Adding More Arrows to the Quiver of Targeted Therapies

A Range of New Targeted Treatments Are Emerging for Breast and Gynecological Cancers

From Turning Point 2020

By Nicole Davis

In 1998, a revolutionary new breast cancer drug won approval. Its power lay in its precision: the drug, trastuzumab (also known by its trade name, Herceptin), was molecularly honed to block a major driver of breast cancer growth, a protein called HER2. At the time, it was among a handful of emerging cancer drugs specifically engineered to kill cancer cells and spare healthy cells with an eye toward minimizing the toxicity of broadly acting treatments like chemotherapy. Trastuzumab signified a watershed advance for breast cancer patients, especially those with HER2-positive tumors. It also signaled that similar targeted therapies for other cancers, including gynecologic tumors, could be on the horizon, provided the relevant molecular targets could be identified.

Fast forward to today, and the landscape of targeted cancer therapies has expanded considerably and continues to grow, thanks in part to the efforts of a distinguished cadre of physicians and scientists at Dana-Farber's Susan F. Smith Center for Women's Cancers. These researchers are discovering ways to make existing targeted drugs work better and pioneering innovative new drugs and drug combinations. Their purpose: to bring powerful treatment options to patients with breast and gynecological cancers.

Multiple Shots on Goal

Trastuzumab's development was an extraordinary achievement, but the drug is not a silver bullet for every patient with a HER2 positive tumor, especially for those with metastatic disease. Even still, scientists have kept this target in their cross hairs because of its central role in breast cancer growth.

"To us the paradigm has been, here's a target that cancer cells are clearly dependent on, so let's just keep attacking it," said Ian Krop, MD, PhD, associate chief of the Division of Breast Oncology in the Susan F. Smith Center for Women's Cancer's. "And we've done that in a variety of ways and each new drug seems to bring some additional efficacy." Now, there are a total of seven drugs all aimed at HER2, three of which were approved by the Food and Drug Administration (FDA) just in the last year.

Over the years, Dr. Krop and others in the field have learned that trastuzumab is somewhat half-hearted in blocking HER2 function. The drug, which consists of an immune molecule known as an antibody, seeks out HER2 proteins scattered on the surface of breast cancer cells and binds to them, but it fails to fully shut down the proteins' activity. Researchers found that these shortfalls could be overcome, at least in part, by combining it with chemotherapy. But the problem with this pairing is that patients lose the benefits of targeted therapy and experience side effects, like hair loss, nausea, and fatigue.

"Since we were using these two classes of drugs together — an antibody that is highly targeted, and chemotherapy, which is not — the idea arose to combine the best of both worlds," explained Dr. Krop.

The result is a kind of "smart bomb," in which an antibody is chemically linked to a chemotherapy drug. Through this linkage, the antibodies seek out and stick to cells (such as cancer cells carrying HER2) and deliver chemotherapy only to those sites. "It's basically a targeted way to give chemotherapy to a patient," said Dr. Krop.

The first smart bomb ever to be developed, known as T-DM1, combines HER2-targeting trastuzumab with the chemotherapy drug DM1. This first-of-its-kind drug (also known as an antibody-drug conjugate) has been used for the last several years to treat patients with metastatic breast cancer. Just last year, the FDA approved it for a subset of patients with early stage disease who have residual cancer following chemotherapy but prior to surgery.

"T-DM1 provided the proof of concept that this smart bomb idea really works," said Dr. Krop. "It is a really nice drug that works quite well in patients with HER2-positive cancers and has relatively few side effects."

Given the success of T-DM1 in patients with advanced disease, Sara Tolaney, MD, MPH, associate director of the Susan Smith Center for Women's Cancers, and her colleagues have been working to figure out if the drug could also benefit those with much smaller tumors, such as patients with stage one, HER2-positive breast cancer.

The researchers recently completed a large randomized clinical trial that compared T-DM1 to the standard treatment of trastuzumab plus the chemotherapy drug paclitaxel. "This is really the first study of its kind looking at T-DM1 in such early stage disease," said Dr. Tolaney. Known as the ATEMPT trial, she and her colleagues determined the efficacy of T-DM1 and compared the toxicities of the two treatment approaches.

"Our data tell us that T-DM1 in stage one disease is associated with very rare recurrences so it's quite efficacious," said Dr. Tolaney. "And while we didn't see significant differences in toxicity between the two regimens, it was clear that quality of life was much better in patients treated with T-DM1."

In addition to expanding the use of T-DM1, Dana-Farber researchers have also been designing new smart bombs that carry different payloads. For example, Dr. Krop and his colleagues have been studying T-DXd, or trastuzumab deruxtecan, which includes the HER2-targeting antibody linked to a highly potent chemotherapy drug.

"What makes T-DXd unique is that once the chemotherapy payload is released, it can also diffuse out of the cell and kill neighboring tumor cells," said Dr. Krop. "This bystander effect may be important for heterogeneous cancers, where some cells may have a lot of HER2 and others have much less." Such tumors could be resistant to drugs like T-DM1 that require HER2 to be present on each cancer cell to be effective.

Last December, Dr. Krop presented data from a phase two trial of T-DXd, which led to an accelerated FDA approval of the drug for metastatic breast cancer. The trial, named DESTINY-Breast01, studied patients with breast cancer who had previously been treated with T-DM1. On average, trial participants had already received six other treatments for their disease.

