Early Trial of Anti-PD-L1 Agent Shows Promise in TNBC

Leisha A. Emens, MD, PhD

The PD-L1 inhibitor MPDL3280A demonstrated a 19% objective response rate (ORR) with 75% of responses ongoing in pretreated patients with metastatic triple-negative breast cancer (TNBC), according to findings from an ongoing phase I study presented at the 2015 AACR Annual Meeting.

“This is very exciting because longer responses are not typical of what occurs when patients with metastatic triple-negative breast cancer are treated with chemotherapy, which is the standard of care for this population," lead author Leisha A. Emens, MD, PhD, member of the Cancer Immunology and the Breast and Ovarian Cancer Programs at the Johns Hopkins Kimmel Cancer Center, said in a statement. “The emergence of approaches for harnessing the immune system to fight cancer is creating a lot of excitement for oncologists and immunologists because many of the responses that are being achieved are prolonged.”

In the multicenter phase Ia study, 54 patients with metastatic TNBC received intravenous MPDL3280A at 15 mg/kg, 20 mg/kg, or a flat 1200 mg dose every 3 weeks. At baseline, PD-L1 expression was measured using immunohistochemistry (IHC) on tumor-infiltrating lymphocytes (TILs) from fresh or archival samples, with 69% testing positive for >5% PD-L1 expression (IHC 2 >5%; IHC 3 >10%).

The median age of patients enrolled in the study was 48 years. Patients had an ECOG performance status of 0 or 1, 59% had visceral metastases and 11% had bone metastases, according to the abstract. In addition, 85% received ≥4 prior systemic regimens, including taxanes (82%), anthracyclines (78%), carboplatin (41%), and cisplatin (15%).

Among 21 evaluable patients who were PD-L1-positive, the investigator-assessed ORR by RECIST criteria was 19%. This was comprised of 9.5% complete responses and 9.5% partial responses. At the analysis, 75% of responses were ongoing, with a median not yet reached (range: 18-56+ weeks).

The 24-week PFS rate in the PD-L1-positive population was 27%. The median duration of survival follow-up was 40 weeks (range: 2-85 weeks). The data cutoff for the AACR presentation was December 2, 2014.

Three patients with PD-L1-positive TNBC (14%) experienced pseudoprogression with MPDL3280A and were indicated as having progressive disease by RECIST criteria. However, these patients continued to receive treatment and later demonstrated responses in the target and newly formed lesions. If these patients were included as responders, the ORR could be as high as 33%.

"There were 3 patients who were recorded as progressive disease who appeared to experience a phenomenon known as pseudoprogession, which is an atypical response pattern seen in some patients treated with this class of agents," Emens said. "These are patients who exhibited a durable shrinkage of their target lesions, while at the same time developing new lesions at other sites. They remained clinically well with this pattern of response."

The safety analysis for the trial included data from all 54 patients. All-grade adverse events were evident in 63% of patients. Overall, 11% of patients experienced a grade 3 adverse event, which included low potassium level, low white blood cell count, dyspnea, and adrenal insufficiency. There was one grade 4 event of pneumonitis.

"MPDL3280A was safe and well-tolerated, with the most common treatment-related adverse events consisting of fatigue, nausea, fever, decreased appetite, and asthenia," Emens said. "Two deaths, which are assessed as related by the investigators, are currently under further investigation by the sponsor [Genentech/Roche]."

MPDL3280A is an engineered monoclonal antibody that binds to the ligand PD-L1, preventing the activation of PD-1. The antibody is modified to prevent the induction of antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

"Inhibiting these interactions between PD-L1 and its receptors PD-1 and B7.1 can enhance T-cell priming and restore antitumor T-cell activity," Emens explained. "In addition, MPDL3280A leaves the PD-L2/PD-1 interaction intact, thereby potentially maintaining immune homeostasis and potentially preventing some of the autoimmunity that can be associated with targeting this particular pathway."

When active, PD-1 limits the expansion and survival of CD8+ T cells, suggesting that blocking this pathway should result in increased levels of CD8 cells and enhance the immune response. To explore this mechanism of action, peripheral biomarkers were assayed using FACS and multiplex immunoassays. This analysis revealed a transient elevation in plasma cytokines and proliferating CD8 cells following MPDL3280A treatment.

At the time of the analysis, data were not available for patients with PD-L1-negative or equivocal TNBC (IHC 0/1). This portion of the study was opened secondarily to the PD-L1-positive group. Further evaluation of the trial is ongoing, and the study continues to enroll participants (NCT01375842).

MPDL3280A has received a breakthrough therapy designation from the FDA as a treatment for patients with bladder cancer and non-small cell lung cancer. At this time, pivotal clinical trials are currently under way for MPDL3280A for these cancer types.

Reports suggest that Genentech/Roche, the developer of MPDL3280A, plan to move the agent into a phase III clinical trial for patients with TNBC later this year. Additionally, a randomized phase III study will assess MPDL3280A in combination with nab-paclitaxel as a first-line therapy for patients with metastatic TNBC, according to Emens.

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 (TNBC). Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 6317.