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738 Interim dose escalation of davoceticept, a conditional CD28 costimulator and dual checkpoint inhibitor, in combination with pembrolizumab in advanced malignancies (NEON-2)
  1. Nehal Lakhani1,
  2. Amita Patnaik2,
  3. Meredith McKean3,
  4. Justin Gainor4,
  5. Cathy Vo Buu5,
  6. Amanda Enstrom5,
  7. Rupert Davies5,
  8. Stacey Dillon5,
  9. Hany Zayed5,
  10. Michael Chisamore6,
  11. James Michael Pluda7,
  12. Allison Naumovski5 and
  13. Stanford Peng5
  1. 1START Midwest, Grand Rapids, MI, USA
  2. 2START San Antonio, San Antonio, TX, USA
  3. 3Sarah Cannon Research Institute and TN Onc, Nashville, TN, USA
  4. 4Massachusetts General Hospital, Boston, MA, USA
  5. 5Alpine Immune Sciences, Seattle, WA, USA
  6. 6Merck and Co., Kenilworth, NJ, USA
  7. 7ICON Clinical Research, Blue Bell, PA, USA


Background PD-1/PD-L1 inhibitors (PD-(L)1i) have improved outcomes for many patients with advanced malignancies; however, most do not respond, or fail to achieve durable anti-tumor immunity. PD-1-mediated inhibition of T-cell effector function works primarily by inactivating the CD28 costimulatory signal. While PD-(L)1i can remove such inhibition, active CD28 costimulation is likely still required for optimal T-cell activation. Davoceticept is a variant CD80 vIgD-Fc fusion protein, engineered to provide PD-L1-dependent CD28 costimulation, while inhibiting PD-1 and CTLA-4. In NEON-1 (NCT04186637), davoceticept monotherapy was well-tolerated up to 10mg/kg, Q3W, and showed evidence of clinical activity in papillary renal cell carcinoma (RCC). A davoceticept + PD-1i approach is supported by preclinical models where combination treatment yielded tumor volume reductions beyond those seen with either monotherapy. Further, PD-1 inhibition may up-regulate PD-L1 in the tumor and sensitize it to PD–L1-dependent CD28 costimulation by davoceticept.

Methods NEON-2 is an open-label dose escalation and expansion study of davoceticept + pembrolizumab in adults with advanced solid tumors or lymphoma (NCT04920383). Eligibility includes tumors for which single agent PD-(L)1i are standard of care, are refractory/resistant to standard therapies, or have no standard or curative treatments available. The study employs a standard 3+3 dose-escalation design with 2 schedules of intravenous (IV) davoceticept: Q1W and Q3W. Pembrolizumab is given per label at 400mg IV Q6W. Study objectives include evaluation of safety and tolerability, identification of the recommended phase 2 dose(s) (RP2D), pharmacokinetic, pharmacodynamic, exploratory biomarker analyses, and preliminary efficacy.

Results As of June 2022, 19 subjects have been treated with davoceticept in dose escalation at 0.1 and 0.3mg/kg, Q1W and Q3W. Seven subjects experienced a total of 9 Grade 3+ treatment–related adverse events, including one Grade 5 cardiogenic shock in the 0.3mg/kg, Q3W cohort. Gr3+ immune-related adverse events were more common in subjects receiving 0.3 vs. 0.1mg/kg regimens of davoceticept, at 27.3% and 12.5%, respectively. Of 14 evaluable subjects, 1 confirmed partial response has been observed in a nivolumab-experienced subject with clear cell RCC. Additionally, tumor reductions have been noted in a second ongoing RCC subject, and in subjects with prostate cancer and serous peritoneal carcinoma. Fifty percent of evaluable subjects achieved a best response of stable disease.

Conclusions The davoceticept + pembrolizumab combination has demonstrated preliminary anti-tumor activity in clear cell RCC, potentially by reversing resistance to PD-(L)1i. Dose escalation efforts will resume at 0.1mg/kg, Q1W and Q3W. Tumor-specific expansion cohorts will open once the RP2D/schedule of the combination treatment is identified.

Trial Registration NCT04920383

Ethics Approval This study received ethics approval from the WCG IRB (Sarah Cannon; ID 20211877), Salus IRB (START Texas; ID START2021.28, START Midwest; ID STMW2021.18), and Mass General Brigham IRB (Massachusetts General Hospital; ID 2021P002079). All study subjects provided their informed consent to participate in this study.

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