Phase I clinical trial shows WNT974 in combination with spartalizumab well tolerated for advanced solid tumor patients

An MD Anderson Phase I clinical trial demonstrated that a combination therapy using WNT974, a drug that targets the WNT pathway in cancer, and the monoclonal antibody spartalizumab, was well tolerated in cancer patients with advanced solid tumors in a variety of cancers.

Study results were presented today at the American Association of Cancer Research (AACR) Virtual Annual Meeting. The study was led by Filip Janku, M.D., Ph.D., associate professor of Investigational Cancer Therapeutics.

“We observed a 67% reduction in sum of target lesions in a patient with melanoma refractory to prior therapies with immune checkpoint inhibitors with treatment ongoing at 68 weeks,” says Janku. “There was high tumor AXIN2 expression at baseline, indicating an active Wnt pathway and which then reduced on therapy. Interestingly, we noted that a ‘cold’ tumor signature on RNAseq at baseline turns ‘hot’ upon treatment.”

Wnt signaling pathways are a group of signal transduction pathways, which begin with proteins that pass signals into a cell through cell surface receptors. Axin2 is a regulator that promotes the phosphorylation and degradation of Beta-catenin, a key effector of the pathway. WNT974 is an oral inhibitor of Porcupine, an acyltransferase that plays a key role in Wnt ligand secretion and activity.

Clinical trial shows tolerance for several types of advanced solid tumors

The clinical trial enrolled 32 patients who had different types of cancer including melanoma (including uveal), squamous cell carcinomas of the lung, head and neck, esophagus, cervix, and triple-negative breast cancer.

Adverse events were largely consistent with those observed with treatment with either agent alone, with 75% of patients experiencing a treatment-related adverse events, the most common being hypothyroidism. Maximum tolerated dose and recommended dose for expansion have not yet been determined. Twenty-five patients discontinued (18 due to disease progression).

Evidence of Porcupine inhibition, assessed by skin AXIN2 suppression by RT-PCR, was detected at all dose levels. One refractory melanoma patient, who had alpha PD-1 therapy, had a high baseline AXIN2 expression and a 67% reduction in the sum of target lesions diameters. The patient remained in the study at 68 weeks as of the cutoff date.

More research needed to explore link between blocking WNT signaling and checkpoint inhibition response

“The PK parameters for WNT974 plus spartalizumab were consistent with prior single-agent data,” says Janku. “Almost half the patients whose cancers were refractory to prior alpha PD-1 therapy had a best response of stable disease, with five patients remaining on the study for more than 24 weeks. Our preliminary data suggests that blocking Wnt signaling may enable response to checkpoint inhibition in some patients.”

Janku added that enrollment of more patients, particularly with melanoma, is needed to further explore this activity.