Our early experience has demonstrated that measuring anti-TNF drug and anti-drug antibody levels can be useful in the optimisation of IBD management. In an increasing number of patients, particularly those with evidence of loss of response, it allows early decisions to be made regarding changing therapy. It also offers the potential for significant cost-saving by preventing pointless dose escalation in the context of therapeutic levels or when high-level anti-drug antibodies are present.

Background Abemaciclib is a selective CDK4 & 6 inhibitor approved on a continuous dosing schedule for HR+, HER2- advanced breast cancer (ABC) as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET). A previous Phase 1b (NCT01394016) cohort of HR+ ABC patients (pts) demonstrated efficacy of abemaciclib monotherapy (150mg and 200mg Q12H starting dose); given the small sample size and nonrandomized design the impact of the starting dose was unclear. nextMONARCH 1 (NCT02747004) evaluated abemaciclib in 2 monotherapy arms, in a randomized setting. Abemaciclib has been associated with dose-dependent early onset diarrhea that is well managed with antidiarrheal therapy. nextMONARCH 1 also explored the 200mg Q12H abemaciclib dose in combination with prophylactic loperamide to reduce incidence/severity of diarrhea and dose adjustments. A third arm evaluated abemaciclib + tamoxifen as a strategy to overcome endocrine resistance. Methods nextMONARCH 1 is a multicenter, randomized, open-label, Phase 2 study of abemaciclib or abemaciclib + tamoxifen in women with HR+, HER2- ABC who have progressed on or after prior ET and previously received chemotherapy. Pts were stratified by presence of liver metastases and prior use of tamoxifen in the advanced setting. Randomization was 1:1:1 to abemaciclib 150mg Q12H + daily tamoxifen 20mg (Arm A) or abemaciclib 150mg Q12H (Arm B); or abemaciclib 200mg Q12H + prophylactic loperamide (Arm C). Key eligibilities were ≥2 chemotherapy regimens (1-2 administered in metastatic setting), measurable disease and no prior treatment with CDK4 & 6 inhibitors. Primary objective was progression free survival (PFS). Key secondary objectives included objective response rate (ORR), dclinical benefit rate (CBR), and safety. PFS analysis tested superiority of Arm A to C at ∼110 events across the 2 arms assuming a hazard ratio (HR) of 0.667 to achieve ∼80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR is <1.2. Results 234 pts were randomized to Arms A (n=78), B (n=79) and C (n=77). 166 PFS events have been observed (A: 57; B: 54; C: 55). Median PFS was 9.1 months in Arm A, 6.5 in Arm B and 7.4 in Arm C (A vs C: HR=.815, 95% CI, .556-1.193, p=.293; B vs C: HR=1.045, 95% CI, .711-1.535 p=.811). Investigator-assessed ORR was 34.6%, 24.1% and 32.5% (confirmed ORR: 25.6%, 19.0%, 28.6%) and CBR was 61.5%, 49.4% and 51.9% in Arms A, B and C, respectively. Prophylactic loperamide reduced the incidence and severity of diarrhea (C: 62.3%, Gr 3: 7.8%) compared to MONARCH 1 (90.2%, Gr 3: 19.7%, Dickler et al. 2017) resulting in similar rates of diarrhea with 150mg abemaciclib without prophylaxis (A: 53.8%, Gr 3: 1.3%; B: 67.1%, Gr 3: 3.8%). The adverse event profile across arms was generally consistent with other breast studies of abemaciclib. Conclusions nextMONARCH 1 confirmed single-agent activity of abemaciclib in heavily pretreated pts with HR+, HER2- ABC. Efficacy of abemaciclib monotherapy at 150mg was similar to 200mg. Combining tamoxifen with abemaciclib did not demonstrate a statistically significant improvement in PFS compared to abemaciclib monotherapy. Addition of prophylactic loperamide to abemaciclib 200mg resulted in diarrhea similar to 150mg without prophylaxis. Citation Format: Hamilton E, Cortes J, Dieras V, Ozyilkan O, Chen S-C, Petrakova K, Manikhas A, Jerusalem G, Hegg R, Lu Y, Bear MM, Johnston EL, Martin M. nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer [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 PD1-11.

