Phase 1/2 study of tiragolumab and atezolizumab in patients with relapsed or refractory SMARCB1 or SMARCA4 deficient tumors.

Abstract

TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if >15 to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients <18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients < 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients <18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients < 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .

Image_1.pdf

“…Patients with prostate cancer with certain RAD51B or CDK12 SNVs, including RAD51B R47*, are FDA-approved for treatment with olaparib (a PARP inhibitor). Certain SNVs in SMARCB1 and IDH2 and amplification of FGF3 were included in inclusion criteria for several clinical trials at the time of testing including trials of olaparib (IDH2) (44), atezolizumab + tiragolumab (SMARCB1) (45), and other therapies. Patients with the specific EGFR A750P variant, in combination with the E746-A750 or L747-E749 deletion, were candidates for a clinical trial of patritumab deruxtecan (HER3-Dxd; a novel, investigational, HER3-directed antibody-drug conjugate) in combination with osimertinib (a tyrosine kinase inhibitor) (46).…”

Table_5.xlsx

“…Patients with prostate cancer with certain RAD51B or CDK12 SNVs, including RAD51B R47*, are FDA-approved for treatment with olaparib (a PARP inhibitor). Certain SNVs in SMARCB1 and IDH2 and amplification of FGF3 were included in inclusion criteria for several clinical trials at the time of testing including trials of olaparib (IDH2) (44), atezolizumab + tiragolumab (SMARCB1) (45), and other therapies. Patients with the specific EGFR A750P variant, in combination with the E746-A750 or L747-E749 deletion, were candidates for a clinical trial of patritumab deruxtecan (HER3-Dxd; a novel, investigational, HER3-directed antibody-drug conjugate) in combination with osimertinib (a tyrosine kinase inhibitor) (46).…”

Table_7.xlsx

“…Patients with prostate cancer with certain RAD51B or CDK12 SNVs, including RAD51B R47*, are FDA-approved for treatment with olaparib (a PARP inhibitor). Certain SNVs in SMARCB1 and IDH2 and amplification of FGF3 were included in inclusion criteria for several clinical trials at the time of testing including trials of olaparib (IDH2) (44), atezolizumab + tiragolumab (SMARCB1) (45), and other therapies. Patients with the specific EGFR A750P variant, in combination with the E746-A750 or L747-E749 deletion, were candidates for a clinical trial of patritumab deruxtecan (HER3-Dxd; a novel, investigational, HER3-directed antibody-drug conjugate) in combination with osimertinib (a tyrosine kinase inhibitor) (46).…”