On November 9, 2023 Xilio Therapeutics, Inc. (Nasdaq: XLO), a clinical-stage biotechnology company discovering and developing tumor-activated immuno-oncology therapies for people living with cancer, reported pipeline progress and business updates and announced financial results for the third quarter ended September 30, 2023 (Press release, Xilio Therapeutics, NOV 9, 2023, View Source [SID1234637429]).

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"Colorectal cancer is the third largest solid tumor cancer in terms of number of patients diagnosed annually and the second leading cause of cancer-related deaths globally," said René Russo, Pharm.D., president and chief executive officer of Xilio. "Rates of MSS colorectal cancer are rising in younger people, particularly in men under 50 years old, and patients often present with advanced Stage 4 disease along with liver metastases. Despite these alarming trends, there are few treatment options and no approved immunotherapies for these patients today. We believe the unique tumor-selective mechanism of XTX101 combined with atezolizumab has the potential to treat MSS colorectal cancer, and we are focused on initiating the co-funded collaboration with Roche to study this combination in patients. We are also encouraged by the recent Phase 1/2 data reported at SITC (Free SITC Whitepaper) for XTX202 demonstrating a 50% disease control rate at higher doses (≥2.8 mg/kg), including patients with cold tumors, and a generally well-tolerated safety profile across all dose levels. We look forward to evaluating the 4 mg/kg dose for XTX202 in Phase 2 for patients with melanoma and renal cell carcinoma."

Pipeline and Business Updates

XTX101: tumor-activated, Fc-enhanced anti-CTLA-4

XTX101 is an investigational tumor-activated, Fc-enhanced, high affinity binding anti-CTLA-4 designed to block CTLA-4 and deplete regulatory T cells when activated (unmasked) in the tumor microenvironment (TME). XTX101 is currently being evaluated at the recommended Phase 2 dose and schedule of 150 mg once every six weeks in monotherapy dose expansion of an ongoing Phase 1 clinical trial in patients with advanced solid tumors.

● In the third quarter of 2023, Xilio reported updated data from the Phase 1 trial for XTX101, including an ongoing durable confirmed partial response through 36 weeks as of an August 3, 2023 data cutoff date in a patient with Stage 4 non-small cell lung cancer treated with XTX101 monotherapy, including resolution of liver metastases.
● Additionally, Xilio recently reported pharmacokinetic (PK) data showing activation of XTX101 in two on-treatment biopsies from patients in the Phase 1 trial, which included a primary melanoma tumor and a metastatic lesion in the liver from a patient with microsatellite stable colorectal cancer (MSS CRC). For both patients, XTX101 was more than 70% activated in the tumor while maintaining a peripheral activation level of 13%, consistent with the tumor-selective design for XTX101.
● In the third quarter of 2023, Xilio entered into a clinical trial collaboration with Roche to evaluate XTX101 in combination with atezolizumab in Phase 1 combination dose escalation in patients with advanced solid tumors and a planned Phase 2 trial in patients with MSS CRC. Xilio anticipates activating clinical trial sites for the Phase 1 combination dose escalation in the fourth quarter of 2023.
In addition, subject to obtaining sufficient additional capital, Xilio plans to:

● Complete Phase 1 combination dose escalation and select a recommended Phase 2 dose for XTX101 in combination with atezolizumab in the second quarter of 2024.
● Subject to the results of Phase 1 combination dose escalation, initiate a Phase 2 trial for XTX101 in combination with atezolizumab in patients with MSS CRC in the third quarter of 2024.
● Report initial Phase 2 data for XTX101 in combination with atezolizumab in approximately 20 patients with MSS CRC in the fourth quarter of 2024 and in approximately 20 additional patients (40 patients total) in the first quarter of 2025.
XTX202: tumor-activated, engineered, beta-gamma biased IL-2

XTX202 is an investigational tumor-activated, engineered, beta-gamma biased IL-2 molecule designed to potently stimulate CD8+ effector T cells and natural killer (NK) cells without concomitant stimulation of regulatory T cells when activated (unmasked) in the TME. XTX202 is currently being evaluated in an ongoing Phase 1/2 clinical trial in patients with advanced solid tumors.

