Cycle [C] 1; ML-3 [no prior ET for ABC subgroup only; NCT02422615]). Premenopausal pts with no prior ET and ≤1 line of chemotherapy for advanced disease received RIB + NSAI (anastrozole [1 mg/day]/letrozole [2.5 mg/day]) + goserelin (3.6 mg every 28 days; ML-7 [NCT02278120]). The primary endpoint for all trials was PFS. PROs were a secondary endpoint of all trials and were evaluated using EORTC QLQ-C30, QLQ-BR23 (ML-2 and ML-7), EQ-5D-5L, WPAI-GH (ML-7 only), and BPI-SF (ML-3 only) questionnaires. Changes from baseline and time to 10% deterioration (TTD) in health-related quality of life (HRQoL) were analyzed using linear mixed-effect and stratified Cox regression models, respectively. Results: A total of 1530 pts were included in this analysis. Questionnaire compliance was high across trials (ML-2/ML-3: >90%; ML-7: >80%). On-treatment HRQoL (EORTC QLQ-C30 global health status/quality of life [QoL] score) was maintained from baseline up to C34, C28, and C17 in both treatment arms for ML-2, ML-3, and ML-7, respectively. In ML-7, mean overall HRQoL scores continued to improve in the RIB arm from C18 to C28, but scores decreased in the PBO arm. At end of treatment, mean overall HRQoL scores decreased in both arms across trials. Median TTD (RIB vs PBO) was similar between arms, favoring the RIB arms (ML-2: 27.7 vs 27.6 months; hazard ratio 0.944; 95% confidence interval [CI] 0.720–1.237; ML-3: not reached [NR] vs 22.4 months; hazard ratio 0.721; 95% CI 0.484–1.074; ML-7: 24.0 vs 19.4 months; hazard ratio 0.759; 95% CI 0.561–1.028). Clinically meaningful reductions in EORTC QLQ-C30 pain score (>5 points from baseline) were observed in the RIB arm of ML-2 from as early as C3 and were sustained vs only at C7 and C13 in the PBO arm. Clinically meaningful reductions in pain were observed from C22 to C28 in the RIB arm of ML-7 vs only at C28 in the PBO arm. In ML-3, clinically meaningful reductions in pain were observed from C3 to C5, C11–17, and at C22 and C28 in the RIB arm vs C17–C25 in the PBO arm. Furthermore, median TTD of the BPI-SF pain severity index score was NR in either arm of ML-3 (hazard ratio 0.858; 95% CI 0.554–1.330). Conclusions: In addition to significantly prolonging PFS, RIB consistently maintains QoL regardless of ET combination partner. RIB + ET is also associated with clinically meaningful reductions in pain vs PBO + ET across a broad population of pts with HR+, HER2– ABC. Citation Format: Beck JT, Neven P, Esteva FJ, Bardia A, Harbeck N, Hurvitz S, O'Shaughnessy J, Verma S, Lanoue B, Alam J, Kong O, Chandiwana D, Chia S. Patient-reported outcomes with ribociclib-based therapy in hormone receptor-positive, HER2-negative advanced breast cancer: results from the phase III MONALEESA-2, -3, and -7 trials [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 P6-18-14.

Background: Selective estrogen receptor modulators and aromatase inhibitors (AI) (+LHRH agonists [premenopausal]) are standard of care (SOC) for hormone–receptor–positive (HR+) metastatic breast cancer (MBC). Many HR+ MBC patients (pts) get limited benefit from adjuvant or advanced endocrine therapy (ET) and develop endocrine resistance, refractory disease. HR+ BC growth relies on cyclin dependent kinases 4/6 that promote G1–S phase cell cycle progression. Palbociclib (PAL) with ET showed efficacy in HR+/HER2– MBC (Turner et al, 2015). We report updated safety and efficacy from PALOMA3 with longer follow–up, focusing on degrees of clinically defined endocrine resistance. Methods: Pts with HR+/HER2– MBC that progressed on prior ET were randomized 2:1 to PAL (125 mg/d oral [3 wks drug, 1 wk off]) + fulvestrant (F, 500 mg, SOC) +/– goserelin or placebo (PLB)+F. One line of chemotherapy (CT) for MBC was allowed. Pt stratification: prior ET sensitivity; visceral metastases; menopausal status. Primary endpoint (EP) was investigator–assessed progression–free survival (PFS). Secondary EP: overall survival, response assessment, patient–reported outcomes, safety. Results: By March 2015, median follow–up was 8.9 mo. 521 pts were randomized (PAL+F, 347; PLB+F, 174). Baseline characteristics were balanced. Median PFS was 9.5 (95% CI 9.2–11.0) mo (PAL+F) vs 4.6 (3.5–5.6) mo (PLB+F) (HR 0.46 [0.36–0.59], P<0.001). Overall response (CR+ PR) was significantly improved with PAL+F (ITT: 19% vs 8.6%, P=0.001; pts with measurable disease: 24.6% vs 10.9%, P<0.001). Clinical benefit (CBR=CR+PR+SD ?24wks) was 66.6% vs 39.7% (P<0.001). Benefit from PAL was confirmed in pre– and postmenopausal pts with PFS in premenopausal 9.5 vs 5.6 mo (HR=0.50 [0.29–0.87], P=0.006) and in postmenopausal 9.9 vs 3.9 mo (HR=0.45 [0.34–0.59], P<0.001). Common adverse events (AEs) for PAL+F vs PLB+F were neutropenia (80.9 vs 3.5%), leukopenia (49.6 vs 4.1%), and fatigue (39.1 vs 28.5%); febrile neutropenia occurred in 0.9% (P+ F) vs 0.6% pts (PLB+F). Discontinuation due to AEs was 4.0% on P vs 1.7% on PLB. The benefit of PAL+F vs PLB+F was compared in pts with various degrees of endocrine resistance: a) progression ≤12 mo of adjuvant ET completion, PFS 9.5 vs 5.4 mo (HR 0.55 [0.32–0.92], P=0.01); b) failed 1 line of ET, 10.2 vs 5.4 mo (HR 0.42 [0.29–0.59], P<0.001); c) failed 2 lines of ET, 9.9 vs 1.8 mo (HR=0.20 [0.10– 0.39, P<0.001); d) proven endocrine sensitive, 10.2 vs 4.2 mo (HR 0.42 [0.32–0.56], P<0.001); e) proven no prior endocrine sensitivity, 7.5 vs 5.4 mo (HR 0.64 [0.39–1.07], P=0.04) f) AI most recent therapy, 9.5 vs 3.7 mo (HR 0.42 [0.31–0.56], P<0.001). Conclusion: Mature efficacy confirmed superior PFS and demonstrated significantly improved clinical response and CBR by the combination of ET and Palbociclib. It also consistently showed therapeutic benefit irrespective of menopausal status and various degrees of endocrine sensitivity. Safety profile is favorable. PAL+F may be an effective option for HR+ MBC pts. Funding: Pfizer. Citation Format: Cristofanilli M, Bondarenko I, Ro J, Im S-A, Masuda N, Colleoni M, DeMichele AM, Loi S, Verma S, Iwata H, Huang Bartlett C, Zhang K, Puyana Theall K, Turner NC, Slamon DJ. PALOMA3: Phase 3 trial of fulvestrant with or without palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy—confirmed efficacy and safety. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-01.

Background Systemic fluoropyrimidines, both oral and intravenous, are an integral part of colorectal cancer (CRC) management. They can be administered either with curative or palliative intent. Objectives This article examines the literature to analyze the efficacy and safety of the oral fixed-dose combination of uracil and tegafur (UFT)/leucovorin (LV) compared with other fluoropyrimidine agents, with an intention to implement the findings into the current treatment algorithms for CRC. Methods An exhaustive systematic literature search was performed for prospective studies using PUBMED, Cochrane Library, and EMBASE database. Studies which met eligibility criteria were shortlisted and grouped into chemotherapy given for curative or palliative intent. Results Eight trials were shortlisted involving 4,486 patients for the analysis. There was no difference between UFT/LV and other fluoropyrimidines in the primary endpoints—disease-free survival (hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.90–.15; p = 0.81) and progression-free survival (HR 0.87; 95% CI 0.66–.66; p = 0.35) for curative and palliative intent CRC patients, respectively. In secondary analyses, there was no significant difference observed between UFT and other fluoropyrimidines in overall survival in CRC patients with curative intent (HR 1.04; 95% CI 0.88–1.23; p = 0.63) and palliative intent (HR 1.02; 95% CI 0.97–1.06; p = 0.42) . In the safety analysis, we found significantly lesser patients on UFT/LV had stomatitis/mucositis (odds ratio [OR] 0.20; 95% CI 0.05–0.85; p = 0.03), fever (OR 0.46; 95% CI 0.29–0.71; p < 0.001), infection (OR 0.42; 95% CI 0.24–0.74; p < 0.01), leukopenia (OR 0.04; 95% CI 0.00–0.95; p = 0.05), febrile neutropenia (OR 0.03; 95% CI 0.00–0.24; p = 0.001), and thrombocytopenia (OR 0.14; 95% CI 0.02–0.79; p = 0.03) compared with other fluoropyrimidines. Conclusion Oral UFT/LV is equally efficacious to other fluoropyrimidines, especially intravenous 5-fluorouracil, in the management of early as well as advanced CRC patients. Importantly, UFT/LV has a superior safety profile compared with other fluoropyrimidines in terms of both hematological and nonhematological adverse events.

