This strategic perspective proposes a governance-oriented conceptual model for sustainable, patient-partnered oncology research in Brazil, with regional relevance for Latin America and broader global implications. It argues that strengthening clinical research ecosystems, currently largely driven by the pharmaceutical industry, requires a refined balance of alignment among sponsors, investigators, institutions, regulators, and patients, recognizing that each operates under distinct strategic, operational, and ethical imperatives. The proposed framework emphasizes equity, meaningful clinical outcomes, and real-world relevance. It is presented as a governance heuristic inspired by strategic interdependence, recognizing that sustainable research ecosystems emerge from coordinated decisions among stakeholders with distinct incentives and responsibilities. A central architectural element is the positioning of patient organizations as institutional integrators of collaborative intelligence across stakeholders. This positioning supports Brazil as a strategic player in globally relevant oncology evidence, strengthening external validity and contributing to the evolution of international standards.
PURPOSE This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate in solid tumors, including advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics. RESULTS Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n = 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression-free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression. CONCLUSION Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing.
We introduce the Regularized Horseshoe (RHS) in the context of covariate selection for population PK/PD models. Unlike stepwise approaches which are commonly used in this context, the RHS can simultaneously assess all possible parameter-covariate relationships in a single model fit by leveraging the fact that such relationships are usually sparse in practice. Furthermore, the RHS avoids the over-estimation of effect sizes that commonly occurs with stepwise approaches and avoids overfitting by averaging over the posterior uncertainty of possible parameter-covariate relationships. This leads to improved predictive performance on held-out data. We first give an overview of common covariate selection methods for population PK/PD modeling, then we define the RHS and provide intuition for how the method works. We then provide Stan code and a set of hyperparameters applicable to general population PK/PD models that can readily be applied by practitioners. Using an extensive simulation study, the beneficial properties of the RHS are illustrated and compared to popular covariate selection methods that are commonly used on population PK/PD models. Lastly, we compare the RHS to other commonly used methods on four real-world PK/PD datasets and illustrate its superior predictive performance on held-out data.
TPS4207 Background: An unmet medical need remains in patients (pts) with HER2+ gastric or GEJ cancer. HER2 is a validated target in up to 20% of pts with gastric or GEJ cancer. The KEYNOTE-811 trial demonstrated that adding pembro to trastuzumab and chemo improved progression-free survival (PFS) and overall survival (OS) versus placebo for first-line treatment of pts with HER2+ gastric or GEJ cancer with a PD-L1 combined positive score (CPS) ≥1 (Janjigian Y et al. N Engl J Med. 391;1360:2024). In the DESTINY-Gastric03 trial, first-line combinations involving T-DXd, a HER2-directed antibody-drug conjugate, and fluoropyrimidine (5-FU or capecitabine [CAPE]) ± pembro showed acceptable safety and encouraging efficacy in pts with HER2+ gastric or GEJ cancer, including pts with CPS < 1 (Janjigian Y et al. Ann Oncol . 35;S878:2024). Building on this evidence, the phase 3 DESTINY-Gastric05 trial aims to bring a potentially improved platinum-free treatment approach for all pts with HER2+ gastric or GEJ cancer. Methods: DESTINY-Gastric05 (NCT06731478) is an open-label, randomized, multicenter, phase 3 global trial designed to evaluate the efficacy and safety of T-DXd in combination with 5-FU (or CAPE) + pembro versus standard-of-care chemo with trastuzumab + pembro as first-line treatment in pts with unresectable, locally advanced or metastatic centrally confirmed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization+) gastric or GEJ cancer with a CPS ≥1. Pts must have ≥1 RECIST v1.1 measurable lesion, a left ventricular ejection fraction ≥50%, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Approximately 576 pts will be randomly assigned in a 1:1 ratio to receive: T-DXd 5.4 mg/kg + either 5-FU or CAPE + pembro (arm M1); or trastuzumab + platinum-based chemo (either cisplatin + 5-FU or oxaliplatin + CAPE) + pembro (arm M2). The primary efficacy endpoint is PFS based on blinded independent central review (BICR), and the key secondary endpoint is OS. Other secondary endpoints include overall response rate, duration of response, and time to response per RECIST v1.1 assessed by BICR and investigator. Safety and tolerability will also be assessed. An exploratory cohort (approximately 150 pts) will evaluate the efficacy and safety of T-DXd in combination with 5-FU or CAPE versus trastuzumab plus standard-of-care chemo in pts with PD-L1 CPS < 1. Clinical trial information: NCT06731478 .
