Xilio Collaborates With Merck to Evaluate Combo of CTLA-4 and PD-1 Blockers Against Solid Tumors

On May 25th, Xilio Therapeutics entered a partnership with Merck, known as MSD outside the US and Canada to test a combination of their respective immune checkpoint inhibitors against solid tumors. The clinical trial collaboration will evaluate XTX101, Xilio’s engineered tumor-selective Fc-enhanced, anti-CTLA-4 monoclonal antibody in combination with Merck’s blockbuster drug Keytruda, a PD-1 inhibitor as monotherapy for patients with solid tumors.

Anti-CTLA-4 and anti-PD-1 combinations tested previously in several clinical and preclinical trials have demonstrated an enhanced anti-tumor effect. However, they have resulted in liver toxicity as indicated by an increase in liver enzymes like aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT). However, animal studies have shown that XTX101 can be effectively combined with anti-PD-1 antibody without enhanced toxicity.

“We believe tumor-selective immuno-oncology has significant potential to provide meaningful treatments to patients with a number of different cancers. The clinical benefit of targeting CTLA-4 as a treatment for cancer is well-established. However, treatment with the combination of an antiCTLA-4 mAb and PD-1 checkpoint inhibitor has been associated with challenging toxicities, preventing patients from receiving effective doses of the anti-CTLA-4 antibody,” said Marty Huber, M.D., Chief Medical Officer of Xilio Therapeutics.

A Fully-Humanized anti-CTLA-4 Monoclonal Antibody

According to the company, XTX101 is specifically designed to target the anti-CTLA-4 effect geographically within the tumor and to minimize off-tumor peripheral effects. It gets activated in a protease-dependent manner binds to CTLA-4 with high affinity. This potentially could overcome the CTLA-4 inhibition of T cell activation and free the T cells to attack cancer.

In the recently concluded Frontiers in Cancer Immunotherapy 2021 virtual symposium, Xilio presented encouraging results for the XTX101, PD-1 inhibitor combo therapy. Data showed that in a colon cancer model, the combination showed robust tumor growth inhibition, including two complete responses (CRs) (n=8). In contrast, treatment with XTX101 or the anti-PD-1 agent as monotherapy achieved only modest tumor growth inhibition and no CRs.

In a bladder cancer model, XTX101 monotherapy demonstrated tumor growth inhibition superior to BMS’ Yervoy. Xilio plans to submit an IND application for XTX101 to the FDA in the second quarter of 2021. Upon clearance, it expects to initiate Phase 1 clinical trials to evaluate the candidate as a monotherapy or a combo therapy with Keytruda for treating solid tumors.

“XTX101 is designed to be tumor-selective and based on data observed in preclinical studies, we believe it could be an ideal CTLA-4-targeting candidate to combine with checkpoint inhibitors like KEYTRUDA. We are pleased to partner with Merck to study this combination in an effort to improve therapeutic options for people with cancer.” Dr. Huner added.

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Author

Rajaneesh K. Gopinath