{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T19:16:50Z","timestamp":1778181410459,"version":"3.51.4"},"reference-count":46,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"unspecified","delay-in-days":49,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"BeOne Medicines","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["bmjonc"],"accepted":{"date-parts":[[2026,1,22]]},"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Many patients with non-small cell lung cancer (NSCLC) have tumours that are either refractory or develop resistance following an initial response to anti-programmed cell death protein (ligand)-1 (PD-(L)1)-based treatment, resulting in limited treatment options. SAFFRON-301 evaluated whether combining the multikinase inhibitor, sitravatinib, with the anti-PD-1 antibody, tislelizumab, may overcome resistance to anti-PD-(L)1 therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      SAFFRON-301 (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04921358\">NCT04921358<\/jats:ext-link>\n                      ) was an open-label, randomised, phase III trial enrolling patients with unresectable locally advanced\/metastatic NSCLC, who had disease progression on or after platinum-based chemotherapy and anti-PD-(L)1 antibodies. No more than two lines of prior systemic therapy were allowed. Patients were randomised 1:1 to receive sitravatinib 100\u2009mg orally once daily plus tislelizumab 200\u2009mg intravenously once every 3 weeks or docetaxel 75 mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      intravenously every 3 weeks. Dual primary endpoints were overall survival (OS) and Independent Review Committee (IRC)-assessed progression-free survival (PFS).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Overall, 377 patients were enrolled and randomised to receive sitravatinib plus tislelizumab (n=187) or docetaxel (n=190); 51.2% had squamous histology and 36.6% had PD-L1 expression in \u22651% of tumour cells. At a median follow-up of 11.7 (sitravatinib plus tislelizumab) and 11.4 months (docetaxel), median OS was similar (11.5 (95% CI 9.4 to 14.6) vs 11.4 (9.9 to 15.0) months, respectively; HR, 1.02 (95% CI 0.75 to 1.39)) between treatment arms. IRC-assessed median PFS was numerically longer with sitravatinib plus tislelizumab (4.4 (95% CI 4.0 to 5.7) months) vs docetaxel (2.9 (95% CI 2.6 to 4.2) months); HR, 0.82 (95% CI 0.62 to 1.07). IRC-assessed overall response rate was 12.3% with sitravatinib plus tislelizumab vs 12.6% with docetaxel. The most commonly reported treatment-emergent adverse events grade \u22653 in sitravatinib plus tislelizumab arm were hypertension (13.4%), pneumonia (9.1%), palmar-plantar erythrodysesthesia syndrome (6.5%) vs white blood cell count decreased (29.4%), neutrophil count decreased (28.8%), pneumonia (8.5%) and neutropenia (7.3%) in docetaxel arm. Grade 5 haemoptysis occurred in 3 (1.6%) patients with sitravatinib plus tislelizumab. The study was terminated due to an unfavourable risk\u2013benefit analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The SAFFRON-301 study was terminated early due to unfavourable risk\u2013benefit assessment in the investigational arm. Due to immature survival data, efficacy results should be interpreted with caution.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04921358\">NCT04921358<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjonc-2025-000890","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T13:10:19Z","timestamp":1771506619000},"page":"e000890","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["SAFFRON-301: a randomised phase III study of sitravatinib in combination with tislelizumab in patients with locally advanced or metastatic non-small cell lung cancer"],"prefix":"10.1136","volume":"5","clinical-trial-number":[{"clinical-trial-number":"nct04921358","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04921358","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04921358","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05633602","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0478-176X","authenticated-orcid":false,"given":"Qing","family":"Zhou","sequence":"first","affiliation":[{"name":"Guangdong Lung Cancer Institute, Guangzhou, Guangdong, China"},{"name":"Guangdong Academy of Medical Sciences, Guangdong Provincial People\u2019s Hospital, Guangzhou, Guangdong, China"},{"name":"Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Gao","sequence":"additional","affiliation":[{"name":"Blacktown Cancer and Haematology Centre, Blacktown, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Shanghai Geriatric Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key laboratory of Carcinogenesis and Translational Research (Ministry of Education\/Beijing), Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9226-5393","authenticated-orcid":false,"given":"Mengzhao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"He","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, James Cancer Hospital, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunling","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Lung Internal Medicine, Xinjiang Cancer Hospital, Urumqi, Xinjiang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3697-4563","authenticated-orcid":false,"given":"Jian","family":"Fang","sequence":"additional","affiliation":[{"name":"Key laboratory of Carcinogenesis and Translational Research (Ministry of Education\/Beijing), Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing ya","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhehai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory, Shandong Cancer