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Background <p>Dual programmed cell death protein (ligand)-1 (PD-[L]1) and lymphocyte-activation gene-3 (LAG-3) blockade has demonstrated improved anti-tumour response in some advanced solid tumours. CITRINO, a two-part, Phase 1 dose-escalation study, evaluated encelimab (TSR-033; novel anti-LAG-3) monotherapy and in combination in patients with advanced/metastatic solid tumours.</p> Methods <p>Part 1 (P1) involved dose escalation (20–720 mg Q2W) of encelimab as monotherapy (P1A/B) and with dostarlimab (500 mg Q3W) in patients with previously treated advanced/metastatic solid tumours (P1C). P2 involved cohort expansion in patients with anti-PD-(L)1-naïve microsatellite stable advanced/metastatic colorectal cancer with recommended phase 2 dose (RP2D) of encelimab with dostarlimab as third/fourth-line therapy (P2A), or with dostarlimab, bevacizumab and mFOLFOX6/FOLFIRI as second-line therapy (P2B). Objectives included RP2D, safety/tolerability, efficacy, pharmacokinetics/pharmacodynamics, and exploratory biomarkers.</p> Results <p>Maximum tolerated encelimab dose was not reached; 720 mg Q2W was used for P2 plus dostarlimab 1000 mg Q6W. One dose-limiting toxicity occurred (Grade 2 myasthenia gravis; P1A). No clinical responses were observed in P1; 1 (3%) and 4 (17%) patients achieved partial response in P2A and 2B, respectively.</p> Conclusions <p>Encelimab has a manageable safety profile as a monotherapy and in tested combinations; however, anti-tumour activity was limited.</p> Clinical trial registration <p>NCT03250832.</p>

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CITRINO: phase 1 dose escalation study of anti-LAG-3 antibody encelimab alone or in combination with anti-PD-1 dostarlimab in patients with advanced/metastatic solid tumours

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月27日

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  • J. Randolph Hecht,
  • Jean-Marie Michot,
  • David Bajor,
  • Amita Patnaik,
  • Ki Y. Chung,
  • Judy Wang,
  • Gerald Falchook,
  • James M. Cleary,
  • Richard Kim,
  • Anuradha Krishnamurthy,
  • Omkar Marathe,
  • Hagop Youssoufian,
  • Catherine Ellis,
  • Angela Waszak,
  • Srimoyee Ghosh,
  • Hailei Zhang,
  • Kaitlin Yablonski,
  • Shruti D. Shah,
  • Ivan Diaz-Padilla,
  • Susanna Ulahannan

摘要

Background

Dual programmed cell death protein (ligand)-1 (PD-[L]1) and lymphocyte-activation gene-3 (LAG-3) blockade has demonstrated improved anti-tumour response in some advanced solid tumours. CITRINO, a two-part, Phase 1 dose-escalation study, evaluated encelimab (TSR-033; novel anti-LAG-3) monotherapy and in combination in patients with advanced/metastatic solid tumours.

Methods

Part 1 (P1) involved dose escalation (20–720 mg Q2W) of encelimab as monotherapy (P1A/B) and with dostarlimab (500 mg Q3W) in patients with previously treated advanced/metastatic solid tumours (P1C). P2 involved cohort expansion in patients with anti-PD-(L)1-naïve microsatellite stable advanced/metastatic colorectal cancer with recommended phase 2 dose (RP2D) of encelimab with dostarlimab as third/fourth-line therapy (P2A), or with dostarlimab, bevacizumab and mFOLFOX6/FOLFIRI as second-line therapy (P2B). Objectives included RP2D, safety/tolerability, efficacy, pharmacokinetics/pharmacodynamics, and exploratory biomarkers.

Results

Maximum tolerated encelimab dose was not reached; 720 mg Q2W was used for P2 plus dostarlimab 1000 mg Q6W. One dose-limiting toxicity occurred (Grade 2 myasthenia gravis; P1A). No clinical responses were observed in P1; 1 (3%) and 4 (17%) patients achieved partial response in P2A and 2B, respectively.

Conclusions

Encelimab has a manageable safety profile as a monotherapy and in tested combinations; however, anti-tumour activity was limited.

Clinical trial registration

NCT03250832.