Background: At least 40% of breast cancers are diagnosed in women ≥65 y old and most are hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-). Palbociclib (PAL) is an oral, small-molecule inhibitor of cyclin-dependent kinases 4 and 6. Randomized studies of PAL combined with endocrine therapy (ET) demonstrated significantly improved progression-free survival (PFS) in patients (pts) with treatment-naive and previously treated advanced breast cancer (ABC). Methods: We evaluated the efficacy of PAL+ET vs ET alone in pts aged ≥65-74 and ≥75 y across multiple pivotal randomized phase 2 and 3 studies. Safety and pharmacokinetics (PK) data (blood samples collected from pts in phase 1/2 [PALOMA-1] and phase 1 studies [NCT00141297 and NCT00420056]) for PAL+ET were pooled and compared across age groups. Pts who had not received treatment for ABC were randomized to receive PAL+letrozole (LET) or LET alone/with placebo (PBO; PALOMA-1, open-label/PALOMA-2, double-blind). Pts who had progressed on prior ET were randomized to receive PAL+fulvestrant (FUL) or PBO+FUL (PALOMA-3, double-blind). The primary endpoint for these studies was investigator-assessed PFS. Safety assessments and blood counts occurred at baseline and every 2 weeks for the first 2 cycles and on day 1 of subsequent cycles. Results: Among 872 pts treated with PAL+ET, 221 (25%) were aged ≥65-74 y and 83 (10%) were ≥75 y (PAL+LET: n=528, 162 and 56, respectively; PAL+FUL: n=347, 59 and 27). Median (range) treatment durations were 440 (1-1615) d, 502 (1-1615) d, and 459 (21-1404) d, respectively. Improvement in efficacy endpoints was seen with PAL+ET vs ET across all age groups (Table 1). Incidence of adverse events (AEs), serious AEs and discontinuations due to AEs were similar in the overall population (99%, 19%, 3%) and in pts aged ≥65-74 (99%, 25%, 5%) and ≥75 y (100%, 30%, 6%). Incidence of all grades and grade 3/4 neutropenia were also similar across age groups (overall: 67% and 54%; ≥65-74 y: 64% and 51%; ≥75 y: 77% and 60%). PK analysis showed no clinically relevant differences between arithmetic means, medians, and geometric means of the apparent oral clearance across age groups. Conclusions: PAL in combination with ET is an effective and well-tolerated treatment option for elderly pts with HR+/HER2- endocrine-sensitive and -resistant ABC. A dose adjustment based on age is not required. Sponsor: Pfizer Table 1. PFS in pts ?65-74 and ?75 y (ITT populations)OverallAged ≥65-74 yAged ≥75 yPALOMA-1/PALOMA-2PAL+LET vs528 vs 303162 vs 9456 vs 26LET/LET+PBO,* nHR (95% CI);0.53 (0.44-0.64);0.66 (0.45-0.97);0.31 (0.16-0.61);1-sided P value&lt;0.00010.01620.0002Median PFS (95% CI), mo24.4 (22.0-26.2) vs27.5 (24.2-NR) vsNR (19.2-NR) vs13.6 (11.1-16.4)21.8 (16.3-31.3)10.9 (4.9-24.9)PALOMA-3PAL+FUL vs347 vs 17459 vs 3727 vs 6FUL+PBO, nHR (95% CI);0.46 (0.36-0.59);0.25 (0.14-0.45);0.87 (0.27-2.79);1-sided P value&lt;0.0001&lt;0.00010.4074Median PFS (95% CI), mo9.5 (9.2-11.0) vs16.1 (12.0-NR) vs13.6 (7.5-NR) vs4.6 (3.5-5.6)3.7 (1.9-5.3)7.4 (1.9-NR)HR=hazard ratio; ITT=intent to treat; NR=not reached. *Does not include 5 pts from phase 1 of PALOMA-1. Citation Format: Rugo HS, Turner NC, Finn RS, Joy AA, Verma S, Harbeck N, Moulder S, Masuda N, Im Y-H, Zhang K, Kim S, Sun W, Schnell P, Huang-Bartlett C, Slamon D. Palbociclib in combination with endocrine therapy in treatment-naive and previously treated elderly women with HR+, HER2– advanced breast cancer: a pooled analysis from randomized phase 2 and 3 studies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-03.