Boosting immunotherapy response in high-risk triple-negative breast cancer with CSF-1R blockade and radiation

IIT2021-01-Shiao-CSF1Ri: Reinvigorating TNBC Response to Immunotherapy With Combination Myeloid Inhibition and Radiation

This will try pembrolizumab with axatilimab and radiation before surgery to see if it increases complete tumor disappearance in adults with high-risk triple-negative breast cancer.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 35 (estimated)
• Ages: 18 Years and up
• Sex: Female
• Sponsor: Cedars-Sinai Medical Center (other)
• Drugs / interventions: pembrolizumab, chemotherapy, radiation
• Locations: 1 site (Los Angeles, California)
• Trial ID: NCT05491226 on ClinicalTrials.gov

What this trial studies

This open-label, single-institution Phase II trial enrolls adults with high-risk triple-negative breast cancer planned for neoadjuvant therapy who have low stromal tumor-infiltrating lymphocytes, node-positive disease, or low PD-L1/CPS. Participants receive pembrolizumab (PD-1 inhibitor) combined with axatilimab (CSF-1R inhibitor) plus radiation therapy prior to standard-of-care surgery, with requirement for archived or newly obtained tumor tissue and research blood draws. The primary endpoint is pathologic complete response (pCR), defined as no invasive disease in the breast and lymph nodes at surgery, while secondary endpoints include changes in TILs, safety and tolerability, progression-free survival, event-free survival, overall survival, and node clearance. The single-arm design aims to detect biological and clinical signals that myeloid inhibition plus radiation can reinvigorate anti-tumor immunity when added to PD-1 blockade.

Who should consider this trial

Good fit: Adult women with histologically confirmed high-risk triple-negative breast cancer (ER/PR <1%, HER2 negative) who are candidates for neoadjuvant therapy and have low sTILs (≤40%), node-positive disease, or low PD-L1/CPS are the intended participants.

Not a fit: Patients with hormone-receptor or HER2-positive tumors, metastatic disease not treated with a neoadjuvant approach, active uncontrolled autoimmune disease, or those unable to receive immunotherapy, CSF-1R inhibition, or radiation are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the combination could raise rates of pathologic complete response before surgery and potentially improve longer-term outcomes for patients with high-risk TNBC.

How similar studies have performed: Pembrolizumab added to neoadjuvant chemotherapy has improved pCR rates in TNBC, but the specific combination of PD-1 blockade with CSF-1R inhibition and radiation is newer and currently supported mainly by preclinical data with limited clinical experience.

Eligibility criteria

Inclusion Criteria:

* Female patients diagnosed with high-risk triple negative breast cancer (TNBC) with intent for neoadjuvant therapy.
* Low tumor-infiltrating lymphocyte (TIL) score, defined as stromal TIL (sTIL) ≤40%; or node-positive; or combined positive score (CPS) \< 10 or PD-L1 tumor positivity \<1%.
* Written informed consent obtained from subject and ability for subject to comply with the requirements of the study, including consent for research blood draws and use of available archived tissue.
* Age ≥ 18 years of age on day of signing informed consent.
* Histologically or cytologically-confirmed TNBC (defined as ER \<1%, PR\<1%, her-2-neu 0-1+ by IHC or FISH-negative).
* If an archived tumor tissue is unavailable, be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1 of RT.
* Have a performance status of 0 or 1 on the ECOG Performance Scale.
* Demonstrate adequate organ function.
* Female subject of childbearing potential should have a negative serum or urine pregnancy test or documentation of absence of pregnancy by a gynecologist within 14 days of initiating first dose of pembrolizumab (1 week lead-in) for eligibility verification.
* Female subjects of childbearing potential should be willing to comply to the contraceptive guidance in Appendix 12.2 during the treatment period through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.

Exclusion Criteria:

* Evidence of metastatic disease.
* Has received prior radiotherapy within 2 weeks of start of study intervention.
* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
* Has a known history of active TB (Bacillus Tuberculosis).
* Hypersensitivity to pembrolizumab or any of its excipients.
* Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., \> Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
* Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., \> Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
* Has a known additional malignancy that progressed or required treatment in the last 5 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain parenchymal metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
* Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has known history of/active, non-infectious pneumonitis requiring treatment with steroids or has history of/active interstitial lung disease.
* Has an active infection requiring systemic therapy.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. A WOCBP who has a positive urine pregnancy test within 2 weeks prior to start of study treatment (first dose of pembrolizumab). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: Negative urine or serum pregnancy test is also conducted within 72 hours prior to C1D1 for study procedures but if screening pregnancy test is done within 72 hours of C1D1, it is not required to be repeated..
* Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* Has a known history of active Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
* Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of pembrolizumab. Administration of killed vaccines is allowed.
* Has had an allogenic tissue/solid organ transplant.

Where this trial is running

Los Angeles, California

• Cedars-Sinai Medical Center — Los Angeles, California, United States (RECRUITING)

Study contacts

• Principal investigator: Stephen L Shiao, MD, PhD — CSMC
• Study coordinator: Clinical Trial Recruitment Navigator

Conditions: TNBC - Triple-Negative Breast Cancer, Breast Cancer, pembrolizumab, axatilimab, radiation therapy