New Antibody-Drug Conjugate Shrinks HER2+ Cancers

Nick Mulcahy

July 02, 2019

A new antibody-drug conjugate that couples trastuzumab (multiple brands), a mainstay of treatment for HER2+ cancers, with duocarmycin, a cytotoxic byproduct of a strain of bacteria, has shown what have been called "impressive" antitumor effects in several types of HER2+ cancers.

Data from the first-in-human studies of the new agent, trastuzumab duocarmazine (Synthon Biopharmaceuticals), were published online on June 27 in Lancet Oncology.

"This phase 1 study of trastuzumab duocarmazine has shown important and relevant clinical activity and a manageable safety profile in heavily pretreated patients with HER2-expressing metastatic cancer," say the study authors, led by Udai Banerji, MD, Institute of Cancer Research, London, United Kingdom.

The product is now being tested in larger clinical trials. The phase 3 TULIP trial, which is currently recruiting patients, will compare trastuzumab duocarmazine to standard chemotherapy for women with HER2+ breast cancer.

Antibody–drug conjugates are designed for "selective delivery of potent cytotoxic drugs to tumor cells by linking the cytotoxins to monoclonal antibodies," the authors explain.

The first such product for breast cancer was trastuzumab emtansine (Kadcyla, Genentech), in which the targeted HER2 drug is linked to DM1, a microtubule inhibitor derived from maytansine. It was first approved in the United States in 2013.

Other such products are also in development, note the authors of an accompanying editorial.

"Several new HER2-targeting antibody–drug conjugates with different linkers and payloads are in clinical development, with promising results," say the editorialists, Xavier Pivot, MD, and Thierry Petit, MD, Center Paul Strauss, Porte de l'Hospital Strasbourg, France.

Study Details

An initial dose-escalation study with trastuzumab duocarmazine was conducted in 39 patients with locally advanced or metastatic solid tumors with variable HER2 status whose conditions were refractory to standard cancer treatment.

On the basis of outcomes, the recommended dose of trastuzumab duocarmazine was set at 1.2 mg/kg.

The dose-expansion study enrolled 146 patients with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease.

Overall, these patients were heavily pretreated and had undergone a mean of 5.2 previous lines of anticancer drug treatments.

Among the breast cancer patients, 33% (16/48) with HER2+ breast cancer achieved an objective response (all partial), according to RECIST results.

Another cohort of breast cancer patients had low levels of HER2 expression. Historically, these patients have not responded as well to anti-HER2 therapies.

Partial responses were recorded in 28% of patients (9/32) with HER2-low, hormone receptor–positive breast cancer and in 40% of patients (6/15 evaluable) with HER2-low, hormone receptor–negative disease, the team reports.

Among the patients with other cancers, partial responses were observed in 6% of patients (1/16) with gastric cancer, 25% of patients (4/16) with urothelial cancer, and 39% of patients (5/13) with endometrial cancer.

These are mostly good results, comment editorialists Pivot and Petit.

"Trastuzumab duocarmazine showed impressive clinical antitumour effects in several types of cancers, including breast cancer with varying expression of HER2," they note.

The toxicity was not excessive, they suggest.

"The drug also showed an acceptable tolerability profile, with few grade 3–4 adverse events and no treatment-related deaths in the dose-expansion phase," write Pivot and Petit.

Place in Therapy?

Where would trastuzumab duocarmazine fit into the scheme of treating patients with HER2+ breast cancers?

The study authors speculate that the experimental trastuzumab duocarmazine might eventually be a "novel" treatment option for patients with HER2+ breast cancer who have been previously treated with trastuzumab plus pertuzumab, or trastuzumab emtansine, or both. It may also have use in patients with HER2-low disease, they say.

However, the editorialists ponder another thought: that HER2-targeting antibody–drug conjugates might be the best option for some patients, instead of, for example, trastuzumab alone.

But that is not in the immediate future. "The complexity of identifying the optimum option in clinical practice seems to be a huge challenge," they write.

Toxicity Details, Including Ocular AEs

The most common treatment-related adverse events of any grade in the dose-expansion study (n = 146) were fatigue (33%), conjunctivitis (31%), and dry eye (31%).

Grade 3 or 4 treatment-related adverse events occurred in 35% of patients. The most common of these were neutropenia (6%), fatigue (4%), and conjunctivitis (3%).

Nearly three quarters of patients (71%) had one or more ocular adverse events. Grade 3 events occurred in 7% of patients.

Occurrence and severity of ocular toxic effects generally increased with prolonged exposure (data not reported). The median time to grade 3 events was 7.6 months.

Reduced dosing, or use of prophylactic eyedrops, or both did not greatly improve tolerability, report the study authors.

However, they report that "several patients seemed to benefit (ie, toxicity remained stable or improved) from dose delays or dose reduction and could continue with trastuzumab duocarmazine treatment beyond 1 year."

On the plus side, most ocular effects improved or patients recovered with treatments such as eyedrops or ointments, although recovery sometimes took several months.

Four patients died in the dose-expansion phase; the deaths were from hepatic failure, upper gastrointestinal hemorrhage, neurologic decompensation, and renal failure. These deaths were all related to disease progression and were not judged to be related to treatment, the study authors comment.

The study was sponsored by Synthon Biopharmaceuticals. Multiple study authors have financial ties to industry, and several authors are Synthon employees. Editorialists Pivot and Petit report no relevant financial relationships.

Lancet Oncol. Published onlineJune 27, 2019. Abstract

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