Cross-border newcomer T-DM1: “New hope” for HER2-positive lung cancer patients

A number of efficacious targeted agents have emerged for non-small cell lung cancer following mutations in EGFR and ALK, but there has been a lack of effective targeted agents for mutations occurring in the HER2 gene.

The emergence of T-DM1 (ado-trastuzumab emtansine; Kadcyla) promises to change this situation. As the name suggests, T-DM1 is a novel antibody-coupled drug (ADC) targeting the HER2 gene, consisting of the anti-HER2 antibody trastuzumab (Trastuzumab) combined with another drug that interferes with tumor cell growth, DM1, to further enhance the effect of trastuzumab.

In February 2013, T-DM1 was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HER2-positive advanced metastatic breast cancer. 2018, the latest version of the National Comprehensive Cancer Network (NCCN) guidelines recommend T-DM1 treatment for patients with advanced non-small cell lung cancer (NSCLC) with HER2 mutations.

T-DM1 rekindles hope for patients with HER2 mutation-positive lung cancer

HER2 gene mutations are less common in patients with non-small cell lung cancer and occur in only 1% to 4% of lung adenocarcinomas, and currently, no anti-HER2 drugs are approved for the treatment of HER2 mutation-positive advanced NSCLC.

In past clinical trials, single-agent efficacy of pan-HER inhibitors such as afatinib, daclatinib, and lenatinib was poor. And clinical benefit was not achieved with the HER2 inhibitors trastuzumab or patuximab for patients with NSCLC with high HER2 gene expression, either with anti-HER2 therapy alone or in combination with chemotherapy.

In 2017, a clinical study reported at the American Society of Clinical Oncology (ASCO) rekindled hope for patients with HER2 mutation-positive lung cancer. The study included 18 patients with HER2-mutant lung cancer on T-DM1 every three weeks, with an objective remission rate (ORR) of 44% and a median progression-free survival (mPFS) of 4 months. The study also enrolled six patients with HER2 amplified lung cancer, three of whom experienced partial remission after treatment.

Adverse reactions caused by T-DM1 were mainly mild infusion reactions, decreased platelets, and elevated transaminases, and no lethal adverse reactions occurred in this reported clinical study.

Based on the good efficacy achieved with T-DM1 in the above study, the latest version of the 2018 NCCN guidelines wrote T-DM1 into the regimens available for patients with HER2 mutated NSCLC.

The path to T-DM1 treatment still needs to be further explored

But with every new therapy that comes along, it doesn’t always start out smoothly.

For example, the results of another phase II clinical study on the efficacy of T-DM1 in NSCLC were not as promising. The study included 15 patients with HER2-mutated NSCLC, and after using T-DM1, their mPFS was only 2 months and median overall survival (mOS) was only 10.9 months.

But at the same time, investigators have begun to explore the efficacy of T-DM1 in treating HER2-positive small cell lung cancer (SCLC). Preclinical model studies have shown that T-DM1 inhibits HER2-positive SCLC cell lines, but there is still a lack of evidence for effective clinical studies.

Summary

T-DM1, a novel antibody drug, has been recommended by the 2018 NCCN guidelines as an option for patients with HER2 mutation-positive NSCLC because of its coupling effect, further enhanced antitumor effect in HER2-positive NSCLC, and tolerable toxic side effects. However, the evidence from clinical studies on T-DM1 for HER2-positive NSCLC is still insufficient, and more medical evidence is needed to guide its clinical use.