Encouraging pCR Rate Seen With T-VEC Plus Chemo in TNBC

Hatem Soliman, MD

Hatem Soliman, MD

Five of 9 patients with large triple-negative breast tumors (TNBC) treated with the viral oncolytic talimogene laherparepvec (T-VEC, Imlygic) plus neoadjuvant chemotherapy achieved pathologic complete response (pCR), according to findings from a preliminary trial.

The remaining 4 patients on the trial had only small residual foci. pCR was defined as no invasive disease in the breast or lymph nodes.

According to Hatem Soliman, MD, of Moffitt Cancer Center and Research Institute, who presented the findings during the 2019 AACR Annual Meeting, T-VEC was generally well tolerated, and relative dose intensity (RDI) of the chemotherapy approached 100%.¹

“Even in some cases where the tumor may not completely resolve with neoadjuvant chemotherapy, it did appear that some tumors were still able to resolve when T-VEC was used in conjunction with the therapy,” said Soliman. “It’s still very early days and this is preliminary data that still needs to be borne out in subsequent studies.”

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

In patients with TNBC, attaining a pCR is associated with improved prognosis.²Standard neoadjuvant chemotherapy with a taxane/anthracycline-based regimen achieves pCR in about 30% of cases, Soliman noted. Additionally, increased tumor infiltrating lymphocytes also is associated with a higher rate of pCR and improved prognosis in TNBC.³

Investigators hypothesized that adding an oncolytic virus to neoadjuvant chemotherapy would improve pCR by means of tumor cell lysis and induction of an antitumor response.

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

“[The immune response] not only attacks the primary tumor but may potentially spread systemically to improve host surveillance and possibly eradicate micrometastatic disease,” he said.

T-VEC was evaluated as an adjunct to neoadjuvant chemotherapy in a standard phase I 3+3 trial design to evaluate 2 different dosing regimens. Chemotherapy consisted of paclitaxel followed by doxorubicin and cyclophosphamide. The trial had a primary endpoint of maximum-tolerated dose, and secondary endpoints included toxicity, 5-year relapse-free survival, overall survival, and characterization of immune infiltrates in tumor specimens.

Dose-limiting toxicity (DLT) had two definitions: 1) grade 3/4 toxicity probably/definitely related to T-VEC and leading to treatment delays >14 days or permanent discontinuation of neoadjuvant therapy; 2) Any grade of active herpetic infection requiring treatment with oral acyclovir.

Eligible patients had nonmetastatic (stage T2-T3N0-2) TNBC, visible tumor on ultrasound and performance status 0-1. The 9 patients enrolled in the trial consisted of 6 with stage II disease and 3 with stage III. Two patients had tumors >5 cm and the remaining patients had tumors 2 to 5 cm.

Soliman said adverse events (AEs) occurred throughout neoadjuvant therapy. T-VEC—related AEs included fever in 8 patients, injection-site reaction in 4, and chills in 3. Grade 3/4 T-VEC–related AEs consisted of one episode of grade 4 fever and one episode of grade 3 chills.

Two serious adverse events occurred during the study: One case each of pulmonary embolism and severe bradycardia, both of which occurred postoperatively. One patient had reactivation of latent genital herpes. No DLTs occurred, and the RDI of chemotherapy was 95% for paclitaxel and 100% for doxorubicin/cyclophosphamide.

Of the 4 patients who did not attain pCR with the treatment, one patient had a small residual focus of ductal carcinoma in situ and a 0.08-mm focus of disease in one lymph node (ypTisN1mic); one patient had a 0.6 mm focus remaining from a 3-cm tumor (ypT1miN0); one patient had a 9-mm residual focus from a 2.5l-cm tumor and five of 12 lymph nodes exhibited treatment-related changes even though only the primary tumor was treated (ypT1bN0); and one patient had no residual primary tumor but six of 15 nodes remained positive and six others showed treatment-related changes (ypT0N2).

Comparison of pre- and posttreatment immune correlates by multiplex immunofluorescence showed a significant increase in CD45R0+ T cells (P= .0048) following treatment, an observation that will be investigated further in the phase II trial, said Soliman.

References:

1. Soliman H, Hogue D, Han H, et al. A Phase I trial of talimogene laherparepvec combined with neoadjuvant chemotherapy for non-metastatic triple negative breast cancer. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CT040.
2. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.Lancet.2014;384(9938):164-172. doi: 10.1016/S0140-6736(13)62422-8.
3. Savas P, Salgado R, Denkert C, et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic.Nat Rev Clin Oncol. 2016;13(4):228-241. doi: 10.1038/nrclinonc.2015.215.