8-K: Xilio Therapeutics Reports Promising Phase 2 Vilastobart Data in Difficult-to-Treat Colorectal Cancer, Highlighting Differentiated Safety and Efficacy

Xilio Therapeutics announced updated positive Phase 2 clinical trial data for its tumor-activated anti-CTLA-4 therapy, vilastobart, in combination with atezolizumab, demonstrating a 26% objective response rate and a differentiated safety profile in heavily pre-treated metastatic microsatellite stable colorectal cancer patients without liver metastases.

Summary

• Xilio Therapeutics presented updated Phase 2 data for vilastobart in combination with atezolizumab in patients with metastatic microsatellite stable colorectal cancer (MSS CRC) at the 2025 ASCO Annual Meeting.
• In heavily pre-treated MSS CRC patients without liver metastases (80% had 3 or more prior lines of therapy), a preliminary objective response rate (ORR) of 26% was observed, with 7 partial responses (6 confirmed) among 27 evaluable patients.
• Responses were deep and durable, lasting up to 37 weeks, and were accompanied by substantial decreases in tumor biomarkers like circulating tumor DNA (ctDNA) and carcinoembryonic antigen (CEA) levels, along with improvements in clinical symptoms.
• The combination demonstrated a differentiated safety and tolerability profile, with a low incidence of immune-mediated adverse events (imAEs), including only 7% of patients experiencing colitis.
• Only 5% of patients discontinued treatment due to a treatment-related adverse event, and no Grade 5 or only two Grade 4 treatment-related AEs were reported, both of which resolved.
• A patient from the Phase 1C trial with MSS CRC and a metastatic liver lesion achieved a confirmed partial response, including full resolution of the liver lesion, and remains on treatment after more than 14 months.
• Xilio plans to enroll approximately 10 additional patients in the Phase 2 trial at a higher vilastobart dose level (150 mg Q6W) to further evaluate efficacy and safety, with additional data anticipated in the first half of 2026.
• The company is actively seeking partnership opportunities to accelerate and expand the vilastobart program's development, particularly for a potential Phase 3 study in 3L+ MSS CRC without liver metastases.
• Xilio's pipeline also includes XTX301 (tumor-activated IL-12) in Phase 1 with Gilead, XTX501 (tumor-activated PD-1/IL-2 bispecific) targeting IND submission in mid-2026, and multiple masked T cell engager programs (PSMA, CLDN18.2, STEAP1) with AbbVie, targeting development candidate nominations in Q3 2025, Q4 2025, and 1H 2026 respectively, and IND submissions for at least two in 2027.
• As of March 31, 2025, Xilio reported cash and cash equivalents of $89.1 million, with an anticipated cash runway into Q1 2026, prior to any potential future contingent payments from collaborations.

Sentiment

Score: 8

Explanation: The document presents highly encouraging clinical data for vilastobart in a very challenging cancer type (MSS CRC) with a differentiated and favorable safety profile, which addresses a significant unmet medical need. The ongoing deep and durable responses, coupled with a robust pipeline and strategic partnerships, indicate strong scientific and clinical progress. While the cash runway is limited to Q1 2026, this is a common characteristic for clinical-stage biotech companies, and the positive data could facilitate future capital raises or partnership expansions.

Positives

• Vilastobart demonstrated a preliminary 26% objective response rate in heavily pre-treated metastatic MSS CRC patients without liver metastases, a population with significant unmet medical need and typically poor response to immunotherapy.
• Responses were deep and durable, with some patients remaining on treatment for up to 37 weeks and showing substantial reductions in tumor biomarkers and improvements in clinical symptoms.
• The combination of vilastobart and atezolizumab exhibited a differentiated and favorable safety profile, with a low incidence of immune-mediated adverse events (e.g., only 7% colitis) and low treatment discontinuation rates (5%) compared to other anti-CTLA-4 agents.
• A previously reported confirmed partial response in an MSS CRC patient with liver metastasis from Phase 1C continues to deepen, with the patient remaining on treatment for over 14 months.
• The company has active collaborations with top-tier pharmaceutical companies like AbbVie, Gilead, and Roche, providing significant potential future contingent payments and co-funded clinical supply.
• Xilio's proprietary tumor-activated platform technology is clinically validated, with over 250 patients enrolled across clinical programs, demonstrating tumor-selective activation and low immunogenicity.