Hospital, Jinan, Shandong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Matos","sequence":"additional","affiliation":[{"name":"Pindara Private Hospital, Benowa, Queensland, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vineet","family":"Kwatra","sequence":"additional","affiliation":[{"name":"Cancer Research South Australia, Adelaide, South Australia, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjuan","family":"Zheng","sequence":"additional","affiliation":[{"name":"BeOne Medicines Ltd. (Beijing) Co., Ltd, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenyang","family":"Wang","sequence":"additional","affiliation":[{"name":"BeOne Medicines Ltd. (Beijing) Co., Ltd, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaxi","family":"Chen","sequence":"additional","affiliation":[{"name":"BeOne Medicines, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Zhang","sequence":"additional","affiliation":[{"name":"BeOne Medicines Ltd. (Beijing) Co., Ltd, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"BeOne Medicines Ltd. (Beijing) Co., Ltd, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3611-0258","authenticated-orcid":false,"given":"Yi-Long","family":"Wu","sequence":"additional","affiliation":[{"name":"Guangdong Academy of Medical Sciences, Guangdong Provincial People\u2019s Hospital, Guangzhou, Guangdong, China"},{"name":"Southern Medical University, Guangzhou, Guangdong, China"},{"name":"Guangdong Provincial People\u2019s Hospital Guangdong Lung Cancer Research Institute, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"2026021905101006000_5.1.e000890.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.12.013"},{"key":"2026021905101006000_5.1.e000890.2","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2204.0023"},{"key":"2026021905101006000_5.1.e000890.3","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.1200\/JCO.22.00825","article-title":"Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline","volume":"40","author":"Singh","year":"2022","journal-title":"J Clin Oncol"},{"key":"2026021905101006000_5.1.e000890.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801005"},{"key":"2026021905101006000_5.1.e000890.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1810865"},{"key":"2026021905101006000_5.1.e000890.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.09.010"},{"key":"2026021905101006000_5.1.e000890.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1716948"},{"key":"2026021905101006000_5.1.e000890.8","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30167-6"},{"key":"2026021905101006000_5.1.e000890.9","doi-asserted-by":"crossref","DOI":"10.1177\/1758835920937902","article-title":"Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies","volume":"12","author":"Walsh","year":"2020","journal-title":"Ther Adv Med Oncol"},{"key":"2026021905101006000_5.1.e000890.10","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2023.100879","article-title":"Controversies in NSCLC: which second-line strategy after chemo-immunotherapy?","volume":"8","author":"Moliner","year":"2023","journal-title":"ESMO Open"},{"key":"2026021905101006000_5.1.e000890.11","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1200\/JCO.1999.17.7.2081","article-title":"Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: A phase II trial","volume":"17","author":"Crin\u00f2","year":"1999","journal-title":"J Clin Oncol"},{"key":"2026021905101006000_5.1.e000890.12","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60845-X"},{"key":"2026021905101006000_5.1.e000890.13","first-page":"4535","article-title":"Single-agent gemcitabine as second-line treatment in patients with advanced non small cell lung cancer (NSCLC): a phase II trial","volume":"19","author":"Gridelli","year":"1999","journal-title":"Anticancer Res"},{"key":"2026021905101006000_5.1.e000890.14","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.lungcan.2016.10.011","article-title":"Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial","volume":"102","author":"Hanna","year":"2016","journal-title":"Lung Cancer (Auckl)"},{"key":"2026021905101006000_5.1.e000890.15","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(13)70586-2"},{"key":"2026021905101006000_5.1.e000890.16","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2000.18.10.2095"},{"key":"2026021905101006000_5.1.e000890.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.03.027"},{"key":"2026021905101006000_5.1.e000890.18","doi-asserted-by":"crossref","DOI":"10.1186\/s12943-020-01260-z","article-title":"Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook","volume":"19","author":"Horvath","year":"2020","journal-title":"Mol Cancer"},{"key":"2026021905101006000_5.1.e000890.19","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.70958"},{"key":"2026021905101006000_5.1.e000890.20","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.124184","article-title":"Sitravatinib potentiates immune checkpoint blockade in refractory cancer models","volume":"3","author":"Du","year":"2018","journal-title":"JCI Insight"},{"key":"2026021905101006000_5.1.e000890.21","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1200\/JCO.19.01598","article-title":"Phase IB\/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors","volume":"38","author":"Taylor","year":"2020","journal-title":"J Clin Oncol"},{"key":"2026021905101006000_5.1.e000890.22","doi-asserted-by":"crossref","first-page":"9005","DOI":"10.1200\/JCO.2022.40.16_suppl.9005","article-title":"Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non\u2013small cell lung cancer (aNSCLC) previously treated with an immune checkpoint inhibitor (ICI): Results from Cohorts 7 and 20 of the COSMIC-021 