IntroductionThere is an unpredictable relationship between thiopurine methyl transferase (TPMT) and hypermethylation. It is likely that cytochrome P450 (CYP450) enzymes play a role in the demethylation of methylated mercaptopurine (MMP), altering the MMP:Thioguanine nucleotide (TGN) ratio(Table 1). Smoking has been shown to induce CYP450 enzymes. One study on smoking and olanzapine demonstrated a 6 fold increase in CYP450 activity through smoking.1 This might suggest that smoking could upregulate the demethylation process, reducing MMP.MethodsPatients on thiopurines had their smoking status recorded as they attended the inflammatory bowel disease (IBD) clinic. Retrospective data on demographics was collected (Table 1). Only measurable TGNs after 6 weeks of therapy were used for analysis. Metabolites measured whilst on allopurinol were excluded. Average TGNs over the treatment period, MMP and MMP:TGN ratios were compared between smokers and non-smokers. Hypermethylators were defined as any patient with an MMP:TGN ratio of ≥11 during their treatmentResults230 patients were analysed(117 males).Table 1 shows comparison in demographics between smokers and non-smokersAbstract PWE-006 Table 1Smokers n = 106Non-smokers n = 124Male:female51%:49%47%:53%Age3733Ethnicity – White:Black:Other81%:19%:0%80%:9%:11%Crohn’s:Ulcerative colitis82%:18%72%:27%Previous Surgery45%27%Mean TPMT38.4 (median 35)34.1 (median 35)Hepatotoxicity15.1%13.7%Hypermethylation28.3%42.7%Mean MMP for smokers was 1683(SD 2565, median 840) versus 2041 in non-smokers(SD 2401, median 1340)(P = 0.713). Mean MeMP:TGN ratio for smokers was 6.15 (SD 9.06, median 2.22) versus 7.81 in non-smokers (SD 8.01, median 4.70)(P = 0.593).ConclusionThere were more hypermethylators in the non-smoking cohort than in the smoking cohort (42.7% versus 28.3%(P < 0.05)), however the difference between average MMP and MMP:TGN ratios were not significant although the median differences are compelling. There were significant differences between quantity smoked and the MMP:TGN ratio. Paradoxically, the reduction in methylation if smoking <5 cigarettes/day was reversed when smoking ≥15 cigarettes/day. This may suggest an alternative pathway affected by smoking. Smoking status and quantity should be taken into account when monitoring metabolites. Additionally, polymorphisms for CYP450 (CYP1A2*F and CYP1A2*1 C), known to affect drug metabolism between individuals, may be responsible for variation and require further research.Reference1 Carrillo JA, Herráiz AG, Ramos SI, Gervasini G, Vizcaíno S, Benítez J. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol. 2003 Apr;23(2):119–27.Disclosure of InterestNone Declared

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Background: Resistance to endocrine therapy remains an important clinical problem in hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC), necessitating alternative treatment options. The insulin-like growth factor (IGF) axis and cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway have been implicated in the pathogenesis and resistance mechanisms of a variety of cancers, including BC. Binding of IGF-I and -II to the IGF receptor results in upregulation of cyclin D1, and subsequent progression through the cell cycle, thus providing rationale for the simultaneous inhibition of IGF-I and -II and CDK4/6. This Phase Ib trial assesses the maximum-tolerated dose (MTD)/recommended phase II dose (RP2D), safety and preliminary efficacy of the IGF-ligand-neutralizing antibody, xentuzumab, in combination with abemaciclib, a selective, small-molecule inhibitor of both CDK4 and 6, in patients (pts) with solid tumors. The trial includes four dose finding cohorts followed by two expansion cohorts. Only those cohorts that will include pts with postmenopausal HR+, HER2- BC will be presented here. Trial design: In this phase Ib multicenter, non-randomized, open-label, dose escalation trial (BI 1280.18 [NCT03099174]), the key aims in the BC cohorts (Cohorts B–D, F) are to define the MTD or recommended phase 2 dose (RP2D), and to evaluate the preliminary efficacy, safety and tolerability of xentuzumab plus abemaciclib in combination with endocrine therapies. Eligible pts include adults ≥18 yrs (≥20 for Japan), with measurable or evaluable disease, adequate organ function, ECOG PS ≤1, and postmenopausal locally advanced or metastatic HR+, HER2- BC (Cohorts B–D, F). CDK4/6 inhibitor-naïve pts (Cohorts B–D) and pts who have received prior CDK4/6 inhibitors (palbociclib or ribociclib) plus aromatase inhibitors (Cohort F) are included. The MTD/RP2D of xentuzumab plus abemaciclib to be used in Cohorts B–D will be established in pts with solid tumors (Cohort A) who will receive xentuzumab (starting dose 1000mg weekly iv) plus abemaciclib (starting dose 150mg every 12 hours). CDK4/6 inhibitor-naïve pts with BC will receive xentuzumab plus abemaciclib at the RP2D determined in Cohort A in combination with letrozole (2.5mg/day; Cohort B), anastrozole (1mg/day; Cohort C), or fulvestrant (500mg/month; Cohort D). CDK4/6 inhibitor pre-treated pts with BC (Cohort F) will receive xentuzumab plus abemaciclib and fulvestrant at the RP2D determined in Cohort D. Primary endpoints in the BC cohorts are the MTD and/or RP2D of xentuzumab plus abemaciclib in combination with endocrine therapies, and the objective response (OR) in CDK4/6 inhibitor pre-treated pts with advanced BC (Cohort F); disease control (DC), duration of DC, time to OR, duration of OR, and progression-free survival (PFS) in Cohort F are secondary endpoints. Additionally, PK outcomes, safety and tolerability will be assessed in all cohorts. This study will be conducted in the US, Europe and Japan. Pt screening started in May 2017. Target enrolment is ˜88 pts, including ˜56 pts with advanced HR+, HER2- BC, of whom ˜20 had previously been treated with CDK 4/6 inhibitors. Citation Format: Yee D, Sablin MP, Iwata H, Johnston EL, Bogenrieder T, Serra J, Hua H, Lo Russo P, Prat A. A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2-negative breast cancer (plus endocrine therapy) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-02.