205 Dual antiplatelet therapy with third generation P2Y12 inhibitors in STEMI patients: impact of body mass index on high on-treatment platelet reactivity

Aims High on-treatment platelet reactivity (HTPR) has been associated with high risk of ischaemic events in STEMI patients. Body mass index (BMI) and specifically overweight and obesity are risk factors for increased platelet reactivity in different series of patients; however, data regarding their relationship with pharmacodynamic response to oral 3rd generation P2Y12 inhibitors is still lacking. This study aims to assess the association between BMI and HTPR in STEMI patients treated with oral 3rd generation P2Y12 inhibitors. Methods Overall, 429 STEMI patients were enrolled in this study. Patients were divided into two groups according to BMI (BMI <25 vs. ≥25 kg/m2). A propensity score matching (1:1) was performed to balance potential confounders in baseline patients characteristics. Platelet reactivity was assessed by VerifyNow at baseline and after 3rd generation P2Y12 inhibitor (ticagrelor or prasugrel) loading dose (LD). Blood samples were obtained at baseline (T0), 1 h (T1), 2 h (T2), 4–6 h (T3) and 8–12 h (T4) after the LD. HTPR was defined as a platelet reactivity unit values ≥ 208 units. Results Mean age was 62 ± 12 years, and males were 75%. Patients with a BMI ≥25 were younger (61 ± 12 vs. 64 ± 11, P= 0.006), with a higher prevalence of male gender (78% vs. 68%, P = 0.035), and they were less frequently treated with morphine before PCI (30% vs. 42%; P=0.018). After propensity score matching, patients with BMI ≥25 had similar values of baseline platelet reactivity [T0: 308 (285–342) vs. 300 (281–330), P= 0.396], while they had higher level of platelet reactivity at 1 and 2 h after the LD [T1: 285 (200–308) vs. 265 (196–320), P= 0.047; T2: 241 (87–305) vs. 200 (56–256), P= 0.004] and higher rate of HRPT [T1: (66% vs. 47%, P= 0.004); T2: (40% vs. 24%, P= 0.006)]. Furthermore, multivariable analysis demonstrated that BMI ≥25 was an independent predictor of HTPR at 2 h (OR 2.01, 95% CI 1.18–3.42; P=0.009). Conversely, starting from 4 h after the LD, platelet reactivity values [T3: 68 (7–173) vs. 15 (6–71), P = 0.76; T4: 38 (4–104) vs. 44 (4–82), P=0.958] and HRPT rates (T3: 13% vs. 10%, P = 0.595; T4: 1% vs. 1%, P= 0.320) were comparable among the two study groups. Conclusions A BMI ≥25 kg/m2 is associated with decelerated pharmacodynamic response to oral 3rd generation P2Y12 inhibitors LD, and it is a strong predictor of HRPT in STEMI patients treated by dual antiplatelet therapy with ticagrelor or prasugrel.

