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.

Keywords: NSCLC; atezolizumab; hyaluronanidase; pharmacokinetics; subcutaneous.

Figure 1

Trial profile. CIT, cancer immunotherapy; IV, intravenous; NSCLC, non–small cell lung cancer; SC, subcutaneous. ^aReason for study exclusion [number]: did not meet eligibility criteria [9] (inadequate hematologic and end‐organ function as determined by laboratory results within 14 days before initiation of study treatment [2]; body mass index too low [2]; treatment with systemic immunosuppressive within 2 weeks before enrollment [2]; severe infection within 4 weeks before initiation of study treatment [1]; Eastern Cooperative Oncology Group performance status >1 [1]; hepatitis core antibody B positive [1]); disease progression [3] (symptomatic, untreated, or actively progressing central nervous system metastases [2]; disease progression or recurrence after treatment with a platinum‐containing regimen for NSCLC [1]); withdrawal [1] (withdrew consent during screening [1]); withdrawn by investigator [1] (inability to comply with study protocol, investigator's judgment [1]). ^bCohort 1: one single dose of atezolizumab SC (in the thigh). Cohort 2: 3 cycles of atezolizumab SC (in the thigh). Cohort 3: 3 cycles of atezolizumab SC (first injection in the abdomen and subsequent injections in the thigh). Loss of clinical benefit includes progressive disease and pseudo‐progression.

Figure 2

Serum atezolizumab cycle 1 concentration vs time profile by cohort (mean ± SD). SC, subcutaneous. ^aCohort 1: 1800 mg of SC atezolizumab (in the thigh). ^bCohort 2: 1200 mg of SC atezolizumab (in the thigh). ^c Cohort 3: 1800 mg of SC atezolizumab (in the abdomen).

Figure 3

Simulated pharmacokinetic profiles of atezolizumab 1875 mg SC administration in the thigh in (A) cycle 1 and (B) at steady state, overlaid with 1200‐mg every‐3‐week IV administration. Solid lines are the medians of geometric means for each simulated dose; shaded areas are the 5th and 95th percentiles interval of geometric means for each simulated dose. IV, intravenous; SC, subcutaneous.