Andrew D. Smith
Elizabeth A. Mittendorf, MD, PhD
Elizabeth A. Mittendorf, MD, PhD, needs only a single word to answer this question: Is immunotherapy ready for prime time in breast cancer?
The most advanced treatment candidates are just beginning later stage trials.
That said, their performance so far suggests that immunotherapy may become a powerful tool against breast cancer for those oncologists who follow the research and prepare for its arrival.
Mittendorf differentiated the main types of immunotherapy and highlighted some of the most interesting results in breast cancer trials during her presentation at the 32nd Annual Miami Breast Cancer Conference. She also discussed why different types of immunotherapy might be appropriate for different types of breast tumors at various stages of development.
“Researchers have dreamed of turning the immune system against tumors for more than half a century now, and—after decades of incremental progress—the science has reached the sort of tipping point that has produced a large number of promising compounds,” Mittendorf, an associate professor of surgical oncology at The University of Texas MD Anderson Cancer Center in Houston, said in an interview.
Breast cancer specialists once assumed that the relative paucity of nearby T cells limited the potential of immunotherapy in their field, so they concentrated (very effectively) on targeted treatments. Patients with breast cancer have thus had limited access to the kinds of immunotherapies that are currently available to people with melanoma or prostate cancer. But that may change.
Immunotherapy development currently tends to focus broadly on three treatment categories: chimeric antigen receptor (Car) T-cell therapies, vaccines, and checkpoint blockade strategies. Car therapies, which coat the patient’s T cells to help those cells recognize tumor antigens, remain largely untested against breast cancer, so Mittendorf focused on vaccines and checkpoint inhibitors.
Vaccine Leads Field
For patients with breast cancer, the most advanced vaccine is nelipepimut-S (neuvax). The formulation is a peptide derived from HER2 protein, combined with the immunoadjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF). Patients receive it monthly for 6 months and then every 6 months thereafter for up to 3 years.
In a phase I/II trial as adjuvant therapy on 187 women with node-positive and high-risk node-negative tumors that expressed any degree of HER2, the 5-year rate of disease-free survival (DFS) was 89.7% overall for those who received the vaccine compared with 80.2% for unvaccinated women.1
For optimally dosed patients, the DFS rate rose to 94.6%.
The phase III PRESENT trial now under way seeks to randomize 700 women with early-stage, node-positive breast cancer with low to intermediate HER2 expression (HER2 1+ by IHC or HER2 2+ by IHC/FISH) to NeuVax or an active comparator composed of the GM-CSF sargramostim (Leukine).2
To be eligible for the trial, patients must have primary tumor stage T1-3 at initial diagnosis that was completely excised through surgery or are receiving neoadjuvant therapy before surgery.
“Vaccination takes months to produce an immune response, so it’s probably not an appropriate treatment strategy for very late-stage cancers, but it appears to be particularly appropriate in an adjuvant setting,” said Mittendorf, who has been leading the nelipepimut-S trials.
“At that point, when most patients are already disease-free, harsh treatments make no sense. The tradeoff between toxicity and benefit is not in the patient’s favor. Effective vaccines, on the other hand, make perfect sense because they rarely subject patients to anything worse than mild pain or itching at the injection site. NeuVax is no more grueling than a flu shot.”
There is also reason to think that many vaccines will prove more effective in the adjuvant setting than they have, to date, in the advanced-disease setting. Vaccines against infectious diseases rank among the most beneficial tools created by medical science, but they have a major limitation. They’re far better at prevention than treatment. In general, the more a patient already suffers from the target disease at the time of vaccination, the less a vaccine helps the patient.
“We don’t know enough yet to make blanket statements about the optimal timing for different immunotherapies, but anecdotal evidence suggests that vaccines are less effective in patients with advanced metastatic cancer,” Mittendorf said. “It would explain why many of the earliest vaccine trials, which enrolled patients with diffusely metastatic tumors, failed to demonstrate benefit.
“Timing, in general, is critical in oncology, and it may prove particularly important with immunotherapy,” she said. “Research needs to demonstrate not only whether treatments work but when and how they work the best so that clinicians can prescribe each patient the right treatment at the right time.”
Determining “how” they work best will eventually entail testing combinations of immunotherapies that, logically, should produce synergies, but testing to date has mostly involved supplementing existing standards of care with a single vaccine or, in other cases, a single checkpoint inhibitor.
Regulators have approved three such compounds to date: ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo). The first of those drugs makes it harder for tumors to call off immune attack via the cytotoxic T-lymphocyte-associated protein–4 (CTLA-4) pathway. The others reduce similar communication via the programmed death receptor-1 (PD-1) pathway.
At present, all three agents are approved exclusively for melanoma, but they may work against other tumors. Both of the anti-PD-1 medications are already in late-stage trials against certain lung cancers and early-stage trials against breast cancer.
A phase 1b trial of pembrolizumab in metastatic triple-negative breast cancer produced an overall response rate of 18.5%.3
The experimental compound MPDL3280A also produced responses in a similar patient group.4
Such apparent effects may be explained, at least in part, by a finding from Mittendorf’s research group: 20% of all triple-negative breast tumors express the PD-1 ligand, PD-L1.5
PD-L1 expression levels are considered a potential biomarker for PD-1–targeted agents.
Given that triple-negative tumors respond so little to all existing treatments, significant progress against even 20% of them would be cause for celebration, but separate research suggests there are ways to increase PD-L1 expression on tumors and ways to boost the number of T cells available to attack the tumor.
“There are a lot of promising ideas for improving response rates and increasing the strength of those responses, though there is also concern that the relative lack of T cell activity inside the breast will effectively prevent a large percentage of patients from responding to checkpoint blockade,” Mittendorf said.
“Still, even if the latter idea proves right and response rates never exceed 20%, immunotherapy would still constitute a breakthrough in treatment. Only 20% of breast cancers express HER2 and nobody would call the treatments that target such tumors anything less than a breakthrough,” she said.
Mittendorf EA, Clifton GT, Holmes JP, et al. Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients [published online June 6, 2014]. Ann Oncol. 2014;25(9):1735-1742.
Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S1-09.
Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract PD1-6.
Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer [published online January 10, 2014]. Cancer Immunol Res. 2014;2(4):361-370.