868 Overall survival on tebentafusp in metastatic uveal melanoma (mUM) across the range of tumor gp100 expression levels

BackgroundTebentafusp is a TCR–anti-CD3 bispecific fusion protein that targets melanoma-expressed gp100 antigen and has shown survival benefit in a randomized phase 3 trial in 1L patients with metastatic uveal melanoma.1 2 In phase 2 and 3 trials (NCT02570308, NCT03070392) enrolling late-stage mUM patients, we explored associations between gp100 expression in the tumor and pharmacodynamic response and clinical outcomes on tebentafusp.Methods2L+ (NCT02570308) or 1L (NCT03070392) HLA-A*02:01+ mUM patients were treated weekly with 68mcg tebentafusp after intra-patient dose escalation. Archival or fresh tumor biopsies were obtained prior to dosing. Expression of baseline gp100 was determined by immunohistochemistry (IHC) and RNAseq analysis (2L+ only) in up to 118 (2L+) and 187 (1L) samples. RNAseq analysis was used to evaluate association between baseline mRNA levels of gp100 and T cell infiltration and activation after 3 doses of tebentafusp (n=35). Serum samples (n=118, 2L+ only) collected at baseline and on-treatment were analyzed for ctDNA. An H-Score quantified tumoral gp100 protein expression. gp100 H score or mRNA levels were cut at the lowest quartile to identify gp100 low patients.ResultsDistribution of gp100 protein by IHC was similar in both studies with median H-Scores of 170 (IQR 60–260) (2L+) and 155 (IQR 68–229) (1L). Over 70% of samples had ≥ 50% gp100+ tumor cells at any intensity. gp100 H-scores were similar in archival and fresh tumor biopsies.High baseline gp100 mRNA levels were associated with ~2-fold increased CD3 and CD8 cell infiltration on tebentafusp compared to little or no change in the gp100 low group. There was greater T cell activation in the gp100 mRNA high group as demonstrated by induction of IFNα (fold change in gp100 high=2.5 p=0.00005,), IFNγ signatures (FC in gp100 high=5.7 p=0.00004) and cytotoxic genes GZMB (FC high=4.6 p=0.000006,) and PRF1 (FC high=2.4 p=0.00051,) compared to little or no activation in the gp100 mRNA low group.Tumor shrinkage (TS) and overall survival (OS) > 12 months were observed in low and high gp100 H-score subgroups (table 1), and a RECIST partial response was observed at very low gp100 (H-score 11). ctDNA reduction on tebentafusp was also observed across the range of gp100 expression levels.Abstract 868 Table 1TS and OS in gp100 high and gp100 low patient groupsConclusionsHigh gp100 expression was associated with the acute pharmacodynamic response to tebentafusp including greater T cell infiltration and activation in the tumor microenvironment. However, clinical outcomes on tebentafusp—TS, OS and ctDNA reduction—were observed across the range of gp100 expression levels.Trial RegistrationNCT02570308, NCT03070392ReferencesMiddleton MR, McAlpine C, Woodcock VK, et al. Tebentafusp, a TCR/Anti-CD3 bispecific fusion protein targeting gp100, potently activated antitumor immune responses in patients with metastatic melanoma. Clin Can Res 2020;26:5869–5878.Sacco JJ, Carvajal R, Butler MO, et al. A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM). Ann Oncol 2020;31:S1442-S1143.Ethics ApprovalThe institutional review board or independent ethics committee at each center approved the trial. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

Evaluation of sensitivity to endocrine therapy index (SET2,3) for response to neoadjuvant endocrine therapy (NET) and subsequent prognosis.

