# A Phase I/II Trial Investigating Safety and Efficacy of Autologous TAC01-HER2 in Relapsed or Refractory Solid Tumors (TACTIC-2)

## INTRODUCTION

• The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the re-direction of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex, with the goal to elicit a safe and durable anti-tumor response. In preclinical models, TAC-engineered T cells effectively eradicate tumor cells in vitro and in vivo without toxicities typically associated with engineered T cell products. TAC01-HER2 is an autologous T-cell product comprising T cells expressing the HER2 TAC, which specifically recognize HER2+ cells.

• We present updated preliminary data from Cohorts 1-4 (20 participants) that highlights safety and efficacy data; the study further elucidates potential therapeutic impact to patients with HER2 overexpressed solid tumors.

• TACTIC-2 (NCT04727151) is an open-label, multicenter phase I/II study that aims to establish safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetic profile, and efficacy of TAC01-HER2 in patients with HER2-positive solid tumors by immunohistochemistry that are 1+, 2+, or 3+ (i.e. breast, lung, pancreatic, colorectal, gastric, endometrial, ovarian, and others) whom have progressed on prior anti-cancer therapies.

## TAC SCIENCE

TAC achieves TCR activation via a CD3 binding domain while tightly binding the target of interest, HER2. TAC thus co-opts natural TCR function and provides intracellular co-receptor signaling via LCK, mimicking physiologic TCR activation.

## TRIAL DESIGN

## Phase II Dose Expansion

**Lymphodepleting Chemotherapy:**

**3 consecutive days of fludarabine (Flu)* IV (30 mg/m²) and cyclophosphamide (Cy) IV (300 mg/m²) +/- Mesna IV**  
***due to national shortage of fludarabine, modified LDC given per institutional standard**

## PHASE I TRIAL PROGRESS

## Secondary Endpoints

## Primary Endpoints

## Safety: DLTs, AEs

## Eligibility Criteria

**Patients with advanced, metastatic, unresectable solid tumors which express HER2 after at least 2 lines of therapy, at least 1 measurable lesion per RECIST version 1.1, ECOG performance score 0-1, grade 1 or baseline for any prior treatment related toxicities.**

| Demographics and Tumor Intrinsic Characteristics(all cohorts,n=20) |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Median Age(Range),by Year |  | 59(40-70) | Tumor Type,n(%) | Gastroesophageal Junction | 5(25) |  |
| Sex:Male/Female,n(%) | M | 12(60) | Tumor Type,n(%) | Gastric | 3(15) |  |
| Sex:Male/Female,n(%) | F | 8(40) | Tumor Type,n(%) | Esophageal | 2(10) |  |
| Race,n(%) | White | 18(90) | Tumor Type,n(%) | Breast | 3(15) |  |
| Race,n(%) | Other | 2(10) | Tumor Type,n(%) | Colorectal | 4(20) |  |
| ECOG PS,n(%) | 0 | 11(55) | Tumor Type,n(%) | Gall Bladder | 1(5) |  |
| ECOG PS,n(%) | 1 | 9(45) | Tumor Type,n(%) | NSCLC | 1(5) |  |
| HER2 Expression,n(%) | 3+ | 11(55) | Tumor Type,n(%) | Ovarian | 1(5) |  |
| HER2 Expression,n(%) | 2+/FISH+ | 6(30) | Previous HER2 Therapy | Trastuzumab | 16(80) |  |
| HER2 Expression,n(%) | 2+/FISH- | 1(5) | Types,n(%) | Trastuzumab Deruxtecan | 8(40) |  |
| HER2 Expression,n(%) | 1+ | 2(10) | Investigative | 6(30) |  |  
| Previous Anti-Cancer Therapy,Median(Range) |  | 4(2-12) | Pertuzumab | 4(20) | Tucatanib | 1(5) |
| Previous Lines of HER2 Therapy,Median(Range) |  | 2(0-9) | Trastuzumab Emtansine | 1(5) | Lapatinib | 1(5) |

## PHASE I SAFETY DATA

## Safety Summary

• **1 patient experienced a DLT (grade 3 pneumonitis) that resolved with standard of care intervention**

