Dual-Targeting Approach for CD40 and 4-1BB

Preliminary data from a first-in-human phase I/II trial of GEN1042 (Genmab) suggest that this investigational bispecific antibody is active and well tolerated in patients with advanced solid tumors. The findings were presented by Melissa Johnson, MD, during the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting in Washington, DC, November 10–14.

GEN1042 “combines simultaneous targeting and conditional activation of two costimulatory molecules,” explained Johnson, of Sarah Cannon Research Institute in Nashville, TN. The first molecule, CD40, is expressed on dendritic and other antigen-presenting cells; the second, 4-1BB, is found on T cells.

There are ongoing efforts to develop agonists for CD40 and 4-1BB respectively, Johnson said, but their potential in the lab has not translated to much clinical success so far, “due to minimal efficacy, severe toxicity, or both.” By jointly activating these molecules via one bispecific antibody, the hope is that “we get enhanced priming of tumor-specific immunity.” This seems to have been borne out preclinically, she added: GEN1042 strengthens the immunologic synapse between dendritic and T cells, and it has superior activity to that of combining individual CD40 and 4-1BB antibodies.

Johnson reported results from 50 patients in the trial's dose escalation phase, all with metastatic or inoperable solid tumors, including colorectal cancer and melanoma. They were enrolled across 10 different flat doses of GEN1042, from 0.1 mg to 400 mg, given every 3 weeks.

Half of the patients experienced stable disease, and two with melanoma and neuroendocrine lung cancer achieved partial responses to 3 mg and 30 mg of GEN1042, respectively. Both responses have been durable—in the melanoma case, for more than a year, Johnson noted.

Theresa LaVallee, PhD, of the San Francisco, CA–based Parker Institute for Cancer Immunotherapy, who was not involved in the research, remarked that “as to why activity was seen at a low dose, this often occurs in phase I studies … and [it] may be that the individual was particularly well suited” for GEN1042.

The trial's pharmacodynamic data “nicely show that for strong immune activation, higher doses are required,” LaVallee added. At SITC, Johnson disclosed that GEN1042 dose levels above 30 mg were much better at stimulating cytokine production and T-cell proliferation. Based on predictive modeling, the investigators will move forward with 100 mg as the optimal dose in the study's expansion phase.

GEN1042 was well tolerated, with low-grade fatigue, nausea, and dyspnea as the main side effects. Importantly, Johnson said, there were no occurrences of thrombocytopenia or cytokine release syndrome, which have been associated with CD40 agonists. The most severe adverse event, grade 4 transaminase elevation in one patient with oropharyngeal cancer, was resolved with corticosteroids.

Despite this elevation being a dose-limiting toxicity for the patient, “we still saw evidence of obvious clinical benefit, including almost immediate regression of his palpable skin lesions and stable disease at 5 weeks,” Johnson said. Because he previously received nivolumab (Opdivo; Bristol Myers Squibb), his reaction “suggested an augmentation of response that may be possible with rational combinations” of GEN1042 and other immunotherapies.

This hypothesis was duly tested preclinically and demonstrated that concurrent administration of pembrolizumab (Keytruda; Merck) alongside GEN1042 did increase IFNγ induction. As such, combination therapy with PD-1 inhibitors will be evaluated in the study's next phase, Johnson said.

Overall, GEN1042′s “dual targeting to induce antigen presentation and activate T cells is an attractive approach,” LaVallee said. “While the data are encouraging, in later-stage trials, we'd benefit from a deeper understanding of biomarkers to know who to treat with this agent.” –Alissa Poh

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