Results of a Dose‐Finding Phase 1b Study of Subcutaneous Atezolizumab in Patients With Locally Advanced or Metastatic Non–Small Cell Lung Cancer

Abstract

Intravenous (IV) atezolizumab is approved for non-small cell lung and other cancers. Subcutaneous (SC) atezolizumab coformulated with recombinant human hyaluronidase, a permeation enhancer for SC dispersion and absorption, is being developed to improve treatment options, reduce burden, and increase efficiency for patients and practitioners. IMscin001 (NCT03735121), a 2-part, open-label, global, multicenter, phase 1b/3 study, is evaluating the pharmacokinetics (PK), safety, and efficacy of SC atezolizumab. The part 1 (phase 1b) objective was determination of an SC atezolizumab dose yielding a serum trough concentration (C trough ) comparable with IV. Patients enrolled in 3 cohorts received SC atezolizumab 1800 mg (thigh) once (cohort 1), 1200 mg (thigh) every 2 weeks for 3 cycles (cohort 2), or 1800 mg (abdomen) every 3 weeks cycle 1, then cycles 2 and 3 (thigh) every 3 weeks (cohort 3). In subsequent cycles, IV atezolizumab 1200 mg every 3 weeks was administered until loss of clinical benefit. SC atezolizumab 1800 mg every 3 weeks and 1200 mg every 2 weeks provided similar C trough and area under the curve values in cycle 1 to the corresponding IV atezolizumab reference, was well tolerated, and exhibited a safety profile consistent with the established IV formulation. Exposure following SC injection in the abdomen was lower (20%, 28%, and 27% for C trough , maximum concentration, and area under the concentration-time curve from time 0 to day 21, respectively) than in the thigh. Part 1 SC and IV PK data were analyzed using a population PK modeling approach, followed by simulations. Part 2 (phase 3) will now be initiated to demonstrate that SC atezolizumab PK exposure is not lower than that of IV.

C-Terminal Lysine Processing of IgG in Human Suction Blister Fluid: Implications for Subcutaneous Administration

“…Fortunately, a wide range of k a values were simulated as part of this study and should cover k a values of most antibody therapeutics with rhuPH20. It is also worth noting that the respective population PK model parameters for atezolizumab , and pertuzumab used in this study were derived from clinical trials where each molecule was co-formulated or co-administered with rhuPH20. The second case involves molecules exhibiting significant target-mediated drug disposition, which means that target engagement leads to more rapid clearance, usually manifesting as non-linear PK.…”

“…In this model, subcutaneously administered IgG + 1CTK molecules either directly absorb into the central compartment or get processed by carboxypeptidase into IgG + 0CTK; a 6 h delay in the carboxypeptidase activity was also included to account for equilibration of the SC depot with the surrounding SC interstitial fluid (Figure S1). PK simulations were performed using the respective model-estimated clearance (CL), central compartment volume of distribution ( V c ), peripheral compartment volume of distribution ( V p ), intercompartmental clearance ( Q ), SC bioavailability ( F ), and absorption rate constant ( k a ) from either atezolizumab , or pertuzumab population PK models (Table ). Additional parameters of the model used for simulation included the absorption rate constant ( k a,CTK ) and bioavailability of the IgG + 1CTK molecule ( F CTK ), which were assumed to be the absorption rate constant and 50% of the bioavailability of the parental IgG + 0CTK molecule, respectively (the rationale for these two assumptions are discussed in the Results section).…”

Emerging PD-1/PD-L1 targeting immunotherapy in non-small cell lung cancer: Current status and future perspective in Japan, US, EU, and China

“…As some patients with cancer who received ICIs achieve long-term survival and are able to continue receiving them for extended periods of time, companies are also developing ICIs that can be administered subcutaneously in the pursuit of improving convenience during long-term administration and to gain approval for alternative routes of administration. Not only the subcutaneous formulations of approved ICIs, such as nivolumab (NCT03656718), pembrolizumab (NCT04956692), a t e z o l i z u m a b ( N C T 0 3 7 3 5 1 2 1 ) , a n d d u r v a l u m a b (NCT04870112), but also newer agents such as sasanlimab and envafolimab have completed phase I trials and are in further development without any notable safety differences compared with the intravenous formulations, and it will not take long before they are approved and become part of our treatment options (43,45,64).…”

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology

“…45 Atezolizumab, PD-L1 inhibitor, is also being investigated for SC administration and phase I studies have been successfully concluded. 46 Finally, a couple of new mAbs have also been developed in the SC form. Phase I study of sasanlimab demonstrated its antitumour activity across various tumour types and routes of administration.…”