Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose-escalation phase 1 trial

Abstract

Purpose: New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study.

Methods: Part 1 featured a 3 + 3 weight-based dose-escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator's decision, or death.

Results: The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed.

Conclusions: Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class.

Trial registration: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016.

Keywords: Advanced cancer; Dostarlimab; Phase 1 clinical trial; Programmed cell death receptor 1; TSR-042.

Conflict of interest statement

Dr. Patnaik reports institutional grants from GlaxoSmithKline. Dr. Weiss is an employee of SOTIO, LCC, outside of this submitted work, and a former employee of Unum Therapeutics outside of this submitted work; he reports personal fees from Spring Bank Pharmaceuticals, Imaging Endpoints II, MiRanostics Consulting, Gossamer Bio, Paradigm, International Genomics Consortium, Angiex, IBEX Medical Analytics, GLG Council, Guidepoint Global, Circulogene, and Genomic Health, all outside this submitted work; he has received travel reimbursement from Cambridge Healthtech Institute, GlaxoSmithKline, and Tesaro; has ownership interest in MiRanostics Consulting, Unum Therapeutics (now Cogent Biosciences), Exact Sciences, Moderna, and Circulogene, all outside the submitted work; and has issued patents PCT/US2008/072787, PCT/US2010/043777, PCT/US2011/020612, and PCT/US20211037616, all outside this submitted work. Dr. Rasco reports institutional grants from GlaxoSmithKline. Dr. Blaydorn has nothing to disclose. Dr. Mirabella has nothing to disclose. Dr. Beeram has nothing to disclose. Dr. Guo, Dr. Lu, Dr. Danaee, and Dr. Im are all former employees of GlaxoSmithKline. Dr. McEachern is a former GlaxoSmithKline employee. Dr. Sachdev reports advisory roles at Celgene, PUMA, TTC Oncology, Pfizer, Novartis, TapImmune, Ipsen, Tempus, and AstraZeneca; honoraria from Ipsen, Celgene, PUMA, Novartis, Pfizer, Tempus, and AstraZeneca; and institutional grants from Pfizer, Celgene, and Genentech.

© 2021. The Author(s).

Figures

Fig. 1

*CD3+ binding assays and interleukin-2 (IL-2) stimulation assays demonstrate PD-1 receptor occupancy by dostarlimab following administration of dostarlimab 1, 3, and 10 mg/kg (CD3+ : A; IL-2: B) and dostarlimab 500 mg Q3W (CD3+ : C; IL-2: D) and 1000 mg Q6W (CD3+ : E; IL-2: F). *Anomalous data were observed infrequently within the data sets; however, no obvious issue in sample handling or processing could be identified

Fig. 2

Individual dostarlimab clearance versus body weight on day 1 of cycle 1 for part 1 (A), part 1 plus 2A (B), and intercept and slope data for the populations in A and B