In DESTINY-PanTumor01, the first tumour-agnostic study of a HER2-directed antibody drug conjugate conducted in patients with solid tumours harbouring activating HER2 mutations, trastuzumab deruxtecan showed encouraging and durable anti-tumour activity in heavily pretreated patients with limited treatment options, including those who had disease progression after previous HER2-directed therapy.
The study data provide clinical evidence for trastuzumab deruxtecan in heavily pretreated patients with solid tumours harbouring HER2 mutations. Further research is warranted to better define which patients with different tumour histology subtypes and activating HER2 mutations will derive the most benefit from trastuzumab deruxtecan according to Assoc. Prof. Bob T Li of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues who published the findings on 3 May 2024 in The Lancet Oncology.
Overexpression of the HER2 protein or amplification of the HER2 gene has been observed as a target in various solid tumours, including breast, gastric, biliary tract, pancreatic, and endometrial cancers. Additionally, activating HER2 mutations might act as oncogenic drivers in various cancers. In a big analysis of multiple cancer types, 3.5% of all tumours had HER2 mutations. Most mutations occur in the kinase and extracellular domains (around 40% each) of the HER2 protein, and the prevalence of activating HER2 mutations varies by tumour type.
In the DESTINY-Lung01 study, trastuzumab deruxtecan showed durable anticancer activity in patients with metastatic HER2-mutated non-small cell lung cancer (NSCLC) that was refractory to standard treatment. Activity was observed across different HER2 mutations, and in patients with no detectable HER2 expression or amplification.
The authors wrote in the background that few treatment options exist for patients with HER2-mutated solid tumours beyond lung cancers. Preclinical studies showed that HER2-mutated cancer cells might have increased ubiquitination and internalisation of the HER2 receptor, resulting in increased trafficking of the receptor antibody drug conjugate, which might be preferentially targeted by trastuzumab deruxtecan. This evidence provides a novel mechanistic basis for trastuzumab deruxtecan to selectively target tumours with HER2 mutations, regardless of histology or protein expression.
In an open-label, phase II, basket DESTINY-PanTumor01 study done in 29 centres in Asia, Europe, and North America, the study team investigated trastuzumab deruxtecan, 5.4 mg/kg given every 3 weeks by intravenous infusion, in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Antitumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This study is active, but no longer recruiting.
Between 30 December 2020 and 25 January 2023, a total 102 patients of whom 62 female (61%) and 40 male (39%), median age 66.5 years (interquartile range [IQR] 58–72), 51 White (50%), two Black or African American (2%), 38 Asian (37%), and 11 did not have race information reported (11%), with solid tumours and activating HER2 mutations received trastuzumab deruxtecan and were included in the antitumour activity and safety analyses sets. Patients had a median of three (IQR 2–4) previous treatment regimens. The median duration of follow-up was 8.61 months (IQR 3.71–12.68).
The objective response rate by independent central review was 29.4% (95% confidence interval [CI] 20.8–39.3). Responses were durable, with more than half of patients who had a response continuing to have a response after 18 months of treatment, leading to clinically meaningful progression-free survival (PFS) and overall survival (OS) across a broad range of tumour types and HER2 mutation subtypes. Median PFS was 5.4 months (95% CI 2.7–7.1) by independent central review and 4.4 months (95% CI 2.8–5.6) by investigator assessment (60% maturity). Median OS was 10.9 months (95% CI 8.3–14.9).
In total, 52 patients (51%) had a treatment-emergent adverse event of grade 3 or worse; the most common events in ≥5% of patients were anaemia (16%) and neutrophil count decreased (8%). Drug-related treatment-emergent serious adverse events occurred in 10% of patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11% (three grade 1, five grade 2, one grade 3, and two cases of grade 5); there were two cases (2%) of fatal adjudicated drug-related interstitial lung disease or pneumonitis.
Although most mutations were in the protein kinase domain, the most frequent mutation was S310F in the extracellular domain. More research is required to identify which HER2 mutations and histology subtypes might be most sensitive to trastuzumab deruxtecan and to define the patients who would derive most benefit.
This study excluded patients with locally assessed HER2-positive (immunohistochemistry 3+ or immunohistochemistry 2+ and in situ hybridisation positive) breast, gastric, or gastro-oesophageal junction cancer. Responses were observed across all HER2 expression levels (centrally determined) in HER2-mutated tumours, including patients with low or no detectable HER2 protein expression.
In DESTINY-PanTumor01, objective response seemed to be highest in patients with HER2-expressing tumours. This finding is consistent with the DESTINY-PanTumor02 study, in which response to trastuzumab deruxtecan was highest in patients with HER2 immunohistochemistry 3+ tumours and durable clinical benefit with meaningful survival outcomes were shown in pretreated patients with HER2-expressing solid tumours. Together, these data suggest that HER2 mutations and HER2 expression might be independent predictive biomarkers, individually increasing the likelihood of response to trastuzumab deruxtecan.
The authors commented the limitations of tumour-agnostic, basket design of DESTINY-PanTumor01. All HER2-mutated tumour types were eligible for inclusion except for NSCLC. Therefore, it was not possible to include a single comparator group because the established standard of care for each of the tumour types included is different.
Given the diverse patient population, further subgroup analyses are warranted to explore outcomes by HER2 mutation subtype, HER2 mutation domain, HER2 protein expression or amplification, and tumour type. However, this phase II study had a small sample size, particularly when considering the broad range of patient subgroups. The interpretation of outcomes by subgroup is therefore limited. Furthermore, the median duration of follow-up limits interpretation of the long-term safety and antitumour activity of trastuzumab deruxtecan from this study, and additional follow-up data would provide a more comprehensive understanding.
This study was sponsored by AstraZeneca in collaboration with Daiichi Sankyo. Assoc. Prof. Bob T Li was funded, in part, by the Memorial Sloan Kettering Cancer Center Support Grant and Research Project Grant from the US National Institutes of Health.
Reference
Bob T Li, Funda Meric-Bernstam, Aditya Bardia, et al. on behalf of the DESTINY-PanTumor01 study group. Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study; The Lancet Oncology; Published online 3 May 2024. DOI: https://doi.org/10.1016/S1470-2045(24)00140-2