T-VEC Injections Safe in Patients with Advanced-Stage Liver Metastases

Steven S. Raman, MD

Steven S. Raman, MD

According to early results of an ongoing early-phase study presented at the 2018 Society of Interventional Radiology Annual Scientific Meeting, image-guided injections of talimogene laherparepvec immunotherapy (T-VEC, Imylgic) were deemed tolerable in patients with advanced-stage liver metastases.

T-VEC is a genetically modified version of the Herpes simplex virus-1 that contains a gene for granulocyte-macrophage colony-stimulating factor. It is administered directly into the active cancer, using ultrasound or CT imaging, where it stimulates the immune system to destroy cancer cells throughout the body. Based on results from the phase III OPTiM trial, T-VEC was given FDA approval in October 2015 for the local treatment of unresectable advanced melanoma.¹

“Advanced-stage liver tumors, including ones that have spread from other locations, have limited treatment options because the patients can be in poor health; further, the complex structure of the organ can make it difficult to target with standard approaches,” Steven S. Raman, MD, lead author of the study and professor of radiology, surgery, and urology at the David Geffen School of Medicine at the University of California Los Angeles, said in a statement. “This minimally invasive treatment offers patients a novel way to directly and indirectly attack the cancer cells.”

The phase I multicenter, open-label trial evaluated the safety and tolerability of intrahepatic injections of the immunotherapy in patients with progressive hepatocellular carcinoma (HCC), or liver metastases from advanced-stage cancer, including breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non—small lung cancer, and renal cell cancer, all measurable for injection.²Patients with cirrhosis were also included in the trial.

Patients were stratified into 2 dose-escalating groups: A (non-HCC) and B (HCC), and were given an initial dose of 10⁶plaque-forming units (PFU)/mL of T-VEC. If tolerated well, patients in cohort 1 from group A were given up to 4 mL of 10⁷PFU/mL, patients in cohort 2 were given 10⁸PFU/mL every 21 days, and patients in cohort 3 were administered up to 8 mL of the maximum-tolerated dose every 21 days. The volume of the injection was based on the size of the patient’s lesion.

The analysis included 14 patients in cohort 1 and 2 from group A. Patients were treated at multiple different centers within the United States, Switzerland, and Spain, with escalating doses of T-VEC using ultrasound or CT-guided needles to begin immunomodulation. The volume of the injections was based on lesion size. The median age was 66.5 years (range, 33-73).

The primary endpoint of maximum-tolerated concentration was determined to be 10⁸PFU/mL after the initial injection. Of the 14 patients treated, 12 patients—including 9 with primary colorectal cancer and 3 with breast cancer—were evaluable for dose-limiting toxicities (DLT). Patients received a median of 3 injections, and 1 patient received all 12 injections. The maximum tolerated concentration was 10⁸PFU/mL.

Secondary endpoints included safety and cancer-specific outcomes, such as overall survival.

Although the treatment was generally well-tolerated, expected adverse effects were noted, including flu-like symptoms. Four patients (28.6%) experienced grade 3/4treatment-related adverse events (TRAEs), including anemia and inc gamma-glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase (AST) increases. Serious AEs were noted in 6 patients (42.9%) and 2 deaths were deemed to be disease-related. Of the 12 evaluable patients, there was 1 case of a DLT of grade 3 AST and grade 2 bilirubin increase after 1 dose of T-VEC.

Several limitations were noted by the authors of the study, including the small number of patients treated and the preliminary nature of the results, however, they will continue to follow the patients for up to 2 years. Additional trials are underway to further investigate the efficacy of the drug alone and in combination with a PD-1 inhibitor to activate a stronger response.

“The results to date, it is an ongoing study, is that the treatment was well tolerated. This is the first step towards making this treatment more accessible. The next steps are to finish this phase I trial and move to a phase II trial for efficacy, and that is what we have coming up,” Raman said during his presentation.

References:

1. Andtbacka HIR, Collichio F, Harrington K, et al. Long-term follow-up (LTFU) of overall survival (OS) data from the phase 3 OPTiM study of talimogene laherparepvec (T-VEC) for metastatic melanoma. 7th European Post-Chicago Melanoma/Skin Cancer Meeting; June 29-30, 2017; Munich, Germany.
2. Raman S, Pless M, Cubillo A, et al. Targeted immunotherapy treatment shows promise for treating advanced stage liver tumors. Presented at: 2018 SIR Annual Scientific Meeting; March 17-22, 2018; Los Angeles, CA. Abstract 375.