TAVO Boosts Responses to Keytruda in Triple-negative Breast Cancer Patients, Interim Phase 2 Data Show

Treatment with TAVO (intratumoral IL-12) appears to increase the sensitivity of previously treated advanced triple-negative breast cancers (mTNBC) to the immune checkpoint inhibitor Keytruda (pembrolizumab), interim data from a Phase 2 study show.

The results highlight TAVO’s potential in this hard-to-treat population, even in patients with PD-L1-negative tumors — who are less likely to benefit from immune checkpoint inhibitors.

The study, “Phase 2, 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 (mTNBC) (KEYNOTE- 890/OMS-I141)” was recently presented in a poster at the 2019 San Antonio Breast Cancer Symposium, in Texas.

Keytruda, marketed by Merck (known as MSD outside the U.S. and Canada), works by preventing the interaction between the PD-1 receptor in immune T-cells and its ligand PD-L1 in cancer cells. This interaction is frequently used by cancer cells to evade anti-tumor immune responses. By preventing it, Keytruda boosts T-cells’ ability to detect and fight tumor cells.

Since triple-negative breast cancers typically lack tumor-infiltrating T-cells, immune checkpoint inhibitors such as Keytruda are usually ineffective against these cancers, with fewer than 10% of patients responding to treatment. Therefore, approaches that boost the recruitment of T-cells within tumors, such as TAVO, are thought to increase clinical responses to checkpoint inhibitors.

TAVO, developed by OncoSec, involves the intratumoral injection of the DNA sequence of interleukin-12 (IL-12) — an immune-stimulating protein — immediately followed by electroporation. Electroporation is a technique that increases the permeability of the cell membrane, allowing the DNA molecules to enter.

This approach promotes IL-12 production in the tumor microenvironment, which has been shown to stimulate the recruitment and expansion of immune T-cells into the tumor.

A previous Phase 1 trial (NCT02531425) showed that TAVO was generally safe and well-tolerated in mTNBC patients, while significantly increasing the number of infiltrating T-cells in targeted cancer lesions.

The KEYNOTE-890 Phase 2 study (NCT03567720) was designed to evaluate whether adding TAVO to Keytruda safely and effectively increased treatment responses in up to 25 patients with previously treated mTNBC.

To be eligible, patients must have locally advanced, inoperable cancer or their cancer must be metastatic (spread to regions outside the breast), and they should have received at least one prior treatment with chemotherapy or immunotherapy. To date, the trial has recruited 24 patients; for more information on recruitment contacts and locations, click here.

The study’s main goal is to determine the proportion of patients who respond to treatment — defined as at least 30% reduction in tumor size — while secondary goals include safety and tolerability, duration of response, and several measures of survival. As an exploratory goal, researchers will also assess the association between immunological changes within the tumor microenvironment and treatment responses.

At the symposium, OncoSec presented the results of an interim analysis that included 14 patients with evaluable data, who were 52 years old (mean average) and had received a median of three prior therapies.

Data showed that four of them (28.6%) experienced rapid tumor shrinkage (after a mean time of 3.6 months) and a confirmed partial response. Three of them showed deepening tumor shrinkage over six months, including one who had multiple metastases.

All four patients were still responding to treatment when the data was taken, and a median response duration had not been reached yet. Interestingly, three of them had PD-L1-negative tumors, while the PD-L1 status of the fourth patient is unknown.

Also, three patients (21.4%) showed stable disease — with at least 20% tumor shrinkage in two of them — while the disease progressed in seven patients (50%). Among those with disease progression, two patients had received one treatment cycle before showing a rapid clinical deterioration.

“These data show a strong signal for clinical benefit with TAVO enhancing sensitivity to [Keytruda] in treating metastatic TNBC patients who were previously unresponsive to multiple prior rounds of therapy,” Kellie Malloy, OncoSec’s chief clinical development officer, said in a press release.

The researchers also found that combination treatment induced immunological changes both in the tumor microenvironment and blood, which were consistent with IL-12’s mechanism of action. Analyses on potential disease biomarkers are still ongoing.

TAVO-Keytruda combination therapy was well-tolerated, with local pain and fatigue being the most frequently reported adverse events. Three patients experienced treatment-related serious adverse events — fatigue, kidney damage, or high blood sugar.

“I’m encouraged by the tumor responses observed in PD-L1 negative patients and the overall safety profile,” said Melinda L. Telli, MD, from Stanford University School of Medicine, who presented the poster at the symposium.

Malloy added: “We look forward to continuing development and plan to expand this clinical program and the KEYNOTE-890 trial.”

OncoSec expects to report KEYNOTE-890’s full data in 2020.