Trastuzumab-deruxtecan: New treatment, familiar complications

Not long after its identification in 1966, the anti-neoplastic medication bleomycin was recognized to cause significant pulmonary toxicity, occurring in roughly 10% of patients.^1,2 Its pro-fibrotic properties have established bleomycin as the most common agent used for inducing interstitial lung disease (ILD) in animal models.² Decades of experience has primed clinicians to monitor for bleomycin related ILD, often prompting baseline pulmonary function testing and screening protocols.³ Anti-neoplastic medications have been reported to be the most common class of medications causing drug-induced lung injury, with ILD being the most frequent manifestation.⁴ In 2020, Health Canada approved 17 new anti-neoplastic and immunomodulating treatments, more than any other class of medication.⁵ Maintaining familiarity with the ever-growing list of cancer treatments is challenging, but respirologists working in Canadian cancer centers need to be aware of new treatments with associated pulmonary toxicity. Even when adverse events are rare, the large volume of patients receiving treatment ensures some will suffer adverse events.

Breast cancer comprises approximately one-quarter of new cancer diagnoses, making it the most common cancer among Canadian women.⁶ Roughly 20% of breast cancers demonstrate overexpression of the human epidermal growth factor receptor 2 (HER-2, now termed ERBB2), and is associated with reduced survival.⁷ The anti-HER-2 monoclonal antibody trastuzumab has been used in first-line treatment regiments for eligible patients for over 20 years, resulting in improved disease response and survival.⁸ Recent trials have shown new antibody-drug conjugates (ADCs) to be effective in the treatment of refractory metastatic HER-2 positive breast cancer; these ADCs combine trastuzumab and small cytotoxic molecules using covalent linkers, allowing targeted delivery of chemotherapeutic treatments to cancer microenvironments.^9,10

The recently published DESTINY-Breast 03 trial, studied the effects of trastuzumab-deruxtecan (T-Dxd) versus trastuzumab-emtansine (T-DM1) in metastatic HER-2 positive breast cancer refractory to trastuzumab and taxane therapy. Interim results show progression-free survival was improved with T-Dxd as compared to T-DM1, the previously recommended treatment in this setting [HR 0.28 (0.22-0.37), P < 0.001].^10,11 However, 10.5% of patients receiving T-Dxd experienced ILD, with grade 2 or 3 disease comprising 74% of events. Fatal cases of ILD from T-Dxd were reported in 2.2% of cases in an earlier phase 2 trial in breast cancer.¹² Despite this, the survival benefits from T-Dxd are anticipated to result in its widespread prescription in this population. Furthermore, phase 2 studies of T-Dxd have shown positive treatment effects in HER-2 expressing non-small cell lung cancer (NSCLC), colorectal cancer, gastric cancer and breast cancer not overexpressing HER-2, broadening the potential treatment indications.^13–16 Grade 2 or higher pneumonitis occurred in 23% of patients treated with NSCLC, including 2 deaths.¹³ In a recent systematic review of clinical trials across several HER-2 positive tumor types, the incidence of T-Dxd induced ILD of any grade was 11.4%, with death occurring in 10.7% of cases.¹⁷

T-Dxd (Enhertu®) is currently approved by Health Canada for patients with HER-2 positive breast cancer refractory to T-DM1 and may be soon recommended over T-DM1 given the DESTINY-Breast 03 trial results. A boxed warning for ILD and pneumonitis has been added to the manufacturer’s product prescribing information, and they provide recommendations for dose modification and corticosteroid treatment when ILD is detected.¹⁸ Of importance, holding T-Dxd and consideration of corticosteroid treatment is recommended in the setting of grade 1 pneumonitis (asymptomatic radiographic changes). Permanent discontinuation of T-Dxd is suggested in the setting of grade 2 (any symptoms) ILD or higher. These recommendations are more conservative than those outlined for other ILD management of other anti-neoplastic treatments, such as checkpoint inhibitors.¹⁹

The real-world use of T-Dxd outside of clinical trials will require careful patient selection, monitoring and timely evaluation when pneumotoxicity is suspected. Patients with preexisting ILD were excluded from previous trials, and study protocols performed CT chest imaging every 6 weeks for monitoring with immediate drug discontinuation when abnormalities were identified.¹⁰ A similar degree of patient selection and monitoring may be impractical outside of clinical trials and relaxed supervision could result in a higher incidence and severity of lung toxicity. Close follow-up for ILD seems sensible with T-Dxd prescription, but how this should be performed is unclear. Despite decades of experience, the optimal screening recommendations for bleomycin lung toxicity still remain unclear, with significant heterogeneity in physician practice patterns.³ Research focused on risk factor identification and pragmatic screening strategies will be helpful to establish protocols for ILD monitoring. For now, respirologists should familiarize themselves with the available data regarding T-Dxd lung toxicity and prepare for what appears to be an inevitable influx of new drug related ILD.

Disclosure statement

Dr. Fidler has accepted speaking honoraria from Boehringer Ingelheim, Pfizer, and AstraZeneca. Dr. Sehdev has accepted speaking honoraria and participated in advisory boards for AstraZeneca and Roche.

Funding

The author(s) reported there is no funding associated with the work featured in this article.