● In November 2023, Xilio announced initial Phase 1/2 monotherapy safety, PK, pharmacodynamic (PD) and anti-tumor activity data for XTX202 at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting. As of a data cutoff date of October 26, 2023, these data included:
● Initial evidence of a dose-dependent increase in disease control rate (DCR) for XTX202 across all dose levels in a range of solid tumors, including cold tumors, with a 50% DCR in response-evaluable patients at higher doses (≥2.8 mg/kg) and a 31% DCR in response-evaluable patients across all dose levels, including a patient with Stage 4 MSS CRC with ongoing stable disease at 57 weeks and resolution of three out of four non-target lesions.
● No signs or symptoms of vascular leak syndrome were reported by investigators through the 4.0 mg/kg dose. In addition, XTX202 was generally well-tolerated with treatment-related adverse events (TRAE) primarily Grade 1 or 2 and no treatment discontinuations due to TRAEs.
● Preliminary PK analysis demonstrated tumor-selective activation of XTX202, including an approximately 40-fold higher concentration of activated XTX202 in the tumor as compared to peripheral blood based on an analysis of an on-treatment biopsy from a patient at the 2.8 mg/kg dose level, which demonstrated approximately 15% activated XTX202 in the tumor compared to <1% activated XTX202 in plasma across patients at the 2.8 mg/kg dose level.
● Consistent with IL-2 beta-gamma biology, preliminary PD analysis of four available on-treatment tumor samples showed an average increase >200% of CD8+ effector T cells in the tumor as compared to pre-treatment biopsies.
● For more information, read the press release here.
● As previously announced, XTX202 recently cleared dose level seven (4.0 mg/kg) in Phase 1 monotherapy dose-escalation, and Xilio recently opened enrollment at a second dose level of 4.0 mg/kg in the ongoing Phase 2 monotherapy trial for XTX202. Based on the initial monotherapy data for XTX202, Xilio also plans to explore opportunities for strategic partnerships to evaluate XTX202 as a combination therapy.
● Subject to obtaining sufficient additional capital, Xilio plans to report Phase 2 monotherapy data for XTX202 in approximately 20 patients treated at the 4.0 mg/kg dose with metastatic renal cell carcinoma (RCC) or unresectable or metastatic melanoma in the second quarter of 2024.
XTX301: tumor-activated, engineered IL-12

XTX301 is an investigational tumor-activated, engineered IL-12 molecule designed to potently stimulate anti-tumor immunity and reprogram the TME of poorly immunogenic "cold" tumors towards an inflamed or "hot" state.

● Xilio is currently dosing patients in monotherapy dose escalation of an ongoing Phase 1 clinical trial evaluating the safety and tolerability of XTX301 in patients with advanced solid tumors.
● As previously announced, Xilio anticipates reporting preliminary safety data from the Phase 1 clinical trial into the third dose level in the fourth quarter of 2023.
● Subject to obtaining sufficient additional capital, Xilio plans to report Phase 1 safety and PK/PD data for XTX301 in advanced solid tumors in the second half of 2024.
Corporate Highlights

● In September 2023, Xilio announced the promotions of Katarina Luptakova, M.D., to Chief Medical Officer and Scott Coleman, Ph.D., to Chief Development Officer.
Upcoming Presentations

Xilio will present a poster for XTX101 with updated preliminary Phase 1 data and outlining the planned Phase 2 trial design at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology Annual Congress on December 6-8, 2023.

