Overview of serious adverse events reported with targeted therapies in breast cancer

Targeted therapies are increasingly used in the treatment of cancers. These novel agents act by, directly or indirectly, attacking a specific genetic biomarker found in a given cancer, leading to the killing or inhibition of tumour growth. Several targeted therapy agents have been approved in breast cancer and may be divided into the following five classes:

1. Human epidermal growth factor receptor 2 (HER2) inhibitors

2. Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors

3. Phosphoinositide 3-kinase (PI3K) Inhibitors

4. Polyadenosine diphosphate ribose polymerase (PARP) inhibitors

5. Programmed death ligand 1 (PD-L1) inhibitors

CDK 4/6, PI3K and PARP inhibitors are orally administered agents while HER2 receptor inhibitors and PD-L1 inhibitors are intravenously administered antibody-based agents. The drug classes, brands and locally approved indications of the targeted cancer therapies used in breast cancer are listed in Table 1. 

Table 1. Recently approved targeted therapy agents used in breast cancer

This review article aims to provide an analysis on the serious adverse events (AEs) reported locally with the use of targeted breast cancer therapies as of 30 June 2021. AEs from targeted therapies manifest in a wide range of organ systems and may be less predictable in terms of onset, severity and type, relative to that of traditional cytotoxic chemotherapy, which has a more predictable adverse effect profile.¹

Table 2 provides the number of serious AE reports received as of 30 June 2021, for each targeted therapy class as well as the potential for drug interactions with the oral agents (PARP, CDK 4/6 and PI3K inhibitors). Drug interactions can increase the risk of serious AEs when administered with interacting agents as all oral targeted therapies used in breast cancer are substrates of the CYP3A4 metabolic pathway.

Table 2. Local reports of serious adverse events and the risk of drug interactions with targeted therapy agents approved in breast cancer.

Serious adverse events

1. Pneumonitis

Drug-induced pneumonitis is a serious immune-related AE that can arise following the use of several classes of targeted therapies in breast cancer. Early detection and immediate discontinuation of the offending agent can result in reversible lung injury (with or without treatment). However, continued exposure may lead to a permanent disease condition (e.g. pulmonary fibrosis) and death.² The onset and progression of pneumonitis are often insidious and symptoms can be non-specific, with latency spanning between months to years following drug exposure.²

Locally, six reports of pneumonitis associated with targeted therapy agents from three different drug classes have been reported to date (Table 2). Two reports of pneumonitis associated with pertuzumab (Perjeta®, Roche Singapore Pte Ltd) had occurred approximately after five months of exposure, while two other reports involving atezolizumab (Tecentriq®, Roche Singapore Pte Ltd) occurred after approximately two months. One report involving olaparib (Lynparza®, Astrazeneca Singapore Pte Ltd) had a latency of over a year. Another report involving trastuzumab emtansine (Kadcyla®, Roche Singapore Pte Ltd) did not report a latency period. However, published literature has suggested that pneumonitis associated with the use of trastuzumab emtansine can occur anytime between two and 53 months post-exposure to the drug.^3,4

Internationally, there have been reports of pneumonitis following the use of CDK 4/6 inhibitors [Palbociclib (Ibrance®, Pfizer Pte Ltd), Ribociclib (Kisqali®, Novartis (Singapore) Pte Ltd) and Abemaciclib (Verzenio®, DKSH Singapore Pte Ltd)]. In 2019, the US Food and Drug Administration (FDA) had released a Drug Safety Communication warning on the risk of pneumonitis with CDK 4/6 inhibitors.⁵ A recent analysis of reports in the FDA’s Adverse Event Reporting System (FAERS) also suggested a higher-than-expected number of reports of pneumonitis in association with CDK 4/6 inhibitors.⁶ In June 2021, the UK Medicines and Healthcare products Regulations Agency (MHRA) had similarly issued a drug safety update following 27 reports of pneumonitis with CDK 4/6 inhibitors as of January 2021. To date, HSA has not received reports of pneumonitis associated with CDK 4/6 inhibitors.

Pneumonitis has also been reported in clinical trials of PI3K inhibitor, alpelisib (Piqray®, Novartis Singapore Pte Ltd) and is listed in the locally approved package insert with an incidence of 1.8%.⁷ However, as of 30 June 2021, there have not been any local reports of pneumonitis associated with the PI3K inhibitor, alpelisib, reported to HSA.

While early detection is ideal, drug-induced pneumonitis remains a diagnosis of exclusion. Causality assessments can be challenging in cancer patients owing to a variety of possible alternative causes including radiation exposure from concurrent radiotherapy for breast cancer. However, emerging evidence describing the unique radiographic features of pneumonitis from specific targeted therapy agents are beginning to elucidate useful indicative features that may aid causality assessments.^8-10

2. Haematological toxicities

As with cytotoxic chemotherapy, targeted therapies for breast cancer are also commonly associated with different types of haematological toxicities, including anemia, neutropenia and thrombocytopenia. Other rare AEs include venous thromboembolism risks with selected CDK 4/6 inhibitors (e.g. abemaciclib) and myelodysplastic syndrome with PARP inhibitors. Hematological AEs are among the most frequently reported AEs with CDK 4/6 and PARP inhibitors (Table 2).

