Lung cancer is one of the leading causes of cancer death among men and women in the US. One option to improve survival in patients is targeted therapy, a type of treatment that attacks specific genes and proteins within a cancer cell. Initial results from the CHRYSALIS Phase I Study showed that amivantamab may be the first biologic therapy to be effective in non-small cell lung cancer (NSCLC) patients with a specific epidermal growth factor receptor (EGFR) mutation.
EGFR mutations in NSCLC
Lung cancer is the third most common cancer in the UK, with approximately 47,000 people diagnosed every year. NSCLC accounts for over 87% of lung cancer cases and is commonly driven by mutations in the EFGR gene. EGFR is normally involved in cell growth and division, but genetic aberrations dysregulate the cell cycle and lead to uncontrolled cell proliferation.
One type of EGFR mutation, exon 20 insertion (Ex20ins), occurs in less than 12% of NSCLC patients but is associated with poor prognosis. Furthermore, patients harbouring this mutation are resistant to existing FDA-approved targeted therapies, such as tyrosine kinase inhibitors. These patients have limited treatment options, with the standard of care still being platinum-based chemotherapy. Moreover, patients with EGFR Ex20ins have considerably lower median overall survival compared to NSCLC patients who are sensitive to tyrosine kinase inhibitors.
Therefore, efforts are currently underway to develop targeted therapies that effectively treat NSCLC in patients harbouring the EGFR mutation.
CHRYSALIS trial for amivantamab
Amivantamab is a bispecific antibody designed to engage two distinct pathways that drive NSCLC. It specifically targets both the EGFR and mesenchymal-epithelial transition factor (MET) receptors. Upon binding, amivantamab inhibits ligand binding and direct immune cells to kill tumour cells. Given its unique mechanism of action, amivantamab has been proposed as a novel biologic therapy for NSCLC patients with EGFR Ex20ins mutations.
CHRYSALIS is a phase I dose-escalation and dose-expansion clinical trial to evaluate the efficacy, safety and pharmacokinetics of amivantamab in advanced NSCLC. It is a two-part study of amivantamab as a monotherapy and in combination with other therapies. The trial is being conducted by an international team of researchers from different institutions, including the Samsung Medical Centre in Korea and the H. Lee Moffitt Cancer Centre and Research Institute in the US.
A previous investigation indicated that amivantamab is efficacious in 29 NSCLC patients with the EGFR Ex20ins mutation. The current paper expanded the study population, with the initial results now published in the Journal of Clinical Oncology.
Safety and efficacy of amivantamab on EGFR Ex20ins patients
To investigate the safety of amivantamab, researchers analysed 114 patients who were treated with the recommended amivantamab dose. The safety profile was in line with the expected toxicities associated with EGFR and MET inhibition. Although infusion-related reactions were frequent, they were low grade and rarely recurred with more doses. Severe toxicity and toxicity-related discontinuations were uncommon.
Out of the 114 patients, 81 had at least 3 scheduled disease assessments or had cancer progression, discontinued treatment, or died by the data cut-off time point. Amivantamab efficacy was studied in these 81 patients. The overall response rate, or the percentage of patients who responded to amivantamab, was 40% in the EGFFR Ex20ins population. In total, 3 patients achieved complete response, or a lack of evidence of cancer after therapy. Meanwhile, 29 patients showed a partial response. The median duration of response was 11.1 months.
These preliminary results confirmed those obtained from the previous efficacy study. Together, the findings suggest that amivantamab demonstrates clinically meaningful efficacy in EGFR Exon20ins NSCLC patients.
Study limitations
The present study on the efficacy of amivantamab did not include all EGFR Ex20ins patients who were enrolled in CHRYSALIS. Instead, it only includes a subset of such patients who had ceased platinum-based chemotherapy treatment and had sufficient follow-up. Furthermore, patients with active brain metastases were excluded.
Summary
Overall, these preliminary results from CHRYSALIS demonstrated that amivantamab is the first bispecific antibody to be safe and efficacious against NSCLC patients who harbour the EGFR Ex20ins mutation. Though the results are promising, future investigation is needed to study amivantamab’s efficacy in broader EGFR Ex20ins NSCLC patient groups.
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