580 Background: Patients (pts) in Cohort A of the American College of Surgeons Oncology Group Z1031 (Alliance) trial of NET for cStage II-III breast cancer were randomized to anastrozole [ANA], letrozole [LET] or exemestane [EXE] for 16-18 weeks (wks). In Cohort B, pts chose between ANA and LET and switched to chemotherapy or surgery if a tumor biopsy after 2-4 wks of NET had Ki67 >10%. Treatments after surgery were not defined by the trial protocol. SET2,3 measures nonproliferation gene expression related to estrogen and progesterone receptors adjusting for a baseline prognostic index that combines clinical tumor and nodal stage and a 4-gene molecular subtype (RNA4) defined by ESR1, PGR, ERBB2 and AURKA. High SET2,3 in a pre-treatment biopsy using cStage information is defined as SET2,3 >1.77. Methods: 379 pts had gene expression data from a research tumor biopsy prior to NET (Agilent 44K microarrays). A bioinformatician blinded to pt treatment and clinical outcomes determined SET2,3. The trial statistician then examined the association between SET2,3 and pharmacodynamic response at 2-4 wks (N=141, Cohort B): Ki67 ≤10% and complete cell cycle arrest (CCCA Ki67 ≤2.7%); pathologic outcomes in pts who completed NET: ypStage 0/1 (N=329, Cohorts A&B), PEPI-0 rate (N=155, Cohort B); and event-free survival (EFS) post-registration (N=244, Cohorts A&B). We used Fisher’s exact tests to assess whether responses, and Cox modeling to evaluate whether EFS, differed with respect to SET2,3 status. Results: High SET2,3 in 48% of pts (183/379) was associated with older age (median: 66 vs 63 years; p=0.012); cStage II (95% vs 75%; p <0.001); and pre-NET Ki67 ≤10% (37% vs 20%; p< 0.001) in pts with low SET2,3. In Cohort B, pts with high SET2,3 had a higher rate of pharmacodynamic response in their tumor at wk 2-4 than pts with low SET2,3 (Table). In the subset of Cohort B pts with wk 2-4 Ki67 ≤10%, pre-treatment SET2,3 trended numerically higher in pts who achieved PEPI-0 score (p=0.049) but the proportion achieving PEPI-0 did not differ by SET2,3 high/low status (Table). EFS was significantly longer for pts with high SET2,3 than pts with low SET2,3 (HR[H/L]: 0.52; 95% CI: 0.34-0.80; p=0.003). Conclusions: An exploratory analysis of Z1031 data demonstrated that the rate of pharmacodynamic suppression of proliferation by NET at 2-4 wks was greater and EFS was longer for pts with breast cancer expressing high SET2,3 disease than pts with low SET2,3. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Clinical trial information: NCT00265759. [Table: see text]

De-escalation strategy with half-dose prasugrel or ticagrelor on pharmacodynamics and outcome in East Asians patients with acute coronary syndrome

Background East Asians treated with potent P2Y12 inhibitors (prasugrel or ticagrelor) are exposed to more potent platelet inhibitory response. Whether half-dose de-escalation strategy would be benefit for chronic antiplatelet strategy in East Asian patients with acute coronary syndrome (ACS) remain uncertain. Method In half-dose de-escalation strategy, 129 Korean ACS patients were assigned to receive standard-dose potent P2Y12 inhibitors (n=86, prasugrel [n=38], ticagrelor [n=48]), followed by half-dose reduction at 1 month for maintenance, and was compared to clopidogrel (n=43) as control. The primary safety outcome was any clinically significant bleeding according to BARC (Bleeding Academic Research Consortium) criteria at 12 months. The pharmacodynamic response is accessed by VerifyNow P2Y12 reaction unit (PRU) at 1 month and 3 months post PCI. Results Ticagrelor achieved significantly lower PRU (7 [4–32] vs. 11 [5–76] vs. 167 [97–212]) than prasugrel and clopidogrel, resulting OPR rate 0% vs. 21.6% vs. 58.5%, respectively at 1 month post PCI. Similar results were observed at 3 months (PRU 12 [6–43] in ticagrelor vs. 88 [58–148] in prasugrel vs. 169 [107–199] in clopidogrel), with OPR rate 7.1% vs. 51.5% vs. 65.9%, respectively. At 12 months, the incidence of BARC type-1 or -2 bleeding was significantly higher in potent P2Y12 inhibitors (37.5% in ticagrelor, 34.2% in prasugrel) than in clopidogrel (36.0 vs. 14.0%; HR, 2.86; 95% CI, 1.19–6.87; p=0.018). Conclusion In Korean ACS patients, pharmacodynamic response (OPR rate) with half-dose prasugrel appears comparable to that with clopidogrel, whereas ticagrelor still exhibit potent platelet inhibition either standard or half doses. De-escalation strategy with half-dose potent P2Y12 inhibitor was associated with higher incidence of clinically insignificant bleeding compared with clopidogrel. Optimal dose reduction strategies in potent P2Y12 inhibitors to balance safety and effectiveness remain uncertain, and require further studies. Pharmcodynamics to oral P2Y12 inhibitors Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): National Research Foundation of Korea