Title: Phase 1/2 study of XTX101, a masked, tumor-activated Fc-enhanced anti-CTLA-4 in patients with advanced solid tumors

Presentation Date and Time: Thursday, December 7, 2023, from 12:00 to 1:00 p.m. CET

Abstract number: 490

Third Quarter 2023 Financial Results

● Cash Position: Cash and cash equivalents were $59.8 million as of September 30, 2023, compared to $120.4 million as of December 31, 2022.
● Research & Development (R&D) Expenses: R&D expenses were $11.1 million for the quarter ended September 30, 2023, compared to $13.0 million for the quarter ended September 30, 2022. The decrease was primarily driven by decreased manufacturing and preclinical activities for XTX301 and a reduction of XTX101 costs due to a cost-sharing payment earned under the clinical trial collaboration with Roche. These decreases were partially offset by increases in clinical activities for XTX202 and XTX301, preclinical activities for other early programs and indirect research and development expenses.
● General & Administrative (G&A) Expenses: G&A expenses were $6.3 million for the quarter ended September 30, 2023, compared to $7.2 million for the quarter ended September 30, 2022. The decrease was primarily driven by a decrease in professional and consulting fees.
● Net Loss: Net loss was $16.7 million for the quarter ended September 30, 2023, compared to $19.8 million for the quarter ended September 30, 2022.
Financial Guidance

Xilio continues to anticipate that its existing cash and cash equivalents will be sufficient to fund its operating expenses and capital expenditure requirements into the end of the second quarter of 2024.

About XTX101 (anti-CTLA-4) and the Phase 1 Monotherapy and Phase 1/2 Combination Clinical Trials

XTX101 is an investigational tumor-activated, Fc-enhanced, high affinity binding anti-CTLA-4 monoclonal antibody designed to block CTLA-4 and deplete regulatory T cells when activated (unmasked) in the tumor microenvironment (TME). The Phase 1 clinical trial is a first-in-human, multi-center, open-label trial designed to evaluate the safety and tolerability of XTX101 for the treatment of adult patients with advanced solid tumors. Xilio has completed monotherapy dose escalation (Part 1A) and is currently enrolling patients at the recommended Phase 2 dose and schedule of 150 mg once every six weeks in monotherapy dose expansion (Part 1B). Please refer to NCT04896697 on www.clinicaltrials.gov for additional details.

In addition, Xilio plans to evaluate the safety, tolerability and efficacy of XTX101 in combination with atezolizumab (Tecentriq) in the Phase 1/2 clinical trial. The Phase 1 portion is designed to assess the safety and tolerability of XTX101 in combination with atezolizumab in dose escalation in patients with advanced solid tumors. The planned Phase 2 portion is designed to evaluate the safety and efficacy of the combination in patients with microsatellite stable colorectal cancer (MSS CRC).

About XTX202 (IL-2) and the Phase 1/2 Clinical Trials

XTX202 is an investigational tumor-activated beta-gamma biased, engineered IL-2 molecule designed to potently stimulate CD8+ effector T cells and natural killer (NK) cells without concomitant stimulation of regulatory T cells when activated (unmasked) in the tumor microenvironment (TME). The Phase 1 clinical trial for XTX202 is a first-in-human, multi-center, open-label trial designed to evaluate the safety and tolerability of XTX202 as a monotherapy in patients with advanced solid tumors. The Phase 2 clinical trial for XTX202 is a multi-center, open-label trial designed to evaluate the safety and efficacy of XTX202 as a monotherapy in patients with unresectable or metastatic melanoma and metastatic renal cell carcinoma who have progressed on standard-of-care treatment. Please refer to NCT05052268 on www.clinicaltrials.gov for additional details.

About XTX301 (IL-12) and the Phase 1 Clinical Trial

XTX301 is an investigational tumor-activated, engineered IL-12 molecule designed to potently stimulate anti-tumor immunity and reprogram the tumor microenvironment (TME) of poorly immunogenic "cold" tumors towards an inflamed or "hot" state. The Phase 1 clinical trial for XTX301 is a first-in-human, multi-center, open-label trial designed to evaluate the safety and tolerability of XTX301 as a monotherapy in patients with advanced solid tumors. Please refer to NCT05684965 on www.clinicaltrials.gov for additional details.