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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.”