MEDI9253 Plus Durvalumab Delivers Little Efficacy in Advanced/Metastatic Solid Tumors

The results showed that best response was PR in 1/40 patients (2.5%). Additional results demonstrated that 8 patients (20%) had stable disease and 26 patients (65%) had progressive disease. Five patients (12.5%) were not evaluable.

The PR occurred in a 49-year-old patient with stage III metastatic melanoma who had been previously treated with adjuvant pembrolizumab (Keytruda) and nivolumab (Opdivo) plus ipilimumab (Yervoy) before experiencing progressive disease. At baseline, the patient had 2 target lesions in the right axillary lymph node and liver measuring 33 mm, and non-target lesions in the subclavian and right axillary lymph nodes, skin, and liver nodules. At the 8-week scan, the patient had experienced a 42% decrease in target lesions, which was further reduced to 55% at last assessment.

The patient received their first dose of MEDI9253 (August 29, 2022), second dose of MEDI9253 and first dose of durvalumab (September 5, 2022), and third dose of MEDI9253 (September 14, 2022) within 12 days of each other. The patient received their seventh and final infusion of durvalumab in February 2023.

“Administration was feasible and safe with desensitization at all dose levels explored with sequential or concomitant durvalumab. Limited anti-tumor efficacy was observed in evaluated tumor types,” lead study author Sophie Postel-Vinay, MD, PhD, senior medical oncologist and clinician scientist, Drug Development Department at Gustave Roussy in Villejuif, France, said in a presentation of the data.

MEDI9253 is a novel, modified oncolytic virus that houses a human IL-12 transgene, an immune stimulatory cytokine that activates the innate and adaptive immune system. Through this design, MEDI9253 can lead to local IL-12 expression, innate and adaptive immune activation, and selectively replicate in tumor cells causing tumor cell death.

Preclinically, MEDI9253 has been evaluated in combination with durvalumab in microsatellite stable colorectal cancer (MSS CRC), melanoma, and renal cell carcinoma (RCC).

To be eligible for enrollment in this first-in-humn trial, patients had to have advanced or metastatic MSS CRC, RCC, or cutaneous melanoma; adequate organ function; and an ECOG performance status of 0 or 1.

The trial consisted of a dose-expansion and dose-escalation phase. In dose escalation, patients will receive a single dose of intravenous (IV) MEDI9253 with sequential IV durvalumab, followed by multiple-dose cohorts of up to 4 escalating dose levels of MEDI9253 with sequential or concurrent durvalumab. Dose expansion will include 3 cohorts of no more than 20 patients each with melanoma, RCC, or MSS CRC. In both phases, durvalumab will be dosed for up to 2 years or until disease progression, clinical deterioration, withdrawal of consent or unacceptable toxicity.

Determination of safety and tolerability, as well as the dose and schedule of the combination served as the primary objective of the study. Secondary objectives included evaluation of preliminary efficacy, viral genome copies and IL-12 plasma concentrations, as well as the immunogenicity of MEDI9253.

Dose-limiting toxicity (DLT) was defined by grade 3 or greater effects that occurred during the DLT evaluation period––day 14 for single-dose cohorts and day 28 for multiple-dose cohorts––grade 2 or greater myocarditis; grade 2 non-infectious pneumonitis that did not resolve to grade 1 or 0 within 7 days; and any grade 2 or greater MEDI9253-related toxicity that prevented the administration of more than 1 dose of the agent or the first dose of durvalumab.

Baseline characteristics indicated that the median age in the overall population (n = 40) was 57.5 years (range, 20-80) and more than half of patients were male (57.5%). Most patients were White (83.8%) and enrolled in the United States (n = 30). MSS CRC (75%) represented the most common disease type, followed by melanoma (22.5%) and RCC (2.5%).

During the DLT period, treatment-related adverse effects (AEs) included chills (TRAEs; grade 1/2, 42.5%), pyrexia (grade 1/2, 37.5%), headache (grade 1/2, 32.5%), fatigue (grade 1/2, 25.0%), nausea (grade 1/2, 22.5%), vomiting (grade 1/2, 22.5%), cytokine release syndrome (grade 1/2, 22.5%), dizziness (grade 1/2, 12.5%), diarrhea (grade 1/2, 10.0%), asthenia (grade 1/2, 10.0%), infusion-related reaction (grade 1/2, 10.0%), acute kidney injury (grade 3/4, 2.5%), and myocarditis (grade 3/4, 2.5%).

Serious TRAEs occurred in 22.5% of patients. No treatment interruptions, delays, discontinuations, or reductions occurred because of AEs.

Additional analysis indicated the presence of viral genome copies and an increased Type I interferon response signature in tumors treated with MEDI9253. Tumoral CD8 and PD-L1 expression increased in 2 and 7 of 14 patients, respectively. However, treatment with MEDI9253 did not upregulate IL-12 expression and genes or signatures associated with antitumor response. Moreover, the combination did not significantly increase plasma interferon-gamma, failing to show evidence of T-cell activation.

Disclosures: Dr Postel-Vinay served as principal Investigator of clinical trials receiving institutional funding from AstraZeneca, Novartis, GSK, Amgen, and Oxford Biotherapeutics; principal investigator of academy-sponsored clinical trials funded by Roche, Clovis, GSK-Tessaro (institutional funding); member of the advisory board for Daiichi-Sankyo; and received research grants (laboratory funding) from Roche IMCore, and AstraZeneca.

Reference

Postel-Vinay S, Cosaert J, Hattersley M, et al. An open-label, phase 1 study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of MEDI9253, a recombinant newcastle disease virus encoding interleukin-12, in combination with durvalumab in participants with select advanced/metastatic solid tumors (NCT04613492). Ann Oncol. 2023;8(suppl 2):100903. doi:10.1016/esmoop/esmoop100903