SNOW: Sitravatinib and nivolumab in oral cavity cancer (OCC) window of opportunity study.

Abstract

6569 Background: Sitravatinib (receptor TKI against TYRO3, AXL, MERTK and VEGF family of receptors) is predicted to increase M1-type tumor-associated macrophages (TAMs) and decrease MDSCs in the tumor microenvironment. SNOW is a window-of-opportunity study evaluating the immunogenic and antitumor effects of preoperative sitravatinib and nivolumab in patients (pts) with OCC. Early results demonstrated the combination was safe and active (Oliva et al, SITC 2019). Biomarker analyses and updated results are presented. Methods: Pts with untreated T2-4a, N0-2 or T1>1cm-N2 OCC are eligible. All pts receive oral sitravatinib 120mg daily from day (D) 1 up to 48h pre-surgery and 1 dose of Nivolumab 240mg on D15. Surgery planned between D23-D30. Standard of care adjuvant radiotherapy given based on clinical stage. Tumor pictures, fresh tumor biopsies, blood samples taken at baseline, D15 and pre-surgery. Tumor flow cytometry and multiplex immunofluorescence staining performed on all biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing (WES) performed on baseline biopsies. Results: As of Jan 31st 2020, 10 out of 12 planned pts were enrolled. Study treatment was well-tolerated: only 1 pt had grade (G) >3 toxicity (hypertension) and 1 pt required surgery delay due to G2 thrombocytopenia. None had intraoperative complications. 1 pt had wound infection and tracheostomy bleeding 11 days post-surgery, possibly-related to study drugs. All pts had tumor reduction, 9/10 had pathological downstaging, including 1 complete response (Table). All had clear margins with no extranodal extension; none required adjuvant chemotherapy. All pts are alive with no recurrence (median follow-up= 69 weeks). Lower % of MDSCs and increased % of M1-TAMs and M1:M2 ratio trend was seen at D15 and pre-surgery, with stronger effect in major responders. Best responders (Pts S1-S2) had higher % of PD-L1+ TAMs at baseline. Tumor WES revealed an HRAS G12D mutation in pt S2 and a BLM mutation (DNA repair) in pt S6 (no downstaging). Conclusions: Pharmacodynamic analyses support the antitumor and immune effects of sitravatinib and nivolumab in OCC. Immune pathological response assessment and transcriptomics are on-going. Clinical trial information: NCT03575598 . [Table: see text]

A systematic review of neoadjuvant and definitive immunotherapy in locally advanced head and neck squamous cell carcinoma

“…Their study has demonstrated increased pathological response with combination treatment but without statistical significance (60% vs. 37.5%, p = 0.4) 41 . To further explore the influence of the tumour microenvironment on ICI outcomes in the neoadjuvant setting, Bernal et al investigated adding in sitravatinib, a multi‐target tyrosine kinase inhibitor, with nivolumab pre‐operatively 42 . They theorised that increased density of M1‐type tumour‐associated macrophages and decreased incidence of myeloid‐derived suppressor cells from this combination would amplify treatment response.…”

“…They theorised that increased density of M1‐type tumour‐associated macrophages and decreased incidence of myeloid‐derived suppressor cells from this combination would amplify treatment response. In 10 patients they demonstrated a greater disease response in those with a higher percentage of PD‐L1 positive tumour‐associated macrophages 42 . Whether this combination alone leads to survival improvements is still being investigated.…”

“… 41 To further explore the influence of the tumour microenvironment on ICI outcomes in the neoadjuvant setting, Bernal et al investigated adding in sitravatinib, a multi‐target tyrosine kinase inhibitor, with nivolumab pre‐operatively. 42 They theorised that increased density of M1‐type tumour‐associated macrophages and decreased incidence of myeloid‐derived suppressor cells from this combination would amplify treatment response. In 10 patients they demonstrated a greater disease response in those with a higher percentage of PD‐L1 positive tumour‐associated macrophages.…”

“…In 10 patients they demonstrated a greater disease response in those with a higher percentage of PD‐L1 positive tumour‐associated macrophages. 42 Whether this combination alone leads to survival improvements is still being investigated. Recently, indoleamine 2,3‐dioxygenase (IDO) inhibitors have also been trialled, without success, with neoadjuvant immunotherapy in untreated LA HNSCC to improve pathological response.…”

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy

“… 23 The study found that sitravatinib monotherapy resulted in a less immunosuppressive TME and was associated with macrophage repolarization toward the M1 type in patients who responded to sitravatinib with nivolumab. 23 , 24 …”