Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial - 30/01/24

Doi : 10.1016/S1470-2045(23)00579-X

Lei Fan, MD ^a,^{*
Contributed equally as co-first authors}, Zhong-Hua Wang, MD ^a,^{*
Contributed equally as co-first authors}, Lin-Xiaoxi Ma, MD ^a,^{*
Contributed equally as co-first authors}, Song-Yang Wu, MD ^a,^{*
Contributed equally as co-first authors}, Jiong Wu, MD ^a,^{*
Contributed equally as co-first authors}, Ke-Da Yu, MD ^a,^{*
Contributed equally as co-first authors}, Xin-Yi Sui, MD ^a, Ying Xu, MD ^a, Xi-Yu Liu, MD ^a, Li Chen, MD ^a, Wen-Juan Zhang, MD ^a, Xi Jin, MD ^a, Qin Xiao, MD ^b, Ruo-Hong Shui, MD ^c, Yi Xiao, MD ^a, Han Wang, MD ^a, Yun-Song Yang, MD ^a, Xiao-Yan Huang, MD ^a, A-Yong Cao, MD ^a, Jun-Jie Li, MD ^a, Gen-Hong Di, MD ^a, Guang-Yu Liu, MD ^a, Wen-Tao Yang, MD ^c, Xin Hu, MD ^a, Yan Xia, MS ^d, Qian-Nan Liang, MS ^d, Yi-Zhou Jiang, ProfMD ^a,^{^{†
Contributed equally as co-senior authors},}⁎ , Zhi-Ming Shao, ProfMD ^a,^{^{†
Contributed equally as co-senior authors},}⁎

^a Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

^b Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China

^c Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

^d Department of Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals, Shanghai, China

^* Correspondence to: Professor Zhi-Ming Shao, Fudan University Shanghai Cancer Center, Shanghai 200032, China Fudan University Shanghai Cancer Center Shanghai 200032 China ^** Professor Yi-Zhou Jiang, Fudan University Shanghai Cancer Center, Shanghai 200032, China Fudan University Shanghai Cancer Center Shanghai 200032 China

Summary

Background

Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer.

Methods

FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18–70 years, with an Eastern Cooperative Oncology Group performance status of 0–1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m², intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2^mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKT^mut and MES-PI3K/AKT^mut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKT^WT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989).

Findings

Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2–29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6–15·2]) than in the control group (5·8 months [4·0–6·7]; hazard ratio 0·44 [95% CI 0·30–0·65]; p<0·0001). The most common grade 3–4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group.

Interpretation

These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway.

Funding

National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals.

Translation

For the Chinese translation of the abstract see Supplementary Materials section.

Le texte complet de cet article est disponible en PDF.

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Vol 25 - N° 2

P. 184-197 - février 2024 Retour au numéro

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Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial - 30/01/24

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