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599 Single-agent safety and activities of target-preserving anti-CTLA-4 antibody gotistobart (ONC-392/BNT316) in PD-(L)1 resistant metastatic NSCLC and population PK analysis in patients with solid tumors
  1. Kai He1,
  2. Meredith McKean2,
  3. Rama Balaraman3,
  4. Satish Shah4,
  5. Edward Arrowsmith5,
  6. Julio Peguero6,
  7. John Hamm7,
  8. Aiwu He8,
  9. Alexander I Spira9,
  10. Adriana millillo-Naranine10,
  11. Rohit Joshi11,
  12. Mark Goldstein12,
  13. David Carbone13,
  14. Mei Tang14,
  15. Siwen Hu-Lieskovan15,
  16. Zihai Li16,
  17. Dan Chen17,18,
  18. Hung-Yen Chou18,
  19. John Yang19,
  20. Yang Liu18,
  21. Pan Zheng18 and
  22. Tianhong Li20
  1. 1Ohio State University James Cancer Hospital, Columbus, OH, USA
  2. 2Sarah Cannon Research Institute, Nashvlle, TX, USA
  3. 3Florida Cancer Affiliates-US Oncology, Ocala, FL, USA
  4. 4PA Cancer Specialist and Research Institute, Gettysburg, PA, USA
  5. 5Tennessee Oncology Pllc, Chattanooga, TN, USA
  6. 6Oncology Consultants, Houston, TX, USA
  7. 7Norton Healthcare, Louisville, KY, USA
  8. 8Medstar Georgetown University Hospital, Washington, DC, USA
  9. 9Virginia Cancer Specialists, Fairfax, VA, USA
  10. 10Memorial Cancer Institute, Pembroke, FL, USA
  11. 11Cancer Research SA, Adelaide, SA, Australia
  12. 12Center for Cancer and Blood Disorders, Bethesda, MD, USA
  13. 13The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
  14. 14Greater Baltimore Medical Center, Baltimore, MD, USA
  15. 15Huntsman Cancer Institute/University of Utah Health, Salt Lake City, UT, USA
  16. 16The Ohio State University, Columbus, OH, USA
  17. 17OncoC4, Inc., Los Altos, CA, USA
  18. 18OncoC4, Inc., Rockville, MD, USA
  19. 19JP Global Pharma LLC, Rockville, MD, USA
  20. 20UC Davis Comprehensive Cancer Center, Sacramento, CA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Although CTLA-4 was the first validated target in immunotherapy, available anti-CTLA-4 monoclonal antibodies (mAbs) have shown very limited therapeutic activity as a single agent. Preclinical studies showed that gotistobart (ONC-392/BNT316), a CTLA-4 target-preserving anti-CTLA-4 mAb, is more effective and less toxic than other clinically used anti-CTLA-4 mAbs. Using samples from a first-in-human study in patients with advanced solid tumors, we evaluated population pharmacokinetics of gotistobart based on samples from the monotherapy and combination therapy arms. The safety and clinical activities of gotistobart as a single-agent in NSCLC patients who progressed on PD-(L)1-therapy were explored.

Methods PD-(L)1 resistant metastatic NSCLC patients were enrolled in dose escalation and dose expansion Arm I in PRESERVE-001 study (NCT04140526). Safety was evaluated based on treatment emergent and treatment-related adverse events, while efficacy was evaluated by investigators using RECIST1.1 criteria. A population PK model was constructed with 420 measurable PK observations from 70 patients, including 57 patients receiving ONC-392 monotherapy and 13 patients receiving ONC-392 and pembrolizumab.

Results As of May 15, 2023, 35 PD-(L)1 resistant mNSCLC patients received at least one dose of ONC-392 at 10 mg/kg. Among the patients who received 10 mg/kg x 2, followed by 6 mg/kg, Q3W, Gr 3–4 irAE rate was 30% with a median follow up of 12 months in alive patients. No ONC-392-related Gr 5 AEs were observed. Eight responders (1 CR and 7 PR), including 2 unconfirmed responses were observed among 27 evaluable patients with ORR of 29.6%. The median duration of response is greater than 6 months. Survival data will be presented in the meeting. PK of ONC-392 are best described by a 2-compartment model with first-order elimination. The systemic clearance (CL) of ONC-392 was estimated to be 182 mL/day, and the terminal t1/2 was estimated to be 25.7 days. Increased albumin level is associated with decreased CL, while that of body weight is associated with increased V1 and V2. No effects of age, sex, race, AST, bilirubin, creatinine clearance, cancer type and concurrent immunotherapy with pembrolizumab were significant PK covariates.

Conclusions Gotistobart (ONC-392/BNT316) monotherapy at 10 mg/kg x 2 followed by 6 mg/kg, Q3W is safe and tolerable and appears to be the first anti-CTLA-4 mAb with significant single agent anti-tumor activity in IO-resistant NSCLC. Gotistobart has the desirable PK characteristics of long half-life and delayed clearance for an immunotherapy antibody.

Acknowledgements The study is sponsored by OncoC4, Inc and BioNTech SE.

Trial Registration NCT04140526.

Ethics Approval This study obtained ethic approval from WCG IRB with study #20193108 or the local institutional IRBs. All participants gave informed consent before taking part of the study.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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