Trastuzumab deruxtecan treatment of advanced gastric cancer recommended for EU approval 

28th November 2022

Trastuzumab deruxtecan has been recommended for EU approval as monotherapy for patients with HER2-positive advanced gastric cancer

Trastuzumab deruxtecan (brand name Enhertu) been recommended for approval in the European Union (EU) as monotherapy for the treatment of adult patients with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen according to a press release from the manufacturer, AstraZeneca.

Gastric cancer is the 5th most common cancer worldwide and there were more than 1 million new cases in 2020 and 719,523 deaths. If a gastric cancer is diagnosed and treated when localised, the 5-year survival rate is 70%. However, if the cancer has spread to surrounding areas and/or the regional lymph nodes, the 5-year survival rate is 32% and this rate reduces to 6% if the cancer undergoes metastases. Given this poor prognosis it is important to have gastric biomarkers one of which is the Human epidermal growth factor receptor 2 (HER2) protein. While over expression is increasingly recognised as a molecular abnormality in breast cancer, there is mounting evidence of the role of HER2 over expression in patients with gastric cancer, and it has been correlated to poor outcomes and a more aggressive disease. The frequency of HER2 over expression in gastric and gastro oesophageal cancer ranges from 4.4% to 53.4%, with a mean of 17.9%. Trastuzumab is a recombinant humanised monoclonal antibody that targets the HER2 protein. In fact, trastuzumab in combination with chemotherapy is a treatment option for patients with HER2-positive advanced gastric cancer. Data obtained from two clinical trials, suggests treatment with trastuzumab deruxtecan, improves both the response and overall survival in patients with metastatic gastric cancer.

Trastuzumab deruxtecan and gastric cancer outcomes

In an open label, dose-escalation and dose-expansion phase 1 trial, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, who received Trastuzumab deruxtecan (T-Dx-T) had a manageable safety profile and showed preliminary activity in heavily pre-treated patients with HER2-positive patients. These findings prompted the authors to suggest that T-Dx-T should be further investigated for HER2-positive gastric or gastro-oesophageal junction cancer patients. In a second phase 2 trial with HER2-positive advanced gastric cancer patients, researchers compared T-Dx-T with a physician’s choice of chemotherapy. The results showed that an objective response was seen in 51% of T-Dx-T compared with 14% of those in the physician’s choice group. In addition, the median overall survival was also longer with T-Dx-T than with chemotherapy (12.5 vs. 8.4 months).

The most recent data on T-Dx-T comes from a study reported at the ESMO Congress 2022 and provided an update from a second trial, DESTINY-GASTRIC-02, a T-Dx-T monotherapy open-label, single-arm trial in HER2-positive, unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma patients. The results demonstrated after a median duration of follow up of 10.2 months, a confirmed objective response rate of 41.8% was seen in T-Dx-T patients with a median duration of response of 8.1 months a progression-free survival of 5.6 months.

These two trials provided the necessary data to enable CHMP to give a positive opinion for the drug and it follows on from FDA approval of the drug in 2021.

Trastuzumab deruxtecan shows durable anti-cancer activity in non-small-cell lung cancer

27th September 2021

A phase 2 trial of trastuzumab deruxtecan in patients with non-small-cell lung cancer demonstrated a median overall survival of 17.8 months.

Lung cancer is extremely common and figures from 2018, suggest a global incidence of 17 million cases and 9.6 million associated deaths. Primary lung cancers can be either small cell or non-small cell, with the latter being the most common, accounting for around 80 to 85% of all lung cancer cases. Research has identified the presence of various genetic mutations in lung cancer, one of which is a mutation in the human epidermal growth factor 2 (HER2). This mutation is present in roughly 2 to 4% of non-small cell lung cancer (NSCLC) cases. Given the over-expression of HER2, potential treatments include the anti-HER2 agent, trastuzumab, but when used in combination with chemotherapy, there was a lack of benefit. The antibody-drug conjugate, trastuzumab deruxtecan, has been shown to be effective in both HER2 positive gastric and breast cancers but data on its efficacy in NSCLCL is limited to a single phase 1 trial in 11 patients, which showed an objective response rate in 72.7% (8/11) of patients.

Based on these preliminary findings, an international team, the DESTINY-Lung01 trial investigators, conducted a multi-centre, phase 2 trial of trastuzumab deruxtecan given at a dose of 6.4 mg/kg body weight, to patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment. Eligible patients had unresectable or metastatic non-squamous NSCLC with at least one measurable lesion as defined according to the Response Evaluation Criteria in Solid Tumours (RECIST), which provides a simple and pragmatic methodology to evaluate the activity and efficacy of a new anti-cancer therapy in solid tumours. The primary end point was confirmed objective response, independently assessed on the basis of RECIST. Secondary endpoints included the duration of response, disease control and progression-free survival and overall survival. The study also examined the safety of treatment.

Findings
A total of 91 patients with a median age of 60 years (66% female) were enrolled in the study and who had a median of 2 previous cancer therapies. There were 50 (55%) patients who achieved a confirmed objective response, with one patient having a complete response and just over half (54%) having a partial response. In addition, the majority (91%) of patients had disease control and a reduction in tumour size. The median progression-free survival time was 8.2 months and the median overall survival, 17.8 months. In terms of safety, 51% of patients experienced a grade 1 – 2 adverse event and grade 3 or higher drug-related adverse events occurred in 41% of patients. The most common adverse effects were nausea (64%) and fatigue (46%) although these were mainly of grade 1 – 2 severity.
The authors concluded that the use of trastuzumab deruxtecan had shown a response in a high number of patients and durable clinical benefit and that a further randomised trial to further evaluate the drug conjugate is underway.

Citation
Li BT et al. Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer. N Eng J Med 2021.