A Phase 2 Single Arm Trial of Stereotactic Body Radiation Therapy Followed by Dual Immune Checkpoint Inhibition for Patients With Metastatic Pancreatic Ductal Adenocarcinoma - The Miami "EMPIRE" Trial - Eradication of Metastatic Pancreatic Cancer With Immuno-Radiation

The purpose of this study is to assess if radiation therapy (which uses high-energy radiation to damage or destroy cancer cells) combined with immune checkpoint inhibitors (medications that helps the body recognize and attack cancer cells) will be beneficial for patients with metastatic pancreatic ductal adenocarcinoma.

Balstilimab (AGEN2034, BAL) is a fully human monoclonal IgG4 antibody that binds with high affinity to programmed death 1 (PD-1), preventing its interaction with PD-L1 and PD-L2 ligands. The drug is designed to enhance T cell activation and effector function [1]. It is being developed by Agenus Inc. as both a monotherapy and in combination with other immunotherapy agents, particularly botensilimab (an anti-CTLA-4 antibody).

Clinical Trial Results

As a monotherapy, balstilimab showed activity in a phase II trial for recurrent/metastatic cervical cancer, with an objective response rate (ORR) of 15% and median duration of response of 15.4 months. In PD-L1 positive patients with squamous cell carcinoma, the ORR was 21%. The drug also showed some activity in PD-L1 negative patients [2]. When combined with zalifrelimab (anti-CTLA-4), the ORR increased to 25.6% in cervical cancer patients, with a disease control rate of 52% [3].

Safety Profile

The safety profile appears manageable based on clinical trials. In combination therapy with zalifrelimab for cervical cancer, the most common treatment-related adverse events were hypothyroidism (16.8%), diarrhea (14.2%), fatigue (11.6%), and nausea (9.0%) [3]. Development history includes a withdrawn BLA for cervical cancer in 2021, but the drug continues to be studied in various combinations and indications, particularly with botensilimab in colorectal cancer and other solid tumors [4].

Sources:

[1] Phase II Trial Results in Journal of Clinical Oncology [2] Clinical Trial Results in Gynecologic Oncology [3] Phase II Combination Trial Results in Journal of Clinical Oncology [4] Recent Development Update from BioSpace

Last updated: Dec 2024

Botensilimab is an investigational Fc-enhanced anti-CTLA-4 monoclonal antibody being developed by Agenus Inc. for cancer immunotherapy. It is designed to boost both innate and adaptive anti-tumor immune responses through multiple mechanisms: enhanced T cell priming and activation, depletion of regulatory T cells (Tregs) in the tumor microenvironment, activation of myeloid cells, and induction of long-term memory responses [1]. The drug's novel Fc-enhanced design allows it to bind more effectively to both high and low-affinity FcγRIIIA variants, potentially extending its benefits to a broader patient population compared to first-generation CTLA-4 inhibitors. Additionally, botensilimab is engineered to reduce complement-mediated toxicity through reduced C1q binding [2].

Clinical Efficacy

The drug has shown promising results in clinical trials, particularly in combination with the PD-1 inhibitor balstilimab. In a phase 1 trial of patients with microsatellite stable (MSS) metastatic colorectal cancer without liver metastases, the combination achieved a 23% objective response rate with a median overall survival of 21.2 months [3]. More recently, in the neoadjuvant NEST-1 trial for resectable colorectal cancer, the combination showed impressive pathologic response rates, with tumor shrinkage of ≥50% observed in 67.5% of MSS CRC patients [4]. The drug has demonstrated clinical responses across nine different types of metastatic, late-line cancers, including traditionally immunotherapy-resistant tumors.

Safety

The safety profile of botensilimab appears manageable based on clinical trial data. In the phase 1 trial combining botensilimab with balstilimab, the most common treatment-related adverse events were diarrhea/colitis, fatigue, and decreased appetite. Grade 3-4 adverse events occurred in approximately 39% of patients, with diarrhea/colitis being the most frequent serious adverse event. Notably, unlike some other CTLA-4 inhibitors, no cases of hypophysitis were reported in the monotherapy arm, which may be attributed to the drug's reduced complement activation [2]. As of 2024, approximately 1100 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials.

