ATLANTA – Adding intratumoral talimogene laherparepvec (TVEC) to neoadjuvant chemotherapy appears to improve response rates in patients with nonmetastatic triple-negative breast cancer, according to findings from a phase 1 trial.
The pathologic complete response rate (pCR) in nine patients aged 18-70 years with stage T2-T3NO-2 disease who were enrolled in the single-center trial was 55%, whereas the expected rate with neoadjuvant chemotherapy alone was 30%, Hatem Soliman, MD, reported at the annual meeting of the American Association for Cancer Research.
“Even in the patients with residual disease, they had almost complete obliteration of their tumors, as well,” said Dr. Soliman of Moffitt Cancer Center, Tampa, Fla., adding that preliminary analyses of T cell subtypes indicated that CD45RO+ cells, which are associated with activated memory effector phenotype cells, were found in higher percentages in tumor specimens from patients who had pCR vs. those who did not.
“This could be an emerging marker that could be associated with pCR from TVEC,” he said, stressing, however, that “this is preliminary data [that] needs to be borne out in subsequent studies.”
Of the nine participants, six had stage II disease and three had stage III disease, and tumor size was greater than 5 cm in 2 patients, and 2-5 cm in 7 patients. Three received 106 plaque-forming units (PFUs) x 5 injections (dose level 1), and 6 received 106 PFUs for the first injection then 108 PFUs for 4 additional injections. Patients also received neoadjuvant paclitaxel followed by doxorubicin/cyclophosphamide chemotherapy.
They then went on to surgery and were evaluated for pCR.
No dose-limiting toxicities occurred, therefore the maximum-tolerated dose was dose level 2, Dr. Soliman noted.
The most common toxicities due to TVEC were fevers, chills, and injection site reactions, and “these are considered expected side effects of TVEC administration and were manageable,” he said.
Two serious adverse events occurred in the trial: a pulmonary embolism and a postoperative case of severe bradycardia thought to be a vasovagal episode; there were no deaths or any sequelae from these adverse events and they completely resolved.
One latent genital wild type herpes simplex 1 virus (HSV1) reactivation event occurred and was treated with a topical agent.
Early-stage triple-negative breast cancer is associated with a higher risk of early relapse, but attaining a pCR after neoadjuvant chemotherapy is associated with improved prognosis, Dr. Soliman said.
“Historically, standard regimens used for triple-negative breast cancer include an anthracycline and a taxane, and the rates of pCR in those patients hover around 30%,” he said. “Others have looked at the relationship of increased tumor infiltrating lymphocytes (TILs] in triple-negative breast cancers and other breast cancers, and found that those tumors that did have a higher de novo TIL infiltrate, either at the beginning of treatment or acquired during treatment, seemed to have a higher rate of pCR and also seemed to have improved prognosis.”
This suggested that these TIL infiltrates may be both a predictive and prognostic biologic marker for the biology of the disease, he noted.
Further, promising prior research on the role of oncolytic viruses as a potential treatment modality for cancer led to interest in their use during neoadjuvant chemotherapy “with the idea that we could potentially improve pathologic complete response rates both through direct tumor cell lysis of treated tumors, but also through recruitment of a robust antitumor immune response caused by the viruses’ mechanism of action,” he said, adding that “this could be beneficial, particularly in those immunologically ‘cold’ tumors.”
This led to the incorporation of TVEC, a genetically engineered oncolytic HSV1 currently approved for the treatment of melanoma, in this neoadjuvant trial. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces granulocyte-macrophage colony-stimulating factor to activate dendritic cells, and stimulates T cells to provoke an adaptive immune response, he explained.
“[This] then can not only potentially attack tumor cells at the primary site, but then may potentially spread around the body to improve host surveillance and try to eradicate micrometastatic disease, as well,” he said.
The current findings show that adding TVEC to neoadjuvant chemotherapy is feasible at the full Food and Drug Administration–approved dose and has manageable toxicity, he concluded, noting that “a phase 2 single-arm trial of this regimen is ongoing, and we are actively accruing patients to further evaluate the efficacy signal and formally test the hypothesis along with immune correlates.”
Dr. Soliman reported relationships with Eli Lilly, Pfizer, Celgene, AstraZeneca, PUMA, Novartis, Eisai, and Amgen.
SOURCE: Soliman H et al. AACR 2019, Abstract CT040.