Targeted therapies in HER2 positive breast cancer

Missed the other parts?

Part 1: An introduction to the different subtypes of breast cancer can be found here.

Part 3: Targeted therapies in HER2 negative breast cancer can be found here.

Part 4: Targeted therapies in triple negative breast cancer can be found here.

The HER2 positive breast cancer subtype is characterised by a high rate of metastasis and drug resistance; however, there are several useful therapies available.

Herceptin (trastuzumab)

First approved in 1998, Herceptin (trastuzumab) – with biosimilars known as Herzuma, Ogivri, Ontruzant – is the first-generation targeted therapy drug, a humanised monoclonal antibody. For metastatic breast cancer, trastuzumab can be given in combination with different types of chemotherapy or with hormonal therapy. Trastuzumab can be provided as a weekly infusion, or once every 3 weeks. Patients receiving trastuzumab have a small (2% to 5%) risk of heart problems and should have monitoring with an echocardiogram. Trastuzumab, administered either as a single agent or injected in combination with a series of chemotherapy agents (such as docetaxel or vinorelbine plus trastuzumab) shows improved time to progression, response and survival rate. Further, several trials have revealed that trastuzumab plus chemotherapy drugs significantly reduces the risk of recurrence and death and promotes survival compared to chemotherapy drugs alone, making trastuzumab the cornerstone of adjuvant treatments for HER2 positive breast cancer. [Ref 1]

Herceptin Hylecta (trastuzumab and hyaluronidase-oysk)

In February 2019, Genentech/ Roche Group announced the FDA has approved Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) for subcutaneous injection for the treatment of certain people with HER2-positive early breast cancer (node-positive, or node-negative and ER/PR-negative or with one high-risk feature) in combination with chemotherapy and HER2 positive metastatic breast cancer in combination with paclitaxel or alone in people who have received one or more chemotherapy regimens for metastatic disease. This new treatment includes the same monoclonal antibody as intravenous Herceptin in combination with recombinant human hyaluronidase PH20, an enzyme that helps to deliver trastuzumab under the skin. Herceptin Hylecta is a ready-to-use formulation that can be administered in two to five minutes, compared to 30 to 90 minutes for intravenous Herceptin.

Perjeta (pertuzumab)

First approved in 2013, Genentech/Roche’s Perjeta (pertuzumab) is a second-generation targeted drug family, which elicits similar effects to Herceptin and can significantly promote survival outcomes. Research shows that adding pertuzumab to Herceptin and chemotherapy as part of first-line therapy for HER2 positive metastatic breast cancer lengthens lives with few additional side effects. Based on this data, the combination of trastuzumab, pertuzumab, and chemotherapy has become a standard of care for the first-line treatment of untreated metastatic HER2 positive breast cancer. Pertuzumab is an intravenous medication and generally causes few side effects, although it can occasionally cause diarrhoea. Pertuzumab was approved by FDA in 2017 as a neoadjuvant therapy in combination with trastuzumab and cytotoxic chemotherapy. Research shows that pertuzumab in combination with trastuzumab is more effective in the blockade of HER2 signaling pathways in vitro and in vivo than either antibody alone and has transformed the drug’s role, making it a highly lucrative therapy: EvaluatePharma estimated Perjeta’s 2022 sales at $4.73 billion, up from about $1.9 billion in 2016.

Kadcyla (ado-trastuzumab emtansine)

Genentech/Roche’s drug Kadcyla (ado-trastuzumab emtansine) or T-DM1 was first approved in 2013 for the treatment of metastatic breast cancer for patients who have previously received trastuzumab and chemotherapy with either paclitaxel or docetaxel. T-DM1 is a combination of trastuzumab linked to very small amount of a strong chemotherapy. This allows the drug to deliver chemotherapy into the cancer cell while lessening the chemotherapy received by healthy cells. T-DM1 is given by vein every 3 weeks. The phase III EMILIA study and RESA study proved that T-DM1 was efficacious and facilitated better prognosis and improvements in health-related quality of life. T-DM1 has been investigated to promote progression-free survival (PFS) and overall survival (OS) in patients who were HER2 positive and previously treated with trastuzumab and taxane. In addition, the Phase III KATHERINE study met its primary endpoint, showing single agent Kadcyla significantly reduced the risk of disease recurrence or death versus Herceptin as an adjuvant treatment in people with HER2-positive early breast cancer who have residual disease following neoadjuvant treatment. Originally predicted to have sales of $4.1 billion by 2019, forecasts have been reduced due to the drug’s high cost and some less than favourable data: in the phase III MARIANNE study, Kadcyla treatment did not significantly improve patient progression free survival (PFS) compared to Herceptin.