study","volume":"40","author":"Neal","year":"2022","journal-title":"JCO"},{"key":"2026021905101006000_5.1.e000890.23","doi-asserted-by":"publisher","DOI":"10.1200\/jco.22.00912"},{"key":"2026021905101006000_5.1.e000890.24","first-page":"100537","article-title":"Phase 3 LEAP-008 study of lenvatinib plus pembrolizumab versus docetaxel for metastatic non-small cell lung cancer (NSCLC) that progressed on a PD-(L)1 inhibitor and platinum-containing chemotherapy","volume":"20","author":"Leighl","year":"2023","journal-title":"Ann Oncol"},{"key":"2026021905101006000_5.1.e000890.25","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1200\/JCO.23.02166","article-title":"CONTACT-01: A Randomized Phase III Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy","volume":"42","author":"Neal","year":"2024","journal-title":"J Clin Oncol"},{"key":"2026021905101006000_5.1.e000890.26","unstructured":"National Library of Medicine . ClinicalTrials.gov: ramucirumab plus pembrolizumab vs usual care for treatment of stage IV or recurrent non-small cell lung cancer following immunotherapy, pragmatica-lung study. 2024. Available: https:\/\/clinicaltrials.gov\/study\/NCT05633602 [Accessed 24 Feb 2025]."},{"key":"2026021905101006000_5.1.e000890.27","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1007\/s10637-022-01274-y","article-title":"First-in-human phase 1\/1b study to evaluate sitravatinib in patients with advanced solid tumors","volume":"40","author":"Bauer","year":"2022","journal-title":"Invest New Drugs"},{"key":"2026021905101006000_5.1.e000890.28","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6547"},{"key":"2026021905101006000_5.1.e000890.29","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12522"},{"key":"2026021905101006000_5.1.e000890.30","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0676"},{"key":"2026021905101006000_5.1.e000890.31","doi-asserted-by":"crossref","DOI":"10.3390\/ijms18112291","article-title":"Synergies of Targeting Tumor Angiogenesis and Immune Checkpoints in Non-Small Cell Lung Cancer and Renal Cell Cancer: From Basic Concepts to Clinical Reality","volume":"18","author":"Pircher","year":"2017","journal-title":"Int J Mol Sci"},{"key":"2026021905101006000_5.1.e000890.32","doi-asserted-by":"crossref","DOI":"10.1177\/10732748221111296","article-title":"Tislelizumab: A Modified Anti-tumor Programmed Death Receptor 1 Antibody","volume":"29","author":"Zhang","year":"2022","journal-title":"Cancer Control"},{"key":"2026021905101006000_5.1.e000890.33","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-018-2160-x"},{"key":"2026021905101006000_5.1.e000890.34","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-006055","article-title":"SAFFRON-103: a phase 1b study of the safety and efficacy of sitravatinib combined with tislelizumab in patients with locally advanced or metastatic non-small cell lung cancer","volume":"11","author":"Zhao","year":"2023","journal-title":"J Immunother Cancer"},{"key":"2026021905101006000_5.1.e000890.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"2026021905101006000_5.1.e000890.36","unstructured":"U.S. Department of Health and Human Services . Common terminology criteria for adverse events (CTCAE) version 5.0. 2017. Available: https:\/\/ctep.cancer.gov\/protocoldevelopment\/electronic_applications\/docs\/ctcae_v5_quick_reference_5x7.pdf [Accessed 24 Feb 2025]."},{"key":"2026021905101006000_5.1.e000890.37","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.77.6385"},{"key":"2026021905101006000_5.1.e000890.38","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx225"},{"key":"2026021905101006000_5.1.e000890.39","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdr463"},{"key":"2026021905101006000_5.1.e000890.40","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19800701)46:1<200::AID-CNCR2820460133>3.0.CO;2-V"},{"key":"2026021905101006000_5.1.e000890.41","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.11.022"},{"key":"2026021905101006000_5.1.e000890.42","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.annonc.2023.10.004","article-title":"SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer","volume":"35","author":"Borghaei","year":"2024","journal-title":"Ann Oncol"},{"key":"2026021905101006000_5.1.e000890.43","doi-asserted-by":"crossref","first-page":"5059","DOI":"10.2147\/OTT.S166151","article-title":"Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials","volume":"11","author":"Xiao","year":"2018","journal-title":"Onco Targets Ther"},{"key":"2026021905101006000_5.1.e000890.44","unstructured":"Eli Lilly and Company . CYRAMZA - ramucirumab solution. Prescribing information. 2022. Available: https:\/\/uspl.lilly.com\/cyramza\/cyramza.html#section-1 [Accessed 24 Feb 2025]."},{"key":"2026021905101006000_5.1.e000890.45","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1638"},{"key":"2026021905101006000_5.1.e000890.46","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-004863","article-title":"Addressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects","volume":"10","author":"Peters","year":"2022","journal-title":"J Immunother Cancer"}],"container-title":["BMJ Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjonc-2025-000890","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T13:10:24Z","timestamp":1771506624000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjoncology.bmj.com\/lookup\/doi\/10.1136\/bmjonc-2025-000890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,2,19]]},"published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1136\/bmjonc-2025-000890"],"URL":"https:\/\/doi.org\/10.1136\/bmjonc-2025-000890","relation":{},"ISSN":["2752-7948"],"issn-type":[{"value":"2752-7948","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]}}}