Date Published: July 26, 2018
Publisher: Public Library of Science
Author(s): Benjamin Daniels, Federico Girosi, Hanna Tervonen, Belinda E. Kiely, Sarah J. Lord, Nehmat Houssami, Sallie-Anne Pearson, Aamir Ahmad.
Targeted cancer therapy is often complex, involving multiple agents and chemotherapeutic partners. In Australia, prescribing restrictions are put in place to reflect existing evidence of cost-effectiveness of these medicines. As therapeutic options continue to expand, these restrictions may not be perceived to align with best practice and it is not known if their use in the real-world clinic adheres to these restrictions. We examined the treatment of women receiving trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) to determine the extent to which treatment adhered to national prescribing restrictions.
Our population-based, retrospective cohort study used dispensing records for every Australian woman initiating publicly-subsidised trastuzumab for HER2+MBC between 2001–2013, followed through 2016. We used group-based trajectory models (GBTMs) to cluster patients, first on their patterns of trastuzumab exposure, and then on their patterns of lapatinib and chemotherapy exposure. We described the characteristics of patients within each cluster, and examined their treatments and combinations of treatments to determine restriction adherence.
Of 5,052 patients initiating trastuzumab, 1,795 (36%) received at least one non-adherent HER2-targeted treatment. The most common non-adherent treatments were trastuzumab combinations involving vinorelbine (24% of non-adherent treatments); capecitabine (24%); and anthracyclines (10%). Non-adherent lapatinib use was observed in 4% of patients. GBTM identified three trastuzumab exposure clusters, each containing three further sub-clusters. The largest proportions of non-adherent treatments were in sub-clusters with longer trastuzumab exposure and more non-taxane chemotherapy. Patients in these sub-clusters were younger than those in sub-clusters with less non-adherent treatment.
Our study highlights that, even during the relatively simpler treatment era of our study period, a substantial amount of treatment did not adhere to prescribing restrictions. As more trials are conducted exploring pertuzumab and T-DM1 in combination with different chemotherapies and other HER2-targeted therapies, the regulation and funding of HER2-targeted treatment will become more challenging.
The discovery and use of trastuzumab over the past two decades has revolutionised the treatment and survival of patients with HER2-positive metastatic breast cancer (HER2+MBC). More recently, clinical trials of lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1) have demonstrated further survival gains.[2–4] Currently, clinicians have “an abundance of riches” in terms of HER2-targeted, antineoplastic, and hormonal treatment options for patients with HER2+ metastatic breast cancer. Despite this, little is known about how these treatments are sequenced and combined in the “real-world” setting, outside of clinical trials.
There were 5,052 patients who initiated trastuzumab for MBC between 3 December 2001 and 30 June 2013. Overall, 1,795 patients (36%) received non-adherent HER2-targeted treatment at some point during therapy (Table 1). The most frequent non-adherent treatments were trastuzumab plus: vinorelbine (24%); capecitabine (24%); anthracycline (10%); and taxane with platinum (TCH; 9%). A total of 193 patients (4%) received non-adherent lapatinib treatment: 165 patients initiated lapatinib as monotherapy while 28 patients received lapatinib in combination with chemotherapy other than capecitabine. Non-adherent concomitant therapy with trastuzumab and lapatinib was observed in 37 patients (<1%) who had dispensings of lapatinib while continuing trastuzumab treatment. Our study highlights the considerable heterogeneity in the real-world treatment of HER2+ MBC and demonstrates that just over one third of Australian patients receiving trastuzumab between 2001 and 2016 received treatment that did not adhere to prescribing restrictions. In Australia, the medicine funding bodies put in place prescribing restrictions to promote cost-effective treatment. This is a delicate balancing act between providing access to new, costly cancer treatments and ensuring the sustainability of public funding. The case of HER2-targeted therapy is particularly interesting because of how effective and well-tolerated these medicines are, and their safety and efficacy when used in combination with a variety of chemotherapeutic partners. When trastuzumab for HER+MBC was approved for public subsidy in Australia the approval was based on its efficacy as demonstrated in pivotal trial where it was used in combination with a taxane, and the restrictions were put in place to align with that trial evidence. The treatment paradigm for HER2+ breast cancer is rapidly evolving, with recent trials exploring the efficacy of multiple HER2-targeted therapy as well as treatment without chemotherapy. Funding these high cost medicines in this dynamic environment is a considerable challenge for payers and Australian prescribing restrictions are in place to promote the cost-effective use of these treatments. Our study highlights that, even during the relatively simpler treatment era of our study period, a substantial amount of treatment did not adhere to prescribing restrictions. As more trials are conducted exploring pertuzumab and T-DM1 in combination with different chemotherapies and other HER2-targeted therapies, the regulation and funding of HER2-targeted treatment will only become more complex. Source: http://doi.org/10.1371/journal.pone.0198152