042: Pharmacokinetics & Exposure-safety Analyses Across Tumor Types for Ifinatamab Deruxtecan (I-DXd) in the First-in-Human Study IDeate-Pantumor01 (DS7300-A-J101)

Statement of Purpose, Innovation or Hypothesis: I-DXd demonstrated manageable safety and promising antitumor activity in patients with advanced solid malignant tumors, including small cell lung cancer (SCLC) in dose escalation and in the tumor types [esophageal squamous cell carcinoma (ESCC), castration-resistant prostate cancer (CRPC), and squamous non-small cell lung cancer (sqNSCLC)] in the dose expansion cohorts of the ongoing phase 1/2 IDeate-Pantumor01 study (NCT04145622) at 12 mg/kg IV Q3W.¹ In the ongoing phase 2 dose optimization IDeate-Lung01 study in subjects with SCLC (NCT05280470), ² 12 mg/kg Q3W was determined to be the optimal SCLC monotherapy dose. Pharmacokinetic (PK) and exploratory exposure-safety (ES) analyses across tumor types from data in IDeate-Pantumor01 were performed to support dose selection considerations in indications beyond SCLC for I-DXd.

Description of Methods & Materials: PK and safety data from all dose groups (0.8–16 mg/kg Q3W) in IDeate-Pantumor01 as of 31 Jan 2023 were analyzed. PK parameters, as calculated by non-compartmental analysis, were evaluated for I-DXd (ADC) and DXd (released payload). Univariate logistic regression was used to explore relationships between exposure and safety endpoints that had a frequency of >10%. Observed exposure metrices of I-DXd and DXd (AUC_21d and C_max) were used in the ES analyses.

Data & Results: PK and safety results from 168 subjects were evaluated. I-DXd exposures generally increased with dose level, with the AUC_21d for doses of 8 mg/kg and above approaching dose proportionality, suggesting nearing saturation of target-mediated drug disposition. Observed PK parameters at 12 mg/kg in subjects with SCLC (N=8) and in the dose expansion cohorts [ESCC (N=25), CRPC (N=38), and sq-NSCLC (N=6)] were comparable across tumor types for both I-DXd and DXd. Mean (CV%) Cycle 1 AUC_21d for I-DXd (d*µg/mL) at 12 mg/kg for SCLC, ESCC, CRPC, and sq-NSCLC was 1700 (14.6%), 1230 (21.4%), 1490 (32.3%), and 1420 (36.3%), respectively, and for DXd (d*ng/mL) was 32.0 (40.1%), 33.0 (52.1%), 40.9 (55.7%), and 42.2 (38.7%), respectively. In Cycle 1, I-DXd was absorbed with a median T_max from 1.75 to 2.95 hours (5 to 6.6 hours for DXd) and then eliminated with a mean t_1/2 from 4.56 to 6.94 days (apparent t_1/2 7.32 to 8.64 days for DXd) at 12 mg/kg. Of the 17 safety endpoints evaluated, 7 occurred with a frequency of >10% and were statistically significant with exposure. Positive ES relationships were identified between both I‑DXd and DXd Cycle 1 exposure (AUC_21d and C_max) and any grade gastrointestinal (GI) adverse events, grade ≥3 treatment-emergent adverse event (TEAE), and dose reduction associated with an adverse event (AUC_21d only). Positive ES relationships were identified between Cycle 1 DXd AUC_21d exposure and any serious adverse event, any grade anemia, anemia grade ≥3, and AE leading to dose interruption. ES relationships were generally consistent across tumor types.

Interpretation, Conclusion or Significance: Along with previously published IDeate-Pantumor01 safety and efficacy data for ESCC, CRPC and sqNSCLC¹, the PK and exploratory ES analysis suggested comparable PK and ES relationships across indications at the 12 mg/kg Q3W dose in IDeate-Pantumor01 expansion cohorts. Overall, the favorable benefit-risk balance across tumor types supports continued development of I-DXd in indications beyond SCLC.

Disclosures: BPT, SSV, NMM, NO, JS, MQ, NY, and YL are employees of Daiichi Sankyo Inc.

Citations/References: 1. Patel MR, et al. ESMO 2023. Abstract 690P. 2. Rudin C, et al. WCLC 2023. Abstract 156.

Additional Information/Authors: Brittany P. Tran1, Soniya S. Vaidya1, Narasimha M. Midde1, Naoko Okamoto1, Jasmeet Singh1, Meng Qian1, Naoto Yoshizuka1, Pengcheng Lu2, Yvonne Lau1
1Daiichi Sankyo, Inc., Basking Ridge, NJ, USA; 2Sarah Cannon Research Institute, Nashville, TN, USA