Triple-negative breast cancer (TNBC) is one of the more challenging, complex forms of the disease. According to the American Cancer Society, this form of the disease (which accounts for about 10% to 15% of all breast cancers) grows and spread faster, has more limited treatment options and has a worse prognosis than other invasive forms of the disease.
Outsourcing-Pharma recently spoke with Andrew Foxley, VP R&D franchise head for AKT & SERD with AstraZeneca, about an ongoing trial exploring the effectiveness of a pairing of drugs in treating TNBC.
OSP: What is metastatic triple-negative breast cancer—what distinguishes it from other forms of breast cancer, and what if anything makes it particularly challenging to treat and diagnose?
AF: Triple negative breast cancer (TNBC) is a collective term that refers to a subtype of breast cancer that occurs in about 10%-20% of diagnosed breast cancers and is more likely to affect younger people, African Americans, Hispanics, and those with a BRCA1/2 gene mutation.
TNBC is a particularly challenging-to-treat tumour and has an aggressive clinical course, including higher risk of development of distant metastases than other subtypes of breast cancer. Compared to women with other types of breast cancer, women with TNBC have an increased likelihood of death within 5 years of diagnosis.
What we do know is that TNBC lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and expresses a normal number of copies of HER2. These subtypes are differentially diagnosed using standard histopathology techniques such as immunohistochemistry for determination of ER, PR and HER2 expression, complemented by in situ hybridization (e.g. FISH) for HER2 testing by which the number of copies of the gene are detected using a fluorescence staining technique - the greater the number of copies of the gene, the more likely that a an anti-HER2 agent will be effective, whereas those whose tumour is positive for ER receptor can be treated with anti-hormonal therapies.
OSP: I understand treatment of triple-negative BC has been limited to sequential chemo—could you please explain some of the reasons for that?
AF: Until recently, sequential chemotherapy has been the only option for patients with this difficult to treat disease type - initially to shrink the tumour(s) before surgery and/or afterwards to seek to reduce the risk of relapse and then again if the disease becomes metastatic. For metastatic disease, chemotherapy has been the mainstay of therapy; this has been primarily driven by the lack of identification of clear markers of what may be driving the disease.
This is beginning to change as we understand more about this complex tumour type. For example, it is now known that patients who test positive for the BRCA gene benefit from PARP inhibitors. More recently, the addition of immunotherapy has been shown to be effective in association with chemotherapy in the metastatic setting, but this approach is only suitable for those who test positive for the PD-L1 protein.
Further therapeutic approaches are needed for patients whose disease is not suitable for these newer modalities – which is why we are studying capivasertib in this setting.
OSP: Could you explain some of the other treatments used for other forms of BC, and why they haven’t been used for triple-negative?
AF: TNBC is a subtype of breast cancer that tests negative for ER, PR, and excess HER2 protein. This translates to TNBC being unresponsive to anti-hormonal therapies, as well as treatments that target HER2.
In TNBC the PI3K/AKT/PTEN signalling pathway that mediates cell proliferation and resistance to cell death (apoptosis) is often activated. Activation of this pathway is also associated with resistance to multiple therapies, including chemotherapies.
This has turned attention to studying novel agents, including our AKT inhibitor capivasertib, which in a randomized Phase 2 clinical study has shown the potential to work in tandem with chemotherapy to extend disease progression time and patient survival. These findings were especially encouraging in a sub-group of patients whose tumour tested positive for alterations in one or more of the PIK3CA/AKT1/PTEN genes; We are seeking to confirm these findings in the Phase 3 CAPItello-290 study.
OSP: Could you tell us about the characteristics of capivasertib+paclitaxel (used separately, and in combination) and why the researchers chose that pairing for this P3 study?
AF: Paclitaxel is a chemotherapeutic agent administered as an intravenous infusion and is part of the standard of care for TNBC treatment; capivasertib is an oral potent, selective inhibitor of a protein called AKT and is active against three sub-forms. The AKT pathway is essential to cell growth, survival and metabolism, and cancers cells may rely on it in some circumstances to evade the attack from chemotherapy.
In an earlier Phase II study of patients with advanced TNBC, addition of capivasertib to the first-line chemotherapy paclitaxel resulted in significantly longer progression-free survival (PFS) and overall survival (OS) compared to placebo plus paclitaxel, especially but not exclusively in a sub-group of patients whose tumour tested positive for an alteration in one or more of PIK3CA/AKT1/PTEN genes. The combination was generally well tolerated, with a manageable safety profile. We are seeking to confirm these findings in the Phase 3 CAPItello-290 study.
OSP: Please tell us about your patient recruitment efforts. Do they involve any novel sources or outreach avenues that might be considered unique?
AF: We are building a connected infrastructure of digital and innovative tools across R&D and we’re piloting different solutions and platforms across our trials to best match patients and investigators. The quest for new therapies for patients with TNBC makes this a competitive space for patient recruitment, and we’re looking at innovative software and solutions so that we can efficiently identify and recruit patients for our trials.
OSP: I understand the trial is underway—is there anything you can tell us about preliminary results, observations or anything else you might have discovered?
AF: This ongoing double-blind randomized Phase 3 trial is evaluating the efficacy and safety of capivasertib in combination with paclitaxel chemotherapy in the first-line treatment of patients with metastatic TNBC. We have chosen to recruit all TNBC patients who are candidates for paclitaxel chemotherapy as this will enable us to identify those who most benefit from the combination. The trial has recently started recruiting and we look forward to presenting the results once available.
OSP: What lessons has your research team learned along the way?
AF: Our ongoing work has confirmed the profound heterogeneity that exists in this difficult to treat TNBC and breast cancer more generally, and novel treatments for both early and advanced TNBC remains a significant unmet need. We are beginning to understand more about how tumours respond to therapy and potential ways of making existing therapies more effective, which may provide the rationale for usage of targeted agents like capivasertib to bring benefit to patients.