PowerPoint Presentation
Evaluation of HVEM and PD-L1 Expression Profile in Tumors as Potential Predictive Biomarkers for HFB200603, a BTLA Antagonist, as Monotherapy and in Combination with Tislelizumab
Authors
María de Miguel, Eladio Marquez, Germain Margall-Ducos, Victor Moreno, Valentina Gambardella, Gennaro Daniele, Jessica Menis, Ana Landa Magdalena, Anthony B. El-Khoueiry, Emiliano Calvo, Alice Rossi, Francesca Zacchi, Olja Rapaic, Melissa Harney, Juying Li, Hombline Poullain, Alexander Chung, Francisco Adrian, Jinping Gan
Institutions
START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, HiFiBiO Therapeutics Inc., START Madrid - Hospital Fundación Jiménez Díaz, Hospital Clinico Universitario de Valencia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS – Università Cattolica del Sacro Cuore, Azienda Ospedaliera Universitaria Integrata di Verona, Clinica Universidad de Navarra, University of Southern California Norris Comprehensive Cancer Center.
Background
- BTLA is a co-inhibitory immune checkpoint molecule primarily expressed on B cells, T cells, and dendritic cells. The binding of HVEM to BTLA induces the recruitment of SHP1 and SHP2, leading to the inhibition of T cell proliferation and cytokine production.
- Previously, we reported Phase 1 results that demonstrated a tolerable safety profile and clinically meaningful efficacy with HFB200603 as monotherapy and in combination with tislelizumab (TIS) in advanced refractory solid tumors.
- In addition, we report potential biomarkers predictive of response to HFB200603 monotherapy and in combination with TIS.
Study Design and Patient Demographics
DL (Dose Level); HFB (HFB200603); Q3W (once every 3 weeks); TIS (tislelizumab)
Demographics and Clinical Characteristics
| Characteristic | Monotherapy (n=17) | Combination (n=43) |
|---|---|---|
| Median age, years (range) | 62 (39-77) | 63 (44-82) |
| Female | 6 (35) | 15 (35) |
| Male | 11 (65) | 28 (65) |
| ECOG PS 0 | 13 (76) | 27 (63) |
| ECOG PS 1 | 4 (24) | 16 (37) |
| Median time since initial diagnosis (range), years | 2.5 (0.9-13.7) | 3.5 (0.4-24.3) |
| Median number of prior systemic cancer therapy regimens (range) | 3 (1-4) | 3 (1-7) |
| Received prior anti-PD-(L)1 therapy: Yes | 8 (47) | 22 (51) |
| Received prior anti-PD-(L)1 therapy: No | 9 (53) | 21 (49) |
| Median follow-up time (range), months | 2.7 (0.9-12.0) | 3.5 (0.5-18.2) |
| Tumor types, PD-L1+ Colorectal cancer | 7 (41) | 14 (33) |
| Tumor types, Clear cell renal cell carcinoma | 3 (18) | 9 (21) |
| Tumor types, PD-L1+ Non-small cell lung cancer | 3 (18) | 8 (19) |
| Tumor types, PD-L1+ Gastric cancer | 3 (18) | 7 (16) |
| Tumor types, PD-L1+ Melanoma | 1 (6) | 5 (11) |
ECOG PS, Eastern Cooperative Oncology Group performance status; PD-(L)1, programmed cell death protein (ligand) 1.
- Grade 3 TRAEs in 3 of 5 subjects were lab abnormalities (AST/ALT, lipase increase) which quickly resolved without medication.
- HFB200603 monotherapy was well tolerated with treatment-related adverse events (TRAEs) limited to Grade 1 and no Grade 3.
- HFB200603 + TIS was also well tolerated with TRAEs mostly Grade 1-2 and few incidences of Grade 3.
Safety Profile
| Adverse Event | Treatment Related Adverse Events (TRAE), ≥2 Incidence or Grade 3 |
|---|---|
| HFB200603 Monotherapy (n=17) | |
| Any, n (%) | Gr 1, n (%) |
| Overall | 6 (35) |
| ALT / AST increased | 1 (6) |
| Anemia | - |
| Amylase increased | - |
| Arthralgia | - |
| Diarrhea | 1 (6) |
| Fatigue / Asthenia | 5 (29) |
| Lipase increased | - |
| Myalgia | 1 (6) |
| Nausea | 1 (6) |
| Pneumonitis | - |
| Pruritus | 1 (6) |
| Rash / dermatitis acneiform / psoriasis | - |
| Thrombocytopenia | - |
Potential Baseline Biomarkers Predictive of Response to HFB200603 ± TIS
- HFB200603 monotherapy efficacy observed with preliminary clinical activities.
- Tumor – mIF: HVEM and PD-L1 expression on immune cells may be predictive of responses.
- Increased levels of HVEM expressing CD8 T cells may be predictive of prolonged PFS in response to HFB200603 monotherapy.
- Higher expression levels of HVEM and PD-L1 on immune-suppressing macrophages may be predictive of prolonged PFS in response to HFB200603 + TIS combination.
Summary
- Integrative analysis of tumor mIF dataset identified biomarkers potentially predictive of responses.
- HVEM+CD8T aligns with HFB200603 MOA in activating BTLA+ CD8 T cells.
- CPS may be a surrogate for selecting patients with higher HVEM+ PDL1+ macrophages as a potential response enrichment strategy.
- MSS-CRC and ccRCC warrant further evaluation with additional patients.
We extend our thanks to the patients, their families, and the investigators and staff members who made this trial possible.
- de Miguel. et al., (2024) ESMO 2024. Barcelona, Spain. Study sponsored by HiFiBiO Inc.