RO7122290 Active in First-in-Human Trial for Patients With Select Solid Tumors

Ignacio Melero, MD, PhD

A first-in-human study of the bispecific antibody RO7122290 (RO) alone or in combination with atezolizumab (Tecentriq) showed preliminary antitumor activity and a good safety profile for patients with advanced solid tumors, according to findings of the trial presented at the ESMO Virtual Congress 2020.

RO is a novel 4-1BB agonist that targets fibroblast activation protein-a (FAP), which is abundantly expressed by cancer-associated fibroblasts in many tumors. Simultaneous binding of FAP and 4-1BB results in clustering and activation of T- and natural killer cells at the tumor site and simultaneous antitumor activity, which has been demonstrated in preclinical models.

“Systemic administration of first-generation anti–4-1BB antibodies, although effective, have not been advanced to phase 3 clinical trials because of hepatotoxicity adverse effects,” Ignacio Melero, MD, PhD, of the University of Navarra in Pamplona, Spain, said during a presentation of the data. “To overcome these issues, the antibody-like fusion protein RO7122290 was engineered to simultaneously target 4-1BB and fibroblast activity protein that is expressed by cancer fibroblasts in the tumor microenvironment, but not in healthy tissue.”

The 3-part study was designed to determine safety, the recommended dose for expansion, and antitumor activity in selected FAP-positive tumors. The data presented at ESMO included results from the dose-escalation phases of the trial, parts A and B. In part A, single-agent RO was administered in 62 patients at doses ranging from 5 mg to 2000 mg. Part B included 39 patients who were administered the combination of atezolizumab at 1200 mg every 3 weeks plus RO at doses ranging from 45 mg to 1000 mg.

“The safety and tolerability of RO was similar across both dose-escalation parts A and B without observed dose dependency of toxicities,” Melero said. “However, there was a trend for higher occurrence of immune-related adverse events in combination part B versus single-agent part A.”

Grade 3/4 adverse effects (AEs) occurred in 50% of patients in part A, with the most common being asthenia (6.5%) and aspartate aminotransferase increase (4.8%). Fifty-seven percent of patients experienced grade 3/4 AEs in part B, with the most common being pneumonia (11.3%), pneumonitis (7.5%), alanine aminotransferase increase (5.7%), lymphopenia (5.7%), and neutropenia (5.7%).

In total, 3 dose-limiting toxicities were observed in parts A and B. Grade 3 febrile neutropenia was observed at a dose level of 45 mg RO and grade 3 cytokine release syndrome at 130 mg RO in part A; in part B, grade 3 pneumonitis was observed in a patient receiving 500 mg RO.

Immune-related AEs (irAEs) of any grade were reported in 25.8% of patients treated in part A and 37.7% of those in part B. Rash was the most common all-grade irAE in both groups, at rates of 21.0% in part A and 24.5% in part B. Corticosteroids were required to treat irAEs in 9.7% and 17.0% of patients in parts A and B, respectively.

As of the data cutoff of March 31, 2020, 102 patients were assessed for antitumor activity. Of all patients treated, 10 patients experience partial responses. In part B, 2 patients with mesothelioma, 2 with small cell lung cancer, 2 with triple-negative breast cancer (TNBC), 1 with thymoma, and 1 with Merkel cell carcinoma had a partial response. Responses were confirmed in 6 out of 8 patients and mostly occurred in patients with T-cell–inflamed tumors, according to Melero. There were 2 responses to single-agent therapy in part A. Most patients with responses had not been treated with immunotherapy prior to receiving RO.

Pharmacokinetic data revealed nonlinear elimination of RO at lower doses, suggestive of target-mediated drug disposition and this is likely due to FAP binding. The investigators attempted to characterize pharmacodynamic treatment effects of RO, with the activity observed demonstrating CD8+ T-cell activation and proliferation in blood and CD8+ T-cell proliferation and infiltration into the tumor.

The expansion part 3 is ongoing and will included up to 60 patients to be treated at the recommended dose for expansion of 250 mg RO every week. No maximum tolerated dose was observed. Those with second-line metastatic mesothelioma or thymoma/thymus cancer who have not been previously treated with immune checkpoint inhibitors will receive RO at 250 mg plus atezolizumab. Patients with first-line metastatic TNBC and positive PD-L1 expression will be treated with RO at 250 mg plus atezolizumab and nab-paclitaxel (Abraxane).

_Reference:

_{Melero I, Sanmamed MF, Calvo E, et al. First-in-human (FIH) phase I study of RO7122290 (RO), a novel FAP-targeted 4-1BB agonist, administered as single agent and in combination with atezolizumab (ATZ) to patients with advanced solid tumours. Presented at: European Society of Medical Oncology Virtual Congress 2020; September 19- 21, 2020; Virtual. Abstract 1025O.}