BMJ oncology · 2026
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.
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Zhou Qing, Gao Bo, Hu Jie, Zhao Jun, Wang Mengzhao, He Kai, Zhang Wei, Liu Chunling, Fang Jian, Li Xing Ya, Wang Zhehai, Matos Marco, Kwatra Vineet, Zheng Wenjuan, Wang Chenyang, Chen Yaxi, Zhang Juan, Wang Jun, Wu Yi-Long
Аннотация
BACKGROUND: 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.
METHODS: SAFFRON-301 (NCT04921358) 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 mg orally once daily plus tislelizumab 200 mg intravenously once every 3 weeks or docetaxel 75 mg/m2 intravenously every 3 weeks. Dual primary endpoints were overall survival (OS) and Independent Review Committee (IRC)-assessed progression-free survival (PFS).
RESULTS: 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 ≥1% 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 ≥3 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-benefit analysis.
CONCLUSIONS: The SAFFRON-301 study was terminated early due to unfavourable risk-benefit assessment in the investigational arm. Due to immature survival data, efficacy results should be interpreted with caution.
TRIAL REGISTRATION NUMBER: NCT04921358.
METHODS: SAFFRON-301 (NCT04921358) 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 mg orally once daily plus tislelizumab 200 mg intravenously once every 3 weeks or docetaxel 75 mg/m2 intravenously every 3 weeks. Dual primary endpoints were overall survival (OS) and Independent Review Committee (IRC)-assessed progression-free survival (PFS).
RESULTS: 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 ≥1% 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 ≥3 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-benefit analysis.
CONCLUSIONS: The SAFFRON-301 study was terminated early due to unfavourable risk-benefit assessment in the investigational arm. Due to immature survival data, efficacy results should be interpreted with caution.
TRIAL REGISTRATION NUMBER: NCT04921358.