PII-030 - ETRUMADENANT CAN BE COADMINISTERED WITH STRONG CYP3A4 INHIBITORS: CONCLUSIONS FROM A CLINICAL DRUG INTERACTION STUDY AND EXPOSURE-SAFETY ANALYSIS

L. Adeojo¹, I. Linsmeier¹, J. Johnson¹, B. Agoram¹, L. Zhou¹; ¹Arcus Biosciences, Hayward, CA, USA.

Background: • Etruma, a selective adenosine receptor antagonist, is an orally bioavailable small molecule being evaluated for cancer treatments in combination with PD-1 inhibitor zimberelimab (zim) and chemotherapy.
• Etruma is a CYP3A4 substrate, and its concomitant use with strong CYP3A4 inhibitors is restricted.
• A drug-drug interaction study with itraconazole, a strong CYP3A4 inhibitor, showed an 18% and 62% increase in etruma Cmax and AUC, respectively, in healthy subjects receiving etruma 150 mg1

OBJECTIVE
• To evaluate preliminary exposure-safety (ES) relationship of etruma in combination with zim in patients to support the removal of the restriction of concomitant use of CYP3A4 strong inhibitors.

Methods: • PK modelling. Population PK model was built using NONMEM. Its methodology was reported previously 2.
• ES analysis. The exploratory ES analysis was conducted with etruma exposure at 75-200 mg QD in combination with zim (5 studies, n=361 patients), by Kaplan-Meier method and logistic regression approach using R. A potential correlation was explored between simulated individual Cavg or Cmax at day 1 and steady state, and probability of occurrence of first Grade 3+ treatment emergent adverse events (Gr3+ TEAEs) and serious adverse events (SAEs) anytime from start of treatment.

Results: • The exposure range tested (75-200 mg) overlapped with the observed etruma exposure (150 mg) in the presence of a strong CYP3A4 inhibitor, indicating the exposure range tested is appropriate.
• Incidences of experiencing Gr3+ TEAE (Figure 1a) or SAE in each tertile of exposure were similar, suggesting no apparent relationship between Gr3+ TEAE or SAE and etruma exposure.
• Consistently, Logistic regression analysis showed no apparent trend, suggesting increase in exposure after 75-200 mg (QD) of etruma is not associated with higher probability of Gr3+ TEAE (Figure 1b) or SAE.

Conclusion: • The absence of correlation of etruma exposure (75-200 mg) with G3+ TEAE or SAE, along with limited exposure change in presence of itraconazole, supports the safe co-administration of 150 mg etruma with strong CYP3A4 inhibitors. Removal of the restriction of concomitant use of CYP3A4 strong inhibitors in the current clinical protocols is recommended.

REFERENCES
1. Zhou L, et al. 2022 ASCPT Poster Number PII-057
2. J. Johnson et al. 2024 ASCPT Poster Number LB-015