Diana Spencer investigates therapies in clinical development for triple-negative breast cancer and asks what future treatments might look like.
Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancer cases and is one of the main causes of death in women. However, because these cancers are not driven by any of the three molecules that can be blocked by targeted hormone receptor drugs, current treatment options are limited.
Standard therapy for early-stage TNBC is cytotoxic chemotherapy with carboplatin or docetaxel, though this approach is associated with significant side effects.
A recent study by researchers at The Institute of Cancer Research, London, has shown that certain characteristics within TNBC patients’ primary tumours can predict how they will respond to different treatments after their tumours have spread around the body.
The researchers say that the presence of these biomarkers could be used to accelerate the development of more personalised treatments for TNBC. Though a positive step in the right direction, this is just a starting point. Are there other treatments in the pipeline that could successfully target this difficult to treat group of cancers?
Combination therapy with pembrolizumab
In July 2021, the Food and Drug Administration (FDA) approved Merck’s pembrolizumab (Keytruda) for high-risk, early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. The regulator had already approved the combination treatment in advanced cancers the previous year.
The FDA also granted approval to pembrolizumab in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumours express PD-L1. This was based on the results of the KEYNOTE-522 trial, which showed a pathological complete response rate of 63% for patients who received pembrolizumab in combination with chemotherapy compared with 56% for patients who received chemotherapy alone.
The addition of pembrolizumab was supported by further trial results in 2022. In the trial, KEYNOTE-355, overall survival improved only among patients whose tumours had relatively high levels of the PD-L1 protein – a PD-L1 combined positive score of at least 10. Among patients with this combined positive score, median overall survival was 23 months for those who received pembrolizumab and chemotherapy versus 16.1 months for those who received chemotherapy alone.
Despite the positive result, more than half of all patients with TNBC have PD-L1 combined positive scores of less than ten, so it was clear that more work was needed to find effective treatments for these patients.
Immunopheresis
In 2022, Immunopheresis was introduced as a new immuno-oncology option for advanced TNBC patients, both as monotherapy and adjunct therapy. As Immunopheresis is a subtractive therapy that occurs outside the body, it is intended to be much better tolerated than chemo- and immunotherapies, and used as an adjunct with these therapies, possibly in lower doses to reduce their toxicity.
Immunicom presented data from its ongoing clinical investigation at the American Society of Clinical Oncology’s (ASCO) 2022 Annual Meeting, which showed that its Immunopheresis LW-02 Column helps spur upregulation of a patient’s TNF-α pathway. Twenty-eight patients with advanced TNBC underwent 862 LW-02 Column Immunopheresis procedures. Ten patients received Immunopheresis LW-02 Column as a monotherapy, and 18 patients received it in addition to various chemotherapy regimens. After 30 minutes of therapy, the mean capture efficiencies for sTNF-R1 and sTNF-R2 – the proteins shed by tumours that suppress endogenous TNF-α – were 95.2% and 79.6%, respectively.
Commenting on the data, Immunicom Chief Clinical Officer Dr Victoria Manax, says: “LW-02 Column Immunopheresis data suggest that removing these factors is an increasingly promising modality for cancer patients. We continue to find evidence that this is an exciting new option in immuno-oncology.”
Oncolytic virus treatment to stimulate the immune system
In February 2023, investigators at Moffitt Cancer Center in Florida shared results from a Phase II clinical trial of the oncolytic virus talimogene laherparepvec (TVEC) combined with standard chemotherapy in patients with early stage TNBC. Studies have shown that patients who have higher levels of immune cells within their tumours tend to have better responses to therapy, which suggests that agents that stimulate the immune system may be beneficial in TNBC.
TVEC is a modified herpes simplex 1 virus that includes coding sequences for the protein GM-CSF, which can stimulate the immune system. It is injected directly into the tumour and undergoes replication within the tumour cells, resulting in the breakdown of the tumour cell and production of tumour derived antigens. Immune cells can recognise the antigens, infiltrate the tumour and target the cancer cells for destruction. In addition, GM-CSF made by the virus acts as a beacon to help recruit immune cells to the tumour.
TVEC is approved to treat advanced, late-stage melanoma. The Moffitt Phase II trial was designed to assess whether the oncolytic virus also could be effective in combination with standard chemotherapy when given to TNBC patients before surgery. The results showed that 45.9% achieved a response, 89% of the patients remained disease free two years post-treatment, and no recurrences occurred in patients who achieved strong responses.
“Our results demonstrate that TVEC, when added to systemic chemotherapy, may increase responses in high risk, early stage triple-negative breast cancer. There is evidence of robust immune activation within the tumour, and additional investigation of TVEC in combination with current chemoimmunotherapy for triple-negative breast cancer is warranted,” concludes Soliman, lead study author, medical director of Moffitt’s Clinical Trials Office and senior member of Moffitt’s Breast Oncology Department.
LAG-3 immunotherapies
Later the same year, Immutep initiated AIPAC-003 (Active Immunotherapy, Eftilagimod Alpha, and Paclitaxel), an integrated Phase II/III trial to evaluate eftilagimod alpha (efti) in combination with paclitaxel for the treatment of metastatic HER2-neg/low breast cancer (MBC). Based on feedback from the FDA/EMA, the trial has been expanded to include (TNBC) patients.
According to the company, as a first-in-class soluble LAG-3 protein targeting MHC Class II ligands on antigen-presenting cells (APC), efti can improve clinical outcomes from standard-of-care chemotherapy. Its activation of APCs (e.g., dendritic cells, monocytes) triggers a broad immune response that includes significant increases in cytotoxic CD8 plus T cells armed with chemo-induced tumour antigens to target cancer. This was demonstrated in the AIPAC Phase IIb trial’s encouraging results, including an over 2.9-month median overall survival improvement.
Conclusion
Treatments for TNBC have seen some progress in recent years, with the addition of pembrolizumab to standard chemotherapy offering hope to some patients. However, despite a number of promising new approaches in the pipeline, like Immunopheresis and modified viruses, this is still an area in desperate need of more targeted therapies and an opportunity for drug discovery innovation to make a significant impact.