As of 30 June 2021, there have been four reports of anaemia following PARP inhibitor use occurring between three weeks and six months after therapy initiation, of which all the patients required red blood cell transfusion. One report of severe neutropenia (Grade 3) with co-reported Grade 4 thrombocytopenia was received, occurring three weeks after PARP inhibitor initiation.

Conversely, more cases of neutropenia (25) than anaemia (1) were reported with CDK 4/6 inhibitors. Based on the reports received, the time-to-onset for neutropenia ranged between one week and six months following CDK 4/6 inhibitor initiation. There has been no deaths from neutropenia reported to HSA.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are infrequent AEs that can occur with PARP inhibitors at an estimated incidence of 1.8%.¹¹ A numerically higher number of MDS and AML were observed in several randomised controlled trials (RCTs) of PARP inhibitors. A combined meta-analysis and retrospective analysis of the World Health Organization’s pharmacovigilance database suggests a significantly increased risk of MDS and AML following PARP inhibitor exposure [Peto odds ratio: 2·63 (95% CI 1·13–6·14), p=0·026].¹²  The latency for MDS may range between one and 67 months while for AML, it can occur between eight and 30 months following PARP inhibitor therapy. ¹²

As of 30 June 2021, HSA has received one report of MDS in a female in her 50s who had received olaparib for two months. Severe anemia was also reported, which is often present in MDS (sometimes accompanied with neutropenia and thrombocytopenia). As MDS consists of a heterogeneous spectrum of blood disorders, the risk of progression to AML and outcomes is equally wide ranging with the presence or absence of various other prognostic factors influencing overall survival.¹³

Close monitoring of blood counts and further evaluation in patients with prolonged haematological abnormalities may be necessary to detect such potential delayed toxicities that may arise in patients on PARP inhibitors.

3. Glucose-related disorders

Hyperglycaemia can occur in up to 65% of patients on the PIK inhibitor, alpelisib and can be a potentially therapy limiting AE. Grade 3 hyperglycaemia [fasting blood glucose (FPG) levels > 14 mmol/L] and Grade 4 (FPG > 28 mmol/L) can occur at incidences of 33% and 4%, respectively and can precipitate risks of ketoacidosis which can be life-threatening. RCT evidence suggests that the median time to first occurrence of hyperglycaemia is approximately 15 days (range: 5 to 517 days).

HSA has received one report of ketoacidosis in a female in her 50s with a history of Type 2 Diabetes, following seven months of alpelisib therapy. The first sign of hyperglycaemia appeared 28 days after drug initiation. She required significant medical intervention before her blood glucose levels returned to acceptable baseline, where oral antihyperglycemic agents were deemed sufficient.  

A variety of oral agents and insulin may be used in the treatment of alpelisib-related hyperglycaemia. This may include Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors which are increasingly prescribed for managing hyperglycaemia, but independently is also associated with the risk of euglycaemic ketoacidosis. While it remains unclear if the concomitant use of a PI3K inhibitor and a SGLT2 inhibitor increases the risk of DKA, there has been one published report of ketoacidosis following concomitant use of both agents.¹⁴

Drug interactions as precipitants of serious AEs

All three classes of oral targeted therapies used in breast cancer carry significant risks of drug-drug interactions as they are substrates of the cytochrome P450 3A4 metabolic pathway (Table 2). This is noteworthy given that all three class agents are administered daily (typically as tolerated or till disease progression) or given on a three-weeks on, one-week off dosing regimen. Continual exposure of these oral agents can increase the risk of interactions with commonly prescribed 3A4 inhibitors and inducers which can potentiate the risk of AEs from targeted therapies and/or the interacting drug. For instance, the concomitant use of antimicrobial agents [e.g. clarithromycin (CYP 3A inhibitor)] or antifungal agents [e.g. azoles (CYP 3A inhibitor)] with CDK 4/6 inhibitors can increase the risk of QT prolongation.¹⁵ The high incidence of All-Grade neutropenia (75 to 80%) in patients on CDK 4/6 inhibitors may put patients at risk of infections where potentially interacting antimicrobial/antifungal agents may be prescribed for use.^16,17 Where appropriate, close monitoring with/without dose adjustments or avoidance and use of alternative agents may be necessary.¹

Conclusion

Healthcare professionals are advised to look out for the various serious AEs associated with targeted cancer therapies and their potential for drug interactions that may increase the risk of serious AEs from these agents. Healthcare professionals are also encouraged to report suspected targeted therapy-induced adverse events to the Vigilance and Compliance Branch of HSA.

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7. Singapore package insert for Piqray® (approved 19 July 2021).

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15. Micromedex Drug-drug Interactions (ribociclib). IBM Corporation 2021

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