Initial results from a first-in-human phase 1 study of SNS-101 (pH-selective anti-VISTA antibody) alone or in combination with cemiplimab in patients with advanced solid tumors.
Authors: Sen Shiraj , Call Justin A , Papadopoulos Kyriakos P. , Smith F. Donelson , McDermott Janine , van der Horst Edward , Weitzman Aaron 
Published: June 2024

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Background: VISTA (V-domain Ig suppressor of T-cell activation), an inhibitory T-cell checkpoint expressed on myeloid-lineage cells, is a promising target in cancer immunotherapy. However, therapeutically targeting VISTA effectively has been challenging. We developed SNS-101, a novel pH-selective VISTA antibody, to address issues of rapid clearance and cytokine release syndrome (CRS) faced by previous VISTA antibodies. Methods: First in human, Ph 1/2, open-label, multicenter, dose escalation/expansion study of anti-VISTA (SNS-101) as monotherapy (mono) or in combination (combo) with cemiplimab (cemi) in pts with advanced solid tumors that have either progressed on prior anti-PD-1 therapy (acquired resistance) or are unfavorable candidates for immunotherapy (primary resistance). Primary objectives include safety and MTD/RP2D. Secondary objectives include PK and anti-tumor activity. SNS-101 +/- cemi was given once every 3 wks at dose levels of 0.3, 1, 3, 10 and 15 mg/kg for mono and 3, 10 and 15 mg/kg + cemi 350 mg for combo. Patients are not routinely prophylaxed for CRS. The study employs a BOIN design. Results: As of February 2, 2024, the dose escalation portion of the study completed accrual (n=31) to highest dose levels in both mono (n=16) and combo arms (n=15); 12 pts remain ongoing (2 mono/10 combo). Most common tumor types are colon (n= 7), kidney (n=4), pancreatic (n=3), and ovarian (n=2). Median age is 62 years. Median number of prior metastatic therapies is 2; 12 pts (39%) received ≥1 prior anti-PD-1/PD-L1 agent. No DLTs were observed. Most frequent AEs: cough (n=3), dermatitis acneiform and pyrexia (n=2 each) in the mono arm; fatigue (n=3), anemia, nausea and rash maculo-papular (n=2 each) in the combo arm. Immune-mediated AEs included CRS (G1, 15 mg/kg, n=1) in the mono arm; diabetic ketoacidosis (G3, 3 mg/kg, n=1), rash maculo-papular (G2, 3 mg/kg, n=1), and ALT increased (G3, 10 mg/kg, n=1) in the combo arm. One pt had a confirmed PR and 10 pts had SD as best response. In the mono arm, 1 pembrolizumab-resistant HPV+ H&N pt at 15 mg/kg had tumor regression of 17%. In the combo arm, 1 MSS endometrial pt at 3 mg/kg + cemi had a confirmed PR (45% decrease) and 1 MSS colon pt at 10 mg/kg + cemi had tumor regression of 27%. PK appears dose-proportional and consistent with lack of target-mediated drug disposition, with no notable difference between mono vs combo dosing. Dose-dependent changes in specific T-cell populations indicate potential SNS-101-related pharmacological effects. Conclusions: pH selective SNS-101, both alone and in combo with cemi, has been safely administered at doses that are ~50x higher than doses where severe CRS was observed with prior VISTA agents. Both mono and combo therapy have been generally well tolerated. Early signs of clinical activity were observed in both the acquired and primary PD-1 resistant tumor settings. Clinical trial information: NCT05864144 .