Antibody-Drug Conjugate Shows Efficacy in Heavily Treated Cancers

An investigational antibody-drug conjugate made of the HER2-targeting antibody trastuzumab (marketed as Herceptin and others) attached to a kind of chemotherapy compound has demonstrated notable efficacy in heavily treated patients with breast and other cancer types, a Phase 1 trial showed.

“Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study” was published in The Lancet Oncology.

Around a quarter of breast cancer tumors have high levels of HER2, a protein that can drive tumor growth. These tumors often develop resistance to standard treatments, so there is a need for new strategies to treat them.

The antibody therapy Herceptin (trastuzumab) can bind to HER2, blocking its activity. This can be beneficial for patients, and when resistance appears, patients benefit from an antibody-drug conjugate called Kadcyla (trastuzumab emtansine).

This treatment combines the antibody in Herceptin, trastuzumab, with the cytotoxic agent DM1. But what happens when patients develop resistance to both Herceptin and Kadcyla?

In the new study, researchers examined a different antibody-drug conjugate, which had the same antibody attached to another compound: a chemotherapy drug called duocarmazine.

“The approach used in this study of combining the antibody and drug is a highly successful way of targeting tumors,” Udai Banerji, MD, PhD, a professor at the United Kingdom’s Institute of Cancer Research and co-author of the study, said in a press release. “With the antibody acting as a guide to find and target the cancer, the duocarmazine drug can be released directly to the tumor cells, destroying them [while] minimizing the damage to surrounding healthy cells.”

The Phase 1 clinical trial (NCT02277717), funded by Synthon Biopharmaceuticals, tested this antibody-drug conjugate — called trastuzymab duocarmazine — in humans for the first time.

It included patients with advanced solid tumors — including breast, gastric, urothelial, and endometrial cancers — whose cells were positive for the HER2 receptor.

The trial consisted of two phases. The first, a dose-escalation phase, included 39 adults with cancer (mostly breast cancer, but other types were also included) who were not responding to standard therapies.

These patients were treated with ascending doses of trastuzymab duocarmazine — ranging from 0.3 to 2.4 mg/kg — given as an injection once every three weeks; the goal of this phase was to determine safety and find an optimal dose for subsequent trials.

In this phase, there were two deaths, one from disease progression and one from treatment-related lung inflammation. The most common serious side effects reported in this phase were inflammation of the cornea and fatigue.

The second phase of the trial, the dose-expansion phase, included 146 cancer patients — including 50 with HER2-positive metastatic breast cancer, 32 with HER2-low hormone receptor-positive metastatic breast cancer, 17 with HER2-low hormone receptor-
negative metastatic breast cancer, 17 with stomach cancer, 16 with bladder cancer, and 14 with endometrial cancer.

They were treated with trastuzymab duocarmazine at a dose of 1.2 mg/kg once every three weeks,  chosen based on the results of the dose-escalation phase. As in the first phase, these patients were not responding to conventional treatment.

Among those with HER2-positive breast cancer, 33% achieved a partial response to the treatment, but interestingly, 32% of patients with low levels of the HER2 receptor also had partial responses to this therapy.

Partial responses were also observed in 6% of people with stomach cancer, 25% of those with bladder cancer, and 39% of women with endometrial cancer.

The most common treatment side effects in the dose-expansion cohort were fatigue (3%) and adverse reactions of the eyes, including dry eye and conjunctivitis (71%). There were no treatment-related deaths in this group; there were four deaths due to disease progression.

“Trastuzumab duocarmazine has shown promising anti-tumor activity in breast cancer patients with varying levels of the cancer-driving HER2 protein. As these cancers often develop resistance to the current standard of care, this treatment could extend the lives of patients who have otherwise run out of options,” Banerji said.

A Phase 3 trial (NCT03262935) directly comparing this antibody-drug conjugate to standard-of-care is currently recruiting patients. This trial is also funded by Synthon, and its primary objective is to determine the time patients live without their disease worsening.