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 .
BACKGROUND:Ifinatamab deruxtecan is a novel B7-H3-directed antibody-drug conjugate that leverages the clinically validated deruxtecan technology. We report dose-escalation results from a trial of ifinatamab deruxtecan in patients with solid tumours. METHODS:In this two-part, multicentre, open-label, first-in-human, phase 1/2 study of ifinatamab deruxtecan conducted at clinics in ten hospitals and cancer centres in the USA and Japan, we recruited patients aged 18 years or older who had advanced treatment-refractory solid tumours (small-cell lung cancer, oesophageal squamous cell carcinoma, castration-resistant prostate cancer, squamous non-small-cell lung cancer, head and neck squamous cell carcinoma, bladder cancer, sarcoma, endometrial cancer, melanoma, or breast cancer), and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received ifinatamab deruxtecan at doses of 0·8-16·0 mg/kg intravenously every 3 weeks. The primary outcome of dose escalation was the safety profile, which was evaluated in patients who received one or more dose of ifinatamab deruxtecan. Antitumour activity (per Response Evaluation Criteria in Solid Tumours version 1.1; secondary outcome) was evaluated in patients receiving ifinatamab deruxtecan at doses of 4·8 mg/kg or higher. The data cutoff was Jan 31, 2023. This trial is registered with ClinicalTrials.gov (NCT04145622) and is ongoing. FINDINGS:Between Oct 25, 2019, and July 13, 2022, 97 patients were enrolled and treated. 77 (79%) patients were male and 20 (21%) were female, 56 (58%) patients were White, and 31 (32%) were Asian. Three patients (3%) had dose-limiting toxicities; however, on the basis of protocol-defined criteria, the maximum tolerated dose was not reached. The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were anaemia (17 [18%] patients), neutropenia (four [4%]), lymphocyte count decreased (three [3%]), and neutrophil count decreased (three [3%]). Serious TEAEs occurred in 31 (32%) patients. TEAEs associated with death were reported in five patients (5%; pneumonia, pneumonia aspiration, COVID-19 pneumonia, interstitial lung disease, and one death of undesignated cause); death due to interstitial lung disease was considered related to study medication by the investigator. After a median follow-up of 8·6 months (IQR 4·1-12·9), the confirmed objective response rate across tumour types was 34% (95% CI 23-47; 24 of 70 evaluable patients). INTERPRETATION:The maximum tolerated dose was not reached with ifinatamab deruxtecan; however, one death due to treatment-related interstitial lung disease highlights the importance of prompt evaluation and careful management of patients who develop interstitial lung disease. Promising antitumour activity was observed across various solid tumours. These findings support further evaluation of ifinatamab deruxtecan in randomised controlled trials. FUNDING:Funding for this study was provided by Daiichi Sankyo Company (Daiichi Sankyo) and Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA.
