Drugs that rev up a patient’s immune system have changed how we treat cancers of the skin, lung, and more, offering people whose tumors have spread a chance to live longer than ever thought possible. But until this year, the field had nothing for breast cancer, which kills more women than any other cancer type.
That changed in March, when the FDA approved a combination of the immunotherapy atezolizumab (Tecentriq), made by Roche, and chemotherapy for a subset of patients with an aggressive form of the disease called triple-negative breast cancer. Other immunotherapy regimens, now in advanced testing, could follow in the next few years.
Yet success in breast cancer has been elusive, which is reflected by the paucity of immunotherapy data expected this weekend at the American Society of Clinical Oncology conference, the world’s biggest cancer meeting. The most noteworthy results will be an update from the study that led to the Tecentriq approval in March.
Breast cancer’s biological complexity and the availability of other treatments have presented a challenge for the immunotherapies known as checkpoint inhibitors, which work by shutting down a mechanism that tumors use to hide from the immune system. (Seven checkpoint inhibitors have been approved, and the scientists who discovered checkpoint inhibition won a Nobel Prize last year.) But many believe these drugs will make a difference in breast cancer when all is said and done.
“I have no doubt that immunotherapy has a role,” says Roger Perlmutter, the executive vice president of Merck (NYSE: MRK), whose pembrolizumab (Keytruda) is the leading cancer immunotherapy, with approvals to treat a wide range of cancer types—but not breast cancer. “I just don’t think we can describe exactly what that role is going to be.”
While the American Cancer Society estimates 41,760 women are expected to die from the disease in the US this year, the number of breast cancer-related deaths declined 40 percent between 1989 and 2016 because of advances in early detection and a slew of therapies, from genetically-targeted drugs to hormone therapies, chemotherapy, and much more.
The average five-year survival rate of women diagnosed with breast cancer is 90 percent. And 83 percent of women live an average of ten years, according to statistics from ASCO.
The outlook is bleaker for women whose disease has spread. An average of 27 percent live five years after their diagnosis, according to ASCO figures. That’s because the available treatments just delay the disease’s progression. They don’t cure breast cancer. “We still need to do better,” says Leisha Emens, coleader of the University of Pittsburgh Medical Center Hillman Cancer Immunology and Immunotherapy Program.
One hope is that immunotherapy may complement existing drugs and boost their effects. And when immunotherapy works, the results can be jaw-dropping. Adam Cohen, an investigator at the Huntsman Cancer Institute at the University of Utah, says that one of his patients had breast cancer and melanoma that had spread to her brain. After immunotherapy several years ago, her cancer was wiped out and hasn’t returned. “We don’t see that kind of thing with the traditional treatments for breast cancer,” Cohen says.
With checkpoint inhibitors such as Keytruda, long-lasting responses have also occurred in patients with cancers of the skin, lung, bladder, kidney, head and neck, and more. A regimen of Keytruda and chemotherapy, for instance, has become the first option for a majority of patients with the most common form of lung cancer. Keytruda, and separately, a combination of the Bristol-Myers Squibb (NYSE: BMY) immunotherapies ipilimumab (Yervoy) and nivolumab (Opdivo), have changed the treatment of advanced melanoma. Similar advances are happening in kidney cancer.
But breast cancer is different. It’s actually “many diseases,” not one, notes Amreen Husain, product development global head of breast and gynecologic cancers at Roche’s Genentech division. There are four main subtypes associated with certain proteins or hormones: Triple-negative breast cancer, HER2-positive, and two forms of estrogen-receptor (ER)-positive disease.
Within those groups are a slew of subtypes with different biological features. “Some we have some understanding of,” Cohen of the University of Utah says, but with others, “we don’t really know anything about them.”
Barrier to Entry
That complexity means drug makers have to “customize immunotherapy approaches” for each biological subtype, says Husain. Whereas an immunotherapy-chemotherapy regimen might benefit a majority of patients with lung cancer, drug makers have to use more nuanced strategies for different types of breast cancer. A HER2-positive patient, for instance, might need a completely different regimen than a patient with ER-positive disease.
What’s more, the barrier to entry for immunotherapy is higher in breast cancer because in some cases, the tumors grow slowly and can be countered with many current drugs—sometimes with dramatic life-extending results. That means the clinical studies of a promising immunotherapy need to be much larger and longer to show meaningful benefit.
