Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study.
Abstract | BACKGROUND: 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: TRIAL REGISTRATION NUMBER: NCT03575598.
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Authors | Marc Oliva, Douglas Chepeha, Daniel V Araujo, J Javier Diaz-Mejia, Peter Olson, Amy Prawira, Anna Spreafico, Scott V Bratman, Tina Shek, John de Almeida, Aaron R Hansen, Andrew Hope, David Goldstein, Ilan Weinreb, Stephen Smith, Bayardo Perez-Ordoñez, Jonathan Irish, Dax Torti, Jeffrey P Bruce, Ben X Wang, Anthony Fortuna, Trevor J Pugh, Hirak Der-Torossian, Ronald Shazer, Nickolas Attanasio, Qingyan Au, Antony Tin, Jordan Feeney, Himanshu Sethi, Alexey Aleshin, Isan Chen, Lillian Siu |
Journal | Journal for immunotherapy of cancer
(J Immunother Cancer)
Vol. 9
Issue 10
(10 2021)
ISSN: 2051-1426 [Electronic] England |
PMID | 34599023
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. |
Chemical References |
- Anilides
- Pyridines
- Nivolumab
- sitravatinib
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Topics |
- Aged
- Anilides
(pharmacology, therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology, therapeutic use)
- Female
- Humans
- Male
- Middle Aged
- Mouth Neoplasms
(drug therapy)
- Nivolumab
(pharmacology, therapeutic use)
- Preoperative Period
- Pyridines
(pharmacology, therapeutic use)
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