Negatives

• The 26% ORR was observed only in patients without liver metastases; no objective responses were reported in the 17 patients with liver metastases, although 3 showed stable disease.
• The cash runway is anticipated only into Q1 2026, indicating a need for additional capital to fund operations and advance the pipeline beyond this period, prior to any potential contingent payments from partnerships.
• The data presented for vilastobart is preliminary, and further evaluation at a higher dose level (150 mg Q6W) is ongoing, with additional data expected in 1H 2026, which could alter the current findings.

Risks

• General market conditions and geopolitical uncertainties could impact business operations and financial performance.
• Risks and uncertainties related to ongoing and planned research and development activities, including initiating, conducting, or completing preclinical studies and clinical trials, and the timing and results of such studies or trials.
• Potential delays in any current or planned preclinical studies or clinical trials or the development of Xilio's current or future product candidates.
• Ability to obtain and maintain sufficient preclinical and clinical supply of current or future product candidates.
• Initial, preliminary, or interim preclinical or clinical data or results may not be replicated in or predictive of future preclinical or clinical data or results.
• Ability to successfully demonstrate the safety and efficacy of product candidates and gain regulatory approval on a timely basis, if at all.
• Results from preclinical studies or clinical trials for product candidates may not support further development.
• Actions of regulatory agencies may affect the initiation, timing, and progress of current or future clinical trials.
• Ability to obtain, maintain, and enforce patent and other intellectual property protection for current or future product candidates.
• Need to obtain additional cash resources to fund operations beyond the first quarter of 2026, including to advance the pipeline of tumor-activated I-O molecules.
• Impact of international trade policies on Xilio's business, including U.S. and China trade policies.
• Ability to maintain collaboration or partnership agreements with AbbVie, Gilead, and Roche.

Future Outlook

Xilio Therapeutics anticipates reporting additional Phase 2 data for vilastobart in MSS CRC, including results from the 150 mg Q6W dose level, in the first half of 2026. The company is actively seeking partnership opportunities to accelerate and expand the vilastobart program's development, potentially leading to a Phase 3 study. For its broader pipeline, Xilio expects to submit an IND for XTX501 by mid-2026 and nominate development candidates for its masked T cell engager programs (PSMA, CLDN18.2, STEAP1) between Q3 2025 and 1H 2026, with IND submissions for at least two masked T cell engagers targeted for 2027. The company's cash runway is projected into Q1 2026, prior to any potential contingent payments from existing collaborations.

Management Comments

• Katarina Luptakova, M.D., Chief Medical Officer of Xilio, stated: "These Phase 2 data for the combination of vilastobart and atezolizumab demonstrate a meaningfully differentiated safety and tolerability profile for an anti-CTLA-4 combination therapy, together with a preliminary 26% objective response rate in patients with late-line metastatic MSS CRC without liver metastases. Responses were deep and durable for up to 37 weeks and were accompanied by substantial decreases in tumor biomarkers such as circulating tumor DNA and improvements in clinical symptoms. We are very encouraged by these data demonstrating the potential of vilastobart, a next generation anti-CTLA-4, as a combination therapy not only for patients with MSS CRC but also a range of other tumor types traditionally resistant to treatment with immunotherapy."
• Marwan G. Fakih, M.D., Professor in the Department of Medical Oncology and Therapeutics Research and Division Head, GI Medical Oncology at City of Hope, commented: "These data further highlight the potential for vilastobart, a tumor-activated anti-CTLA-4, in combination with PD-(L)1 inhibitors to provide a meaningful clinical benefit for patients with metastatic MSS CRC without liver metastases, an area of significant and increasing unmet need, especially in younger people. I am particularly excited to see the depth and durability of responses in these late-line patients, as well as the low incidence of colitis and other immune-related adverse events that are common dose-limiting adverse events for other anti-CTLA-4 agents. Beyond MSS CRC, I believe these data support the potential for vilastobart as a combination therapy across a range of tumor types, including those where toxicity has limited the significant opportunity for anti-CTLA-4 to date."

