Targeted Delivery of IL-12 Shows Preliminary Antitumor Activity in Advanced Solid Tumors

Giuseppe Curigliano, MD, PhD

Treatment with the antibody-cytokine fusion protein L19-IL12 led to stable disease (n = 10) and partial response (PR; n = 1) lasting 4 months in patients with metastatic solid tumors (n = 22), according to findings from the phase 1 dose-escalation DODEKA trial (NCT04471987) that were presented at the 2024 ESMO Targeted Anticancer Therapies Congress.¹

“L19-IL12 is well tolerated between 0.1 and 8 μg/kg,” Giuseppe Curigliano, MD, PhD, lead study author, full professor of Medical Oncology at the University of Milano, and chief of the Clinical Division of Early Drug Development at European Institute of Oncology, in Milano, Italy, said in a presentation of the data.

IL-12 is a potent immunostimulatory cytokine that strengthens T- and natural killer cell–mediated antitumor immunity. The agent is designed to deliver IL-12 to the tumor microenvironment through conjugation to the tumor-targeting antibody L19, which binds to the alternatively spliced extra domain B of fibronectin—an element of the stroma found in most solid tumors and undetectable in most healthy tissues. In prior mouse models, L19-IL12 was shown to increase the therapeutic index, leading to strong antitumor activity.²

To be eligible for inclusion in the first-in-human study, patients had to be between the ages of 18 and 80 years, have an ECOG performance status of 2 or less, and a life expectancy of at least 12 weeks. Histological or cytological diagnosis of advanced or metastatic solid carcinoma for which checkpoint inhibition is approved was also required. Only patients who had experienced clinical benefit (≥3-month progression-free survival) from prior treatment with a checkpoint inhibitor–based regimen were included in the study cohort.1

Patients with other treatment options that had curative or life-prolonging potential were excluded from enrollment. Other exclusion criteria included autoimmune disease; inadequate liver, kidney, and heart function; inadequate hematologic values; acute vascular events within 6 months; pregnancy or breast feeding, surgery; participation in a clinical trial or exposure to anticancer therapy within 4 weeks prior to the start of study therapy; and any severe concomitant condition which makes it undesirable for the patient to participate.

During dose escalation, patients will be sequentially assigned to 8 dose levels (0.1 μg/kg to 16 μg/kg) until the dose-limiting toxicity (DLT) rate reaches 33% in a cohort of 2 to 6 patients. Once the recommended dose is established, another 40 patients will receive IL12-L19L19 in dose expansion, including 10 patients with melanoma, 10 with non–small cell lung cancer (NSCLC), and 20 with other solid tumors. Curigliano noted that the latter cohort will be amended to include 10 patients with a particular tumor type in the event that promising signs of activity are seen in the dose-escalation phase.1,2

According to the protocol, patients will receive 8 weekly intravenous infusions of IL12-L19L19, followed by biweekly administration as maintenance until disease progression, unacceptable toxicity, consent withdrawal, or investigator decision.

Regarding baseline demographics, the median patient age was 62 years (range, 37-76), with 8 reported female patients and 12 reported male patients. Melanoma and NSCLC represented the most common tumor types (n = 6 and n = 5, respectively).1

Additional findings from the study showed that treatment-related adverse effects (TRAEs) that occurred in at least 1 patient in order of frequency were pyrexia, chills, fatigue, decreased lymphocyte count, increased aspartate (AST) aminotransferase, cytokine release syndrome, increased alanine (ALT) aminotransferase, headache, decreased white blood cell count, anemia, arthralgia, asthenia, increased gamma-glutamyl transferase, nausea, increased amylase, decreased appetite, leukopenia, increased lipase, lymphopenia, myalgia, and decreased platelet count.

A total of 22 patients treated in cohorts 1 through 8 were evaluable for DLTs. One DLT occurred in cohort 3 (0.5 μg/kg) of grade 3 AST and ALT elevation. Two DLTs occurred in cohort 8 (16 μg/kg) of grade 3 syncope and patient withdrawal owing to TRAEs.

Serum pharmacokinetics of L19-IL12 were also evaluated at the 0.5-, 1-, 2-, 4-, and 8-μg/kg dose levels. “L19-IL12 shows a short and dose proportional circulatory half-life, but nuclear medicine studies with radiolabeled L19 antibody showed prolonged residence time in the tumor,” Curigliano reported.

Pharmacodynamics were also evaluated in the context of serum biomarkers of IL-12 activity. Results showed a substantial increase in serum concentration of IFN-γ (pg/mL), IP-10 (ng/mL), Neopterin (nmol/L) and IL6 (pg/mL) 24 hours following administration of L19-IL12 across the 0.5, 1, 2, 4, 8, and 16 μg/kg dose levels.

Curigliano concluded by sharing a case study illustrating preliminary signs of activity with the agent. The patient was a 68-year-old female who had received a diagnosis of triple-negative breast cancer in 2017. The patient had experienced progressive disease within months of receiving both carboplatin plus paclitaxel and doxorubicin plus paclitaxel before undergoing mastectomy with lymphadenectomy resulting in complete remission. Despite subsequent therapy with PDR-001, LAG-525, and canakinumab (Ilaris) the patient again developed progressive disease. Upon enrollment in cohort 5 (2.0 μg/kg) of the study at the Istituto Europeo di Oncologia, in Milan, the patient achieved partial response on CT imaging with IL12-L19L19.

Editor’s Note: Dr Curigliano reported being a board member for Ellipses; consultant for Lilly, Novartis, Seagen, Pfizer, Roche, Menarini, Gilead, and Exact Sciences; his institute receiving research grants from MSD and AstraZeneca; and serving on the speakers bureau for Lilly, Novartis, Seagen, Pfizer, Roche, Menarini, Gilead, and Exact Sciences.

References

1. Curigliano G, Belli C, Colombo I, et al. Phase I dose-escalation trial with tumor-targeted interleukin-12 (IL12-L19L19) in patients with solid tumors. Presented at: 2024 ESMO Targeted Anticancer Therapies Congress. February 26-28, 2024; Paris, France. Abstract 26O.
2. Mach N, Belli C, Fernandez E, et al. Phase I dose-escalation trial with tumor-targeted interleukin-12 (IL12-L19L19) in patients with solid tumors. Ann Oncol. 2023;34(suppl 2):S629-S630. doi:10.1016/j.annonc.2023.09.2176