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MPDL3280A shows promise in metastatic triple-negative breast cancer
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PHILADELPHIA — The investigational immunotherapy MPDL3280A appeared well tolerated and demonstrated favorable efficacy in patients with metastatic triple-negative breast cancer, according to study results presented at the American Association for Cancer Research Annual Meeting.
“Triple-negative breast cancer tends to have a higher mutation rate than other breast cancer subtypes,” Leisha A. Emens, MD, PhD, associate professor of oncology and member of the cancer immunology and breast/ovarian cancer programs at Johns Hopkins Kimmel Cancer Center, said during a press conference. “This lends to its ability to produce neoantigens, which can be recognized as foreign by the immune system and can be more effective targets for the immune response than other antigens.”
Triple-negative breast cancer displays higher levels of programmed death-ligand 1 (PD-L1) expression compared with other breast cancer subtypes. There currently are no targeted therapy regimens for triple-negative breast cancer and prognosis for these patients typically is poor, according to the study background.
MPDL3280A (Genentech) is a monoclonal antibody that blocks the interaction between PD-L1 and PD-1, a protein found in T-cells. The interaction between PD-L1 and PD-1 terminates the ability of T cells to fight cancers and eradicate tumor cells.
The current study included 54 patients with metastatic triple-negative breast cancer, 69% of whom had PD-L1–positive disease, defined as PD-L1 on 5% or more of their immune cells.
Patients received MPDL3280A every 3 weeks at either 15 mg/kg, 20 mg/kg or an IV flat dose of 1,200 mg.
Sixty-three percent of patients experienced at least one drug-related adverse event, the most common of which were fever, fatigue, nausea and loss of appetite. Eleven percent of patients experienced at least one grade 3 event, including low potassium level within the blood, low white blood cell count, skin rash and adrenal insufficiency. One patient experienced grade 4 pneumonitis.
Two patient deaths were reported. The deaths were assessed as related by the investigator but are undergoing further review by the sponsor.
Twenty-one patients with PD-L1–positive disease were evaluable for efficacy. In this subgroup, researchers reported an objective response rate of 19% (95% CI, 5-42), including two complete responses and three partial responses. Median duration of response had not been reached, but researchers reported a 24-week PFS rate of 27% (95% CI, 7-47).
Two complete responses and two partial responses were observed in this patient cohort, and three of the four responses were ongoing at the time of study closure. Three patients who were reported as progressive disease were later identified as having experience “pseudo-progression,” a response pattern sometimes observed in patients treated with this class of agents. These patients exhibited durable shrinkage of their targeted lesions while simultaneously developing new lesions in other sites. Pseudo-progression patients remained clinically well.
“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,” Emens said in a press release. “However, we need to validate these findings in larger cohorts of patients.”
Further evaluation is ongoing in both patients PD-L1 positive and PD-L1 negative metastatic triple-negative breast cancer.
“We are preparing to launch a phase 3 global, randomized trial testing MPDL3280A in combination with abraxane [Paclitaxel, Abraxis Bioscience] as first line therapy for patients with metastatic triple-negative breast cancer,” Emens said. “This very well could be the first targeted therapy that bears out in a larger trial [in this setting].” – by Cameron Kelsall
Reference:
Emens LA, et al. Abstract 6317. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.
Disclosure: The study was funded by Genentech. Emens reports research funding from Genentech and a research grant from Roche. See the full study for a complete list of the researchers’ relevant financial disclosures.
Perspective
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Louis M. Weiner, MD
Triple-negative breast cancer is a disease for which there are no known effective, targeted therapies and for which even standard chemotherapies have shown relatively limited impact in the treatment of women with metastatic disease. Encouragingly, there is a significant anti-tumor activity profile seen in a very small patient sample of roughly 21 patients who were evaluable for efficacy determinations. With four objective responses — two of them complete and two others that were technically classified as progressive disease but were actually pseudo-progressions that led to subsequent clinical benefits — it is quite clear that this is an active agent and a useful strategy.
This set of data reinforces prior studies using other antibodies in targeting PD-1 or PD-L1 access, showing similar levels of activity. I think we can add PD-1/PD-L1 access as an important target in triple-negative breast cancer and we can add triple-negative breast cancer to the list of potentially important tumors to be treated with antibodies targeting these receptors.
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Mateusz Opyrchal, MD, PhD
Emens and colleagues report early results from their clinical trial investigating MPDL3280A — an anti-PD-L1 antibody — in a cohort of patients with metastatic triple-negative breast cancer expressing PD-L1. This population of patients is extremely difficult to treat with very few treatment options; therefore, new treatment modalities are sorely needed. Immuno-modulatory therapies and specifically targeted checkpoint inhibition have generated excitement in the oncology world with pembrolizumab (Keytruda, Merck) recently approved for patients with metastatic melanoma. This study provides important hints of clinical activity from this class of drugs in triple-negative breast cancer. Further, the observation that responses in some patients were durable is very exciting. The overall response rate of 24% reported in this heavily pre-treated group with at least four previous lines of chemotherapy adds to the belief that immune-modulatory therapies will play a role in treatment of breast cancer in the future.
It will be interesting to learn in the future if the PD-L1 immunohistochemistry 0 or 1 cohort of patients had clinical responses as well, and if any new biomarkers for response to the anti-PD–L1 treatment emerge from the correlative studies. The treatment was very well tolerated with a low level of greater than grade 3 toxicities, which is on par with what has been observed in other clinical trials with this class of drugs.
All of the oncologists treating breast cancer are paying close attention to developments in this field. There is still a lot we do not know, such as if the PD-L1 protein is the right biomarker for response in breast cancer and if or what combination therapies will yield higher response rates. This excellent study provides more evidence that immune-modulatory therapies have a place in treatment of breast cancer and more research is warranted.
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