Citations

Abstract Background: Preclinical and clinical data indicate a key role for the PI3-kinase (PI3K) pathway in the pathogenesis of resistance to endocrine therapies in hormone receptor-positive (HR) breast cancer (BC) and suggest that combining PI3K inhibitors with endocrine therapy may partially overcome this resistance. FERGI is the first randomized Phase II study testing pictilisib (GDC-0941), a PI3K inhibitor, in combination with fulvestrant to evaluate this hypothesis in MBC patients with and without PIK3CA-mutant tumors. Methods: 168 post-menopausal pts with ER-positive, HER2-negative MBC were randomized (1:1) to receive fulvestrant with either pictilisib 340 mg QD (n=89, "combination" arm) or matching placebo (n=79, "control" arm). To be eligible, pts had to have relapsed during or within 6 mos of completing adjuvant AI treatment or have progressed on an AI for MBC. Pts were stratified based on tumor PIK3CA mutation status, resistance to prior AI therapy and presence of measurable disease. The primary endpoint was PFS by investigator assessment in the intent-to-treat (ITT) group and in pts with centrally confirmed PIK3CA-mutant tumors. The primary analysis was based on a 6 mo median duration follow up. Results: Baseline disease and prior treatment characteristics were similar between study arms. Observed treatment-emergent AEs were consistent with those previously described for single agent pictilisib and fulvestrant (primary toxicities were rash and GI disorders). In the ITT population (84 events) the median PFS (mPFS) was 6.2 mo in the combination arm vs 3.8 months for the control arm (HR, 0.77; 95% CI, 0.50-1.19). For pts with PIK3CA-mutant tumors (37 events), mPFS was 6.2 mo in the combination arm vs 5.1 mo in the control arm (HR, 0.92; 95% CI, 0.48-1.76). For pts without a detectable PIK3CA mutant tumor (43 events), mPFS was 5.8 months in the combination arm vs 3.6 months in the control arm (HR, 0.64; 95% CI, 0.35-1.17). Exploratory post-hoc subgroup analysis suggested improvement in PFS in pts with ER+ and PR+ tumors (centrally confirmed) treated with pictilisib plus fulvestrant. In the ER+/PR+ subgroup (57 events) mPFS was 7.2 mo in the combination arm vs 3.7 mo in the control arm (HR, 0.46; 95% CI, 0.27 to 0.78). This improvement was independent of tumor PIK3CA mutation status. Multivariate analysis suggests that this treatment effect in pts with ER+/PR+ tumors is maintained after adjusting for possible baseline imbalances. A similar analysis on pts with luminal A tumors (per PAM50 analysis) was also consistent with the findings in pts ER+/PR+ disease. Conclusions: This is the first report of a blinded, randomized clinical study evaluating a PI3K inhibitor in pts with MBC. In the ITT population, the addition of pictilisib to fulvestrant was associated with a mPFS improvement of 3.8 mo to 6.2 mo. Exploratory subgroup analyses suggested in pts with ER+/PR+ tumors are more likely to derive benefit from the addition of pictilisib to fulvestrant irrespective of PIK3CA mutation status, though the subgroup analyses are limited by the sample size. Additional biomarker analyses will be reported. Citation Format: Ian Krop, Stephen Johnston, Ingrid A Mayer, Maura Dickler, Vinod Ganju, Andres Forero-Torres, Bohuslav Melichar, Serafin Morales, Richard de Boer, Steven Gendreau, Mika Derynck, Mark Lackner, Jill Spoerke, Ru-Fang Yeh, Gallia Levy, Vivian Ng, Carol O'Brien, Heidi Savage, Yuanyuan Xiao, Timothy Wilson, Soo Chin Lee, Katarina Petrakova, Susanne Vallentin, Denise Yardley, Matthew Ellis, Martine Piccart, Edith A Perez, Eric Winer, Peter Schmid. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-02.

Purpose We examined the utility of post-therapy surveillance imaging in a large, prospectively enrolled cohort of patients with diffuse large B-cell lymphoma (DLBCL) from the United States and confirmed our results in an independent cohort of patients from France. Methods Patients with newly diagnosed DLBCL and treated with anthracycline-based immunochemotherapy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence and the Léon Bérard Cancer Center, Lyon, France. In those with relapse, details at relapse and outcomes were abstracted from records. Results 680 individuals with DLBCL were identified from the MER, 552 (81%) of whom achieved remission after induction. 112 of the 552 patients (20%) suffered a relapse. The majority (64%) of relapses were identified before a scheduled follow-up visit. Surveillance imaging detected DLBCL relapse before clinical manifestations in nine out of 552 patients (1.6%) observed after therapy. In the Lyon cohort, imaging identified asymptomatic DLBCL relapse in four out of 222 patients (1.8%). There was no difference in survival after DLBCL relapse in patients detected at scheduled follow-up versus before scheduled follow-up in both the MER (P = .56) and Lyon cohorts (P = .25). Conclusion The majority of DLBCL relapses are detected outside of planned follow-up, with no difference in outcome in patients with DLBCL detected at a scheduled visit compared with patients with relapse detected outside of planned follow-up. These data do not support the use of routine surveillance imaging for follow-up of DLBCL.