Targeted therapies in HER2 negative breast cancer
Missed the other parts?
Part 1: An introduction to the different subtypes of breast cancer can be found here.
Part 2: Targeted therapies in HER2 positive breast cancer can be found here.
Part 4: Targeted therapies in triple negative breast cancer can be found here.
HER2 negative breast cancer is harder to treat than HER2 positive cancer and there are fewer approved therapies. Endocrine therapy might be suitable for patients with HR-positive, HER2-negative metastatic BC [Ref 1], but endocrine agents have also now been studied in combination with inhibitors of cyclin-dependent kinases (CDK) 4 and 6. DNA damage repair targeting therapies such as olaparib and talazoparib, both PARP inhibitors, also show great promise in treating HER2 negative breast cancers for patients who present inactivating mutations in the BRCA1/2 genes.
Ibrance (palbociclib)
Pfizer’s Ibrance (palbociclib) was first approved in 2015. This oral drug targets a protein in breast cancer cells called CDK4/6, which may stimulate cancer cell growth. Used along with the Aromatase inhibitor letrozole, the drug is an option for women who have been through menopause and have HR positive, HER2 negative metastatic breast cancer. Palbociclib can also be used with Faslodex (fulvestrant) if the cancer has worsened after receiving other hormonal therapy. Palbociclib generally has few side effects. It can lower the number of white blood cells. But it does not appear to increase the risk of serious infections that are linked to low numbers of white blood cells.
Kisqali (ribociclib)
Kisqali (ribociclib) from Novatis was first approved in 2017. This oral drug also targets CDK4/6. Used with an aromatase inhibitor or Faslodex (fulvestrant), it is an option for women who have been through menopause and have ER positive, HER2 negative metastatic breast cancer. Side effects of ribociclib can include low numbers of white blood cells, increases in enzymes linked with liver damage, and changes in heart rhythms. In the phase III MONALEESA-2 trial, an analysis of overall survival with an additional 11 months of follow-up demonstrated a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole and a placebo. According to Novartis, Kisqali has characteristics that make it distinct from other CDK4/6 inhibitors: in particular, Kisqali shows especially strong inhibition against CDK4. In pre-clinical data, Kisqali is four- to five-fold more potent against CDK4 compared to CDK6. CDK4 is likely the dominant CDK in breast cancer and a pivotal driver of disease progression, the company suggests.
Verzenio (abemaciclib)
Verzenio (abemaciclib) from Eli Lilly was first approved in 2017, and is another oral drug that targets CDK4/6. It is approved by the FDA as a first-line treatment along with an aromatase inhibitor for women who have been through menopause and have ER positive, HER2 negative metastatic breast cancer. It may also be used along with fulvestrant if the cancer has worsened with other hormonal therapies. Abemaciclib may also be used alone as a treatment. It does not lower blood counts as much as the other CDK4/6 drugs, but it is more likely to cause diarrhoea, which can be severe at times. In the phase III MONARCH 3 trial, the drug demonstrated efficacy in an interim analysis with a 46% reduction in the risk of progression or death in patients receiving initial therapy for metastatic disease.
Afinitor/Zortress (everolimus)
First approved in 2012, Afinitor/Zortress (everolimus) from Novartis, is an mTOR inhibitor. Everolimus is used with the aromatase inhibitor exemestane for ER positive, HER2 negative metastatic breast cancer that has grown despite treatment with another aromatase inhibitor. Side effects of everolimus can include mouth sores, rash, diarrhoea, and, rarely, an inflammation of the lungs called interstitial pneumonitis.
PIK3CA gene mutation
Piqray (alpelisib) from Novartis was approved by the FDA in 2019. This PI3K inhibitor is an option along with the hormonal therapy fulvestrant for patients with hormone receptor-positive, HER2 negative metastatic breast cancer with a PIK3CA mutation that has worsened during or after hormonal therapy. About 30-40% of breast cancers have a mutated PIK3CA gene. Side effects include diarrhoea, rash, fatigue, changes in numbers of blood cells, nausea and vomiting, mouth sores, and changes in certain substances found in the blood, including high sugar levels and enzymes linked with liver damage.
BRCA1 or BRCA2 gene mutation
Lynparza (olaparib) from Merck Inc./AstraZeneca was first approved in 2018. This new oral drug may be used for patients with metastatic HER2 negative breast cancer and a BRCA1 or BRCA2 gene mutation who have previously received chemotherapy. It is a type of drug called a PARP inhibitor, which destroys cancer cells by preventing them from fixing damage. Common side effects include fatigue, anaemia, and occasionally nausea, vomiting, and diarrhoea. In the Phase III OlympiAD trial, patients treated with Lynparza had a 42% reduction in risk of their disease worsening or death (median 7.0 vs 4.2 months) compared to those who received chemotherapy (capecitabine, vinorelbine, eribulin).
Talzenna (talazoparib)
Talzenna (talazoparib) is a PARP inhibitor from Pfizer/Medivation that was FDA approved in 2018 and approved by the EU in June 2019. It is another option for patients with metastatic HER2 negative breast cancer and a BRCA1 or BRCA2 gene mutation. In the Phase III EMBRACA trial in patients with germline (inherited) BRCA1/2-positive (gBRCA+) locally advanced and/or metastatic breast cancer (MBC)there was demonstrated superior progression-free survival (PFS) in patients treated with talazoparib, compared to patients who received physician’s choice standard of care chemotherapy. Median PFS was 8.6 months (95% CI: 7.2, 9.3) for patients treated with talazoparib and 5.6 months (95% CI: 4.2, 6.7) for those treated with chemotherapy [HR: 0.54 (95% CI: 0.41, 0.71), p<0.0001]. This represents a 46% reduction in the risk of disease progression.
Next generation treatments for HER2 negative breast cancer include:
The combination of endocrine treatment with targeted agents has shown increased response rates and improved PFS in many trials. Unfortunately such combination therapy is also associated with increased toxicity, and this has helped spur the drive for new treatments. For example, tesetaxel from Odonate Therapeutics is related to taxane and this oral drug is not expected to cause hypersensitivity, which has been a problem. Phase II trials in combination with capecitabine have shown a confirmed response rate of 45% and the drug is progressing into phase III. Research has shown one advantage over other drugs: preclinical results indicate that following oral administration, tesetaxel achieves brain concentrations that exceed concentrations required for tumor killing for a sustained period of time. This is in contrast to paclitaxel and docetaxel, the most commonly prescribed taxanes, which do not substantially cross the blood-brain barrier. This should help to tackle brain metastases.
Join us next week for the fourth and final part of our series on breast cancer treatments. We will discuss the combination and next generation treatments available for the most difficult to treat breast cancer subtype, triple negative breast cancers. Part 1: An introduction to the different subtypes of breast cancer can be found here.Part 2: Targeted therapies in HER2 positive breast cancer can be found here.Part 4: Targeted therapies in triple negative breast cancer can be found here.Ref 1- “Hormone receptor–positive, HER2-negative metastatic breast cancer: redrawing the lines” A. Matutino et al. Current Oncology, VOLUME 25, SUPPLEMENT 1, June 2018 doi: http://dx.doi.org/10.3747/co.25.4000Learning Zones
The Learning Zones are an educational resource for healthcare professionals that provide medical information on the epidemiology, pathophysiology and burden of disease, as well as diagnostic techniques and treatment regimens.
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