Merck’s Perlmutter notes that, by comparison, Keytruda has proven its worth in studies that show it can extend patients’ lives with other cancers by matters of months. It’s a higher bar for Merck to show the same type of benefit in a test of Keytruda in, say, ER-positive breast cancer patients who have effective hormone therapies available. So Merck wants to understand how the immune system responds to these tumors, and how that response helps predict who would respond to Keytruda in a trial. That way, Merck has a better shot of taking patients “who don’t seem to have a response and treat them in such a way that they become responders,” he says.
Breast cancer has been a difficult immunotherapy target for biological reasons as well. Breast tumors have fewer genetic mutations than, say, skin or lung cancer, and they tend to express less of a protein, PD-L1. A higher mutational “burden” and more PD-L1 expression are two measures that suggest a cancer patient could be more responsive to immunotherapy.
Not many immune cells can penetrate the defenses of a breast tumor, which means it’s less likely the immune system has seen the cancer and can be pumped up for an attack. (Tumors with a lack of these penetrating cells, called tumor-infiltrating lymphocytes, or TILs, are known as “immunologically cold.”)
“This is probably the predominant reason that we’re not seeing the responses in breast cancer that we’re seeing in other types of cancers,” says Cesar Santa-Maria, an oncologist at Johns Hopkins Medicine in Baltimore, MD.
Husain says we need to know exactly what role TILs play and find better ways to activate them. We need to know what can help “prime” the immune system to attack, she says. We also need to understand the immediate surroundings—the “microenvironment”—of breast cancer cells, says Bora Lim, an assistant professor within the Breast Medical Oncology department at The University of Texas MD Anderson Cancer Center.
“If we learn these secrets, there will be hope for immunotherapy” to play an important role in breast cancer, says Lim. “As of 2019, its role is still quite limited.”
The best responses so far have come in a portion of patients with triple-negative breast cancer, which primarily afflicts younger women and accounts for 15 for 20 percent of cases. Triple-negative tumors are the most likely type of breast tumor to be immunologically “inflamed,” or hot, says Emens, the lead investigator on the Roche IMPassion130 study that led to the Tecentriq approval.
No surprise, then, that drug makers have focused a majority of their immunotherapy resources on triple-negative disease.
But other than the landmark Tecentriq approval this March, the results have disappointed. Merck’s Keytruda is now a first-line option in lung cancer because a Keytruda-chemotherapy combination cut the risk of death in half compared to chemotherapy alone, and in a separate trial, Keytruda alone beat chemotherapy head to head. But Keytruda against chemotherapy in triple-negative breast cancer patients, in a study called Keynote-119, recently failed.
Perlmutter says Merck saw “a signal” of a benefit in those results and will present them at a future medical meeting. “It’s not that it’s bereft of effect,” Perlmutter says of Keytruda. “The question is how to maximize that benefit.”
Even the Tecentriq approval came with caveats. The FDA made a streamlined decision, but it must be confirmed through further tests. (The nod came after Tecentriq and chemotherapy held triple-negative tumors expressing PD-L1 in check for a median of 7.2 months, compared to 5.5 months for chemotherapy alone.)
Since then, more analysis has suggested that the combination extended patients’ lives, especially if their tumors have PD-L1. The results are “quite modest,” says Santa-Maria, but have at least helped immunotherapy “get its foot in the door” with breast cancer. More details are expected at ASCO. “We’re anxiously anticipating that,” Santa-Maria says.
The Tecentriq-chemotherapy combination is a herald of what’s to come, experts say. Monotherapy is “unlikely to work in a majority of [breast cancer] patients,” says Roche’s Husain. Multiple trials from Merck, Bristol-Myers, Roche, and others are focused on immunotherapy in combination with other drugs. The idea is to shake up the immune system in one way or another—from chemotherapy to radiation, vaccines, and other drugs—so that immunotherapy can do its work.
One strategy experts are closely watching is to give immunotherapy before surgery to remove a tumor, what’s known as the neoadjuvant setting. “That’s a highly attractive setting for developing these drugs,” Emens says.
Cancers at this stage have “less heterogeneity,” Perlmutter says, meaning they might not yet have the wealth of genetic mutations that can shield them from attack. Huge bets are currently underway. Among them: Merck’s 1,174-patient Phase 3 study, Keynote-522, in triple-negative patients, which should produce results within a year, Perlmutter says. Similarly, Roche is testing Tecentriq as a neoadjuvant therapy in multiple studies in triple-negative breast cancer.
Further afield are combinations of checkpoint inhibitors and relatively new medicines, known as PARP inhibitors and CDK 4/6 inhibitors. Each may make tumors more susceptible to immunotherapy.
“There’s work to be done,” Santa-Maria says. “But there’s reason to be optimistic.”