T-VEC Plus chemotherapy reaches high pCR in TNBC

Hatem Soliman, MD

A majority of patients with large triple negative bad tumors (TNBC) achieved a complete pathological response (pCR) when treated with viral oncolytic talimogen laherparepvec (T-VEC, Imlygic) and neoadjuvant chemotherapy, according to a small preliminary test.

Five of the nine patients achieved pCR, defined as no invasive bad or lymph node disease. The remaining four patients had only small residual foci. T-VEC was generally well tolerated and the relative dose intensity (RDI) of chemotherapy was close to 100%.¹

"Even in some cases where the tumor would not fully resolve with neoadjuvant chemotherapy, it appeared that some tumors were still able to resolve when T-VEC was used at the same time as the treatment," Hatem Soliman, MD, of Moffitt Cancer Research Institute Center said at the 2019 AACR Annual Meeting. "It is still very early and these are preliminary data that have yet to be corroborated in subsequent studies."

"Specific T-cell subsets may correlate with the response. A single-arm phase II trial is underway to further evaluate the efficacy and immune correlates, "he added.

In patients with TNBC, obtaining a pCR is badociated with a better prognosis.² Standard neoadjuvant chemotherapy with a taxane / anthracycline regimen provides a pCR in about 30% of cases, stressed Soliman. In addition, an increase in the number of tumor infiltrating lymphocytes is also badociated with a higher level of pCR and a better prognosis in TNBC.³

The researchers hypothesized that adding an oncolytic virus to neoadjuvant chemotherapy would improve pCR by lysing tumor cells and inducing an antitumor response.

Derived from herpes simplex virus 1, T-VEC produces local and systemic effects after intratumoral injection. The virus has been genetically engineered to replicate selectively in cancer cells with defective interferon signaling, Soliman said. The virus is encoded with macrophage and granulocyte colony stimulating factor, which is released upon rupture of cancer cells, and then recruits and activates nearby dendritic cells to elicit an adaptive immune response.

"[The immune response] not only attacks the primary tumor but can also spread systemically to improve host surveillance and eventually eradicate micrometastatic disease, "he said.

T-VEC has been evaluated as adjunctive therapy to neoadjuvant chemotherapy in standard 3 + 3 phase I trials to evaluate two different regimens. The chemotherapy consisted of paclitaxel, followed by doxorubicin and cyclophosphamide. The primary endpoint was to determine the maximum tolerated dose, and the secondary endpoints included toxicity, 5-year survival without recurrence, overall survival and characterization of immune infiltrates in tumor specimens.

Dose limiting toxicity (DLT) had two definitions: 1) Grade 3/4 probably / definitively linked to T-VEC resulting in treatment delays> 14 days or permanent discontinuation of neoadjuvant therapy; 2) Any active herpes infection requiring treatment with oral acyclovir.

Eligible patients had non-metastatic TNBC (T2-T3N0-2 stage), a tumor on ultrasound, and a 0-1 performance index. The 9 patients included in the trial included 6 stage II and 3 stage III patients. Tumors were greater than 5 cm in two patients and 2 to 5 cm in the remaining patients.

Soliman stated that adverse events (AEs) occurred throughout the neoadjuvant treatment. T-VEC-related adverse events included fever in 8 patients, injection site reaction in 4 and chills in 3. Grade 3/4 adverse events related to T-VEC consisted of an episode of fever. degree 4 and an episode of chills of degree 3.

Two serious adverse events occurred during the course of the study: a case of pulmonary embolism and severe bradycardia, both occurring after the operation. One patient had reactivated latent bad herpes. No DLTs appeared and the IDR of chemotherapy was 95% for paclitaxel and 100% for doxorubicin / cyclophosphamide.

Of the 4 patients who did not have pCR with treatment, one patient had a small residual focus of ductal carcinoma in situ and a focus of 0.08 mm of disease in a lymph node (ypTisN1mic); one patient had a remaining focus of 0.6 mm on a 3 cm tumor (ypTmiOn0); one patient had a residual focus of 9 mm on a 2.5-liter tumor and five of the twelve lymph nodes had treatment-related changes, even though only the primary tumor had been treated (ypT1bN0); and one patient had no residual primary tumor, but six of the 15 ganglia remained positive and six others had treatment-related changes (ypT0N2).

Comparison of the immune correlates before and after multiplex immunofluorescence treatment showed a significant increase in the number of CD45R0 + T lymphocytes (P = 0.0048) after treatment, an observation that will be investigated further in the Phase II trial, said Soliman.