New targeted drugs show promise in patients with advanced HER2-positive breast cancer in two clinical trials

New targeted drugs show promise in patients with advanced HER2-positive breast cancer in two clinical trials to be presented at SABCS/NEJM

In trials led by Dana-Farber Cancer Institute investigators, both agents demonstrate ability to help thwart advance of disease.

One agent is first to show clinical trial effectiveness in patients whose HER2-positive breast cancer has metastasized to the brain.

For patients with HER2-positive breast cancer no longer responding to standard therapies, a pair of clinical trials led by investigators at Dana-Farber Cancer Institute and other institutions offer substantial promise, including for those whose cancer has spread to the brain. 

Results of the trials were presented at the San Antonio Breast Cancer Symposium today and are being co-published in the New England Journal of Medicine. The trials tested two new targeted agents in patients whose HER2-positive breast cancer had become resistant to multiple previous therapies. In both cases, the new agents helped halt or reverse the advance of the disease in many patients. In one trial, the study agent reduced the risk of worsening disease by approximately half and reduced the risk of death by one third.

“The development of drugs targeting the HER2 protein has dramatically improved outcomes for patients with this form of breast cancer, but nearly all patients with metastatic HER2+ breast cancer eventually become resistant to these drugs, creating a need for new and better therapies,” said Eric Winer, MD, Chief of the Division of Breast Oncology, Susan F. Smith Center for Women's Cancers at Dana-Farber and the senior author of one of the studies. “The results of these trials represent significant progress toward this goal, including the first evidence from a clinical trial of a targeted agent that can improve survival for patients with HER2-positive breast cancer that has metastasized to the brain.”

HER2-positive breast cancer, which tests positive for the cancer growth-promoting protein HER2, accounts for 15-20% of breast cancers.  Prospects for patients improved markedly with the introduction of drugs such as trastuzumab (Herceptin) and pertuzumab (Perjeta), which target the HER2 protein, and T-DM1, a conjugate drug that uses an antibody to deliver a chemotherapy drug directly to cancer cells. But the development of resistance to these agents ultimately means news and different drugs are needed. The NEJM article can be found here.

The two trials involve agents that take a new line of attack against HER2 proteins that have become inured to standard therapies. Results from both trials point to the drugs’ clinical effectiveness for many patients.

International trial of new targeted agent

One trial, an international effort called HER2CLIMB, tested the oral agent tucatinib in patients with HER-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1. Tucatinib is a targeted compound that binds to a different portion, or domain, of the HER2 protein than other existing drugs. The trial enrolled 615 patients at 155 sites in 15 countries in North America, Europe, Asia, and Australia. 410 participants were randomly chosen to receive tucatinib combined with trastuzumab and the chemotherapy agent capecitabine; 202 patients – the control group – received trastuzumab, capecitabine, and a placebo.

A year after beginning treatment, 33% of patients in the tucatinib group were alive with no worsening of their disease, compared to 12% in the control group.  The two-year overall survival – the percentage of patients alive two years after the start of treatment – was 45% for the tucatinib group and 27% for the placebo group.

Among patients whose cancer had metastasized to the brain, 25% of those in the tucatinib group were alive with no advance of the disease a year after beginning treatment, compared to none in the control group.

The most common adverse effects in the tucatinib group were diarrhea, palmar-plantar erythrodysesthesia (a condition that produces redness, pain, or swelling in the palms of the hand and/or soles of the feet), nausea, fatigue, and vomiting.

“Our results show that for this group of patients, for whom effective standard treatment options are extremely limited, the addition of tucatinib to trastuzumab and capecitabine provided a clinically meaningful reduction in the risk of disease or death,” said Winer, the study’s senior author. “Most importantly, tucatinib reduced the risk of death by a third, which is unprecedented in a population of patients who had received extensive prior therapy.

“This combination has the potential to become a new standard of care for all patients with HER2-positive breast cancer after treatment with trastuzumab, pertuzumab, and T-DM1.”

New antibody-drug conjugate

The other trial, named DESTINY-Breast01, involved trastuzumab deruxtecan (T-DXd), a conjugate drug that, like T-DM1, links an antibody to an anticancer drug.  Where the anticancer drug in T-DM1 is an agent that kills cancer cells by interfering with their ability to build an inner scaffold, the drug in T-DXd interrupts the process by which cancer cells copy their DNA before dividing.

This international study enrolled 253 patients with metastatic HER2-positive breast cancer previously treated with T-DM1.  Patients on the study had received a median of six prior treatments for their metastatic disease.

Of the 184 patients who received the recommended dose of T-DXd, 61% had a response to the drug, including 6% with a complete response (the disappearance of all signs of the cancer) and 55% with a partial response (a decrease in the size of the tumor or extent of cancer in the body).  The median progression-free survival – how long patients lived before the disease worsened – was 16.4 months.

“Both of these measures of efficacy are substantially higher than has been seen in any other study of patients with pretreated HER2-positive metastatic breast cancer,” said Ian Krop, MD, PhD, Associate Chief, Division of Breast Oncology at Dana-Farber Cancer Institute and the senior author of the study.

The disease control rate in the 184 patients was 97%. “This suggests that the vast majority of cancers in this population seem to have at least some sensitivity to this agent,” Krop noted. “The high rate of durable responses observed with trastuzumab deruxtecan in patients whose cancers had progressed on T-DM1 and other therapies suggests this agent could provide a new treatment option for this patient population.”

Almost all of the patients experienced treatment-related adverse events (TEAEs), with 57 percent experiencing TEAEs of grade 3 or higher, including decreased neutrophil count, nausea, anemia, decreased lymphocyte count, and fatigue. 15 percent of patients discontinued treatment because of TEAEs. Interstitial lung disease (ILD) was observed in 25 patients.

“ILD is a serious concern in patients treated with T-DXd,” said Krop. “While these events were primarily grade 1 or 2, there were unfortunately four ILD-related deaths (2.2 percent) on the study. Because of this potential toxicity, close monitoring for signs and symptoms of ILD is recommended for early detection. If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests. If ILD is diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended.”

Funders

The HER2CLIMB trial was supported by Seattle Genetics.  The T-DXd study was sponsored by Daiichi Sankyo, Inc., and AstraZeneca.  Winer received funding from Carrick Therapeutics, Genentech/Roche, Genomic Health, GSK, Jounce, Leap, Lilly, Merck, and Seattle Genetics.

Krop received grant support and research support from Genentech/Roche and Pfizer, personal fees from Daiichi Sankyo, Macrogenics, AstraZeneca, and Genentech/Roche.