465 Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety and pharmacokinetic results of the INTR@PID LUNG 024 study

Abstract

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ”trap”) fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site’s independent ethics committee.

Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1

“…This sub-SMQ is based on the SMQ 'Haemorrhages (SMQ)'. Details on the selection of Table 1 Studies and endpoints included in exposure-safety analysis BTC biliary tract cancer, DE dose escalation, Exp expansion, NSCLC non-small cell lung cancer, Q2W every 2 weeks, Q3W every 3 weeks, bleed_TEAE, treatment-related bleeding events of any grade, bleed_TEAE3 treatment-related bleeding events of grade ≥ 3, bleed_GI gastrointestinal bleeding events of any grade, bleed_GI3 gastrointestinal bleeding events of grade ≥ 3 a See Supplemental Table 1 for additional details NCT number and reference for study results NCT02517398 [9] NCT02699515 [11] NCT03840915 [12] NCT04246489 [30] Total terms is provided in the 'Introductory Guide for Standardised MedDRA Queries (SMQs) Version 23.0' [24]. GI bleeding events were identified considering all preferred terms on the primary path to the system organ class gastrointestinal disorders within this SMQ.…”

“…In multiple expansion cohorts of phase 1 trials NCT02517398 and NCT02699515, BA has demonstrated antitumor activity and a manageable safety profile when administered as a single agent at a dose of 1200 mg Q2W [1,[7][8][9][10][11]. In addition, BA is being investigated in combination with chemotherapies or targeted agents in several tumor types (e.g., non-small cell lung cancer [NSCLC], cervical cancer [CC], and biliary tract cancer [BTC]) at a dose of either 2400 mg Q3W or 1200 mg Q2W (NCT03840902, NCT0455195, and NCT04066491), and the safety profile of BA with combination regimens is also considered manageable based on the data available to date [12].…”

Risk assessment of drug–drug interaction potential for bintrafusp alfa with cytochrome P4503A4 substrates: A totality of evidence approach

“…This study included patients with heavily pretreated solid tumors and had multiple expansion cohorts in specific tumor types. 14 , 15 …”

“…12,13 Clinical safety data, together with population PK assessments, have indicated a low risk of victim DDI for bintrafusp alfa as monotherapy or in combination with chemotherapeutics, thus enabling the design of multiple combination phase II and III clinical trials NCT02517398, NCT04066491, and NCT03840915. 14,15 Bintrafusp alfa has a unique mechanism of action and is a direct cytokine modulator via neutralization of TGFβ. 7 Preclinical studies showed that exogenous TGF-β can decrease mRNA levels of several CYP enzymes, including CYP3A4.…”

“… 12 , 13 Clinical safety data, together with population PK assessments, have indicated a low risk of victim DDI for bintrafusp alfa as monotherapy or in combination with chemotherapeutics, thus enabling the design of multiple combination phase II and III clinical trials NCT02517398, NCT04066491, and NCT03840915. 14 , 15 …”