Article Text

Download PDFPDF

407 Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors
  1. Elaine Shum1,
  2. Adil Daud2,
  3. Matthew Reilley3,
  4. Yana Najjar4,
  5. John Thompson5,
  6. Joaquina Baranda6,
  7. R Donald Harvey7,
  8. Rom Leidner8,
  9. Anthony Shields9,
  10. Ezra Cohen10,
  11. Roger Cohen11,
  12. Alain Mita12,
  13. Shubham Pant13,
  14. Mark Stein14,
  15. Bartosz Chmielowski15,
  16. Siwen Hu-Lieskovan16,
  17. Catherine Fleener17,
  18. Ying Ding17,
  19. Sowmya Chollate17,
  20. Hector Avina17,
  21. Jolene Shorr17,
  22. Raphael Clynes17 and
  23. Barbara Hickingbottom17
  1. 1New York University, New York, NY, USA
  2. 2University of California, San Francisco, San Francisco, CA, USA
  3. 3University of Virginia, Charlottesville, VA, USA
  4. 4University of Pittsburgh, Pittsburgh, PA, USA
  5. 5University of Washington, Seattle, WA, USA
  6. 6University of Kansas, Kansas City, KS, USA
  7. 7Emory University School of Medicine, Atlanta, GA, USA
  8. 8Providence Cancer Institute, Portland, OR, USA
  9. 9Karmanos Cancer Center, Detroit, MI, USA
  10. 10University of California San Diego, La Jolla, CA, USA
  11. 11Perelman School of Medicine at the University Of Pennsylvania, Philadelphia, PA, USA
  12. 12Cedars-Sinai Medical Center, Los Angeles, CA, USA
  13. 13MD Anderson Cancer Center, Houston, TX, USA
  14. 14Columbia University, New York, NY, USA
  15. 15UCLA, Los Angeles, CA, USA
  16. 16Huntsman Cancer Institute, Salt Lake City, UT, USA
  17. 17Xencor, Inc., San Diego, CA, USA

Abstract

Background XmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report preliminary data from an ongoing, multicenter, Phase 1 study investigating the safety/tolerability, pharmacokinetics/pharmacodynamics, and clinical activity (RECIST 1.1) of XmAb20717 in patients with selected advanced solid tumors.

Methods A 3+3 dose-escalation design was used to establish a maximum tolerated (MTD)/recommended dose for evaluation in parallel expansion cohorts, including melanoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), prostate cancer, and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI; n≤20 each). XmAb20717 was administered as an infusion on Days 1 and 15 of each 28-day cycle.

Results As of 08Jul2020, 109 patients had been treated (table 1), and 30 were continuing treatment. In escalation, 6 dose levels (0.15–10.0 mg/kg) were evaluated (n=34); an MTD was not established. Expansion cohorts were initiated at 10 mg/kg (n=72), and a 15 mg/kg escalation cohort was added (n=3). T-cell proliferation was noted in peripheral blood at doses as low as 3 mg/kg and was highest at 10 mg/kg. At this dose, consistent proliferation of CD8+ and CD4+ T cells was observed, indicative of dual PD-1 and CTLA-4 checkpoint blockade (figure 1). Paired pre- and post-dosing biopsies showed increased intratumoral T-cell infiltration and IFN-response signatures following treatment. Grade 3/4 treatment-related adverse events (TRAEs) reported for ≥3 patients included rash (13%), transaminase elevations (7%), lipase increased (4% [2% with amylase increased]), and acute kidney injury (3%), all considered immune-related. There were 2 Grade 5 TRAEs: immune-mediated pancreatitis (in the presence of pancreatic metastases) and immune-mediated myocarditis (Grade 4) that contributed to respiratory failure. A complete response was reported as the best overall response for 1 patient (melanoma); partial responses were reported for 5 patients (2 melanoma, 2 NSCLC, 1 ovarian). The objective response rate was 13% overall and 21% at 10 mg/kg (6/46 and 6/29 evaluable patients, respectively). All responders had prior CI exposure. Responses were observed only at 10 mg/kg and, within the 10 mg/kg group, appeared to correlate with higher peak serum concentration and area under the curve.

Abstract 407 Table 1

Demographics and baseline characteristics

Abstract 407 Figure 1

Mean change from baseline in percentage of Ki67+ T–cell expression in peripheral blood during first two cycles of XmAb20717

Conclusions XmAb20717 induced T-cell proliferation in peripheral blood consistent with dual-checkpoint blockade. Preliminary data indicate XmAb20717 was generally well-tolerated and associated with evidence of antitumor activity in CI-pretreated patients with various types of advanced solid tumors.

Trial Registration NCT03517488

Ethics Approval The study was approved by each institution’s IRB.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

Statistics from Altmetric.com

Supplementary materials

Related Data

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.