# DL 2 HFB (n=1)
# DL 1 HFB (n=1)
## Overview
- **DL** (Dose Level)  
- **HFB** (HFB200603)  
- **Q3W** (once every 3 weeks)  
- **TIS** (tislelizumab)

## Adverse Events
| Adverse Event                | HFB200603 (Monotherapy) | HFB200603 + TIS               |
|------------------------------|-------------------------|-------------------------------|
| Nausea                       | 1 (6)                   | 1 (6)                         |
| Intratumoral CD8+ T cell     | Ongoing > 6 mo         |                               |
| Oral dryness                 | 1 (4)                   | 1 (4)                         |
| Palmar erythema             | 1 (4)                   | 1 (4)                         |
| Platelet count decreased     | 3 (12)                  | 3 (12)                        |
| Pruritus                    | 3 (12)                  | 1 (4) 2 (8)                  |
| Rash                         | 2 (8)                   | 2 (8)                         |

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## Trial Summary
HFB200603 was well tolerated in monotherapy and in combination with tislelizumab with no DLTs and no TRAEs leading to dose modification or drug discontinuation.  
### Disease Cell Atlas scRNA of tumors refractory to IO:
- Example from clear cell renal cell carcinoma (52k tumor immune cells)  
- HFB200603 PK is favorable for immune antagonism  
- HFB200603 exposures are linear, dose-dependent, and similar to those projected from preclinical studies.

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### Monotherapy Summary
Monotherapy • HFB200603 shows a favorable safety profile and demonstrates a dose-dependent PK and PD both as a monotherapy and in combination with TIS in subjects with heavily pre-treated refractory solid tumors.

### Research Findings
- **BTLA and PD-1 in exhausted CD8+ T cells:**  
   - Consistent with an inhibitory role of BTLA in these cells.
   - Using bulk RNA expression databases, the expression of BTLA and its ligand HVEM (TNFRSF14) was assessed, showing potential benefit from combination treatment.

- The DIS® platform was used to select tumor types most likely to respond to HFB200603 based on target biology and single-cell insights.

## Objectives and Study Design
### Primary Objectives
- Examine preliminary anti-tumor efficacy, ORR using RECIST 1.1 and iRECIST  
- Establish RDEs and RP2D

### Secondary Objective
- Assess PK, PD, and immunogenicity of HFB200603

### Exploratory Objective
- Establish Proof of Mechanism (POM) in paired tumor biopsies and peripheral blood

## Key Eligibility Criteria
- Adult patients with advanced or metastatic solid tumors, including:  
   - Clear cell renal cell carcinoma  
   - PD-L1+ colorectal cancer  
   - PD-L1+ gastric cancer  
   - PD-L1+ melanoma  
   - PD-L1+ non-small cell lung cancer  
- Measurable disease - RECIST 1.1
- Patient must have exhausted standard lines of systemic therapy

## Treatment Related Adverse Events (N=42)
| Adverse Event                | HFB200603 Monotherapy (N) | HFB200603+TIS (N=25)       |
|------------------------------|---------------------------|-----------------------------|
| Asthenia                     | 4 (24)                    | 1 (4)                       |
| Diarrhea                     | 1 (6)                     | 2 (8)                       |
| Fatigue                      | -                         | 1 (4)                       |
| Nausea                       | 1 (6)                     | 1 (4)                       |
| Oral dryness                 | -                         | 1 (4)                       |
| Palmar erythema             | -                         | 1 (4)                       |
| Platelet count decreased     | -                         | 3 (12)                      |
| Pruritus                    | -                         | 3 (12)                      |
| Rash                         | -                         | 2 (8)                       |

## Immune Activation Results
Peripheral flow cytometry analysis revealed that the proliferating (Ki67+) cell fractions of CD4+ and CD8+ T cells showed moderate expansion following HFB200603 treatment, both as monotherapy and in combination with tislelizumab (Wilcoxon test p<0.05).

## Disease Control Rate (DCR)
- 65% per RECIST 1.1
- Evidence of mechanism in the tumor context  
   - DCR includes stable disease (SD), partial response (PR) and complete response (CR) in target lesion per RECIST 1.1

## Acknowledgments
Using DIS® guided enrichment of tumor types, we generated compelling proof-of-mechanism data reinforcing our confidence in HFB200603, demonstrated by observed clinical activity and associated predictive biomarkers.  
Preliminary clinical activity in liver metastases across several heavily pre-treated tumor types, including MSS-CRC, ccRCC, and gastric cancer, is encouraging and will be further explored in the Dose Expansion part of the trial.