Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study
Background Sitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programm...
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2021-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
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| author | David Goldstein Anna Spreafico Ilan Weinreb Trevor J. Pugh Scott V Bratman Bayardo Perez-Ordonez Aaron R Hansen Lillian Siu Antony Tin Alexey Aleshin Amy Prawira Jonathan Irish John de Almeida Douglas Chepeha Stephen Smith Marc Oliva Daniel V Araujo J. Javier Diaz-Mejia Peter Olson Tina Shek Andrew Hope Dax Torti Jeffrey P. Bruce Ben X. Wang Anthony Fortuna Hirak Der-Torossian Ronald Shazer Nickolas Attanasio Qingyan Au Jordan Feeney Himanshu Sethi Isan Chen |
| author_facet | David Goldstein Anna Spreafico Ilan Weinreb Trevor J. Pugh Scott V Bratman Bayardo Perez-Ordonez Aaron R Hansen Lillian Siu Antony Tin Alexey Aleshin Amy Prawira Jonathan Irish John de Almeida Douglas Chepeha Stephen Smith Marc Oliva Daniel V Araujo J. Javier Diaz-Mejia Peter Olson Tina Shek Andrew Hope Dax Torti Jeffrey P. Bruce Ben X. Wang Anthony Fortuna Hirak Der-Torossian Ronald Shazer Nickolas Attanasio Qingyan Au Jordan Feeney Himanshu Sethi Isan Chen |
| author_sort | David Goldstein |
| collection | DOAJ |
| description | Background Sitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programmed death-1/ligand-1 agents. SNOW is a window-of-opportunity study designed to evaluate the immune and molecular effects of preoperative sitravatinib and nivolumab in patients with oral cavity squamous cell carcinoma.Methods Patients with newly-diagnosed untreated T2-4a, N0-2 or T1 >1 cm-N2 oral cavity carcinomas were eligible. All patients received sitravatinib 120 mg daily from day 1 up to 48 hours pre-surgery and one dose of nivolumab 240 mg on day 15. Surgery was planned between day 23 and 30. Standard of care adjuvant radiotherapy was given based on clinical stage. Tumor photographs, fresh tumor biopsies and blood samples were collected at baseline, at day 15 after sitravatinib alone, and at surgery after sitravatinib–nivolumab combination. Tumor flow cytometry, multiplex immunofluorescence staining and single-cell RNA sequencing (scRNAseq) were performed on tumor biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing and circulating tumor DNA and cell-free DNA were evaluated at each time point.Results Ten patients were included. Grade 3 toxicity occurred in one patient (hypertension); one patient required sitravatinib dose reduction, and one patient required discontinuation and surgery delay due to G2 thrombocytopenia. Nine patients had clinical-to-pathological downstaging, with one complete response. Independent pathological treatment response (PTR) assessment confirmed a complete PTR and two major PTRs. With a median follow-up of 21 months, all patients are alive with no recurrence. Circulating tumor DNA and cell-free DNA dynamics correlated with clinical and pathological response and distinguished two patient groups with different tumor biological behavior after sitravatinib alone (1A) versus sitravatinib–nivolumab (1B). Tumor immunophenotyping and scRNAseq analyses revealed differential changes in the expression of immune cell populations and sitravatinib-targeted and hypoxia-related genes in group 1A vs 1B patients.Conclusions The SNOW study shows sitravatinib plus nivolumab is safe and leads to deep clinical and pathological responses in oral cavity carcinomas. Multi-omic biomarker analyses dissect the differential molecular effects of sitravatinib versus the sitravatinib–nivolumab and revealed patients with distinct tumor biology behavior.Trial registration number NCT03575598. |
| format | Article |
| id | doaj-art-0c91b22ec6d04b31bb0d153a425dbaed |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-0c91b22ec6d04b31bb0d153a425dbaed2025-08-20T02:25:17ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-10-0191010.1136/jitc-2021-003476Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity studyDavid Goldstein0Anna Spreafico1Ilan Weinreb2Trevor J. Pugh3Scott V Bratman4Bayardo Perez-Ordonez5Aaron R Hansen6Lillian Siu7Antony Tin8Alexey Aleshin9Amy Prawira10Jonathan Irish11John de Almeida12Douglas Chepeha13Stephen Smith14Marc Oliva15Daniel V Araujo16J. Javier Diaz-Mejia17Peter Olson18Tina Shek19Andrew Hope20Dax Torti21Jeffrey P. Bruce22Ben X. Wang23Anthony Fortuna24Hirak Der-Torossian25Ronald Shazer26Nickolas Attanasio27Qingyan Au28Jordan Feeney29Himanshu Sethi30Isan Chen31School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, AustraliaTumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaDepartment of Pathology, University Health Network, Toronto, Ontario, CanadaTumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaRadiation Medicine Program, Princess Margaret Hospital, University Health Network, Toronto, Ontario, CanadaDepartment of Pathology, University Health Network, Toronto, Ontario, CanadaDivision of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaDivision of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaNatera Inc, San Carlos, California, USANatera Inc, San