The phase II KEYNOTE-890 trial is a small but interesting study in patients with inoperable advanced triple-negative breast cancer. After one injection of intratumoral tavokinogene telseplasmid, a plasmid encoding the proinflammatory cytokine interleukin-12 (IL-12), followed by electroporation and pembrolizumab, several patients with skin or subcutaneous tumors saw metastatic lesions disappear.1
Electroporation appears to enhance tumor immunogenicity and boost response to the immunotherapy, as has been shown in metastatic melanoma, said lead investigator Melinda L. Telli, MD, Associate Professor of Medicine at Stanford University School of Medicine and Leader of the Breast Oncology Clinical Research Group at the Stanford Cancer Institute, who reported findings at the 2019 San Antonio Breast Cancer Symposium.
“We think this approach has a lot of potential in the primary triple-negative setting, because those patients typically have large intact tumors that could be electroporated.”— Melinda L. Telli, MD
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In the previous KEYNOTE-086 trial, treatment with single-agent pembrolizumab led to a modest response rate of 5.3%.2 Preliminary data from the current study, in which 29% of patients assessed so far have responded, suggest that intratumoral tavokinogene telseplasmid and electroporation may enhance sensitivity to pembrolizumab in this patient population, Dr. Telli said.
“We had seen activity after just one cycle of [tavokinogene telseplasmid] and pembrolizumab in a couple of patients who had refractory disease and limited treatment options. In both those patients, this was the best response they ever had, in terms of durability. In one patient, we saw breast lesions resolve, scalp lesions heal, and metastases regress,” Dr. Telli told The ASCO Post.
How It Works
The tavokinogene telseplasmid injection into the tumor is followed by electroporation in the same region, which aims to destabilize the tumor membrane through electrical pulses, facilitate uptake of IL-12–coded DNA, and stimulate a favorable proinflammatory immune response. Combining tavokinogene telseplasmid with an inhibitor of programmed cell death protein 1 (PD-1) may improve responses in patients with metastatic triple-negative breast cancer by potentially converting tumors that are poorly immunogenic or low in tumor-infiltrating lymphocytes into immunoresponsive tumors. The combination of tavokinogene telseplasmid and pembrolizumab has also shown promise in metastatic melanoma.
“These anecdotes from our pilot study, along with emerging data in melanoma, suggest that this approach might restore sensitivity to checkpoint inhibition, and this led to our study,” she said.
The multicenter, single-arm, open-label phase II KEYNOTE-890/OMS-I141 study was therefore designed to evaluate intratumoral tavokinogene telseplasmid, electroporation, and intravenous (IV) pembrolizumab in patients with metastatic triple-negative breast cancer previously treated with chemotherapy with or without a checkpoint inhibitor. It included 25 patients with inoperable locally advanced or metastatic triple-negative disease and at least one line of prior systemic therapy for advanced disease, including checkpoint inhibition. Patients were required to have measurable disease with at least one anatomically distinct cutaneous or subcutaneous lesion accessible by injection.
Patients received pembrolizumab at 200 mg IV on day 1 of each 3-week cycle and intratumoral tavokinogene telseplasmid/electroporation at a concentration of 0.5 mg/mL and dose volume of approximately one-quarter of the calculated lesion volume to the accessible lesion(s) on days 1, 5, and 8 every 6 weeks. The primary endpoint was objective response rate by investigator review.
Response Rate of 28.6%
Among 25 patients enrolled, 16 were evaluable for safety and 14 for efficacy. Patients had received a median of three prior lines of therapy for advanced disease. Approximately 20% were programmed cell death ligand 1 (PD-L1)–positive.
Partial responses were observed in 4 of 14 patients (28.6%), which included a “deep confirmed response in a patient with multiple liver, bone, skin, and nodal metastases who had a rapid relapse after neoadjuvant chemotherapy and rapid progression on first-line chemotherapy,” she said. “She would not have been a patient we would have expected to respond to checkpoint inhibition, since she was PD-L1–negative by two antibody assays, but she did respond and remains on treatment for more than a year. Her liver disease is essentially gone.”
Of the four responses, three were in patients lacking PD-L1 expression, and one responder’s PD-L1 status was unknown. Regression of untreated lesions has been observed, and three patients (21.4%) achieved stable disease.
Treatment was well tolerated, with treatment-emergent adverse events observed in 18.8% of patients; they included fatigue, acute kidney injury, and hyperglycemia in one patient each. Two-thirds of patients had low-grade administration-site pain. Patients demonstrated immunologic responses in the blood consistent with an IL-12–associated mechanism of action: they have low frequencies of tumor-infiltrating lymphocytes with high relative amounts of suppressive CD163-positive M2 macrophages, she said.
“We think this approach has a lot of potential in the primary triple-negative setting, because those patients typically have large intact tumors that could be electroporated,” Dr. Telli said. The next step will be to expand the study into a first-line metastatic population, in combination with chemotherapy, she said.
According to the manufacturer’s website, tavokinogene telseplasmid is being studied in multiple clinical trials, including a registration-directed pivotal phase II trial in metastatic melanoma and two phase II trials in triple-negative breast cancer and head and neck cancer.
“Ultimately, we will need a randomized study to see whether we are getting improved responses when we add [tavokinogene telseplasmid], especially in PD-L1–negative patients, who would be predicted not to respond to pembrolizumab. We hope to see that this approach is beneficial, especially in those with PD-L1–negative disease, who are the patients with the biggest unmet need.”
DISCLOSURE: The study was sponsored by OncoSec. Dr. Telli has served in a consulting or advisory role for Aduro Biotech, Celgene, Celldex, Genentech/Roche, Immunomedics, Merck, Pfizer, and Tesaro; has received institutional research funding from AbbVie, Biothera, Calithera Biosciences, EMD Serono, Genentech, Medivation, Novartis, OncoSec, Pfizer, PharmaMar, Tesaro, and Vertex; and has served as a member of the data and safety monitoring committee for G1 Therapeutics.
1. Telli ML, Wapnir I, Devitt B, et al: Phase II, open-label study of intratumoral tavokinogene telseplasmid (tavo) plus electroporation in combination with intravenous pembrolizumab therapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (KEYNOTE-890/OMS-I141). 2019 San Antonio Breast Cancer Symposium. Abstract P3-09-04. Presented December 12, 2019.
2. Adams S, Schmid P, Rugo HS, et al: Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: Cohort A of the phase II KEYNOTE-086 study. Ann Oncol 30:397-404, 2019.
Sara M. Tolaney, MD, MPH
Sara M. Tolaney, MD, MPH, Assistant Professor of Medicine at Harvard Medical School and Associate Director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber/Brigham and Women’s Cancer Center, Boston, commented on KEYNOTE-890.
“Previous work has...