Sensei Biotherapeutics has announced encouraging initial results from the dose expansion portion of its Phase 1/2 clinical trial evaluating solnerstotug (formerly SNS-101) in patients with PD-L1 resistant tumors, potentially offering new hope for patients with limited treatment options.
The trial data revealed a 14% overall response rate and a 62% disease control rate among 21 evaluable patients with PD-L1-resistant "hot" tumors, significantly exceeding historical response rates for PD-L1 rechallenge therapy, which typically hover around 5% or less.
"Checkpoint inhibitor resistance remains a significant challenge for patients with advanced cancer, with limited treatment options beyond chemotherapy or clinical trials," said Dr. Ron Weitzman, Chief Medical Officer of Sensei Biotherapeutics. "The initial 14% response rate seen with solnerstotug is nearly three times higher than what would typically be expected in this setting. We believe these early data suggest solnerstotug may provide a meaningful clinical benefit in select tumor types."
Notable Clinical Responses
Among the most striking responses, a patient with Merkel cell carcinoma (MCC) achieved a durable complete response when treated with 15 mg/kg solnerstotug in combination with Libtayo (cemiplimab). This patient remains on treatment after 42+ weeks, following previous progression after 15 months of PD-L1 therapy in the adjuvant setting.
A second MCC patient achieved a partial response at Week 12 with the same combination regimen and continues treatment at 12+ weeks. This patient had previously received multiple lines of checkpoint therapy, including PD-1 and CTLA-4 inhibitors, with only stable disease as best response before progression.
Additionally, a patient with microsatellite instability-high colorectal cancer (MSI-H CRC) achieved a partial response at week 36 after maintaining stable disease throughout treatment. This patient, who remains on therapy at 36+ weeks, had previously experienced a complete response to PD-L1 therapy administered for more than four years before eventually progressing.
Six additional patients with PD-L1-resistant tumors maintained stable disease beyond 12 weeks, with tumor reductions ranging from 0% to 17%, suggesting durable disease control in a subset of patients.
Trial Design and Patient Population
The multi-center, open-label Phase 1/2 trial enrolled a total of 60 patients across two main cohorts:
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40 patients with "hot" tumors (typically responsive to immunotherapy but progressed on prior PD-(L)1 therapy), including non-small cell lung cancer, head and neck cancer, melanoma, renal cell carcinoma, Merkel cell carcinoma, and MSI-H colorectal cancer. All received solnerstotug (3 mg/kg or 15 mg/kg) in combination with Libtayo.
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20 patients with "cold" tumors (microsatellite stable colorectal cancer, typically unresponsive to immunotherapy). Of these, 10 received solnerstotug monotherapy (15 mg/kg) and 10 received the combination with Libtayo.
No patients with microsatellite stable colorectal cancer experienced complete or partial responses, consistent with the historically poor response of this "cold" tumor type to checkpoint inhibitor therapy.
Safety Profile
Solnerstotug demonstrated a favorable safety profile with no dose-limiting toxicities reported. The majority of adverse events were Grade 1 (mild) or Grade 2 (moderate) in severity. Among the 60 patients treated, only four (7%) experienced Grade 1 cytokine release syndrome, all cases being mild and manageable. Two patients in the combination cohort experienced immune-mediated events.
Mechanism of Action
Solnerstotug is a conditionally active monoclonal antibody targeting VISTA (V-domain Ig suppressor of T cell activation), an immune checkpoint regulator that suppresses T-cell activity. By targeting VISTA, solnerstotug aims to reinvigorate anti-tumor immune responses in patients who have developed resistance to PD-(L)1 inhibitors.
Expert Perspective
Dr. Shiraj Sen, medical oncologist and Director of Clinical Research at NEXT Oncology - Dallas, and a principal investigator for the study, commented on the findings: "While we remain in the early stages of evaluating solnerstotug's therapeutic potential, the observed responses — particularly in MCC and MSI-H CRC — are encouraging given the historically poor prognosis of these patients once they have progressed on checkpoint therapy. Continued clinical evaluation will be key in determining which patients are most likely to benefit from this approach."
Future Development
Based on these promising initial results, Sensei Biotherapeutics plans to initiate a Phase 2 study in the first quarter of 2026 to further evaluate solnerstotug's efficacy in specific tumor types.
The early data suggest that solnerstotug may offer a meaningful treatment option for patients with PD-L1 resistant tumors, addressing a significant unmet medical need in oncology. As the trial continues, researchers will work to identify biomarkers that may help predict which patients are most likely to benefit from this novel therapeutic approach.