"Despite the fact that these patients' tumors had developed resistance to current therapies, we saw responses in 60% of patients," said Dr. Krop. Based on these encouraging results, he and his colleagues are now studying the drug in patients with less advanced disease.

Expanding the Armamentarium for Triple-Negative Breast Cancer

In contrast to the myriad treatment options for HER2-positive breast cancer, the picture for triple-negative breast cancer has been much bleaker. This tumor subtype, which is characterized by the absence of HER2 as well as the absence of receptors for estrogen and progesterone, is notoriously difficult to treat.

About a year ago, the outlook brightened when the FDA approved a form of immunotherapy, known as a checkpoint inhibitor, together with chemotherapy for patients with advanced triple-negative breast cancer. The drug, called atezolimab (also known by its trade name, Tecentriq) targets the PD-L1 protein, which is present in about 40% of patients with triple-negative breast tumors.

"This was really a remarkable breakthrough and has given us a new target for patients with PD-L1-positive, triple-negative breast cancer," said Dr. Tolaney.

Now, Dr. Tolaney and her colleagues are working to further expand the slate of options for triple-negative breast cancer patients. For example, she and her team were involved in a clinical trial of a new targeted drug — a smart bomb aimed at a protein called TROP-2 — that showed significant promise in patients with advanced triple-negative breast cancer.

Patients who received the drug, known as sacituzumab govitecan, did not see their cancers worsen for nearly six months. For those treated with standard chemotherapy, their disease progressed in less than two months. Based on this difference and the dire need for novel therapies for this subtype, the drug was approved by the FDA earlier this year.

Dr. Tolaney is also pursuing studies that could increase the number of triple-negative patients who respond to immunotherapy, regardless of their PD-L1 status. She and her colleagues recently discovered a molecular pathway that helps tumors resist the killing effects of checkpoint inhibitors. Drugs that block this pathway, known as AKT inhibitors, are in clinical development. Trials are underway to evaluate their effectiveness in breast cancer when combined with atezolimab, the PD-L1-blocking drug. "The thinking is that maybe we can make immunotherapy work in all triple-negative breast cancers," she said.

Beyond the Vanguard

Breast cancer was among the first cancers to benefit from targeted therapies. Other tumor types have not been as fortunate, as researchers worked first to define potential molecular targets. But fortunes may be changing.

Joyce Liu, MD, MPH, director of clinical research, Division of Gynecologic Oncology and her colleagues are working to bring more therapies to a particularly aggressive form of gynecologic cancer, uterine serous cancer. These tumors represent roughly 10% of all uterine cancer cases, but account for 40% of deaths.

"A couple years ago, we discovered that uterine serous cancers have a few interesting molecular features, including dysregulation of the molecular control switches for cell division," Dr. Liu said. "This molecular profile suggested the tumors might be vulnerable to drugs that inhibit other regulators of cell division, such as WEE1."

A WEE1 inhibitor, called adavosertib is now in clinical development. Liu's team recently completed a phase two trial of the drug in 35 patients with advanced uterine serous cancer. Nearly 30% of patients responded to the treatment. "This is really exciting data that of course must be validated in a larger group of patients," she said. "But it opens the door to thinking about this type of targeted therapy for uterine serious cancer."

Jennifer Veneris, MD, PhD, is working to bring new treatment options to patients with this form of cancer, too. She and her colleagues are exploring whether T-DXd, the second-generation smart bomb targeting HER-2, is effective in patients with uterine serous cancer when combined with another drug, called a PARP inhibitor. The rationale is two-fold: About 25% of patients' tumors harbor genetic abnormalities in HER2, which suggests that targeting this protein could be beneficial. In addition, because the chemotherapy payload in T-DXd cripples the machinery involved in replicating and repairing DNA, it is likely to synergize with other agents, like PARP inhibitors, that also take aim at this machinery.

"We're learning that, just as in breast cancer, not all uterine and ovarian cancers are alike," said Dr. Veneris. "And based on that understanding, we are starting to develop targeted interventions that are more effective for patients and really broaden our armamentarium."

Drs. Liu and Veneris are also trying to broaden the field of targeted treatment options for other gynecological cancers. For example, Dr. Liu and her colleagues recently hatched an idea to combine not just one or two targeted therapies at a time, but three, in an effort to improve the treatment of ovarian cancer. The concept builds on data collected several years ago that showed two targeted drugs, a PARP inhibitor and a VEGF inhibitor, were profoundly more effective when combined together.

"The next question is, can we extend that?" said Dr. Liu. "Of course, one of the things everyone wants to unlock in ovarian cancer is immunotherapy."

Laboratory data suggest that combining immunotherapy, in the form of checkpoint inhibitors, with other drugs, including those that block blood vessel formation, like VEGF inhibitors, can have synergistic effects on tumor killing. Clinical trials are now underway to evaluate such a three-pronged approach in advanced ovarian cancer. Dr. Liu and her team are eager to learn if this triplet therapy will bear fruit.

At the same time, Dr. Veneris is working on a phase two study, which is now open and enrolling patients, that tests a novel combination of two targeted drugs to treat endometrial cancer. This pairing includes a smart bomb that targets the folate receptor (called mirvetuximab soravtansine) and the checkpoint inhibitor pembrolizumab.

More than two decades since the dawn of Herceptin, these efforts, along with recent advances in targeted cancer therapies, are expanding the range of treatment options for women's cancers.