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.