Carlos, California, USADepartment of Medical Oncology, The Kinghorn Cancer Centre, St Vincent’s Hospital, Sidney, New South Wales, AustraliaDepartment of Otolaryngology and Head and Neck Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaDepartment of Otolaryngology and Head and Neck Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaDepartment of Otolaryngology and Head and Neck Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaDepartment of Pathology, University Health Network, Toronto, Ontario, CanadaDivision of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaDivision of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, CanadaTumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaDepartment of Research, Mirati Therapeutics, San Diego, California, USARadiation Medicine Program, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada2 Radiation Medicine Program, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, CanadaTumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaTumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaTumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaTumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaClinical Development, Mirati Therapeutics, San Diego, California, USAClinical Development, Mirati Therapeutics, San Diego, California, USANeogenomics Laboratories, Fort Myers, Florida, USA2NeoGenomics Laboratories, Aliso Viejo, CA, USANatera Inc, San Carlos, California, USANatera Inc, San Carlos, California, USAClinical Development, Mirati Therapeutics, San Diego, California, USABackground Sitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programmed death-1/ligand-1 agents. SNOW is a window-of-opportunity study designed to evaluate the immune and molecular effects of preoperative sitravatinib and nivolumab in patients with oral cavity squamous cell carcinoma.Methods Patients with newly-diagnosed untreated T2-4a, N0-2 or T1 >1 cm-N2 oral cavity carcinomas were eligible. All patients received sitravatinib 120 mg daily from day 1 up to 48 hours pre-surgery and one dose of nivolumab 240 mg on day 15. Surgery was planned between day 23 and 30. Standard of care adjuvant radiotherapy was given based on clinical stage. Tumor photographs, fresh tumor biopsies and blood samples were collected at baseline, at day 15 after sitravatinib alone, and at surgery after sitravatinib–nivolumab combination. Tumor flow cytometry, multiplex immunofluorescence staining and single-cell RNA sequencing (scRNAseq) were performed on tumor biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing and circulating tumor DNA and cell-free DNA were evaluated at each time point.Results Ten patients were included. Grade 3 toxicity occurred in one patient (hypertension); one patient required sitravatinib dose reduction, and one patient required discontinuation and surgery delay due to G2 thrombocytopenia. Nine patients had clinical-to-pathological downstaging, with one complete response. Independent pathological treatment response (PTR) assessment confirmed a complete PTR and two major PTRs. With a median follow-up of 21 months, all patients are alive with no recurrence. Circulating tumor DNA and cell-free DNA dynamics correlated with clinical and pathological response and distinguished two patient groups with different tumor biological behavior after sitravatinib alone (1A) versus sitravatinib–nivolumab (1B). Tumor immunophenotyping and scRNAseq analyses revealed differential changes in the expression of immune cell populations and sitravatinib-targeted and hypoxia-related genes in group 1A vs 1B patients.Conclusions The SNOW study shows sitravatinib plus nivolumab is safe and leads to deep clinical and pathological responses in oral cavity carcinomas. Multi-omic biomarker analyses dissect the differential molecular effects of sitravatinib versus the sitravatinib–nivolumab and revealed patients with distinct tumor biology behavior.Trial registration number NCT03575598.https://jitc.bmj.com/content/9/10/e003476.full |
| spellingShingle | David Goldstein Anna Spreafico Ilan Weinreb Trevor J. Pugh Scott V Bratman Bayardo Perez-Ordonez Aaron R Hansen Lillian Siu Antony Tin Alexey Aleshin Amy Prawira Jonathan Irish John de Almeida Douglas Chepeha Stephen Smith Marc Oliva Daniel V Araujo J. Javier Diaz-Mejia Peter Olson Tina Shek Andrew Hope Dax Torti Jeffrey P. Bruce Ben X. Wang Anthony Fortuna Hirak Der-Torossian Ronald Shazer Nickolas Attanasio Qingyan Au Jordan Feeney Himanshu Sethi Isan Chen Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study Journal for ImmunoTherapy of Cancer |
| title | Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study |
| title_full | Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study |
| title_fullStr | Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study |
| title_full_unstemmed | Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study |
| title_short | Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study |
| title_sort | antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer snow window of opportunity study |
| url | https://jitc.bmj.com/content/9/10/e003476.full |
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