Value of Novel HER2+ Breast Cancer Therapies

HER2+ breast cancer is a clinically distinct entity, due to the striking efficacy of targeted HER2 drugs, both in early stage and metastatic breast cancer (MBC). In the early 1980s, HER2 gene amplification resulting in excess HER2 protein in breast cancer cells, was discovered to stimulate excess cell growth and division. High levels of the HER2 protein were expressed in about 20% of breast cancers, which was associated with a higher risk of metastases and relapse, and reduced overall survival.

Herceptin (trastuzumab; Genentech)  is a HER2 specific monoclonal antibody against the HER2 protein. In 1998 Herceptin received FDA approval for therapy in combination with cytotoxic chemotherapy of HER2 positive metastatic breast cancer overexpressing the HER2 protein based on a randomized clinical trial which demonstrated dramatic improvements in progressing free survival (PFS) and overall survival (OS) over chemotherapy alone. In November, 2006, the FDA expanded the indication for Herceptin to adjuvant therapy in combination with cytotoxic chemotherapy for early stage breast cancer overexpressing the HER2 protein after two large randomized adjuvant trials demonstrated that Herceptin added to chemotherapy improved 5-year disease free survival (DFS) in Stages 1 through 3 breast cancer by almost 20% over chemotherapy alone.

Other novel anti-HER2 therapies have also changed clinical practice. Perjeta (pertuzumab; Genentech) is a monoclonal antibody to the HER2 protein that blocks dimerization on the cell surface of HER2 and HER3, resulting in growth inhibition. Preclinical data suggested that Perjeta would be synergistic with Herceptin. A large randomized clinical trial (CLEOPATRA) demonstrated substantial improvements in PFS and OS when Perjeta was added to Herceptin (THP), and docetaxel over Herceptin and docetaxel alone (TH) as therapy for HER2 positive MBC . The 5-year survival of patients on THP was 60 months, and represents substantial progress in turning this subset of MBC into a chronic, stable disease with long term survival. Additionally, randomized clinical trials in the neoadjuvant setting adding pertuzumab to standard Herceptin-containing chemotherapy regimens (NEOSPHERE, TRYPHANEA) as therapy for locally advanced HER2 positive early stage breast cancer have resulted in better complete pathologic response (pCR) as surgery, and superior 5-year DFS. A recent study (APHINITY) demonstrated that the addition of Perjeta to Herceptin containing regimens as adjuvant therapy for HER2+ early stage breast cancer results in modest improvements in 4 year DFS over Herceptin-based therapy alone.

Kadcyla (ado-trastuzumab emtansine; Genentech) is a novel antibody drug conjugate linking emtansine (a cytotoxic microtuble inhibitor) to Herceptin. The low doses of emtansine coupled with direction of the therapy to HER2 overexpressing cancer cells results in effective therapy with less toxicity than standard agents. A large randomized trial comparing Kadcyla to capecitabine and Tykerb (lapatinib; Novartis) threapy (EMILIA) demonstrated substantial improvements in PFS and OS with Kadcyla, and far less toxicity in women with progressive metastatic HER2+ MBC. Kadcyla is the current standard of care for progressive HER2+ MBC.

Newer anti HER2 therapies and strategies seek to improve on these impressive results. HER2 tyrosine kinase inhibitors (TKIs) seek to inhibit the intracellular portion of the HER2 protein and block downstream signalling. Tykerb has already been approved for this use in combination with capecitabine chemotherapy, and multiple other HER2 TKIs [pyrotinib, tucatinib, and Nerlynx (neratinib; Puma Biotechnology)] are currently under clinical investigation. Nerlynx, when added as extended adjuvant therapy to existing Herceptin-based adjuvant therapy for early stage HER2 positive breast cancer, improved 5-year DFS in a randomized clinical trial, and was recently approved for this use by the FDA.

Targeted HER2 therapies are generally well tolerated. Herceptin is associated with a low risk of cardiotoxicity requiring periodic monitoring by echocardiograms. Perjeta is associated with diarrhea and rash in less than 10% of patients. HER2 TKIs such as Nerlynx and Tykerb are also associated with a 10% to 15% incidence of grade 3 diarrhea. The CONTROL study addressed this issue with Nerlynx, and demonstrated that loperamide reduced the incidence, severity, and duration of associated diarrhea. Adding colestipol or budesonide further reduced frequency and duration of diarrhea in this trial, suggesting further strategies to reduce this side effect.

Outcomes in HER2+ breast cancer have clearly improved with the use of novel HER2 targeted therapies. Assessing the value of these therapies can be measured as a balance of the clinical costs and benefits to the patient in terms of survival benefit, toxicities and quality of life. Several studies from the United States, Canada, Australia, and Europe suggest adjuvant Herceptin for HER2+ breast cancer is cost-effective, with the current costs of novel anti-HER2 therapies are several thousand dollars per quality-adjusted life year (QALY) gained.

Nonetheless, identification of subsets of patients who would benefit from de-escalation of treatment without compromising patient care could possibly improve this cost-effectiveness. Recent data from a phase II study of 12 weeks of adjuvant Herceptin and paclitaxel in women with HER2+ node negative early stage breast cancer, where a 4-year DFS of 97% was demonstrated with minimal toxicity and decreased costs, suggest that such de-escalation is possible. Additionally, with the introduction of multiple biosimilar traztuzumab products in the United States within the next 18 months, it is expected that costs can be further decreased with no detriment to the substantial clinical benefit this agent provides.