ENHERTU as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who previously received trastuzumab and a taxane for metastatic disease, or one prior anti-HER2-based regimen and developed disease recurrence during or within six months of completing neoadjuvant or adjuvant therapy.¹  The limbic spoke with medical oncologist Dr Sally Baron-Hay from Genesis Care at the North Shore Health Hub about the data supporting this treatment option and how it fits into second-line therapy.

Making progress in metastatic disease after first line treatment

“It is great to be able to talk to patients about more second-line treatment options like trastuzumab deruxtecan,” said Dr Baron-Hay. “We see incremental benefits, such as a doubling of the progression-free survival (PFS) at 12 months compared to trastuzumab emtansine.”²

Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) consisting of a humanised anti-HER2 immunoglobulin (Ig)G1 attached to deruxtecan, a topoisomerase I inhibitor payload via a tetrapeptide based cleavable linker.¹  Once trastuzumab deruxtecan binds to HER2 on tumour cells, the drug undergoes internalisation and intracellular linker cleavage so that the topoisomerase I inhibitor is released and can induce DNA damage and apoptotic cell death.¹

The treatment has already been approved in Australia for patients receiving two or more prior anti-HER2 regimens, based on data from the phase II DESTINY-Breast01 study, which demonstrated durable antitumour activity in heavily pre-treated patients with HER2-positive metastatic disease.¹

In March 2022, the results of DESTINY-Breast03 were published in the New England Journal of Medicine. DESTINY-Breast03 is a Phase III, multicentre, open-label, randomised, active-controlled trial evaluating the efficacy and safety of trastuzumab deruxtecan as compared with trastuzumab emtansine in patients with HER2-positive, unresectable or metastatic breast cancer.²  Patients included in the trial were those that had either progressed during or after treatment with trastuzumab and a taxane, in the context of advanced or metastatic disease, or that had progressed within 6 months after neoadjuvant or adjuvant treatment involving trastuzumab or a taxane.²

The primary endpoint, progression-free survival (PFS) as determined by blinded independent central review (BICR), was reported, with overall survival (OS) yet to mature.² The median PFS was not reached in the trastuzumab deruxtecan arm (95% confidence interval [CI], 18.5 to not estimable) and 6.8 months (96% CI 5.6 to 8.2) in the trastuzumab emtansine arm.² At 12 months, the percentage of patients who were alive without disease progression, as assessed by BICR, was 75.8% (95% CI, 69.8 to 80.7) with trastuzumab deruxtecan, compared with 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine.² The hazard ratio (HR) for progression or death from any cause was 0.28 (95% CI, 0.22 to 0.37; P<0.001).² The secondary endpoint of investigator-assessed median PFS was 25.1 months (95% CI, 22.1 to could not be estimated) with trastuzumab deruxtecan, and 7.2 months (95% CI, 6.8 to 8.3) with trastuzumab emtansine (HR, 0.26; 95% CI, 0.20 to 0.35; P<0.001).²  An overall response was achieved in 79.7% (95% CI, 74.3 to 84.4) of patients on trastuzumab deruxtecan versus only 34.2% (95% CI, 28.5 to 40.3) on trastuzumab emtansine.² Almost double the number of patients had a complete response with trastuzumab deruxtecan (16.1%) than on trastuzumab emtansine (8.7%).²

“With trastuzumab deruxtecan, medical oncologists have the best of trastuzumab with the benefit of ADC technology. The tools are getting bigger and better, which is an exciting step forward,“ noted Dr Baron-Hay.

More experience and knowledge make for better use of ADC tools in breast cancer

“As medical oncologists, we are so used to dealing with nausea, fatigue and haematological toxicities from chemotherapy and we’ve got good at managing those aspects. With trastuzumab deruxtecan, the high payload-to-antibody ratio means we may expect to see these in patients. In DESTINY-Breast01 we saw anaemia [8.7%], nausea [7.6%] and decreased neutrophil count [20.7%] at grade 3 or higher.³ But what came as more of a challenge was interstitial lung disease (ILD). Overall, there were 25 patients [13.6%] who had ILD related to the receipt of trastuzumab deruxtecan, [as determined by an independent adjudication committee].³ These events were primarily Grade 1 or 2 [10.9%]; 1 patient [0.5%] had a Grade 3 event, and no patient had a Grade 4 event [graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events; NCI CTCAE].³ ILD wasn’t something medical oncologists were routinely screening for at the time. Since then and with the DESTINY-Breast03 study there have been improvements to monitoring programs. So, while the incidence of ILD/pneumonitis was 10.5% in the trastuzumab deruxtecan arm and in 1.9% of patients in the trastuzumab emtansine arm, none of these were reported as Grade 4 or 5,^”2 explained Dr Baron-Hay.

In DESTINY-Breast03, no drug-related Grade 5 events were reported.² The most common drug-related grade 3 or 4 adverse events in the trastuzumab deruxtecan arm were thrombocytopenia (7.0%), neutropenia (19.1%), leukopenia (6.6%) and nausea (6.6%).² The rates of Grade ≥3 nausea and leukopenia were the same in the trastuzumab deruxtecan arm.²  Comparatively, in the trastuzumab emtansine arm neutropenia was 3.1%, thrombocytopenia (24.9%), leukopenia (0.4%), and nausea (0.4%).²

“So, we should not be hesitant for fear of ILD so long as we continue to have a high index of suspicion, low threshold to investigate symptoms of shortness of breath,” added Dr Baron-Hay. “Guidelines are already reflecting the change in the treatment paradigm, and we can now look to EviQ for further guidance on implementation in practice.”

Both the National Comprehensive Cancer Network (NCCN) guidelines (v4.2022) and the European Society of Medical Oncology (ESMO) guidelines now include further information around use of trastuzumab deruxtecan in clinical practice.^4,5

Disclosure

This article was sponsored by AstraZeneca. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the ENHERTU product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

1. ENHERTU (trastuzumab deruxtecan) Product Information.
2. Cortes J, et al. N Engl J Med 2022; 386:1143-54.
3. Modi S, et al. N Engl J Med 2020;382(7):610-21.
4. National Comprehensive Cancer Network. Breast Cancer [internet]. V4.2022, June 2022.
5. Gennari A, et al. Ann Oncol 2021;32(12):1475-95.