Tykerb (lapatinib)

Originally approved in 2007, the Novartis drug Tykerb (lapatinib) is a reversible HER2 TK inhibitor that reacts with the ATP binding site, which in turn improves PFS and clinical benefit rate. Women with HER2 positive metastatic breast cancer may benefit from lapatinib when other medications are no longer effective. The combination of lapatinib and the chemotherapy capecitabine is approved to treat metastatic HER2 positive breast cancer when a patient has already received chemotherapy and trastuzumab. The combination of lapatinib and letrozole is also approved for metastatic HER2 positive and ER positive cancer. Lapatinib is also used in combination with trastuzumab for patients whose cancer is growing while receiving trastuzumab. Lapatinib may be able to enter into the brain, and could be an option for HER2 positive breast cancer that has spread to the brain. Similarly, in some neoadjuvant clinical trials, lapatinib has been used in dual blockade with trastuzumab to treat patients with HER2 positive cancer.

Nerlynx (neratinib)

Seemingly out-performing Tykerb, Nerlynx (neratinib) from Puma Biotechnology is another kinase inhibitor in the form of a daily pill. Approved in 2017, neratinib is used to treat early-stage breast cancer after a woman has completed one year of trastuzumab and is usually given for one year. Some clinical trials show that it may also be effective in advanced breast cancer as well. In phase III trials, Nerlynx plus chemotherapy reduced the risk of disease progression or death by 24% when compared to Tykerb plus chemotherapy. In the phase III ExteNET trial, after five years of follow-up, invasive disease-free survival was 90.8% in the patients treated with neratinib compared with 85.7% in those receiving placebo.

Next generation treatments for HER2 negative breast cancer include:

DS 8201 ([fam-] trastuzumab deruxtecan) from Daiichi Sankyo and AstraZeneca is an antibody drug conjugate (ADC) developed for targeted delivery of chemotherapy inside cancer cells to minimise systemic exposure compared to the standard delivery. In May 2019, results from the Phase II DESTINY-Breast01 clinical trial in HER2 positive breast cancer showed the treatment met its primary endpoint of objective response rate, with the study drug demonstrating clinically meaningful response. The drug is currently in the DESTINY-Breast02 trial, a global phase III trial comparing safety and efficacy of DS 8201 with trastuzumab plus capecitabine or lapatinib plus capecitabine, in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with standard of care HER2 therapies. Although the HER2 positive breast cancer market is currently dominated by Roche and its group of HER2-targeted regimens (Herceptin, Perjeta, and Kadcyla), competition from these brands should be minimal due to trastuzumab deruxtecan’s positioning. AstraZeneca has aimed trastuzumab deruxtecan at heavily pretreated patients that have already received Kadcyla, Roche’s own antibody drug conjugate, which is typically used post-Herceptin. As such, trastuzumab deruxtecan’s targeted patients have likely already failed several HER2-directed therapies in addition to Kadcyla and have few, if any, treatment options available. 

MGAH 22 (margetuximab) from MacroGenics is an engineered monoclonal antibody. In results from a late-stage study (SOPHIA), margetuximab showed extended progression-free survival in previously treated HER-2 positive metastatic breast cancer patients over Roche's Herceptin, when both were given alongside chemotherapy. Treatment with MacroGenics' drug reduced the risk of disease worsening or death by 24% in the Phase III trial. In a subgroup of patients carrying a certain genetic marker (the CD16A (FcγRIIIa) 158F allele), which correlated with worse responses to Herceptin, the measured risk reduction climbed to 32%. Some 86% of the SOPHIA patients were carriers of CD16A/158F, a figure that probably reflects the real world distribution, and it has long been suspected that patients with this genotype have a poor response to Herceptin. However margetuximab has yet to show a clear benefit in overall survival. The company plans to submit to the FDA for approval in the second half of 2019.

Join us for Part 3 where we focus on the HER2 negative breast cancer subtype that is harder to treat than HER2 positive breast cancer. Learn about new cyclin inhibitors, and DNA repair targeting treatments such as olaparib.

Part 1: An introduction to the different subtypes of breast cancer can be found here.

Part 3: Targeted therapies in HER2 negative breast cancer can be found here.

Part 4: Targeted therapies in triple negative breast cancer can be found here.

 

Ref 1- “Novel treatment strategies for patients with HER2-positive breast cancer who do not benefit from current targeted therapy drugs” Nan Jiang et al. Exp Ther Med. 2018 Sep; 16(3): 2183–2192. Published online 2018 Jul 17. doi: 10.3892/etm.2018.6459.