Industry Context

Metastatic microsatellite stable colorectal cancer (MSS CRC) is an immunologically 'cold' tumor type that accounts for approximately 95% of Stage 4 CRC patients and has historically shown minimal to no efficacy with approved immuno-oncology (I-O) therapies, including PD-1/PD-L1 inhibitors (0-3% ORR). Current standard of care in later lines (3L+) for MSS CRC, such as Regorafenib, Fruquintinib, or Lonsurf, provides minimal benefit with objective response rates typically around 1-6% and overall survival of 6-10 months. Anti-CTLA-4 agents have shown some activity but have been limited by significant systemic toxicities, leading to high discontinuation rates (up to ~30-40% for Grade 3+ AEs). Xilio's tumor-activated approach aims to overcome these systemic toxicity limitations by localizing activity within the tumor microenvironment, potentially expanding the utility of I-O therapies in previously unresponsive or difficult-to-treat cancers.

Comparison to Industry Standards

• Vilastobart's preliminary 26% ORR in heavily pre-treated MSS CRC patients without liver metastases significantly surpasses the 0-3% ORR typically seen with approved immune checkpoint inhibitors (e.g., pembrolizumab/nivolumab) in MSS CRC.
• Compared to current standard of care in 3L+ MSS CRC (e.g., Regorafenib, Fruquintinib, Lonsurf), which show ORRs of 1-6%, vilastobart's 26% ORR represents a substantial improvement in a challenging patient population.
• Other anti-CTLA-4 agents in development have reported ORRs of 8-24% in MSS CRC without liver metastases but were associated with high discontinuation rates due to adverse events (up to ~30% for Fc-enhanced, not masked agents, and up to ~40% Grade 3+ treatment-related AEs for not Fc-enhanced, masked agents).
• Vilastobart's differentiated safety profile, with only 7% incidence of colitis and 5% treatment discontinuation due to TRAEs, appears superior to the toxicity profiles reported for other anti-CTLA-4 agents, which have historically limited their broader application.
• The sustained responses observed for up to 37 weeks with vilastobart are notable given the aggressive nature of late-line MSS CRC and the limited durability of existing treatments.

Stakeholder Impact

• **Shareholders**: Positive clinical data in a difficult-to-treat indication could increase investor confidence and potentially lead to share price appreciation. However, the limited cash runway into Q1 2026 indicates potential future dilution from capital raises.
• **Patients**: The promising efficacy and differentiated safety profile of vilastobart offer a potential new treatment option for metastatic MSS CRC patients, a population with high unmet medical need and limited effective immunotherapy options.
• **Employees**: Continued positive clinical progress and potential partnerships could provide job security and growth opportunities.
• **Partners (AbbVie, Gilead, Roche)**: The positive data for vilastobart could strengthen existing collaborations and potentially trigger milestone payments, reinforcing the value of Xilio's platform.

Next Steps

• Enroll approximately 10 additional patients in the Phase 2 trial for vilastobart in metastatic MSS CRC without liver metastases at the 150 mg Q6W dose level.
• Report updated Phase 2 data for vilastobart in MSS CRC, including results from the 150 mg Q6W dose level, in the first half of 2026.
• Engage with the FDA for feedback on the development path for vilastobart in 3L+ MSS CRC.
• Seek opportunities to partner the vilastobart program to accelerate and expand further development, potentially leading to a Phase 3 study.
• Nominate a development candidate for the PSMA masked T cell engager program in Q3 2025.
• Nominate a development candidate for the CLDN18.2 masked T cell engager program in Q4 2025.
• Nominate a development candidate for the STEAP1 masked T cell engager program in 1H 2026.
• Submit INDs for at least two masked T cell engager programs in 2027.
• Continue advancing XTX301 in Phase 1 dose escalation in partnership with Gilead.
• Advance XTX501 through initial IND-enabling activities towards an IND submission in mid-2026.

Key Dates

Recommendation

Keywords

Xilio Therapeutics, Vilastobart, Metastatic Colorectal Cancer, MSS CRC, Tumor-Activated Immunotherapy, Anti-CTLA-4, Atezolizumab, Phase 2 Clinical Trial, Oncology, Biotechnology, Immuno-Oncology, ASCO, XTX301, XTX501, T Cell Engagers, Clinical-Stage, Drug Development