Mohammed Milhem, MBBS, the Holden Chair of Experimental Therapeutics, associate director of clinical research and director of the Melanoma Program, Holden Comprehensive Cancer Center, director of the Division of Hematology, Oncology, and Blood & Marrow Transplantation, and a clinical professor at the University of Iowa Hospitals & Clinics, discusses the utility of vusolimogeneoderparepvec (RP1) in solid tumors.

RP1 leverages an engineered herpes simplex type 1 virus. Currently, RP1 monotherapy and RP1 plus nivolumab (Opdivo) are being evaluated in an open label, dose escalation and expansion phase 1/2 trial (NCT03767348).

RP1 is administered through an intertumoral injection, delivering the modified herpes directly into the tumor, Milhem says. However, due to a loss in virulence, the virus attacks the tumor cells, rather than healthy host cells, Milhem adds. Moreover, the virus replicates inside the tumor and takes over the DNA, which is then replaced by the viral DNA, leading to the production of granulocyte-macrophage colony-stimulating factor (GM-CSF), the tumor’s killer, Milhem explains.

Additionally, GM-CSF is made in large amounts, luring white blood cells to the tumor, Milhem notes. In the presence of an anti–PD-1, where program cell death is blocked on the T cells, it is possible to have a better and more robust presentation of the tumor to the immune system, where T cells are working harder because of the PD-1, Milhem concludes.

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Mohammed Milhem, MBBS, MBBS, discusses the utility of vusolimogeneoderparepvec in solid tumors.


Dr. Milhem on the Utility of RP1 in Solid Tumors

Mohammed M. Milhem, MBBS, Holden Chair of Experimental Therapeutics, associate director of clinical research at Holden Comprehensive Cancer Center; director of the Melanoma Program, chief of the Section of Oncology in the Department of Internal Medicine, and a clinical professor at the University of Iowa Hospital and Clinics, discusses the design of an open-label, multicenter phase 1b/2 dose escalation/expansion study with AST-008 in combination with a PD-1 inhibitor, such as pembrolizumab (Keytruda) or cemiplimab (Libtayo), in Merkel cell carcinoma and cutaneous squamous cell carcinoma (CSCC).

The phase 1b portion of this research was a dose-escalation study, says Milhem. Patients who were given AST-008 started off by receiving 2 mg of the molecule, which was injected directly into the tumor; this was combined with pembrolizumab. The dose for AST-008 escalated from 2 mg all the way up to 32 mg, adds Milhem. The safety data for that portion of the study were presented at several meetings and did not reveal any dose-limiting toxicities; patients tolerated this approach very well, according to Milhem. Patients with different tumor types, such sarcomas, melanomas, CSCC, and Merkel cell carcinoma tumors, were allowed to participate in the phase 1b dose-escalation trial.

In the trial, AST-008 was given by itself for the first 2 weeks, which helped to define its dose-limiting toxicity. The molecule was then combined with an anti–PD-1 agent, either pembrolizumab or cemiplimab, for another 3 weeks; that was another way to define the dose-limiting toxicity. If no dose-limiting toxicities were reported in both of those 2 periods, the next dose escalation was identified. The final dose that was accepted into the phase 2 portion of this study was 32 mg, notes Milhem.

Two cohorts were selected for exceptional responses: those with Merkel cell carcinoma and those with CSCC. The phase 2 trial further examining the approach in these subgroups is currently ongoing. Investigators plan to enroll 10 patients first to see whether they develop a partial or complete response to the treatment. If they do, then enrollment will be expanded to a total of 29 patients in each of those 2 cohorts, concludes Milhem.

Mohammed M. Milhem, MBBS, discusses the design of an open-label, multicenter phase 1b/2 dose escalation/expansion study with AST-008 in combination with a PD-1 inhibitor, such as pembrolizumab or cemiplimab, in Merkel cell carcinoma and cutaneous squamous cell carcinoma.

Mohammed M. Milhem, MBBS

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Dr. Milhem on the Utility of RP1 in Solid Tumors

Dr. Milhem on Design of Phase 1b/2 Study With AST-008 in CSCC