• **11 patients experienced 14 CRS events which resolved with standard of care intervention:**

**Grade 1, n=7**

◦

◦ **Grade 2, n=6**  
**Grade 3, n=1**
• **No Observed Immune Effector Cell-Associated Neurotoxicity (ICANS)**  
**Most grade ≥2 events were expected and related to LD chemotherapy.**

## CHANGES IN TUMOR MEASUREMENTS ACROSS ALL DOSE LEVELS

Cohort 1  
• Entry DL, however 1st signal of clinical activity, showing 1 pt. with mixed response (SoD reduction but new lesion development)
<u>Cohort 2</u>

<u>Cohort 3</u>  
• 2 pts. with SD and 1 pt. with PD  
<u>Cohort 4</u>

## Follow-Up

• 1 pt. with PR (for 3 months after treatment), 5 pts. with SD and 3 pts. with PD

Disease control rate of 69% at DL2-4, in heavily pretreated pts. with aggressive malignancies  
**ORR of 29% and DCR of 86% in gastric/esophageal AC pts at DL2-4.**

All patients are still in 2-year follow-up per protocol, except for nine patients who died due to PD, two who withdrew consent and one who was lost to follow-up.

## TAC01-HER2 PK and Cytokine Analysis

TAC copies detected in the blood of subjects at the indicated dates post-treatment. Lines represent the mean value of all subjects in a cohort. Cohort 4 subjects (highest dose level) show the highest concentration of TAC transgene, with detectable levels 48 days post-treatment in most subjects.

## TUMOR ASSESSMENT: PATIENT RESPONSES

## Patient 0105-0033

**59 year old male with HER2+ (IHC 2+/FISH+) stage IV metastatic GEJ.**

**Previously treated with 3 lines of HER2-directed therapy (including Trastuzumab Deruxtecan) + chemotherapy.**  
**The patient also received bridging therapy with HER2-directed therapy.**  
**The subject progressed 3 months after treatment.**

## RECIST 1.1 Tumor Response Assessments (Measurable Disease)

| Baseline | Day 29 | % change |
| --- | --- | --- |
| 30mm | 0mm | -100% |

## Patient 0203-0021

**42 year old male with HER2+ (IHC 3+) stage IVb metastatic gastric adenocarcinoma.**

**Previously treated with 2 lines of HER2-directed therapy, chemotherapy & radiation therapy. The patient also received bridging chemotherapy.**

**The subject progressed 3 months after treatment.**

## RECIST 1.1 Tumor Response Assessments (Measurable Disease)

| RECIST 1.1 Tumor Response Assessments (Measurable Disease) |  |  |
| --- | --- | --- |
| Baseline | Day 29 | % change |
| 20mm | 13mm | -35% |

| Tumor | Size Pre | Size Post | SUVmax pre TAC-T | SUVmax post TAC-T |
| --- | --- | --- | --- | --- |
| Right lower paraesophageal node at the level of T10 | - | - | 6.5 | 3.2 |
| Gastrohepatic ligament lymph nodes | 2.4 x 2.3 cm | 1.9 x 1.2 cm | 20.5 | 15 |
| Portacaval nodal mass* | 5.1 x 4.0 cm | 4.8 x 3.4 cm | 22.1 | 29 |
| Left common iliac lymph node | No gross interval change per radiologist |  | 19.3 | 23.1 |

## Lymph Node Reduction

**There has been overall interval decreased size of previously noted metabolically active lymph nodes associated with the mass, however with persistent intense metabolic activity in most of them.**

*Despite SUVmax increase the lesions shows more extensive photopenic areas, representing cystic/necrotic change->cancer cell death.

** There was also a stable cystic/necrotic node (cancer cell death).

## SUMMARY & CONCLUSIONS

## SAFETY

**Interim results from the Phase I TACTIC-02 study suggest manageable safety for TAC-01 HER2 treatment. One DLT of G3 pneumonitis and one G3 CRS were observed, which resolved with standard of care measures.**

## EFFICACY

**No ICANs reported to date across all cohorts.**