Phd in PHARMACOLOGY AND TOXICOLOGY

Thesis title: Real-world clinical outcomes in HER2 positive and negative metastatic breast cancer patients treated with Abemaciclib, Ribociclib and Trastuzumab deruxtecan

Breast cancer (BC) is the most common cancer among women, with an estimated 2.3 million new cases diagnosed globally each year. Of all patients with stage IV breast cancer, approximately 75% are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−). Recently, a novel drug class, cyclin-dependent kinase (CDK) 4/6 inhibitors, has been introduced as a treatment option for patients with HR+, HER2− advanced breast cancer (aBC), either as first-line therapy combined with an aromatase inhibitor or as second-line therapy in combination with fulvestrant. Abemaciclib, a CDK 4/6 inhibitor, has demonstrated clinical benefit in women affected by HR+/HER2− aBC. However, the risk of drug-drug interactions (DDIs) is a relatively common issue in oncology clinical practice, particularly in patients who often require concomitant medications to manage other clinical conditions and may receive CDK4/6 inhibitors as long-term regimens. In cancer patients taking multiple concomitant medications, pharmacokinetics and pharmacodynamics-based DDIs may alter the therapeutic index of anti-cancer drugs, thus causing reduced compliance, unwanted adverse drug reactions, and treatment failure. This first retro-prospective study aimed to evaluate outcomes, the impact of DDIs, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data on comorbidities, concurrent medications, outcomes, and adverse events (AEs) were collected. Drug-PIN® (Personalized Interactions Network) a tool that recognizes multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients were >75 years old. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS was not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia, detected in 63%, 49%, and 49% of patients respectively. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score <12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any grade AE, severe toxicities, and diarrhea was detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11), or drug reduction (p = 0.27). The efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in the elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appears to be an independent predictor of PFS. Furthermore, in another study we evaluated, the impact of DDIs on clinical outcomes and adverse events (AEs) in a post-hoc analysis of the BioItaLEE trial, which enrolled postmenopausal HR+/HER2- advanced breast cancer patients treated with upfront ribociclib plus letrozole. The Median cut-off point was used for Drug-Pin® (DP) score. A post-hoc analysis was performed on the association of DDIs with clinical outcomes and the most common AEs. The multivariate analysis (MVA) was performed using the prespecified stratification factors (recurrent vs de novo, tumor type, tumor burden and visceral disease). DDIs analysis was performed on the 287 patients enrolled in the trial. The median DP score was 10 (range 6-220). The mPFS was 20.7 months (mo) in DP score >10 and 28.0 mo in 10 (HR 1.59, p1⁄40.02). DP tier was Green in 203 (71%), Yellow in 57 (20%), Dark Yellow in 15 (5%) and Red in 12 (4%) patients respectively. The mPFS was 28.0, 22.7, 19.4 and 13.8 mo in patients with Green, Yellow, Dark Yellow, and Red tiers, respectively (p1⁄40.04). The MVA showed that DP score and tier were independently associated with shorter PFS DP score ≤10 vs (DP score 10 vs >10, HR 1.59, p1⁄40.02; DP tier Green vs non-Green, HR 1.75, p<0.01). No association was detected between DP and all grades neutropenia, all grades QT prolongation, and all grades ALT increase. Finally, all grades AST elevation were more frequent in patients with DP score 10 (23% vs 12%, HR 0.39, 95%CI 0.20-0.79, p1⁄40.02). In conclusion, patients with high-risk DDIs (high DP score or tier) have shorter PFS compared to patients with no/low DDIs. No difference in AEs was detected among the groups, except for AST elevation. Our study highlights the importance of evaluating DDI and of therapeutic reconciliation to maximize oncological treatment efficacy in this setting and lays the foundations for further research. Approximately 15 to 20% of metastatic breast cancers (mBC) are characterized by overexpression or amplification of human epidermal growth factor receptor 2 (HER2). Accounting for approximately 15–20% of all invasive BC, human epidermal growth factor receptor 2 (HER2)-positive BC is associated with aggressive tumor behavior and poor prognosis. Although anti-HER2 agents have significantly improved the prognosis of advanced HER2-positive BC, resistance to these drugs almost inevitably develops, and the disease remains incurable in mBC. Therefore, further effective therapy for HER2-positive mBC, especially in later treatment, is urgently needed. Trastuzumab deruxtecan (T-DXd) is also a HER2-targeting ADC with a humanized anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a novel cytotoxic topoisomerase I inhibitor payload. T-DXd demonstrated unprecedented efficacy in patients with pretreated HER2+ mBC. However, few data are available about its efficacy in routine clinical practice. In this multicenter retrospective study, we examined the effectiveness and safety of T-DXd in a real-world population. Clinico-pathological information about patients with HER2+ mBC who received T-DXd was collected from 12 Italian hospitals. HER2 status was determined locally. Patients who received at least one administration of T-DXd, as any therapy line for advanced disease were included in the analysis. The primary endpoint was real-word PFS (rwPFS). One hundred and forty-three patients were included. With a Median age 66 (range: 37-90), including 4 men. Hormone receptor (HR) status was positive in 108 (75%) patients and negative in 35(25%). T-DXd was administered as first, second, third, or subsequent lines in 4 (3%), 16 (11%), 42 (29%), and 81 (57%) patients, respectively. Among 123 patients with measurable disease, the ORR was 68%, and the DCR was 93% (9 CRs, 74 PRs, and 30 SD). Nine (7%) patients had a primary resistance to T-DXd. With a median follow-up of 12 months, the median rwPFS was 16 months. RwPFS was 84%, 59%, and 39% at 6, 12, and 18 months, respectively. A favorable trend in rwPFS was reported in patients receiving T-DXd as I/II line versus later lines (17 vs. 15 months; P = .098). Any-grade toxicity was registered in 84 patients (59%). Most common adverse events (AEs) reported were nausea (33%), neutropenia (21%), and asthenia (21%). Liver toxicity and diarrhea were uncommon (5% and 1%). Severe toxicities were registered in 18% of patients, with the most frequent were neutropenia, nausea/vomiting, and ILD observed in 15, 2, and 3 patients respectively. AEs led to dose reduction in 37 patients (26%). Dose reduction and AEs do not affect patients’ response and survival outcomes. Overall, efficacy and safety of T-DXd were confirmed in an unselected real-world population of HER2+ mBC. These results are consistent with the results of known findings, and no new safety concerns were reported.