Sources:

[1] Cancer Discovery Article on Botensilimab Mechanism and Clinical Results [2] OncoDaily Detailed Review of Botensilimab [3] Phase 1 Trial Results in OncoLive [4] NEST-1 Trial Results Press Release

Last updated: Dec 2024

Inclusion Criteria:

1. ≥18 years old

2. Histologically or cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma.

3. Microsatellite stable (MSS) disease by pathologic assessment.

4. Patients must have measurable disease as defined by RECIST 1.1.

5. Progression on ≥1 line of systemic therapy.

6. No concomitant therapy with any of the following: interleukin (IL)-2, interferon, non study immunotherapy regimens, cytotoxic chemotherapy, immunosuppressive agents, other investigational therapies, and/or chronic use of systemic corticosteroids.

7. No known infection with human immunodeficiency virus (HIV) or active infection with Hepatitis B.

8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

9. Life expectancy ≥3 months.

10. Patients must have the following lab values obtained \<4 weeks prior to starting protocol treatment:

1. absolute neutrophil count (ANC) ≥1,000 cells/μL

2. white blood count (WBC) ≥2,000 cells/μL

3. platelets ≥75,000 per μL

4. hemoglobin ≥8.0 g/dL

5. creatinine clearance ≥40 mL/min)

6. serum total bilirubin ≤ 1.5 times the upper limit of normal (ULN)

7. aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤3 × ULN (or ≤5 × ULN in patients with liver metastases)

8. international normalized ratio or prothrombin time ≤1.5 × ULN

9. activated partial thromboplastin time ≤2.5 × ULN

10. absolute lymphocyte count (ALC) ≥1000 cells/μL at baseline

11. At least 1 previously unirradiated lesion amenable to pre-treatment biopsy.

12. No limit on overall numbers of lesions, but liver tumor burden ≤25% of total liver volume.

13. Women of childbearing potential (WOCBP): negative serum pregnancy test (within 7 days prior to Day 1 of protocol therapy)

a. Females of non-childbearing potential are defined as: i. ≥ 50 years of age and has not had menses for greater than 1 year ii. Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation iii. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation.

14. Male and female patients of reproductive potential must use effective methods of contraception or abstain from sexual activity for the course of the study through at least 6 months after the last dose of balstilimab and/or botensilimab. See Section 4.11, Contraception.

Exclusion Criteria:

1. Liver tumor burden exceeding 25% of total liver volume.

2. Active, untreated central nervous system (CNS) metastases.

3. Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years of the start of study treatment (i.e., with use of disease-modifying agents or immunosuppressive drugs).

4. Participants with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses (≤ 10 mg daily prednisone equivalent) are permitted in the absence of active autoimmune disease.

5. Previous external beam radiation therapy to the liver or radioisotope therapy directed to the liver or any liver embolization.

6. Clinically significant ascites requiring a paracentesis in the last 4 weeks, or clinically significant history of liver failure defined as any prior episode of hepatic encephalopathy and/or any prior history of an elevated serum ammonia level.

7. Partial or complete bowel obstruction within the last 3 months prior to study enrollment, signs/symptoms of bowel obstruction, or known radiologic evidence of impending obstruction.

8. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of study enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication.

a. QT interval corrected using Fridericia's formula (QTcF) of \> 480 ms.

9. Prior allogeneic organ transplantation.

10. Treatment with chemotherapy or targeted therapy within 2 weeks prior to initiating EMPIRE treatment.

11. Persistent grade ≥2 adverse events (aEs) from prior therapy (except neuropathy).

12. Known additional malignancy requiring active treatment.

13. History of non-infectious pneumonitis.

14. Active infection requiring antibiotic.

15. Live vaccine within 30 days of protocol treatment.

16. Severe acute respiratory syndrome (SARS) coronavirus 2 (CoV 2) (SARS-CoV-2) vaccine or booster \< 7 days before Cycle 1 Day 1 (C1D1). For vaccines requiring more than 1 dose, the full series should be completed prior to C1D1, when feasible. Booster shot not required but also must be administered \> 7 days from C1D1 or \> 7 days from future cycle on study.

17. History of severe hypersensitivity reaction to monoclonal antibody.

18. Participants with impaired decision-making capacity.